Hansen forever...???
./Hansen para Siempre...???
Hansen
for ever...Hansen para siempre ??? Chapter II Bibliographic refrences
!!!
DATA-MEDICOS
DERMAGIC/EXPRESS 2-(96)
4 Octubre 2.000 4 October 2.000
~ Hansen para Siempre...??? ~
~ Hansen forever...??? ~
EDITORIAL ESPANOL
=================
Hola amigos de la red, DERMAGIC con otro interesante tema: HANSEN PARA
SIEMPRE ???
En el año 1.997 se registraron unos 690.000 casos nuevos de
la enfermedad y se estimaba el total
en unos 1.200.000 de casos. Para ese año (1.997) unas 2.100.000.000
de personas vivian donde
existe una prevalencia de mas de 1 caso por cada 10.000 habitantes.
Para comienzos de 1.998 el
numero de casos se estimaba en 800.000. Para el año 2.000 el
numero de casos remanentes de
Lepra en el mundo se estima en unos 2.5 a 2.8 millones de pacientes.
Los paises mas afectados son India, Indonesia y Myanmar (sudeste
Asiatico) los cuales tienen el
70% del total de casos de Lepra. Africa la segunda region mas afectada
y en Latinoamerica Brasil
esta severamente afectado representando el 80% de los casos de nuestro
continente.
Enfermedad Biblica, ancestral y apocaliptica, el causante de la enfermedad
Mycobacterium Leprae
descubierto por Armauer Hansen en 1873 todavia se resiste a ser eliminado.el
tratamiento inicial fue
con el aceite de Chalmoogra introducido por el egipcio Tortoulis
Bey en 1894. Fue en los años 40
cuando aparece la Dapsona como una alternativa terapeutica realmente
eficaz contra la enfermedad,
luego la rifampicina y el clofazimine constituyendose estas tres drogas
(MTD) en el tratamiento
oficial de la OMS. En los años 70 se inicio la era de
las (vacunas-inmunoterapia) contra la
enfermedad (Venezuela, India). En 1997 se descubrio que antibioticos
comunes como la minociclina
y Ofloxacina, conjuntamente con rifampicina son altamente bactericidas
contra el bacilo de Hansen y
se instituyeron nuevos esquemas terapeuticos (ROM). Hoy en dia los
Indues utilizan una vacuna
(Mycobacterium w) para detener el flagelo de la enfermedad en
ese Continente.
El 17 de marzo de 1.999 DERMAGIC/EXPRESS salio a la red con el tema;
LA MINOCICLINA, LO BUENO, LO MALO Y LO FEO, donde se señalo
el efecto beneficioso
de este medicamento en la lepra e hice la siguiente pregunta:
" .......realmente la minociclina se esta usando en la lepra
en nuestros paises, ??? "
Este DERMAGIC EXPRESS fue publicado en la revista Chilena de DERMATOLOGIA,
segun me
comento la Dra Altanisia Ramuno (Venezuela).
EL 11 de agosto de 1.999 DERMAGIC EXPRESS volvio a la red con el tema
LEPRA Y
VACUNAS
donde en el editorial se escribio:
....En la India NUEVA DELHI, se ha estado trabajando con 4 cepas, entre
las que destacan
Mycobacterium Habana y Mycobacterium w, este ultimo del cual segun
ellos se pondra al mercado
LA PRIMERA VACUNA contra la Lepra producida por Cadila Pharmaceuticals,
porque NO ES
PATOGENO. Pero si revisamos bien TODAS las referencias, NO SON VACUNAS
PROPIAMENTE DICHAS, en el sentido estricto de la PREVENCION de
la infeccion, puesto
que se usan en combinacion con poliquimioterapia. (MTD).
Recordemos tambien que la clasica
vacuna BCG (bacillus Calmette-Guerin) , que protege conta la tuberculosis,
tambien protege contra
la lepra.....
En enero 26 del 2000 DERMAGIC/EXPRESS volvio a la red con otra revision:
LA LEPRA 2000
AÑOS DESPUES... con 80 referencias bibliograficas...
En el año 1.997 la Organizacion Mundial de la salud considero
en base a un estudio multicentrico
que UNA SOLA DOSIS rifampicina, ofloxacina y minociclina era una buena
alternativa y de bajo
costo para el tratamiento de la lepra pausibacilar (PB) con una sola
lesion, y una dosis MENSUAL
por 24 meses para lepra multibacilar (MB). Tambien se considero la
disminucion del tratamiento
CLASICO con MTD a 12 meses.
En Junio de 1.999 en San Francisco se realizo una conferencia sobre
lepra entre JAPON Y
ESTADOS UNIDOS donde se reconocieron varios aspectos como: la aparicion
de resistencia del
Bacilo de Hansen a la DAPSONA, en los años 70, y actualmente
a las fluoroquinolonas y al nuevo
REGIMEN de tratamiento (ROM), rifampicina-ofloxacina-minociclina, determinandose
las causas
geneticas de tal resistencia.
El año de 1.999 en Londres se realizo un estudio en ratones
infectados con el Mycobacterium
Leprae utilizandose una combinacion de rifampicina (RMP) con claritromicina
(CLARI) y ofloxacina
(OFLO) resultando en la muerte del bacilo en 3 semanas de tratamiento.
La combinacion de
Sparfloxacina (SPAR) mas rifampicina (RMP) tambien provoco el mismo
efecto. Se concluyo que
Esta combinacion de drogas: RMP, OFLO, o (SPAR)-CLARI, con o
sin minociclina (MINO) y
cuya efectividad se observa en 4 SEMANAS puede ser administrada a pacientes
por un periodo
mas corto que el actual de 2 años (reducido a 1 año actualmente)
con MTD.
En el año 1.981 la OMS en base a evidencias cientificas considero
que el tratamiento con MTD
(rifampicina, dapsona y clofazimine) debia ser de 6 meses para la lepra
paucibacilar (PB) y de 2
años para la lepra multibacilar (MB) en la conferencia de 1.994
se ratifico este esquema de
tratamiento por su alta efectividad, habiendose logrado la cura de
unos 84. millones de pacientes.
En la conferencia de 1.997 sobre lepra LA OMS considero una disminucion
del tratamiento con
MTD a 12 meses en la lepra multibacilar (MB) en base a algunos estudios
realizados y
principalmente el hecho de la aparicion de resistencia a las drogas
utilizadas por el
INCUMPLIMIENTO del tratamiento en las zonas de dificil acceso.
En el año de 1.999 en la India se publicaron dos estudios para
detectar bacilos viables en pacientes
con lepra multibacilar despues de 6, 12, 24 y 36 meses de tratamiento
clasico con MTD. SE
DEMOSTRO que despues de 12 MESES DE TRATAMIENTO entre un 25% y 31%
de los
pacientes tenian bacilos viables. Despues de 2 años de tratamiento
solo un 8%-12%. Despues de 3
años de tratamiento un 4%, Y RECOMIENDAN TENER PRECAUCION CON
LA
DISMINUCION DEL TRATAMIENTO DE 24 A 12 MESES.
En un estudio realizado en China y publicado en Diciembre de 1.999
sobre el seguimiento a
pacientes con lepra paucibacilar (PB) y multibacilar (MB) despues de
tratamiento clasico con MTD
se llego a la conclusión de que a los pacientes con lepra paucibacilar
hay que hacerles un
seguimiento de 5 años y a los de lepra multibacilar de 10 años.
En el año de 1.998 la FDA libera de nuevo la talidomida para
su utilizacion en el eritema nodoso
leproso (ELN)
El 15 de noviembre de 1.999 la OMS lanzo una alianza global contra le
lepra con el objetivo de
eliminarla completamente del planeta tierra antes del año 2.005.
India, indonesia y Brasil los paises mas efectados...para 1.998
Cierro con varias preguntas para todos,,,, ???
No es una bomba de tiempo disminuir el clasico TRATAMIENTO CON MTD
de 24 a 12 meses
??? , no provocara esto una nueva ola de lepra a futuro ???,
pues ya se demostro que el numero de
bacilos viables aumenta a medida que se disminuye el tiempo de tratamiento.
Si ya se han curado mas de 84 milones de personas con el clasico tratamiento,,,,
porque no
continuarlo ????
Es realmente confiable la utilizacion del nuevo esquema ROM, ????
Si es realmente confiable,
porque no se esta utilizando en nuestros paises ???
Un hecho interesante lo constituye nuestra hermana republica de Brasil,
quien ocupa el 2do lugar en
prevalencia de la enfermedad (1.998), y estando al lado de Venezuela,
pais pionero en la lucha
contra la enfermedad. Porque Brasil no implemento los esquemas de Venezuela,
???
Porque Venezuela y otros paises no prueban la vacuna en base a Mycobacterium
w utilizada en la
India ???
Si bien es cierto que hay que elogiar a los investigadores en TODO
EL MUNDO, tambien hay que
reconocer que para triunfar hay que unir esfuerzos y no andar dispersos
haciendo cada quien lo que
mejor le convenga y si esta alianza quiere triunfar TODOS tienen
COLABORAR, dejar de un lado
INTERESES PERSONALES o comerciales y poner empeño para matar
el bichito.
En estas 70 referencias los hechos...
Saludos a todos
Dr. Jose Lapenta R.
EDITORIAL ENGLISH
=================
Hello friends of the net, DERMAGIC with other interesting topic: HANSEN
forever???
For the year of 1.997 they registered some 690.000 new
cases of the illness and the total was
considered in 1.200.000 cases. As of 1997 around 2 100 000 000 people
live in countries where
the prevalence of leprosy is more than one case per 10 000 population.At
the beginning of 1998, the
number of leprosy patients in the world was about 800 000. For the
year 2.000 the remaining
leprosy cases in the world are currently estimated at 2.5–2.8
million.
The countries but affected they are India Indonesia and Myanmar (Asian
southeast) which have 70%
of the total of cases of Leprosy. Africa the second region but affected
and in Latinoamérica America
Brasil this severely affected one representing 80% of the cases of
our continent.
Biblical, ancestral and apocalyptic illness, the causing of the illness
Mycobacterium Leprae
discovered by Armauer Hansen in 1873 he still resists to be eliminated.
The initial treatment was with
the oil of Chalmoogra introduced by the Egyptian Tortoulis Bey in 1894.
It was in the forties when
appears the Dapsone like an alternative therapeutic really effective
against the illness, then the
rifampicin and the clofazimine (1981) being constituted these three
drugs (MTD) in the official
treatment of the OMS. In the seventies beginning the time of
those (vaccine-inmunotherapy) against
the illness (Venezuela, India). In 1997 he was discovered that common
antibiotics as the minocycline
and Ofloxacin, jointly with rifampicin they are highly germicides against
the bacillus of Hansen and
new therapeutic outlines were instituted (ROM). Today in day in the
India they uses a vaccine
(Mycobacterium w) to stop the illness in that Continent.
March 17 of 1.999 DERMAGIC/EXPRESS went out to the net with the
topic;
THE MINOCYCLINE, THE GOOD thing, THE BAD thing AND THE UGLY thing,
where I
points out the beneficial effect of this medication in the leprosy
and I asked the following question:
"...... .really the minocycline is it using in the leprosy in our countries???"
This DERMAGIC EXPRESS was published in the Chilean magazine of DERMATOLOGY,
as I
comment myself the Dra Altanisia Ramuno (Venezuela).
August 11 of 1.999 DERMAGIC EXPRESS returned to the net with
the topic LEPROSY AND
VACCINES where in the editorial it was written:
"....in the India NEW DELHI, has been working with 4 strains,
among those are the
Mycobacterium Habana and Mycobacterium w, this last of which will put
on to the market THE
FIRST VACCINE against the Leprosy produced by Cadila Pharmaceuticals,
according to them,
because it IS NONPATHOGEN. But if we revise ALL the references well,
they ARE NOT
VACCINE PROPERLY, this in the strict sense of the PREVENTION of the
infection, since they
are used in combination with multidrugtherapy (MTD). Let us also
remember that the classic
VACCINE BCG (bacillus Calmette-Guerin) that protects against
the tuberculosis, it also protects
against the leprosy.. "
In January 26 of the 2000 DERMAGIC/EXPRESS it returned to the net with
another revision:
THE LEPROSY 2000 YEARS LATER... with 80 bibliographical references...
In the year 1.997 the World Organization of the health considers
based on a Field trial study
that A SINGLE DOSE rifampicin, ofloxacin and minocycline were a good
alternative and of low
cost for the treatment of the paucibacillary leprosy (PB) with a single
lesion, and a MONTHLY dose
for 24 months for multibacillary leprosy (MB). The
WHO also considers the decrease of the
CLASSIC treatment with MTD to 12 months.
In June of 1.999 in San Francisco carries out a meeting about leprosy
between JAPAN AND
UNITED STATES where several aspects were recognized like: the appearance
of resistance of the
Bacillus of Hansen to the DAPSONE, in the seventies, and at the moment
to the fluoroquinolones
and the new treatment RÉGIME (ROM), rifampicin-ofloxacin-minocycline,
being determined the
genetic causes of such a resistance.
