Newer drugs used in leprosy
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NEWER DRUGS IN LEPROSY
Presenter: Dr Anil Kumar
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Introduction Therapy of leprosy has undergone
dramatic changes since the days of Dapsone monotherapy Institution of the multidrug therapy (MDT)
from 1981
To date -three regimens have been officially recommended
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During the last three decades rapid advances have been made in the treatment and management of leprosy
The WHO recommended chemotherapy for leprosy is well accepted tolerated and has greatly helped in controlling the disease
Problems still exist and efforts are being made to overcome them and further improve the treatment of these patients
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Newer--more effective and also operationally less demanding regimens are required so that the duration of treatment is further
reduced Incidence of "reactions" and "relapses"
need to be reduced after the stoppage of treatment
Operationally very helpful if the same treatment schedule with
different time durations could be given to both PB and MB patient
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WHO/MDT for paucibacillary (PB) leprosy (Dapsone 100 mg daily unsupervised, Rifampicin 600mg monthly supervised for 6 months)
WHO/MDT for multibacillary (MB) leprosy (Dapsone 100 mg daily unsupervised, Clofazimine 50 mg daily unsupervised and 300 mg supervised monthly, Rifampicin 600mg monthly supervised for 12 months)
A single dose of the combination of rifampicin (600 mg),ofloxacin (400 mg,), minocycline (100 mg) (ROM) for single lesion PB leprosy To be employed in those countries in which the
proportion of single lesion PB patients is large
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The need for newer drugs In spite of the promising results of
the WHO-advocated MDT the need for new anti leprosy drugs is still immense some of the basic reasons for that are Problem of drug resistance Resistance to components of the
present MDT has been reported since the 1960s Dapsone [DDS] in 1964 Rifampicin [RPM] in 1976 Clofazimine in 1982
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Ever-changing pattern of drug resistance dictates the need for new drugs Acceptance of clofazamine in Europeans Administration of daily drugs like Dapsone
and clofazamine cannot be supervised Dapsone and clofazamine are weekly
bactericidal against M.Leprae
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• Better drug delivery system and distribution Possibly achieved with newer drugs Increase the compliance and adherence of
patients to the treatment regimens offered Decreases the economic impact of the therapy
programmes as a whole
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Treatment durations Possibly be shortened as compared to the
present drugs This impact again on compliance and
adherence for the patients suffering from leprosy
Simplification of drug regimen and methods of administration possibly a single regimen for all spectrums
of the disease
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Pre-requisites for newer anti-leprosy drugs
A new drug for incorporation into a regular anti-leprosy regimen should ideally fulfill the following criteria
Should be able to reduce the duration of therapy significantly to improve the patient compliance and
adherence to the therapy Should be fully supervisable
should not be dependant on self administration
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Should be equally effective for both multi and paucibacillary cases
Drug should be highly acceptable in that it should not have any immediate or long-term side effects If these are unavoidable they should be
temporary and disappear with cessation of therapy
Should be simple to administer and to monitor
Should be more effective than the present drugs being in use or should be at least as effective as they are
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Categorically available “Newer drugs” in leprosy may be divided into Newer anti-leprosy drugs Drugs for use in reactional states
Currently these drugs are in various stages of development in both in vitro and in vivo studies
Some of them have shown desirable results in clinical trials of various sample sizes
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Classifications Following are the various class of drugs Fluroquinolones – Ofloxacin Pefloxacin,
Sparfloxacin, Temafloxacin, Moxifloxacin, Sitafloxacin
Tetracycline: Minocycline Macrolides: Clarithromycin Ansamycin: Rifabutin,Rifapentine, R-76-1 Dihydofolate reductase inhibitirs:
Brodimoprim and K-130 Fusidic acid Betalactam antibiotics
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Anti-leprosy drugs Fluoroquinolones These are orally effective drugs that act by
inhibition of DNA gyrase to introduce negative supercoiling