The year of 1.999 in London carries out a study in mice infected
with the Mycobacterium Leprae
being used a rifampicin combination (RMP) with clarithromycin (CLARI)
and ofloxacin (OFLO)
being in the death of the bacillus in 3 weeks of treatment. The combination
of Sparfloxacin (SPAR)
plus rifampicina (RMP) I also cause the same effect. They concludes
that
This combination of drugs: RMP, OFLO, or (SPAR)-CLARI, with or without
minocycline (MINO)
and whose effectiveness is observed in 4 WEEKS it can be administered
to patient by one period
but I short that the current of 2 years (reduced to 1 year at
the moment) with MTD.
In the year 1.981 the OMS based on evidences scientists considers that
the treatment with MTD
(rifampicin, dapsone and clofazimine)should be of 6 months for the
paucibacillary leprosy (PB) and
of 2 years for the multibacillary leprosy (MB) in the conference
of 1.994 ratifies this treatment
outline for their high effectiveness, there being achieved the cure
of about 84. millions of patient.
In the conference of 1.997 on leprosy THE OMS considers a decrease
of the treatment with MTD
to 12 months in the multibacillary leprosy (MB) based on some
carried out studies and mainly the
fact of the resistance appearance to the drugs used by the NONFULFILMENT
of the treatment in
the areas of difficult access.
In the year of 1.999 in the India two studies were published about
to detect viable bacilluses in
patient with multibacillary leprosy after 6, 12, 24 and 36 months of
classic treatment with MTD. It
was DEMONSTRATED that after 12 MONTHS OF TREATMENT between 25% -31%
of the
patients had viable bacilluses. After 2 years of treatment alone 8%-12%.After
3 years of treatment
4%. AND THEY RECOMMENDED TO HAVE CAUTION WITH THIS REDUCTION OF
THE DURATION OF THE TREATMENT FROM 24 TO 12 MONTHS.
In a study carried out in China and published in December of 1.999
on the pursuit to
patient with leprosy paucibacilar (PB) and multibacilar (MB) after
classic treatment with MTD
they conclude that is necessary to make them a ollow up for at
least 5 years for paucibacillary (PB)
and 10 years for MB patients after being released from WHO/MDT.
In the year of 1.998 the FDA release again the thalidomide for the treatment
the ELN (erythema
nodosum leprosum.)
November 15 1.999 the OMS throws a global alliance against leprosy with
the objective of
eliminating it completely of the planet earth before the year 2.005.
India, indonesia and Brazil the countries but effected...for 1.998
Do I close with several questions for all???
A bomb of time is not to diminish the classic TREATMENT WITH MTD from
24 to 12 months???
, didn't this cause a new leprosy wave in the future??? because it
was already demonstrated that the
one numbers of viable bacilluses it increases as diminishes the time
of treatment.
If they have already been treated but of 84 millionss of people with
the classic treatment, because to
not continue him????
Is the use of the new outline ROM really reliable???? If it is
really reliable,why is not using in our
countries???
An interesting fact constitutes it our sister republic of Brazil who
occupies the 2do place in
prevalence of the illness (1.998), and being beside Venezuela, pioneer
country in the fight against the
illness. Why Brazil doesn't implement the outlines of Venezuela???
Why Venezuela and other countries don't prove the vaccine based on
Mycobacterium w used in the
India???
Although it is certain that it is necessary to eulogize the investigators
in the ENTIRE WORLD, it is
also necessary to recognize that to triumph it is necessary to unite
efforts and to not walk dispersed
making each who that better it suits him and if this alliance wants
to triumph ALL they have to
COLLABORATE, to leave INTEREST PERSONAL or COMMERCIAL and to put zeal
to kill
the bug.
In these 70 references the facts...
Greetings to all
Dr. Jose Lapenta R.,,,
==================================================================
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES
==================================================================
=============================================================
1.) Leprosy: the Disease
2.) The Global Alliance for Elimination of Leprosy
3.) Leprosy in a child of less than two months of age.
4.) 7th WHO Expert Committee on leprosy June 1997
5.) The US-Japan Joint Leprosy Research Program Meeting, San Francisco,
June 28-30, 1999
6.) Another View of the Therapy of Leprosy
7.) Rifampicin/minocycline and ofloxacin (ROM) for single lesions--what
is the evidence?
8.) What are the new antileprosy drugs - ROM - now available for the
treatment of leprosy?
9.)What are the types of leprosy that can be treated by ROM ?
10.)What is the reason for introducing single dose treatment for paucibacillary
leprosy presenting
with a single skin lesion?
11.) What is the basis for the recommended alternative regimen for
the treatment of paucibacillary
leprosy presenting with a single skin lesion?
12.)Does WHO recommend that all programmes should treat single lesion
paucibacillary leprosy
cases with one dose of ROM?
13.) Efficacy of single dose multidrug therapy for the treatment of
single-lesion paucibacillary
leprosy. Single-lesion Multicentre Trial Group.
14.) Minocycline in lepromatous leprosy.
15.) Efficacy of minocycline in single dose and at 100 mg twice daily
for lepromatous leprosy.
16.) Field trial on efficacy of supervised monthly dose of 600 mg rifampin,
400 mg ofloxacin and
100 mg minocycline for the treatment of leprosy; first results.
17.) Bactericidal activity of a single-dose combination of ofloxacin
plus minocycline, with or without
rifampin, against Mycobacterium leprae in mice and in lepromatous patients.
18.) Bactericidal activity of single dose of clarithromycin plus minocycline,
with or without ofloxacin,
against Mycobacterium leprae in patients.
19.) WHO Expert Committee on Leprosy.
20.) Experimental evaluation of possible new short-term drug regimens
for
treatment of multibacillary leprosy.
21.) Powerful bactericidal activities of clarithromycin and minocycline
against Mycobacterium leprae in lepromatous leprosy.
22.) Leprosy resistant to multi-drug-therapy (MDT) successfully treated
with ampicillin-sulbactam combination--(a case report).
23.) Differential protective effect of bacillus calmette-guerin vaccine
against multibacillary and paucibacillary leprosy in nagpur, india.
24.) Protective effect of Bacillus Calmette Guerin (BCG) against leprosy:
a
population-based case-control study in Nagpur, India.
25.) Patient contact is the major determinant in incident leprosy:
implications for future control.
26.) The clinical use of fluoroquinolones for the treatment of mycobacterial
diseases.
27.) A case of relapsed leprosy successfully treated with sparfloxacin.
28.) Active leprosy treated effectively with ofloxacin.
29.) Reactional states and neuritis in multibacillary leprosy patients
following MDT with/without
immunotherapy with Mycobacterium w antileprosy vaccine.
30.) Mycobacterium w vaccine, a useful adjuvant to multidrug therapy
in multibacillary leprosy: a
report on hospital based immunotherapeutic clinical trials with a follow-up
of 1-7 years after
treatment.
31.) What is WHO MDT?
32.) Is WHO-recommended multidrug therapy (MDT) the best combination
available for treatment
of multibacillary (MB) and paucibacillary (PB) leprosy in leprosy control
today?
33.) WHY MULTIDRUG THERAPY FOR MULTIBACILLLARY LEPROSY CAN BE
SHORTENED TO 12 MONTHS
34.) Supervised Multiple Drug Therapy Program, Venezuela
35.) Search for newer antileprosy drugs.
36.) Mycobacterium leprae--millennium resistant! Leprosy control on
the threshold of a new era.
37.) The impact of multidrug therapy on the epidemiological pattern
of leprosy in Juiz de Fora,
Brazil.
38.) Serologic response to mycobacterial proteins in hansen's patients
during multidrug treatment.
39.) HLA linked with leprosy in southern China: HLA-linked resistance
alleles to leprosy.
40.) A Mycobacterium leprae-specific human T cell epitope cross-reactive
with an HLA-DR2 peptide.
41.) Association of HLA antigens with differential responsiveness to
Mycobacterium w vaccine in multibacillary leprosy patients.
42.) HLA antigens and neural reversal reactions in Ethiopian borderline
tuberculoid leprosy patients.
43.) Evidence for an HLA-DR4-associated immune-response gene for
Mycobacterium
tuberculosis. A clue to the pathogenesis of rheumatoid arthritis?
44.) Diaminodiphenylsulfone resistance of Mycobacterium leprae due
to
mutations in the dihydropteroate synthase gene.
45.) Resolution of lepromatous leprosy after a short course of
amoxicillin/clavulanic acid, followed by ofloxacin and clofazimine.
46.) Studies on risk of leprosy relapses in China: relapses after treatment
with multidrug therapy.
47.) An immunotherapeutic vaccine for multibacillary leprosy.
48.) Nasal mucosa and skin of smear-positive leprosy patients after
24 months of fixed duration
MDT: histopathological and microbiological study.
49.) Induction of lepromin positivity following immuno-chemotherapy
with Mycobacterium w
vaccine and multidrug therapy and its impact on bacteriological clearance
in multibacillary leprosy:
report on a hospital-based clinical trial with the candidate antileprosy
vaccine.
50.) SIMLEP: a simulation model for leprosy transmission and control.
51.) Detection of viable organisms in leprosy patients treated with
multidrug therapy.
52.) An immunotherapeutic vaccine for multibacillary leprosy.
53.) Addition of immunotherapy with Mycobacterium w vaccine to multi-drug
therapy benefits
multibacillary leprosy patients.
54.) Immunotherapy with Mycobacterium w vaccine decreases the incidence
and
severity of type 2 (ENL) reactions.
55.) A follow-up study of multibacillary Hansen's disease patients
treated with multidrug therapy
(MDT) or MDT + immunotherapy (IMT).
56.) Immunotherapy of lepromin-negative borderline leprosy patients
with low-dose Convit vaccine
as an adjunct to multidrug therapy; a six-year follow-up study in Calcutta.
57.) Immunotherapy of far-advanced lepromatous leprosy patients with
low-dose convit vaccine
along with multidrug therapy (Calcutta trial).
58.) A longitudinal study of immunologic reactivity in leprosy patients
treated with immunotherapy.
59.) BCG vaccination protects against leprosy in Venezuela: a case-control
study.
60.) Immunoprophylactic trial with combined Mycobacterium leprae/BCG
vaccine against leprosy:
preliminary results.
61.) Why relapse occurs in PB leprosy patients after adequate MDT despite
they are Mitsuda
reactive: lessons form Convit's experiment on bacteria-clearing capacity
of lepromin-induced
granuloma.
62.) A lost talisman: catastrophic decline in yields of leprosy bacilli
from armadillos used for vaccine production.
63.) RESEARCH IN LEPROSY - ( H.D.)/ LEPROSY - RESEARCH AND BEYOND THE
YEAR 2000
64.)THE CHALLENGE OF LEPROSY” at :- INDIA APPROVES LEPROSY VACCINE
(
Ganapati Madur, New Delhi )
65.) A vaccine for leprosy
66.) FREQUENTLY ASKED QUESTIONS about Leprosy / Hansen’s Disease
67.) Leprosy Elimination
68.) 'LEPROSY' IN THE BIBLE - WHAT WAS IT?
69.) TI - Thalidomide's effectiveness in erythema nodosum leprosum
is
associated with a decrease in CD4+ cells in the peripheral blood.
70.) Leprosy in Venezuela, 1.998
=============================================================
=============================================================
1.) Leprosy: the Disease
=============================================================
Leprosy is a chronic infectious disease caused by
Mycobacterium leprae, an acid-fast, rod-shaped bacillus. The
disease mainly affects the skin, the peripheral nerves, mucosa of the
upper respiratory tract and also
the eyes, apart from some other structures. Leprosy has afflicted humanity
since time immemorial. It
once affected every continent and it has left behind a terrifying image
in history and human memory -
of mutilation, rejection and exclusion from society.
Leprosy has struck fear into human beings for thousands of
years, and was well recognized in the oldest civilizations of China,
Egypt and India. A cumulative
total
of the number of individuals who, over the millennia, have suffered
its chronic course of incurable
disfigurement and physical disabilities can never be calculated.
Since ancient times, leprosy has been regarded by the community as a
contagious, mutilating and
incurable disease. There are many countries in Asia, Africa and Latin
America with a significant
number of leprosy cases. As of 1997 around 2 100 000 000 people live
in countries where the
prevalence of leprosy is more than one case per 10 000 population.
It is estimated that there are
between one and two million people visibly and irreversibly disabled
due to past and present
leprosy
who require to be cared for by the community in which they live.
When M.leprae was discovered by G.A. Hansen in 1873, it was the first
bacterium to be identified
as causing disease in man. However, treatment for leprosy only appeared
in the late 1940s with the
introduction of dapsone, and its derivatives. Leprosy bacilli resistant
to dapsone gradually appeared
and became widespread.
In 1997, there were an estimated 1.2 million cases in the world, most
of them concentrated in
South-East Asia, Africa and the Americas. The number of new cases detected
worldwide each year
is about half a million.
===========================================================
2.) The Global Alliance for Elimination of Leprosy
===========================================================
source: THE WHO on leprosy
The Final Push
An Alliance to eliminate leprosy. . .
On November 15 th 1999, representatives of leprosy endemic countries,
the World Health
Organisation (WHO), the Nippon Foundation, Novartis and the International
Federation of the
Anti-Leprosy Associations (ILEP) announced a Global Alliance to eliminate
leprosy as a public
health problem from every country by the year 2005.TheAlliance will
work closely with patients,
communities and all agencies interested in leprosy such as the Danish
International Development
Agency (DANIDA) and the World Bank.
The Alliance and its partners aim to detect and cure all the remaining
leprosy cases in the world –
currently estimated at 2.5–2.8 million – over this six year period.
Efforts will focus on generating
"demand" for treatment through improved awareness of leprosy in conjunction
with better access to
diagnosis and treatment.
Is it really possible to do away with a disease that has afflicted humanity
since time immemorial? It is
no simple matter, since leprosy is an insidious, slowly-developing
disease which flourishes mainly in
the 'poverty belt' of the globe. It once affected every continent and
it has etched a terrifying image in
history and human memory, of mutilation, rejection and exclusion from
society. Leprosy has always
and everywhere been regarded as a special disease.
India, Indonesia and Myanmar account for 70% of all the cases in the
world.
In Africa, the second most affected area, the situation is more difficult
for the moment.The AIDS
epidemic, the resurgence of the major tropical diseases, weaknesses
in health infrastructure, social
unrest and armed conflict make leprosy elimination seem like a luxury,
an impracticable one at that.
The situation remains worrying in Latin America. Brazil is particularly
badly affected, accounting for
over 80% of cases in that continent.
In Central and Eastern Europe, there are sporadic cases; it is impossible
at present to tell how many
such cases go unreported.
============================================================
3.) Leprosy in a child of less than two months of age.
=============================================================
Benerjee, K, Meyers W.M.,
Clinical Dermatology, The CMD Case collection, World Congress
Of Dermatology
Berlin (West),
May 24-29-1.987,: 149.
History. Patient was a less than 2 months oid male baby belonging to
one of the trained nurses of
our Institute. The chud had close, intimate contact with arelative
who suffered
from dimorphous leprosy and who had taken treatment for only 6 months
before discontinuing it on
his own.
Examination. A round, elevated, red-dish lesion was detected on the
face.
Investigations. KOH mount of scrap-ings showed no fungus. A slit smear
for acid fast bacilli was
negative.
Histopathology. Skin biopsy material was sent to 4 different centres.
Ah of them confirmed it to be
Hansen's disease of a tuberculoid nature.
Treatment. The lesion resolved com-pletely within three months' treatment
with D.D.S. 2.5 mg for 5
days each week.
Conclusion. To my knowledge leprosy at less than 2 months of age has
not yet been
reported and may be disputed. Two cases of leprosy at 6 months of age
were reported by Bruce
Baker et al. The precise mode of natural transmission, the incuba-tion
period
and clinical manifestation have not yet been established. Early signs
and diagnosis may be missed in
the mistaken belief that leprosy is non-existent in the very young.
========================================================
4.) 7th WHO Expert Committee on leprosy June 1997
========================================================
MAJOR CONCLUSIONS AND RECOMMENDATIONS
The major conclusions and recommendations of the Expert Committee are
summarized below:
The Global Strategy for the Elimination of Leprosy, based on the implementation
of MDT with
case-finding, is working extremely well in reducing the prevalence
of leprosy and should be
continued.
There is an important need to detect and treat the remaining undetected
cases, for which special
approaches, along with the extension of MDT services to all general
health facilities, are required.
The progressive simplification of diagnostic and treatment technologies
has continued to facilitate
reaching more leprosy patients.
Based on a multicentre trial, it is considered that a single dose of
a combination of rifampicin,
ofloxacin and minocycline is an acceptable and cost-effective alternative
regimen for the treatment of
single-lesion PB leprosy. Furthermore, based on available information,
it is possible that the duration
of the current MDT regimen for MB leprosy could be shortened further
to 12 months.
A fresh strategy for the implementation of disability prevention and
rehabilitation is called for to
ensure a practical, community-oriented approach aimed at reaching the
largest number of persons in
need with-cost effective interventions.
The monitoring of elimination through essential indicators should continue.
Information reported
should be validated and analysed further through independent monitors
in order to identify in good
time problem situations needing action.
Anti-leprosy activities should become, and should remain beyond the
year 2000, an integral part of
general health services everywhere, and should also involve the communities
to the fullest extent
possible. Coordination between various agencies, including local and
international nongovernmental
organizations, should be consolidated.
It is recommended that research in leprosy be continued, especially
in improving patient care and in
addressing post-elimination issues.
It is important to sustain anti-leprosy activities beyond the year
2000 in order to deal with the
remaining problems, including new cases and persons with disability.
========================================================
Executive Summary
========================================================
The WHO Expert Committee on Leprosy met in Geneva from 26 May to 3 June
1997 to review the
global state of leprosy and the technology for dealing with it, to
identify the remaining obstacles to
reaching the goal of elimination, and to make technical and operational
recommendations related to
elimination and beyond.
Definition of a case of leprosy:
A case of leprosy is a person having one or more of the following features,
and who has yet to
complete a full course of treatment:
- hypopigmented or reddish skin lesion(s) with definite loss of sensation;
- involvement of the peripheral nerves, as demonstrated by definite
thickening with loss of sensation;
- skin smear positive for acid-fast bacilli.
The case definition includes retrieved defaulters having signs of active
disease as well as relapsed
cases who have previously completed a full course of treatment, but
does not include cured persons
with late reactions or residual disabilities.
Clinical classification for control programmes
Since single-lesion leprosy may be cured by a shorter regimen than
the standard MDT for PB
leprosy, the Committee suggested that patients be classified into three
groups:
(a) PB single-lesion leprosy (one skin lesion);
(b) PB leprosy (2-5 skin lesions); and (c) MB leprosy (more than 5
skin lesions).
BCG re-vaccination
The widespread application of BCG is likely to be a contributing factor
to the decline in leprosy
incidence observed in certain populations. However, repeated doses
of BCG to prevent leprosy are
not recommended on the grounds of poor cost-effectiveness, lack of
acceptability to recipients,
operational difficulties, and the fact that BCG is contraindicated
in symptomatic HIV individuals.
Shortening duration of MDT regimen for MB leprosy
The results from both nude mouse experiments and a clinical trial have
demonstrated that the
rifampicin-resistant mutants in an untreated lepromatous patient are
likely to be eliminated by 3 to 6
months of treatment with the dapsone-clofazimine component in MDT regimen.
From the
operational point of view, the duration of MDT for MB leprosy is still
very long, which adversely
affects the implementation of MDT among all patients in need of treatment.
When the Study Group
(1981) designed the MDT regimens, MB leprosy referred to those patients
who had a BI of 2 at any
site in the initial skin smears. Currently MB leprosy includes all
smear-positive patients, as well as
patients with more than five lesions. Among the newly detected cases,
the skin-smear positive
patients represent only 12.5% of the total number. Based on all the
available information, the
Committee accepted that it is possible to reduce the duration of the
current MDT regimen for MB
leprosy to 12 months without significantly compromising its efficacy.
Flexible MDT delivery system
Due to poor coverage of the health services in most of the leprosy-endemic
countries, supervision of
the monthly administered drugs by health workers may not always be
possible. In that case, more
than one month's supply of MDT blister packs may be given to the patient,
provided he or she is
given appropriate information and guidance regarding the dosage, rhythm
and necessary duration of
treatment, and is advised to report any untoward signs/symptoms promptly.
Regimen for single skin lesion PB leprosy
Based on the results of a large multicentre randomized double-blind
controlled clinical trial the
Committee considered that a single dose of rifampicin 600 mg plus ofloxacin
400 mg and
minocycline 100 mg, is an acceptable and cost-effective alternative
regimen for the treatment of
single skin lesion PB leprosy.
Other regimens for special situations
The Committee suggested that patients who do not accept clofazimine
can be treated with a monthly
administration of a combination consisting of 600 mg of rifampicin,
400 mg of ofloxacin and 100 mg
of minocycline (ROM) for 24 months. For adult MB patients who cannot
take rifampicin, the
Committee recommended the daily administration of 50 mg of clofazimine,
together with 400 mg of
ofloxacin and 100 mg of minocycline for 6 months; followed by daily
administration of 50 mg of
clofazimine, together with 100 mg of minocycline or 400 mg of ofloxacin
for at least an additional 18
months.
Drug resistance
Rifampicin is by far the most bactericidal drug against M. leprae,
and will still be the backbone of the
MDT regimens in the foreseeable future. Consequently, all efforts should
be made to prevent the
emergence of rifampicin-resistant leprosy. To improve the surveillance
of rifampicin-resistance, it
may be useful to establish the genetic method for rapid detection of
rifampicin-resistant strains at
certain regional reference centres.
Defaulter: definition and management
A defaulter is a patient who started MDT but who has not received treatment
for 12 consecutive
months despite all attempts to trace the patient. If a defaulter patient
returns to the health centre for
treatment and shows signs of active disease such as new skin lesions,
new nerve involvement or new
nodules, he/she should be given a new course of MDT. In the absence
of these, there is no need to
restart MDT.
Drug supply logistics
The provision of an uninterrupted supply of high quality MDT drugs
in blister packs, free of charge,
to all patients is essential, including those living in difficult-to-access
areas. To ensure the availability
of MDT drugs and their proper distribution, a coordination mechanism
between the government,
WHO and donor agencies at the country level is needed.
Management of reactions
The crucial elements in the management of leprosy reactions and, thereby,
the prevention of
disabilities are early diagnosis of reactions together with prompt
and adequate treatment. Most
reactions, and neuritis, can be treated successfully under field conditions
by a standard 12-week
course of prednisolone. If patients do not respond to corticosteroid
therapy in the field, they should
be sent to an appropriate referral centre.
WHO disability grading for leprosy
At its last meeting in 1987, the WHO Expert Committee on Leprosy had
substantially simplified the
grading into a three-grade (0, 1, 2) system. This Committee endorsed
this grading with the
amendment that lagophthalmos, iridocyclitis and corneal opacities be
considered as Grade 2. For
safety reasons the Committee does not recommend the testing of touch
sensibility of the cornea
under field conditions.
Reaching pockets of high prevalence
In most endemic countries, MDT services are able to reach those patients
who can easily contact the
health care system. However, certain areas in some endemic countries
have patients with only limited
access to health care, or have MDT services that are not operating
or not being utilized. In such
areas, leprosy elimination campaigns (LEC) will be able to clear up
undetected cases which have
accumulated over a period of time in the community. Under LEC, three
major activities are grouped
as a new package: capacity building measures for local health workers
to improve MDT services;
increasing community participation; and diagnosing and curing patients,
particularly MB cases.
Reaching special population groups
To reach patients living in difficult-to-access areas, or those belonging
to underserved population
groups, special action projects for the elimination of leprosy (SAPEL)
constitute an important
initiative to ensure the fullest MDT coverage. The essential elements
of SAPEL are, firstly, to find
cases living in difficult areas or situations who are in need of treatment
and, secondly, to cure them.
Innovative and practical strategies involving mainly operational solutions
will be used in order to
provide MDT to these patients. Since the project operates in situations
where the health
infrastructure is weak or does not exist, the strategies used should
promote self-reliance and
self-help, and must involve the community so that the activities begun
under SAPEL can be
sustained.
Leprosy and human rights
Patients on MDT, and those cured of disease, should not suffer from
restrictions in areas such as
employment, education and travel. Any special legal measures that might
increase prejudice against
leprosy or prevent early cases from presenting themselves for diagnosis
and treatment should be
abolished. In some countries, the human rights problem is particularly
serious among female patients,
firstly, because of their gender, and secondly, because of the stigmatization
associated with leprosy.
Strategy beyond elimination
After the year 2000, simplifying MDT services and strengthening the
process of integration into the
general health services are the keys to sustaining anti-leprosy activities,
especially in low prevalence
situations. The uneven distribution of leprosy makes it possible to
have significant endemicity in some
parts of a country, particularly for larger countries, even though
the national elimination target has
been attained. It is important to focus elimination activities at the
most peripheral levels and to plan to
reach the elimination goal at sub-national levels.
Monitoring leprosy elimination
The validity of the essential indicators, reported by the programmes,
should be assessed by
independent monitors in collaboration with the national programmes,
through special activities such
as leprosy elimination monitoring (LEM) and Geographic information
systems (GIS).
Integration of anti-leprosy activities
Programmes fully-integrated into the general health services would
be more appropriate for
strengthening leprosy elimination activities than vertical or combined
programmes.
Community action and participation
The local community and its leaders will play a key role in improving
public awareness about the
disease and about the availability of free and effective treatment.
Indeed, in some situations they may
be the only possibility for delivering MDT drugs, supervising the monthly
drug administration and
retrieving defaulters, thereby ensuring that the patients complete
their treatment. In addition, the
prevention of dehabilitation and the rehabilitation of individual persons
affected by leprosy depends
on the community.
Research priorities
Due to the great success of implementing MDT, there has been a tendency
in recent years for
support for leprosy research to decline, and this may hamper the development
of new technologies
which are needed for leprosy elimination and beyond. The Committee
recommends that national
governments, scientific communities, international organizations and
NGOs continue their support to
leprosy research, particularly operational research in major endemic
countries.