Among the quinolones, ofloxacin, pefloxacin and sparfloxacin have been observed to be active against M leprae
Ofloxacin is the current favourite whereas sparfloxacin appears to be emerging
Pefloxacin and Ofloxacin have been subjected to clinical trials in certain number of lepromatous leprosy (LL) patients
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Therapy with pefloxacin 800mg OD and ofloxacin 400mg OD has resulted in clinical response by 2 months
Pefloxacin is active but is not preferred due to various considerations which include the dosage (800mg needs to be
administered in two divided dosage) to get the same effect as single 400mg dose of ofloxacin
Morphological index (MI) was brought down to zero in 6 months following therapy
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Since they produce acceptable equal results ofloxacin has been chosen for implementation of the ROM therapy for single lesion paucibacillary (SLPB) leprosy
Antimicrobial action is extremely rapid a thousannd fold decrease in viable colony forming unit ( CFU ) is achieved in 1-3 hours at serum levels very close to MIC
High bioavailability on account of low serum protein binding
Complete absorbtion following oral administration
Over 99-99.99% kiling of viable Mleprae observed in less than 1 month therapy
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Moxifloxacin is a fluoro-quinolone whose activity against M. tuberculosis is similar to or slightly better than that of sparfloxacin and is therefore much more powerful than ofloxacin and even levofloxacin
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Side effects include abdominal discomfort joint pains pruritus and photosensitivity
Shortens other MDT regime and chances of drug resistance
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Of the other available Fluoroquinolones, recent literature has
shown that sparfloxacin 200mg OD is as effective as ofloxacin 400 mg once daily
Moxifloxacin, at a dose of 150 mg/kg OD (equipotent to 400mg in man) in mouse model, was shown to have killing power five times more than conventional dose of ofloxacin and rifampicin
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The basic problem that could come in the way of these drugs for implementation into regular anti-leprosy regimen Problem of long term side-effects and
development of drug resistance
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I n a trial of OFLO alone and its combination with dapsone (DDS) and clofazimine (CLF)
24 patients with newly diagnosed lepromatous leprosy were allocated randomly to three treatment groups and treated for 56 days by OFLO daily, 800mg OFLO daily, or 400mg OFLO combined with 100mg DDS and 50mg CLF daily plus 300mg CLF once every 28 days
Bactericidal activities of the above regimens were measured by titrating the proportion of viables in normal and nude mice
More than 99%, > 99.99%, and > 99.99% of the viable M leprae were estimated to be killed by 14,28, and 56 days of treatment respectively
Bactericidal activity did not differ significantly among the three groups
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Cyclines Widely used antibiotics the prototype-
tetracycline and others like doxycycline have no inhibitory effect on the growth of the lepra bacillus
Minocycline is the sole drug found to be effective in leprosy
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Minocycline Minocycline (MINO) is the only tetracycline
that exhibits significant activity against M leprae, perhaps because its lipophilicity permits it to penetrate the bacterial wall
The drug is bactericidal against M leprae but less so than RMP
It binds reversibly to the 30S unit of the ribosome thus blocking the binding of aminoacyl transfer RNA to the messenger RNA-ribosomal complex, thereby inhibiting protein synthesis
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Been included in the ROM regimen with the principle objective that by acting in conjunction with ofloxacin
Will prevent rifampicin resistance Will eliminate whatever resistant strain
of M. leprae that remains in the body
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Macrolides Several members of this group, including
erythromycin have been evaluated and clarithromycin (CLARI) appears the most promising
It acts by linking to the 50s sub-unit, thus inhibiting bacterial protein synthesis
Erythromycin was the first drug to be tried in this group Found to be ineffective in mice probably
because of its poor gastrointestinal absorption
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In humans adequate serum levels are obtained but multiple dosing is required and hence till date the drug has not been used for leprosy
Macrolides are orally effective drugs and act by binding to 50S ribosomes to inhibit bacterial protein synthesis
Clarithromycin ----promising results recently In MB leprosy patients treated daily with