=======================================================
5.) The US-Japan Joint Leprosy Research Program Meeting, San Francisco,
June 28-30, 1999
=======================================================
PATRICK J. BRENNAN
Department of Microbiology, Colorado State University, Fort Collins,
CO 80523-1677, USA
Accepted for publication 1 August 1999
The US-Japan Cooperative Medical Sciences Program was founded in the
1960s by the
then-President of the United States and the Prime Minister of Japan
and, since then, has had the
highest political support from both governments. Leprosy was among
the first disease entities named
as part of the overall program, and the US and Japanese leprosy research
panels and their guests
have met in the alternating countries every year for the past 34 years
(in 1995, the separate leprosy
and tuberculosis panels were amalgamated). These meetings of the joint
US-Japan panels in the form
of scientific conferences have become a highlight of the annual leprosy
research agenda. Some of the
major fundamental research developments in leprosy over the past 30
years have been first reported
at this conference. These include: the early development of the drug
regimens leading to present-day
MDT and ROM; the early development of the mouse footpad; the recognition
of sylvian leprosy in
the armadillo and the development of this model of leprosy and, later,
the Mangabey monkey model;
the original work on the extension of hybridoma technology to leprosy
and the development of banks
of monoclonal antibodies; the first research on the application of
genetic recombinant technology to
Mycobacterium leprae and the production of 15-20 recombinant protein
antigens; the discovery of
the heat-shock proteins and of PGL-I, and the synthesis of corresponding
neoglycoproteins and the
development of ELISA systems; the major developments in the definition
of the genome and
proteome of M. leprae; all major developments in defining the cellular
immune response in leprosy;
the application of thalidomide to leprosy reactions and elucidation
of its action mechanism etc.
The 34th US-Japan Leprosy Research Conference was held in San Francisco
in conjunction with
the US-Japan Tuberculosis Research Conference, June 28-30, 1999. Some
of the highlights are as
follows.
A. Rambukkana (Rockefeller University, New York, USA) described the
latest chapter in his
important work on the molecular basis of the interaction between the
Schwann cell and M. leprae.
Previously, he had described how the G domain of the laminin a 2 chain
in the basal lamina that
surrounds the Schwann cell-axon unit serves as an initial neural target
for M. leprae. This time, he
addressed the nature of the M. leprae surface molecules that bind to
a 2 laminin. By using human a 2
laminins as a probe, a major 28 kDa protein in the M. leprae cell wall
fraction was identified.
Immunofluorescence and immunoelectron microscopy on intact M. leprae,
using monoclonal
antibodies against the recombinant protein, demonstrated that the protein
is surface-exposed. Also,
the recombinant protein was shown to bind avidly to a 2 laminins, the
recombinant G domain of the
laminin-a 2 chain, and the native peripheral nerve laminin. Thus, these
data suggest that this 28 kDa
protein functions as a critical surface adhesin that facilitates the
entry of M. leprae into Schwann
cells.
In subsequent discussion of this work, it was revealed that Dr Cristina
Pessolani (Fio-Cruz, Rio de
Janeiro) had also described a 28 kDa protein as a key bacterial ligand
in M. leprae-Schwann cell
interaction and had shown that this is a member of the histone-like
protein family. It thus seems that
the protein described by Dr Rambukkana is this HLP.
Dr Takeshi Yamada and colleagues (Nagasaki University, Japan) have also
focused on this protein
from a different perspective. They have been investigating the molecular
basis of the slow growth of
M. leprae and other mycobacteria and identified a 28 kDa protein (which
they called MDPI) as the
most abundant protein in M. bovis BCG. The protein was highly polymerized
and localized in the
nucleoid, 50S ribosomal subunit and cell surface. It interfered with
replication, transcription and
translation in E. coli cell-free systems, and was capable of transforming
E. coli to slow growth.
Sequence analysis also indicated a member of the HLP family. Thus,
the 28 kDa HLP is apparently
a major player in the pathogenesis and physiology of M. leprae. Its
immunogenicity and diagnostic
potential should now be examined.
Efforts to 'cultivate' M. leprae continue, but this time through genetic
augmentation of the organism, a
sensible plan in light of a genome that is small and very defective
in gene density. Drs Scott G.
Franzblau (GWL Hansen's Disease Center, Baton Rouge, LA, USA) and William
R. Jacobs (Albert
Einstein College of Medicine, New York, USA) have used a combination
of freshly harvested,
viable nude mouse-propagated M. leprae and a modified D29 mycobacteriophage
vector to achieve
phage infection of M. leprae and foreign gene expression. Therefore,
the key preliminary work has
been achieved as a prelude to constructing a shuttle cosmid vector,
carrying DNA libraries from
slow growing cultivable mycobacteria and capable of stable expression
of foreign DNA in M.
leprae, allowing, in future, perhaps, in vitro growth competence.
Widespread resistance to dapsone in the 1970s was the catalyst for the
development of multiple
drug therapy (MDT) for the treatment of leprosy. However, to date,
researchers have not been
successful in characterizing the molecular basis of dapsone resistance.
Two laboratories have now
conducted crucial preliminary experiments (Dr Y. Kashiwabara, Leprosy
Research Center, Tokyo,
Japan, and Dr Diana Williams, GWL Hansen's Disease Center). An analysis
by others of
sulphonamide resistance in E. coli has shown an association with dihydropteroate
synthase (DHPS),
a key enzyme in the folate biosynthetic pathway, encoded by the folp
gene. Dr Williams has shown
that M. leprae possesses two folp homologs (folP1 and folP2). DDS resistance
was not associated
with mutations in folP2 from two high-level DDS-resistant strains of
M. leprae. However, mutations
were observed within a highly conserved region of folP1 in two of these
high-level DDS-resistant M.
leprae clinical isolates. In addition, this folP1 homolog has been
shown to encode a functional DHPS
which itself is highly sensitive to DDS. These new data thus support
early predictions that DDS
resistance in M. leprae is associated with alterations in folate metabolism
and that one possible
mechanism of resistance is due to mutations in folP1.
Resistance to fluoroquinolones is becoming widespread, at a time when
ofloxacin, one of the
fluoroquinolones, is being used more and more frequently in the form
of ROM (rifampin, ofloxacin,
and minocycline) in leprosy control programs. Dr Y. Kashiwabara has
determined the sequences of
the QRDR (quinolone resistance determining region) of gyrA (the gene
encoding the A subunit of
gyrase, the site of action of the fluoroquinolones) in 13 clinical
isolates of M. leprae, and
demonstrated that eight of them showed mutations in this region. Importantly,
five of the eight also
showed mutations in the rpoB gene (the gene encoding the B subunit
of RNA polymerase, the site of
action of the rifamycins), suggesting that exposure to one or the other
of the two drugs can lead to
resistance to both, a new worry as we develop alternative drug regimens
for leprosy.
The type of molecular epidemiology that is now being applied to M. tuberculosis
isolates and
tuberculosis in general has not been possible with leprosy, because
M. leprae is devoid of the type of
variable but relatively stable genetic polymorphism associated with
the IS6110 insertion sequences in
the M. tuberculosis chromosome. If other forms of DNA polymorphism
could be identified in the M.
leprae genome, the lessons that could be derived from its application
would be profound in terms of
tracking sources of infection, examining the relationship between non-symptomatic
carriage of M.
leprae and disease, probing the possibility of environmental sources
of M. leprae, and differentiating
between reactivation and new infection. Dr Y. Kashiwabara has now found
some evidence of such
polymorphism, albeit limited. The sequences of the rpoT gene from many
M. leprae isolates were
compared, allowing the classification of isolates into two broad categories.
One group had three
tandem repeats of a six-base-pair (AGATCG) sequence, and the other
group had four tandem
repeats. Isolates from Japan and Korea had the four-tandem repeat profile,
whereas isolates from
South-East Asian and Latin American countries had the three-repeat
pattern, indicating that this
genetic characteristic could be used to trace the origins of infections
and the evolution of disease.
The role of various cytokines and different T-cell subsets in leprosy
pathogenesis and immunity to
leprosy has long been a favorite topic of US-Japan participants. The
curious balance between
acquired resistance and pathogenesis is seen in granulomatous infiltration,
a consequence of the
marshalling of the acquired response to essentially contain bacilli,
but with pathological sequelae. In
the hands of Dr Linda Adams (GWL Hansen's Disease Center), mice genetically
incapable of
producing a functional inducible NO synthase (iNOS) showed markedly
enhanced granuloma
formation, and these types of granulomas were composed primarily of
CD4+ cells and
multinucleated giant cells. Thus, iNOS has an unexpected role in leprosy
granulomatosis. Among the
newer cytokines to be involved in the leprosy immune response are IL-12
and IL-10. According to
Dr Robert Modlin (University of California, Los Angeles, CA, USA),
some key lipoprotein ligands
of M. leprae bind to the toll-like receptors in macrophages, evoking
the dual response of NO
production and IL-12 evocation, two new major players in counteracting
infection. We have long
been very conscious of the role of IFN-g in the type-1 protective immune
response in leprosy.
Apparently, part of the mechanism of this effect is to up-regulate
type-1 cytokine expression and
down-regulate IL-10, one of the type-2 cytokines (Drs Y. Fukutomi and
M. Matsuoka, Leprosy
Research Center, Tokyo, Japan). The newest players in these events
are the chemokines. M. leprae
induces elevated levels of MCP-I, MIP-1a , and MIP-1b expression, and
it is now believed that
chemokines will prove to be important in regulating granuloma formation
and other immune
responses in leprosy (Dr Linda Adams).
Preliminary results were also reported by Dr T.P. Gillis (GWL Hansen's
Disease Center) on the
application of DNA vaccines to an animal model of leprosy. A recombinant
construct of the antigen
85A injected intradermally proved to be the most promising with strong
IgG1 and Ig2a antibody
responses and increased IFN-g and IL-2 production. However, protection
studies in the mouse
footpad infection model were disappointing.
With the amalgamation of the US-Japan Leprosy and Tuberculosis Panels
in 1995, a fear of leprosy
research workers within the US-Japan Cooperative Medical Sciences Program
was that leprosy
research would be engulfed by the tuberculosis research juggernaut.
This fear has proved to be
unfounded. Basic research in leprosy is thriving, notably in Japan,
where the Leprosy Research
Center has been incorporated into the prestigious, well-endowed National
Institute of Infectious
Diseases. The formal combination of both panels is clearly benefiting
leprosy research.
=============================================================
6.) Another View of the Therapy of Leprosy
=============================================================
Antimicrobial Agents and Chemotherapy, December 1998, p. 3334-3336,
Vol. 42, No. 12
LETTER/ Dr. Gelber's
From 1943 until 1982 the standard treatment for lepromatous leprosy
was lifelong dapsone
monotherapy. Though dapsone is bacteriostatic and lepromatous leprosy
has the highest bacterial
burden of all human diseases, as well as an impairment in protective
cellular immunity, dapsone
monotherapy proved surprisingly effective. Only 10% of patients developed
resistance (19), and on
cessation after 18 years of treatment only an additional 10% clinically
relapsed (21). In the 1970s
Freekson and Rosenfeld (3) in Malta treated leprosy patients, many
treated previously with dapsone
alone for many years, with a regimen of daily rifampin, prothionamide,
dapsone, and isoniazid (not
active against Mycobacterium leprae) for 2 years and found that patients
were regularly cured. In
1982 the World Health Organization (WHO) (22, 23) recommended another
2-year regimen of
multidrug therapy (MDT) (monthly rifampin, 600 mg, plus clofazimine,
300 mg, and daily dapsone,
100 mg, plus clofazimine, 50 mg). This regimen has been widely implemented,
largely in patients
previously treated with dapsone for prolonged periods, many of whom
no longer harbored
detectable M. leprae, and successfuly (20). However, the one clinical
study in previously untreated
lepromatous patients followed up for a sufficient time found an unacceptably
high relapse rate of 20
to 40%, depending on the initial bacterial burden (12).
Having discovered that minocycline was bactericidal for M. leprae in
mice (5) and in a clinical trial
(7) and having conducted several studies of the three antimicrobials
utilized by Ji et al. (16) in mice
and patients, I was naturally interested in their findings and conclusions.
Against an alternative view
of the reliability of WHO MDT and the further desirability of a once-monthly
supervised regimen, Ji
et al. (16) report that in leprosy patients single doses of minocycline
plus ofloxacin with and without
rifampin are bactericidal and side effects are acceptable; thus, further
clinical application of
intermittent therapy (monthly) is indicated. I do not believe their
results in fact merit these
conclusions.
In their introduction the authors state that further applications of
regimens to be used with rifampin
must prove themselves to be bactericidal. However, the single dose
of minocycline plus ofloxacin
used was entirely inactive in 3 of the 10 studied patients, and 68
and 69% bactericidal in two others,
considered by the authors moderately bactericidal. However, the prototype
bacteriostatic agent
dapsone was previously found by me (4) and others (1), by using these
techniques in mice, to be 72
to 87% bactericidal, and thus, we would consider, 68 to 69% primarily
bacteriostatic. In any case
whether this regimen was bactericidal in 7 of 10 or 5 of 10 of patients,
it certainly was not reliably so
and also far less active in mice than daily dapsone-clofazimine, a
combination which together with
monthly rifampin appears inadequate to effect a cure in previously
untreated lepromatous leprosy
patients (12). Also, in the current studies, 4 of the 10 patients receiving
rifampin, minocycline, and
ofloxacin had gastrointestinal side effects; however mild, this is
consequential and likely would
preclude large-scale utilization of such therapy. Thus, I would conclude,
single doses of ofloxacin
plus minocycline both in mice and in a clinical trial are not reliably
bactericidal, and side effects are
significant.
Monthly therapy for bacterial disease would be unique if found effective
against leprosy. Contrary to
the opinion of Ji et al. (16), the literature does not support a case
for intermittent therapy for each of
three agents utilized, either in experimental mouse infections or in
leprosy patients, particularly the
monthly regimen they envisage.
(i) In an established mouse footpad infection monitored by subpassage
of M. leprae in serial 10-fold
dilutions in mice, Grosset et al. (10) found that daily treatment with
rifampin was significantly more
bactericidal than weekly, fortnightly, or monthly treatment. An analysis
of relapse rates in
lepromatous leprosy patients treated with finite chemotherapy regimens
which included several
different frequencies of rifampin administration found that equivalent
amounts of rifampin daily
resulted in significantly lower relapse rates than more intermittent
rifampin therapy (18).
(ii) My colleagues and I (9) found in mice that once-monthly minocycline
was unreliable, and in
clinical trials we (8) (contrary to the interpretation of Ji et al.
[16]) and others (2) found single doses
to be without activity. Though Ji et al. (16) are correct in saying
that we (8) found that in six of eight
patients single doses of minocycline resulted in a fall of the proportion
of viable M. leprae, only in
one patient was this statistically significant, and two of these six
had a higher proportion of viable
bacilli after an additional week of daily minocycline than was found
prior to the beginning of
treatment. Our data thus hardly support the suggestion that single
doses of minocycline afford
bacterial killing.
(iii) Though pefloxacin in mice was active when administered three times
weekly, it was inactive even
twice weekly, as well weekly and monthly (17). A single dose of ofloxacin
was entirely inactive in
five of eight treated patients (11). Even the study of Ji et al. (16)
itself provides evidence against
monthly therapy: in mice, together with rifampin, daily dapsone plus
clofazimine, which are each far
less active than either minocycline and ofloxacin, were vastly superior
to single doses of minocycline
plus ofloxacin. Though I (6) have also suggested alternative methodological
explanations, the Ji et al.
(16) claim that their case for the bactericidal activity of a single
monthly dose, not found by others, is
a result of the more sensitive "titration" methods they used. However,
several of these other studies
(10, 11, 17) utilized just those methods, and as has been mentioned,
titration results have the pitfall
of labeling activity which is primarily bacteriostatic "bactericidal."
In any event there appears to be a
compelling case favoring daily, as opposed to intermittent, therapy
of leprosy.
Studies of potential synergism or anatagonism of combined treatment
against M. leprae are difficult
to perform and interpret, and the limited results available provide
mixed findings for the agents
proposed by Ji et al. (16). It is noteworthy, however, that the authors'
published literature on mice
(15) and leprosy patients (14) suggests that ofloxacin anatagonizes
the killing provided by
minocycline plus clarithromycin.
Finally, Ji et al. (16) appear now to advocate a duration of monthly
supervised rifampin, minocycline,
and ofloxacin of 2 years, the major bactericidal activity being provided
by rifampin. Such a regimen
includes less rifampin than what was used by them previously in a 1-month
regimen of daily rifampin
plus ofloxacin, which resulted in a very high rate of clinical relapse
(13).
An effective regimen for the cure of lepromatous leprosy is still needed.
Combinations of daily
rifampin and newer bactericidal drugs (minocycline, clarithromycin,
and fluorquinolones), each having
been demonstrated to be more active than dapsone and clofazimine, appear
to be reasonable
treatments.
REFERENCES
1. Colston, M. J., G. R. F. Hilson, and D. K. Banerje. 1978. The
`proportional bactercidal test': a
method for assessing bactercidal activity of drugs against Mycobacterium
leprae in mice. Lepr. Rev.
49:7-15[Medline].
2. Fajardo, T. T., Jr., L. G. Villahermosa, E. G. dela Cruz, R.
M. Abalos, S. G. Franzblau, and P.
Walsh. 1995. Minocycline in lepromatous leprosy. Int. J. Lepr. 63:8-17.
3. Freerksen, E., and M. Rosenfeld. 1977. Leprosy eradication
project of Malta. Chemotherapy
(Basel) 23:356-386[Medline].
4. Gelber, R. H. 1986. The killing of Mycobacterium leprae in
mice by various dietary
concentrations of dapsone and rifampin. Lepr. Rev. 57:347-353[Medline].
5. Gelber, R. H. 1987. Activity of minocycline in Mycobacterium
leprae-infected mice. J. Infect.
Dis. 156:236-239[Abstract].
6. Gelber, R. H. 1997. Regimens to treat lepromatous leprosy.
Antimicrob. Agents Chemother.
41:1618-1620[Abstract].
7. Gelber, R. H., K. Fukuda, S. Byrd, L. P. Murray, P. Siu, M.
Tsang, and T. H. Rea. 1995. A
chemical trial of minocycline in lepromatous leprosy. Br. Med. J. 304:91-92.
8. Gelber, R. H., L. P. Murray, P. Siu, M. Tsang, and T. H. Rea.
1994. Efficacy of minocycline in
single dose and at 100 mg twice daily for lepromatous leprosy. Int.
J. Lepr. 58:568-573[Abstract].
9. Gelber, R. H., P. Siu, M. Tsang, P. Alley, and L. P. Murray.
1991. Effect of low-level and
intermittent minocycline therapy on the growth of Mycobacterium leprae
in mice. Antimicrob. Agents
Chemother. 35:992-994[Abstract/Full Text].
10. Grosset, J. H., and C. C. Guelpa-Lauras. 1987. Activity of
rifampin in infections of normal mice
with Mycobacterium leprae. Int. J. Lepr. 55:847-851.
11. Grosset, J. H., B. Ji, C. C. Guelpa-Lauras, E. G. Perani,
and L. N'Deli. 1990. Clinical trial of
pefloxacin and ofloxacin in the treatment of lepromatous leprosy. Int.
J. Lepr. 58:281-295.
12. Jamet, P., B. Ji, and the Marchoux Chemotherapy Study Group.
1995.
Relapse after long-term follow up of multibacillary patients treated
by WHO multidrug regimen. Int.
J. Lepr. 63:195-201[Medline].
13. Ji, B., Jamet, S. Sow, E. G. Perani, I. Traore, and J. H.
Grosset. 1997. High relapse rate
among lepromatous leprosy patients treated with rifampin plus ofloxacin
daily for 4 weeks.
Antimicrob. Agents Chemother. 41:1953-1956[Abstract].
14. Ji, B., P. Jamet, E. G. Perani, S. Sow, C. Lienhardt, C. Petinon,
and J. H. Grosset. 1996.
Bactericidal activity of single dose of clarithromycin plus minocycline,
with or without ofloxacin,
against Mycobacterium leprae in patients. Antimicrob. Agents Chemother.
40:2137-2141[Abstract].
15. Ji, B., E. G. Perani, C. Petinon, and J. H. Grosset. 1996.
Bactericidal activities of combinations
of new drugs against Mycobacterium leprae in nude mice. Antimicrob.
Agents Chemother.
40:393-399[Abstract].
16. Ji, B., S. Sow, E. Perani, C. Lienhardt, V. Diderot, and J.
Grosset. 1998. Bactericidal activity
of a single-dose combination of ofloxacin plus minocycline, with or
without rifampin, against
Mycobacterium leprae in mice and in lepromatous patients. Antimicrob.
Agents Chemother.
42:1115-1120[Abstract/Full Text].
17. Pattyn, S. R. 1987. Activity of ofloxacin and pefloxacin against
Mycobacterium leprae in mice.
Antimicrob. Agents Chemother. 31:671-672[Medline].
18. Pattyn, S. R. 1993. Search for effective short-course regimens
for the treatment of leprosy. Int.
J. Lepr. 62:72-81.
19. Pearson, J. M. H., R. J. W. Rees, and M. F. R. Waters. 1975.
Sulphone resistance in leprosy.
A review of one hundered proven cases. Lancet ii:69-72.
20. Rajendran, V., C. Vellut, and C. Pushpadass. 1993. Profile
of relapse cases in field trial of
combined therapy in multibacillary leprosy. Int. J. Lepr. 61(Suppl.):4A.
21. Waters, M. F. R., R. J. W. Rees, A. B. G. Laing, K. F. Khoo,
T. W. Meade, W. Parikshah,
and W. R. S. North. 1986. The rate of relapse in lepromatous leprosy
following completion of
twenty years of supervised sulphone therapy. Lepr. Rev. 57:101-109.
22. World Health Organization. 1994. Chemotherapy of leprosy.
Technical report series no. 847.
World Health Organization, Geneva, Switzerland.
23. World Health Organization Study Group. 1982. Chemotherapy
of leprosy for control
programmes. Technical report series, no. 675. World Health Organization,
Geneva, Switzerland.
Robert H. Gelber
Departments of Medicine and Dermatology/ University of California/
San Francisco, California
Dr. Gelber's letter covered many important aspects of chemotherapy
of leprosy, which would be
impossible to address in a single reply. However, his view on the seriousness
of dapsone-resistant
leprosy and the efficacy and achievement of World Health Organization
(WHO)-recommended
multidrug therapy (MDT) for leprosy are beyond the scope of our articles
(5, 6, 8, 9) and have been
clearly addressed in the report of the latest WHO Expert Committee
on Leprosy (14); in addition,
some of the issues, such as a detectable bactericidal effect of single-dose
minocycline (MINO) or
ofloxacin (OFLO) treatment had been raised in his previous letter to
the editor (3) and responded to
by us (7). Therefore, we will focus only on those of his comments that
were not covered by the
previous correspondence.
In one of our pilot trials, 20 lepromatous patients were randomly allocated
to two groups (10 each)
and treated with a single dose of either 600 mg of rifampin (RMP) plus
400 mg of OFLO and 100
mg of MINO or 400 mg of OFLO plus 100 mg of MINO (9). Because the treatment
was inactive
in three patients receiving OFLO-MINO and mild gastrointestinal adverse
events were observed in
two (not four, as wrongly quoted in the letter) patients of this group,
Dr. Gelber concludes that a
single dose of OFLO-MINO is not reliably bactericidal and the side
effects are significant. We
disagree with the conclusion based on the following reasons. (i) By
definition (11), any antibacterial
effect detected by the "proportional bactericidal test" (1) should
be bactericidal, and there is no
reason to consider the 68 to 69% killing of viable organisms as bacteriostatic.
(ii) Bactericidal effect
was observed in a great majority (7 of 10) of patients treated with
a single dose of OFLO-MINO,
and even with RMP, by far the most bactericidal drug against Mycobacterium
leprae (5),
single-dose treatment may not display detectable bactericidal effect
in all patients; e.g., no
bactericidal effect was observed in 1 of 10 patients receiving a single
dose of RMP-OFLO-MINO
(9). Finally, (iii) the adverse events in a clinical trial are not
necessarily equivalent to the side effects
caused by actual treatment, particularly when the events are mild and
transitory (without significant
findings on physical examination). Whether such degree of mild adverse
events is significant is a
matter of judgement. Nevertheless, more and more patients are treated
with a single dose of
RMP-OFLO-MINO in the field with excellent tolerance (12), indicating
that Dr. Gelber's prediction
precluding large-scale utilization of such therapy was wrong.
Besides OFLO and MINO, Dr. Gelber also challenges the justification
for treating leprosy with
monthly administration of RMP, despite the fact that it is the backbone
of the MDT regimens for
both paucibacillary and multibacillary leprosy since 1981. More than
8 million leprosy patients have
been cured by the beginning of 1997 with a very low relapse rate (14).
Numerous publications,
including one by Dr. Gelber himself (2), have indicated that RMP displays
very powerful and rapid
bactericidal activity against M. leprae in experimental animals and
in patients. Immediately after RMP
treatment is begun, the great majority of viable M. leprae organisms
are killed. No one has been able
to convincingly demonstrate that after a few doses of RMP-containing
regimens, daily administration
is more bactericidal than monthly treatment. On the contrary, we have
observed that, in nude mice
with established M. leprae infection (5), monthly administration of
RMP-containing regimens always
produced significantly greater bactericidal activities than the same
number of doses of daily
treatment. To prove that daily treatment with RMP was significantly
more bactericidal than weekly,
fortnightly, or monthly treatment, Dr. Gelber quotes one of our earlier
results for immunocompetent
mice with established M. leprae infection (4). However, we have already
pointed out that because of
the rapid spontaneous killing of M. leprae in untreated controls, established
infection in
immunocompetent mice is not a suitable system for comparing the activities
of different drug
regimens, and the results must be interpreted with caution (4). Furthermore,
the duration of treatment
in the quoted experiments was only 8 to 12 weeks, and the differences
in bactericidal effects
between daily and monthly administrations were marginal though statistically
significant; based on our
experience with infection in nude mice (5), it is likely that the differences
may not exist after a longer
duration, e.g., 6 months, of treatment. To support his argument, Dr.
Gelber also cites studies on
relapse rates for lepromatous patients treated with various RMP-containing
regimens, which
concluded that equivalent amounts of daily RMP resulted in significantly
lower relapse rates than
those in patients treated with intermittent RMP (10). Nonetheless,
one has to be extremely cautious
in drawing conclusions from such an analysis, because the pretreatment
characteristics of the patients
in the different groups may not be comparable. Association between
relapse rate and frequency of
RMP administration was not confirmed for patients treated with the
same regimens by an Institut
Marchoux study after a longer follow-up period (13).
Finally, we would like to point out that, based on the considerations
of cost-effectiveness and
operational feasibility, the main objective of our research activities
is to develop a minimal but not
suboptimal regimen(s) that is effective, simple, and affordable. To
eradicate leprosy, such minimal
regimens are badly needed in many countries of endemicity, particularly
in areas where the health
infrastructure is poor and/or accessibility is difficult. On the other
hand, it is understandable that the
regimen for the treatment of a handful leprosy patients in developed
countries may be far more
sophisticated, as long as it can be justified by the physicians, tolerable
by the patients, and affordable
by the community.
REFERENCES
1. Colston, M. J., G. R. F. Hilson, and D. K. Banerjee. 1978.
The "proportional bactericidal test,"
a method for assessing bactericidal activity of drugs against Mycobacterium
leprae in mice. Lepr.
Rev. 49:7-15[Medline].
2. Gelber, R. H., and L. Levy. 1987. Detection of persisting Mycobacterium
leprae by inoculation
of the neonatally thymectomized rat. Int. J. Lepr. 55:872-878.
3. Gelber, R. H. 1997. Regimens to treat lepromatous leprosy.
Antimicrob. Agents Chemother.
41:1618-1619[Medline]. (Letter to the editor.)
4. Grosset, J. H., and C. C. Guelpa-Lauras. 1987. Activity of
rifampin in infections of normal mice
with Mycobacterium leprae. Int. J. Lepr. 55:847-851[Medline].
5. Ji, B., E. G. Perani, C. Petinom, and J. H. Grosset. 1996.
Bactericidal activities of combinations
of new drugs against Mycobacterium leprae in nude mice. Antimicrob.
Agents Chemother.
40:393-399[Abstract].
6. Ji, B., P. Jamet, E. G. Perani, S. Sow, C. Lienhardt, C. Petinon,
and J. H. Grosset. 1996.
Bactericidal activity of single dose of clarithromycin plus minocycline,
with or without ofloxacin,
against Mycobacterium leprae in patients. Antimicrob. Agents Chemother.
40:2137-2141[Abstract].
7. Ji, B., E. G. Perani, C. Petinon, J. H. Grosset, P. Jamet,
S. Sow, and C. Lienhardt. 1997.
Regimens to treat lepromatous leprosy. Antimicrob. Agents Chemother.
41:1619-1620. (Letter to
the editor.)
8. Ji, B., P. Jamet, S. Sow, E. G. Perani, I. Traore, and J. H.
Grosset. 1997. High relapse rate
among lepromatous leprosy patients treated with rifampin plus ofloxacin
daily for 4 weeks.
Antimicrob. Agents Chemother. 41:1953-1956[Abstract].
9. Ji, B., S. Sow, E. Perani, C. Lienhardt, V. Diderot, and J.
Grosset. 1998. Bactericidal activity of
a single dose combination of ofloxacin plus minocycline, with or without
rifampin, against
Mycobacterium leprae in mice and in lepromatous patients. Antimicrob.
Agents Chemother.
42:1115-1120[Abstract/Full Text].
10. Pattyn, S. R. 1993. Search for effective short-course regimens
for the treatment of leprosy. Int.
J. Lepr. 61:76-81.
11. Shepard, C. C. 1982. Statistical analysis of results obtained
by two methods for testing drug
activity against Mycobacterium leprae. Int. J. Lepr. 50:96-101.
12. Single-Lesion Multicentre Trial Group. 1997. Efficacy of single
dose multidrug therapy for the
treatment of single-lesion paucibacillary leprosy. Indian J. Lepr.
69:121-129[Medline].
13. Sow, S., B. Ji, and Marchoux Chemotherapy Study Group. 1998.
Intervals between stopping
rifampin-containing regimens and occurrence of relapse in multibacillary
leprosy, abstr. CH19. In
Program and abstracts of the 15th International Leprosy Congress, Beijing,
China, 7 to 12
September 1998.
14. WHO Expert Committee on Leprosy. 1998. Seventh report. WHO
Technical Series, no. 874.
World Health Organization, Geneva, Switzerland.
Baohong Ji
Jacques H. Grosset
Faculté de Médecine Pitié-Salpêtrière/
Paris/ France
=============================================================
7.) Rifampicin/minocycline and ofloxacin (ROM) for single lesions--what
is the evidence?
=============================================================
Lepr Rev 1997 Dec;68(4):299-300 Related Articles, Books, LinkOut
Earlier this year the results of a double-blind randomized controlled
trial comparing a potential new
treatment (single dose rifampicin/ofloxacin and minocycline (ROM))
for monolesion paucibacillary
leprosy with the current 6-month treatment with rifampicin and dapsone
(WHO-PB-MDT) were
published. The executive report of the 7th WHO Expert Committee on
Leprosy (Geneva, 26 May-3
June 1997) noted that the Committee considered the single-dose ROM
an acceptable and
cost-effective regimen for the treatment of single skin lesion PB leprosy.
The paper and report have
been highly influential and already strategic planners in several countries,
notably India and Brazil,
have introduced ROM treatment for single-lesion disease into their
national programmes. We are
reprinting this important paper in this issue of Leprosy Review (p.
299-300) by kind permission of
the Editor of the Indian Journal of Leprosy since we feel that readers
may wish to study the original
publication for themselves.
The introduction of single-dose treatment for a subset of leprosy patients
is obviously attractive from
an operational standpoint and will make a significant impact in reducing
prevalence in some areas.
However it is also fraught with dangers, and hence the evidence for
its effectiveness should be
considered in some depth.
The trial involved nine different centres, each recruiting between 103
and 400 patients over a
10-month period to give a total of 1483 patients. Follow-up over an
18-month period was good
with a 93% completion rate.
There are a number of difficulties in interpreting the data. The first
of these relates to the diagnosis of
leprosy in these patients. It is not clear how lesions were tested
for anaesthesia nor which modalities
of sensation were examined. Much of the initial testing (skin biopsy,
histamine testing, lepromin
testing and even detailed neurological examination) was optional. Hence
it is not possible to know
how many patients in the trial had definite evidence of leprosy. The
system used in the Karonga trial,
of grading patients on a scale of diagnostic certainty for leprosy
is a useful way of addressing the
problem of diagnosis.1 From an operational point of view it would be
helpful to know how many
patients were evaluated and prepared for entry to the trial but then
proved to be slit-skin smear
positive and so ineligible for treatment with ROM. There is no information
on how many patients had
skin biopsies with microscopic evidence of leprosy.
Children above the age of 5 were eligible for the trial but no details
are given of numbers of children
treated nor the drug doses used. The side-effects observed in the trial
patients are briefly discussed.
No mention is made of monitoring for specific side-effects and no details
are given of potential
side-effects such as tooth discoloration in children given minocycline.
The major outcome measure was derived from a scoring system based on
five different clinical
observations of the lesions. No details of how this scale was constructed
nor what weights were
given to the five components nor how scoring was standardized between
centres are provided. This
makes interpretation of the results difficult. Of the 1381 patients
who completed the trial only 12
patients failed to improve, and of these 2 deteriorated. The investigators
set an improvement of 13
points in the clinical score as their definition of marked clinical
improvement; their other outcome
measure was complete cure. Patients treated with the conventional WHO-PB-MDT
regimen
showed statistically significantly better results on both these measures
when compared with the
patients treated with the ROM regimen. The significance level for the
difference in complete cure
rates is incorrectly given in Table V as P = 0 04, the correct figure
is actually even more significant at
P = 0 004 as given in the text. It is not possible from the data given
to discern which modalities
improved most. A more detailed analysis of the data such as an analysis
of covariance would have
allowed examination of the effect of age, sex or type of improvement
on response to treatment. This
would be valuable in determining which patients would benefit most
from treatment with ROM.
These details are important because this trial was designed to be a
gold standard trial of ROM
showing its medical effectiveness, not an operational trial showing
that it is an easy treatment to
administer.
The follow-up period of 18 months for ROM treated patients and 12 months
for WHOPB-MDT
treated patients is too short to detect relapses with a relapse rate
for paucibacillary disease of 1%
per year. It is to be hoped that the patients will continue under active
surveillance so that this
important figure can be determined.
ROM is undoubtedly an attractive treatment. It is operationally easy
to administer and is probably
suitable for some patients. If it is to be incorporated into treatment
schedules then it is important that
workers follow good practice guidelines. It is vital that all patients
should be examined carefully to
ensure that there really is only a single lesion. Women may be reluctant
to be examined fully and if
so, should not be prescribed ROM. It is also vital that a careful neurological
examination is done to
ensure that no nerve thickening or impairment of motor or sensory function
is present. There was no
statistical difference in the number of reactions or neuritis in each
of the treatment groups. This serves
as a reminder that even patients with monolesions can suffer reactions
and so need to be kept under
follow-up even after single dose treatment when it will be very tempting
to have less stringent
follow-up.
In conclusion this trial as published leaves many doubts: how many of
the patients treated in this trial
actually had leprosy, which outcome measure improved, did sensation
in the lesions improve, what
side-effects were monitored? The analysis reveals few details but the
two measures reported
showed significant superiority for the existing WHO-PB-MDT regimen.
Thus it is inaccurate to claim
on the basis of the published data, as the authors did in their abstract
that ROM is 'almost as
effective as WHO-PB-MDT'. The implementation of single dose ROM should
be undertaken with
care; it is likely to be of value for some patients, but the attraction
of operational expediency could
easily result in misuse.
DIANA N. J. LOCKWOOD
=============================================================
8.) What are the new antileprosy drugs - ROM - now available for the
treatment of leprosy?
=============================================================
Recently three more drugs have shown bactericidal activity against
M. leprae. These are
ofloxacin-a fluoroquinolone,
minocycline-a tetracycline
clarithromycin-a macrolide
Several experimental and clinical studies have demonstrated that these
drugs either alone or in
combination with other antileprosy drugs have significant bactericidal
activity.
WHO started supplying quantities of special ROM blister packs in late
1997 to India, Bangladesh,
Nepal and Brazil for the treatment of single lesion PB leprosy.
============================================================
9.)What are the types of leprosy that can be treated by ROM ?
============================================================
The 7th WHO Expert Committee on Leprosy recommended the use of a combination
of rifampicin
600 mg, ofloxacin 400 mg and minocycline 100 mg (ROM) for the treatment
of two categories of
leprosy patients:
patients presenting with single skin lesion paucibacillary leprosy can
be treated with only one dose of
ROM
multibacillary leprosy patients who do not accept clofazimine can be
treated with monthly
administration of 24 doses of ROM.
=============================================================
10.)What is the reason for introducing single dose treatment for paucibacillary
leprosy presenting
with a single skin lesion?
=============================================================
Most of the paucibacillary leprosy cases presenting with only one skin
lesion have a high tendency to
heal without any specific antileprosy treatment. However, today it
is not possible to identify those
who will develop progressive disease and all such cases need to be
treated. In some programmes
(especially vertical programmes which have a strong active case finding
component) such patients
constitute a significant proportion of newly detected cases. The six-month
MDT regimen puts a
heavy burden both on patients and the health services as a large proportion
of such patients are
children and the compliance to treatment is usually less than satisfactory.
=============================================================
11.) What is the basis for the recommended alternative regimen for
the treatment of paucibacillary
leprosy presenting with a single skin lesion?
=============================================================
The discovery of effectiveness of ofloxacin and minocycline in the
treatment of leprosy encouraged
WHO to assess the efficacy of single dose treatment for this group
of patients. A large multicentre,
double-blind study was organized. The results demonstrated that single
dose of a combination of
rifampicin 600 mg, ofloxacin 400 mg and minocycline 100 mg (ROM) is
as effective as the standard
6-month WHO MDT for paucibacillary leprosy.
=============================================================
12.)Does WHO recommend that all programmes should treat single lesion
paucibacillary leprosy
cases with one dose of ROM?
=============================================================
No, as such patients are detected in large numbers mainly by vertical
programmes having a strong
active case finding component. The introduction of this regimen in
programmes detecting very few
single-lesion leprosy cases will only add to the logistic problems
of catering to a third regimen and
also complicate the information system. Such programmes should continue
to treat these cases with
the standard WHO MDT for paucibacillary leprosy for six months. Therefore,
WHO recommends
that this regimen may be used only by programmes detecting a large
number of (1 000 or more) such
cases annually.
=============================================================
13.) Efficacy of single dose multidrug therapy for the treatment of
single-lesion paucibacillary
leprosy. Single-lesion Multicentre Trial Group.
=============================================================
Source
Indian J Lepr, 69(2):121-9 1997 Apr-Jun
Abstract
A multicentre double-blind controlled clinical trial was carried out
to
compare the efficacy of a combination of rifampicin 600 mg plus ofloxacin
400 mg plus minocycline 100 mg (ROM) administered as single dose with
that
of the standard six-month WHO/MDT/PB regimen. The subjects included
1483
cases with one skin lesion who were previously untreated, were
smear-negative, and had no evidence of peripheral nerve trunk involvement,
and they were randomly divided into study and control groups. The total
duration of the study from the day of intake was 18 months, and 1381
patients completed study. Only 12 patients were categorized as treatment
failure and no difference was observed between the two regimens. Occurrence
of mild side-effects and leprosy reactions were minimal (less than
1%) in
both groups. This study showed that ROM is almost as effective as the
standard WHO/MDT/PB in the treatment of single lesion PB leprosy.
=============================================================
14.) Minocycline in lepromatous leprosy.
=============================================================
Author
Fajardo TT Jr; Villahermosa LG; dela Cruz EC; Abalos RM; Franzblau
SG;
Walsh GP
Address
Clinical Research Branch, Leonard Wood Memorial Center, Cebu City,
The
Philippines.
Source
Int J Lepr Other Mycobact Dis, 63(1):8-17 1995 Mar
Abstract
Twelve patients were treated with three dose levels of minocycline
for 30
days, primarily to detect the dose-related effects on Mycobacterium
leprae
viability, followed by another 5 months of daily minocycline for overall
efficacy and persistence of clinical and antibacterial effects.
Subsequently, the patients were given standard WHO/MDT chemotherapy
for
multibacillary leprosy. Clinical improvement was recognizable during
the
first month, occurring much earlier among those on minocycline 200
mg daily
than those who received minocycline 100 mg daily. A similar change
also was
observed in one patient 11 days after three daily doses of 100 mg of
minocycline. At the end of 6 months, all patients were clinically improved
with a slight reduction in the average bacterial index (BI) and logarithmic
index of bacilli in biopsy (LIB). The effects of minocycline on viability
by mouse foot pad inoculation and palmitic acid oxidation assays were
noted
beginning at 10 to 14 days of daily dosing and becoming more definite
after
30 days of treatment. Both tests correlated fairly well. Doses of 200
mg
daily did not appear to be more efficient than minocycline 100 daily.
Phenolic glycolipid-I (PGL-I) antigen determinations done on some patients
during the first month remained positive and did not correlate with
changes
in viability results. At the end of 6 months, after 5 months of 100
mg of
minocycline monotherapy, no viable organisms could be demonstrated
by mouse
foot pad inoculation and palmitic acid oxidation assays; assays for
PGL-I
antigen were all negative.(ABSTRACT TRUNCATED AT 250 WORDS)
=============================================================
15.) Efficacy of minocycline in single dose and at 100 mg twice daily
for lepromatous leprosy.
=============================================================
Int J Lepr Other Mycobact Dis (United States), Dec 1994, 62(4)
p568-73
AUTHOR(S): Gelber RH; Murray LP; Siu P; Tsang M; Rea TH
AUTHOR'S ADDRESS: San Francisco Regional Hansen's Disease Program,
CA 94115.
PUBLICATION TYPE: CLINICAL TRIAL; JOURNAL ARTICLE
ABSTRACT: A clinical trial of minocycline in a total of 10 patients
with
previously untreated lepromatous leprosy was conducted in order to
evaluate
the efficacy of a single, initial, 200-mg dose and 100 mg twice daily
of
minocycline for a total duration of up to 3 months. Patients improved
remarkably quickly. Although single-dose therapy did not result in
a
significant killing of Mycobacterium leprae, viable M. leprae were
cleared
from the dermis regularly by 3 months of twice-daily therapy, a rate
similar to that achieved by minocycline 100 mg once daily. Because
more
side effects were noted herein than previously with 100 mg daily, we
recommend that minocycline, when applied, be administered at 100 mg
daily
to leprosy patients.
=============================================================
16.) Field trial on efficacy of supervised monthly dose of 600 mg rifampin,
400 mg ofloxacin and
100 mg minocycline for the treatment of leprosy; first results.
=============================================================
Author
Mane I; Cartel JL; Grosset JH
Address
Institut de Leprologie Appliquee, Dakar CD Annexe, Senegal.
Source
Int J Lepr Other Mycobact Dis, 65(2):224-9 1997 Jun
Abstract
In 1995, a field trial was implemented in Senegal in order to evaluate
the
efficacy of a regimen based on the monthly supervised intake of rifampin
600 mg, ofloxacin 400 mg and minocycline 100 mg to treat leprosy. During
the first year of the trial, 220 patients with active leprosy (newly
detected or relapsing after dapsone monotherapy) were recruited: 102
paucibacillary (PB) (60 males and 42 females) and 118 multibacillary
(MB)
(71 males and 47 females). All of them accepted the new treatment (none
requested to be preferably put under standard WHO/MDT), no clinical
sign
which could be considered as a toxic effect of the drug was noted,
and none
of the patients refused to continue treatment because of any clinical
trouble. The compliance was excellent: the 113 patients (PB and MB)
detected during the first 6 months of the trial have taken six monthly
doses in 6 months, as planned. The rate of clearance and the progressive
decrease of cutaneous lesions was satisfactory. Although it is too
soon to
give comprehensive results, it should be noted that no treatment failure
was observed in the 56 PB patients who have completed treatment and
have
been followed up for 6 months. The long-term efficacy of the new regimen
is
to be evaluated on the rate of relapse during the years following the
cessation of treatment. If that relapse rate is acceptable (similar
to that
observed in patients after treatment with current standard WHO/ MDT),
the
new regimen could be a solution to treat, for instance, patients very
irregular and/or living in remote or inaccessible areas since no selection
of rifampin-resistant Mycobacterium leprae should be possible (a monthly
dose of ofloxacin and minocycline being as effective as a dose of dapsone
and clofazimine taken daily for 1 month). Nevertheless, until longer
term
results of this and other trials become available, there is no
justification for any change in the treatment strategy, and all leprosy
patients should be put under standard WHO/MDT.
=============================================================
17.) Bactericidal activity of a single-dose combination of ofloxacin
plus minocycline, with or without
rifampin, against Mycobacterium leprae in mice and in lepromatous patients.
=============================================================
Author
Ji B; Sow S; Perani E; Lienhardt C; Diderot V; Grosset J
Address
Facult´e de M´edecine Piti´e-Salp^etri`ere, Paris,
France.
[email protected]
Source
Antimicrob Agents Chemother, 42(5):1115-20 1998 May
Abstract
To develop a fully supervisable, monthly administered regimen for treatment
of leprosy, the bactericidal effect of a single-dose combination of
ofloxacin (OFLO) and minocycline (MINO), with or without rifampin (RMP),
against Mycobacterium leprae was studied in the mouse footpad system
and in
previously untreated lepromatous leprosy patients. Bactericidal activity
was measured by the proportional bactericidal method. In mouse experiments,
the activity of a single dose of the combination OFLO-MINO was dosage
related; the higher dosage of the combination displayed bactericidal
activity which was significantly inferior to that of a single dose
of RMP,
whereas the lower dosage did not exhibit a bactericidal effect. In
the
clinical trial, 20 patients with previously untreated lepromatous leprosy
were treated with a single dose consisting of either 600 mg of RMP
plus 400
mg of OFLO and 100 mg of MINO or 400 mg of OFLO plus 100 mg of MINO.
The
OFLO-MINO combination exhibited definite bactericidal activity in 7
of 10
patients but was less bactericidal than the RMP-OFLO-MINO combination.
Both
combinations were well tolerated. Because of these promising results,
a
test of the efficacy of multiple doses of ROM in a larger clinical
trial
appears justified.
=============================================================
18.) Bactericidal activity of single dose of clarithromycin plus minocycline,
with or without ofloxacin,
against Mycobacterium leprae in patients.
=============================================================
Author
Ji B; Jamet P; Perani EG; Sow S; Lienhardt C; Petinon C; Grosset JH
Address
Facult´e de M´edecine Piti´e-Salp^etri`ere, Paris,
France.
Source
Antimicrob Agents Chemother, 40(9):2137-41 1996 Sep
Abstract
Fifty patients with newly diagnosed lepromatous leprosy were allocated
randomly to one of five groups and treated with either a month-long
standard regimen of multidrug therapy (MDT) for multibacillary leprosy,
a
single dose of 600 mg of rifampin, a month-long regimen with the dapsone
(DDS) and clofazimine (CLO) components of the standard MDT, or a single
dose of 2,000 mg of clarithromycin (CLARI) plus 200 mg of minocycline
(MINO), with or without the addition of 800 mg of ofloxacin (OFLO).
At the
end of 1 month, clinical improvement accompanied by significant decreases
of morphological indexes in skin smears was observed in about half
of the
patients of each group. A significant bactericidal effect was demonstrated
in the great majority of patients in all five groups by inoculating
the
footpads of mice with organisms recovered from biopsy samples obtained
before and after treatment. Rifampin proved to be a bactericidal drug
against Mycobacterium leprae more potent than any combination of the
other
drugs. A single dose of CLARI-MINO, with or without OFLO, displayed
a
degree of bactericidal activity similar to that of a regimen daily
of doses
of DDS-CLO for 1 month, suggesting that it may be possible to replace
the
DDS and CLO components of the MDT with a monthly dose of CLARI-MINO,
with
or without OFLO. However, gastrointestinal adverse events were quite
frequent among patients treated with CLARI-MINO, with or without OFLO,
and
may be attributed to the higher dosage of CLARI or MINO or to the
combination of CLARI-MINO plus OFLO. In future trials, therefore, we
propose to reduce the dosages of the drugs to 1,000 mg of CLARI, 100
mg of
MINO, and 400 mg of OFLO.
=========================================================================
19.) WHO Expert Committee on Leprosy.
=========================================================================
Source: World Health Organ Tech Rep Ser, 874():1-43 1998
Abstract
Considerable progress has been made in the fight against leprosy during
the
past 10-15 years, following the introduction of multidrug therapy (MDT)
regimens and the establishment of the goal of eliminating leprosy as
a
public health problem by the year 2000. Current estimates indicate
that
there are about 1.15 million cases of leprosy in the world, compared
with
10-12 million cases in the mid-1980s. This report presents the conclusions
of a WHO Expert Committee convened to review the global leprosy situation
and the technology available for eliminating the disease, to identify
the
remaining obstacles to reaching the goal of eliminating leprosy as
a public
health problem, and to make appropriate recommendations for the future
on
technical and operational matters. The current status of leprosy
elimination is discussed, and the various antileprosy drugs are reviewed,
including the most recently available drugs. On the basis of field
trials
and clinical studies, the Committee concludes that a single dose of
a
combination of rifampicin, ofloxacin and minocycline is an acceptable
and
cost-effective alternative regimen for the treatment of single-lesion
paucibacillary leprosy, and that the duration of the current MDT regimen
for multibacillary leprosy could possibly be shortened to 12 months.
The
Committee points out the need for improved management of reactions
and
neuritis and prevention of leprosy-related disabilities and impairments,
and recommends that antileprosy activities should become an integral
part
of general health services and should involve communities to the fullest
extent possible.
=========================================================================
20.) Experimental evaluation of possible new short-term drug regimens
for
treatment of multibacillary leprosy.
=========================================================================
Author
Banerjee DK; McDermott-Lancaster RD; McKenzie S
Address
Department of Medical Microbiology, St George's Hospital Medical School,
London, United Kingdom. [email protected].
Source
Antimicrob Agents Chemother, 41(2):326-30 1997 Feb
Abstract
Groups of nude mice, with both hind footpads infected with 10(8)
Mycobacterium leprae organisms, were treated with 4-week courses of
different drug combinations. The effect treatment on each group was
evaluated by subinoculating footpad homogenates from the treated mice
into
groups of normal and nude mice for subsequent regrowth, assessed 1
year
later. A combination of rifampin (RMP) with clarithromycin (CLARI),
minocycline (MINO), and ofloxacin (OFLO) resulted in the complete killing
of M. leprae after 3 weeks of treatment. A combination of sparfloxacin
(SPAR) and RMP also resulted in a similar bactericidal effect after
3 weeks
of treatment. Other drug combinations showed variable effects. Very
little
or no effect was observed with any regimen if the treatment was given
for
less than 2 weeks. World Health Organization (WHO) multidrug therapy
(MDT)
given for 8 weeks was as effective as the two combinations described
above.
The results suggest that multidrug combinations consisting of RMP-OFLO
(or
SPAR)-CLARI (and/or MINO) are as effective as the WHO MDT for the treatment
of experimental leprosy. Moreover, they imply that these combinations,
which were found to be active in a 4-week experimental treatment protocol,
could be administered as treatment to patients for a period of time
shorter
than the present 2-year regimen without a loss of effectiveness.
=========================================================================
21.) Powerful bactericidal activities of clarithromycin and minocycline
against Mycobacterium leprae in lepromatous leprosy.
=========================================================================
ARTICLE SOURCE: J Infect Dis (United States), Jul 1993,
168(1) p188-90
AUTHOR(S): Ji B; Jamet P; Perani EG; Bobin P; Grosset JH
AUTHOR'S ADDRESS: Faculte de Medecine Pitie-Salpetriere, Paris,
France.
PUBLICATION TYPE: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED
CONTROLLED
TRIAL
ABSTRACT: Thirty-six patients with newly diagnosed lepromatous
leprosy
were allocated randomly to three groups and treated for 56 days with
minocycline (100 mg daily), clarithromycin (500 mg daily), or
clarithromycin (500 mg) plus minocycline (100 mg daily). All groups
had
rapid and remarkable clinical improvement and significant decline of
the
bacterial and morphologic indices in skin smears during treatment.
More
than 99% and 99.9% of the viable Mycobacterium leprae had been killed
by 28
and 56 days of treatment, respectively, as measured by inoculation
of
organisms recovered from skin samples, taken before and during treatment,
into the footpads of immunocompetent and nude mice. Clinical improvement
and bactericidal activity did not differ significantly among the three
groups. Adverse reactions were rare and mild, and no laboratory abnormality
was detected during the trial. Both clarithromycin and minocycline
displayed powerful bactericidal activities against M. leprae in leprosy
patients and may be considered important components of new multidrug
regimens for the treatment of multibacillary leprosy.
============================================================
22.) Leprosy resistant to multi-drug-therapy (MDT) successfully treated
with ampicillin-sulbactam combination--(a case report).
============================================================
Mehta VR
L.T.M.M. College, Bombay.
Indian J Med Sci (INDIA) Nov 1996 50 (11)
p305-7 ISSN: 0019-5359
Language: ENGLISH
Document Type: JOURNAL ARTICLE
Journal Announcement: 9707
Subfile: INDEX MEDICUS
A 50 year male developed a discoid lesion of leprosy on the
face.
Inspite of Dapsone 100 mg/day and Rifampicin 600 mgm per day the disease
spread to both sides of the face and forehead. It became worse
with
Prednisolone and Clofazimine. It cleared completely when Sultamicillin
was
added to the latter. This seems to be the first patient of leprosy
to be
treated with this combination and reported.
=========================================================================
23.) Differential protective effect of bacillus calmette-guerin vaccine
against multibacillary and paucibacillary leprosy in nagpur, india.
=========================================================================
Public Health 1999 Nov;113(6):311-3
Kulkarni HR, Zodpey SP
Department of Preventive and Social Medicine and Clinical Epidemiology
Unit, Government Medical College, Nagpur, India.
For this paper we conducted a secondary data analysis to test the
hypothesis that a linear trend exists in the protective effect of bacillus
Calmette-Guerin (BCG) vaccine against types of leprosy. We used data
from
two previous case-control studies to perform an unmatched test for
linear
trend. We observed that both the studies revealed a significant linear
trend (P<0.00001). One study that estimated an insignificant protective
effect of BCG against paucibacillary leprosy showed a significant departure
from linearity. We conclude that, the protective effect of BCG vaccination
is differential across severity of leprosy as it brings about a shift
in
the immune response to a higher level of cell mediated immunity. We
recommend that future studies dealing with the protective effect of
BCG
against leprosy should also conduct an analysis for trend.
=========================================================================
24.) Protective effect of Bacillus Calmette Guerin (BCG) against leprosy:
a
population-based case-control study in Nagpur, India.
=========================================================================
Lepr Rev 1999 Sep;70(3):287-94
Zodpey SP, Bansod BS, Shrikhande SN, Maldhure BR, Kulkarni SW
Clinical Epidemiology Unit, Govt Medical College, Nagpur, MS, India.
A population-based pair-matched case-control study was carried out in
an
urban community, Nagpur, India, to estimate the effectiveness of BCG
vaccination in the prevention of leprosy. The study included 212 cases
of
leprosy (diagnosed by WHO criteria), below the age of 35 years, detected
during a leprosy survey conducted by the Government of Maharashtra
over a
population of 20,03,325. Each case was pair-matched with one neighbourhood
control for age, sex and socioeconomic status. A significant protective
association between BCG and leprosy was observed (OR = 0.40, 95% CI
=
0.23-0.68). The overall vaccine effectiveness (VE) was estimated to
be 60%
(95% CI = 32-77). The BCG effectiveness against multi-bacillary and
paucibacillary leprosy was 72% (95% CI = 35-88) and 45% (95% CI = 3-73),
respectively. Vaccine was more effective during the first decade of
life,
among females and in lower socioeconomic strata. The overall prevented
fraction was 39% (95% CI = 16-58). In conclusion, this first ever
population-based case control study performed in Central India, identified
a beneficial role of BCG vaccination in prevention of leprosy in study
population.
=========================================================================
25.) Patient contact is the major determinant in incident leprosy:
implications for future control.
=========================================================================
Int J Lepr Other Mycobact Dis 1999 Jun;67(2):119-28
van Beers SM, Hatta M, Klatser PR
Department of Biomedical Research, Royal Tropical Institute, Amsterdam,
The
Netherlands.
Notwithstanding the elimination efforts, leprosy control programs face
the
problem of many leprosy patients remaining undetected. Leprosy control
focuses on early diagnosis through screening of household contacts,
although this high-risk group generates only a small proportion of
all
incident cases. For the remaining incident cases, leprosy control programs
have to rely on self-reporting of patients. We explored the extent
to which
other contact groups contribute to incident leprosy. We examined
retrospectively incident leprosy over 25 years in a high-endemic village
of
2283 inhabitants in Sulawesi, Indonesia, by systematically reviewing
data
obtained from the local program and actively gathering data through
interviews and a house-to-house survey. We investigated the contact
status
in the past of every incident case. In addition to household contact,
we
distinguished neighbor and social contacts. Of the 101 incident cases
over
a 25-year period, 79 (78%) could be associated to contact with another
leprosy patient. Twenty-eight (28%) of these 101 cases were identified
as
household contacts, 36 (36%) as neighbors, and the remaining 15 (15%)
as
social contacts. Three patients had not had a traceable previous contact
with another leprosy patient, and no information could be gathered
from 19
patients. The median span of time from the registration of the primary
case
to that of the secondary case was 3 years; 95% of the secondary cases
were
detected within 6 years after the primary case. The estimated risk
for
leprosy was about nine times higher in households of patients and four
times higher in direct neighboring houses of patients compared to
households that had had no such contact with patients. The highest
risk of
leprosy was associated with households of multibacillary patients.
The risk
of leprosy for households of paucibacillary patients was similar to
the
risk of leprosy for direct neighboring houses of multibacillary patients,
indicating that both the type of leprosy of the primary case and the
distance to the primary case are important contributing factors for
the
risk of leprosy. Contact with a leprosy patient is the major determinant
in
incident leprosy; the type of contact is not limited to household
relationships but also includes neighbor and social relationships.
This
finding can be translated into a valuable and sustainable tool for
leprosy
control programs and elimination campaigns by focusing case detection
and
health promotion activities not only on household contacts but also
on at
least the neighbors of leprosy cases.
============================================================
26.) The clinical use of fluoroquinolones for the treatment of mycobacterial
diseases.
============================================================
Clin Infect Dis 1997 Nov;25(5):1213-21 Related Articles, Books, LinkOut
Alangaden GJ, Lerner
SA
Department of Biochemistry and Molecular Biology, Wayne State University
School of Medicine,
Detroit, Michigan, USA.
Mycobacterial diseases often require prolonged therapy with multidrug
regimens. Fluoroquinolones
have excellent bactericidal activity against many mycobacteria; achieve
effective serum, tissue, and
intracellular levels following oral administration; and produce few
adverse effects. These properties
have led to the increasing use of fluoroquinolones for the treatment
of mycobacterial infections. We
reviewed clinical studies and reports involving the use of fluoroquinolones
for mycobacterial
diseases. Ofloxacin, ciprofloxacin, sparfloxacin, and pefloxacin exhibit
clinical efficacy against
mycobacterial diseases, especially tuberculosis and leprosy. Fluoroquinolones
have generally been
administered in regimens that include other agents. However, when a
fluoroquinolone has been found
to be the sole active agent in a multidrug regimen, the ready emergence
of resistance to
fluoroquinolones has been recognized, just as when they have been used
as monotherapy. Therefore,
to forestall the emergence of resistance to fluoroquinolones during
the treatment of mycobacterial
diseases, these drugs should always be used in combination with at
least one other active agent, and
they should be used only when effective alternative drugs are not available.
============================================================
27.) A case of relapsed leprosy successfully treated with sparfloxacin.
============================================================
Arch Dermatol 1996 Nov;132(11):1397-8 Related Articles, Books, LinkOut
Sugita Y, Suga C, Ishii N, Nakajima H
Publication Types:
Letter
============================================================
============================================================
28.) Active leprosy treated effectively with ofloxacin.
============================================================
Intern Med 1996 Sep;35(9):749-51 Related Articles, Books, LinkOut
Mochizuki Y, Oishi M, Nishiyama C, Iida T
Department of Neurology, Nihon University School of Medicine, Tokyo.
The patient is a 25-year-old Filipino who showed polymorphous eruptions
over the whole body,
right ulnar nerve paresis, polyneuropathy and hypalgesia in the area
of eruptions. Because the biopsy
specimen showed foam cells, histiocytes, epithelioid cells, many Mycobacterium
leprae and no giant
cells, the diagnosis of borderline-lepromatous (BL) type was made.
The symptoms were improved
by the administration of 300 mg/day ofloxacin. Because the monotherapy
using ofloxacin has been
reported to be effective in all 5 previously reported cases of BL type
leprosy, it may be
recommended for a larger number of leprosy cases.
============================================================
29.) Reactional states and neuritis in multibacillary leprosy patients
following MDT with/without
immunotherapy with Mycobacterium w antileprosy vaccine.
============================================================
Lepr Rev 2000 Jun;71(2):193-205 Related Articles, Books, LinkOut
Sharma P, Kar HK, Misra RS, Mukherjee A, Kaur H, Mukherjee R, Rani R
National Institute of Immunology, New Delhi, India.
A vaccine based on autoclaved Mycobacterium w was administered, in addition
to standard
multidrug therapy (MDT), to 157 untreated, bacteriologically positive,
lepromin negative
multibacillary leprosy patients, supported by a well matched control
group of 147 patients with
similar type of disease, who received a placebo injection in addition
to MDT. The MDT was given
for a minimum period of 2 years and continued until skin smear negativity,
while the vaccine/placebo
was given at 3-monthly intervals up to a maximum of eight doses. The
incidence of type 2 reaction
and neuritis during treatment and follow-up showed no statistically
significant difference in the
vaccine and placebo groups. The incidence of type 1 reaction (mild
in most cases), however, was
higher in the vaccine group (P = 0.041, relative risk ratio 1.79),
considering LL, BL and BB leprosy
types together, and considerably higher (P = 0.009) in LL type, probably
because of confounding
due to higher number of patients with previous history of reaction
in this group. The occurrence of
reactions and neuritis in terms of single or multiple episodes was
similar in the vaccine and placebo
groups. The association of neuritis and reactions, as well as their
timing of occurrence (during MDT
or follow-up), was also similar in the two groups, with more than 90%
of occurrences taking place
during MDT. The incidence of reversal reaction was significantly higher
among the males in the
vaccine group (34.5% versus 8.3%, P = 0.019). Patients with high initial
BI (4.1-6.0) showed higher
incidence of reactions (70.3%) as compared to those with medium (2.1-4.0)
and low (0.3-2.0) BI
where the reactions were observed with a frequency of 56.1% and 38.8%,
respectively. However,
unlike reactions, neuritis incidence did not seem to be affected by
initial BI to the same extent in the
vaccine group, with frequencies of 35.3%, 36.3% and 25.9% in the three
mentioned BI ranges.
Overall, the vaccine did not precipitate reactional states and neuritis
over and above that observed
with MDT alone.
============================================================
30.) Mycobacterium w vaccine, a useful adjuvant to multidrug therapy
in multibacillary leprosy: a
report on hospital based immunotherapeutic clinical trials with a follow-up
of 1-7 years after
treatment.
============================================================
Lepr Rev 2000 Jun;71(2):179-92 Related Articles, Books, LinkOut
Sharma P, Misra RS, Kar HK, Mukherjee A, Poricha D, Kaur H, Mukherjee
R, Rani R
National Institute of Immunology, New Delhi, India.
A vaccine based on autoclaved Mycobacterium w was administered, in addition
to standard
multidrug therapy (MDT), to 156 bacteriologically positive, lepromin
negative multibacillary leprosy
patients compared to a well matched control group of 145 patients with
a similar type of disease
who received a placebo injection in addition to MDT. The MDT was given
for a minimum period of
2 years and continued until skin smear negativity, while the vaccine
was given at 3-month intervals up
to a maximum of eight doses. The fall in clinical scores and bacteriological
indices was significantly
more rapid in vaccinated patients, from 6 months onward until years
2 or 3 of therapy. However, no
difference was observed in the fall in bacteriological index in the
two groups from year 4 onwards.
The number of LL and BL patients released from therapy (RFT) following
attainment of skin smear
negativity, after 24-29 months of treatment was 84/133 (63.1%) in vaccinated
and 30/120 (25.0%)
in the placebo group; the difference was highly statistically significant
(P < 0.0001). In all, 90.2%
patients (146/162) converted from lepromin negativity to positivity
in the vaccine group, as against
37.9% (56/148) in the placebo group. The average duration of lepromin
positivity maintained
following eight doses of vaccine administered over 2 years was 3.016
years in the vaccine and 0.920
years in the placebo group. Histological upgrading after 2 years of
treatment in the LL type was
observed in 34/84 (40.5%) cases in the vaccine and 5/85 (5.9%) cases
in the placebo group, the
difference being statistically significant (P < 0.001). The incidence
of type 1 reactions was
significantly higher (30.5%) in the vaccine group than (19.7%) in the
placebo group (P = 0.0413);
the difference was mainly observed in LL type (P = 0.009). The incidence
of type 2 reactions was
similar (31.8 and 34.6%) in vaccine and placebo groups. The vaccine
did not precipitate neuritis or
impairments over and above that encountered with MDT alone. After 5
years of follow-up following
RFT, no incidence of bacteriological or clinical relapses was observed
in both groups.
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