500mg CLARI, the clinical response, the MI decrease and the killing of viable M leprae were also of the same as that of OFLO and minocycline (MINO)
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In mice given at 0.125 microgram/ml, it caused significant inhibition of M. leprae
In human it has been found to be effective when given at 12.5mg/kg OD for up to 20 days
Drug has now been subjected to phase I and II clinical trials Result so far have shown that absorption is affected
by high gastric pH and hence the need for enteric coated tablets
Since the drug is concentrated intracellularly Serum level achieved is not indicative of its tissue
level Found to show synergism with Minocycline and
rifampicin Gastrointestinal irritation, nausea, vomiting and
diarrhoea are the common side effects observed
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Newer phenazine derivatives These are derivatives of clofazimine Derived by halogenation (bromo/chloro) of the
parent drug para-anilino group at its 3-7 position Seven new drugs in this category are under trial both
in vitro and in vivo compared to clofazimine, they are found to be more
effective against M. leprae MIC ranges from 0.03-0.20 μg/ml (MIC of clofazimine
is 0.30μg/ml) Mouse-footpad studies also show favourable results
when compared to clofazimine, particularly for B-4071 and B-4100
The other drugs in this group are B-746, B-3770, B-3786, B- 4019, and B-4087
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Benzylamines Compound 93 (N Methyl-3, 5- dichloro-
benzylamine hydrochloride) in mousefootpad , has shown strong synergism with Good clinical response Tolerability at high dose studies in combination
therapy with dapsone and rifampicin Shows rapid development of resistance as
monotherapy This drug can form part of the combination
regimen
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Hydrazones Thiacetazone (150 mg OD) is found to show very
good synergism with rifampicin, dapsone and INH by inhibiting bacterial ribonucleotide reductase to inhibit DNA synthesis
Side effects include on skin, liver and bone marrowDihydrofolate reductase inhibitors D rugs inhibit the conversion of dihydrofolate to
tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase
Included in this group are K-130, brodimoprim and epiroprim
Found to be effective both against dapsone sensitive and dapsone resistant M. leprae and also show synergism with dapsone
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Rifampicin derivatives Orally effective drugs that act by
inhibiting DNA dependent RNA synthesis Group includes– rifabutin, rifapentine, T9, KRM 1648,
KRM 1657, KRM 1668, and KRM 2312. KRM 1648 is found to be most bactericidal at lesser
dose and is effective against rifampicin-resistant strains
KRM 1648 and others like KRM 2312, T9, rifabutin are also found to show synergism with ofloxacin
These drugs are potential implements for MDT Recently rifapentine (P) has shown a high anti-
leprosy activity when given as a single dose of 10 mg/kg in mice
Showed twenty times more killing power than a single dose of 10mg/kg of rifampicin
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Other anti-leprosy drugs included in miscellaneous group of drugs are:
Fusidic acid Inhibits protein synthesis by binding to
protein elongation factor G In vitro studies show activity equal to or
better than rifampicin, minocycline and ofloxacin
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Indian J Lepr. 2000 Oct-Dec;72(4):451-5. Intranasal administration of fusidic acid
cream in leprosy. Mahajan PM, Jadhav VH, Jogaikar DG, Mehta JM. The effect of local treatment of nostrils with
fusidic acid cream was investigated in 30 previously untreated lepromatous leprosy patients
The cream was applied in the nostrils after flushing the nostrils with normal saline, twice a day for a period of four weeks
It was found that 20 mg/gm of sodium fusidate was effective in reducing the morphological index of the nose-blow smear to zero in two weeks in majority of the patients.
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Diuciphone Pyrimidine sulphone derivative This drug developed in the
erstwhile USSR is found to complement dapsone action by
Increasing it’s bacterial killing Decreasing its side effect and
decreasing reactional episodes Additional anti-inflammatory
properties T cell stimulation
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Deoxyfructo-serotonin ( DFS ) A human metabolite from serum
extract, found to be bacteriostatic in in-vitro and in mouse foot-pad studies
Clinical trials in lepromatous leprosy patients showed good clinical response by increasing bacillary clearance
Found to prevent nerve damage as a monotherapeutic agent
Histological improvement Significant finding was killing of bacilli
within Schwann cells and macrophages
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Newer regimens under trial The efficacy of multiple monthly doses
of ROM for the treatment of PB and MB leprosy has been tested in field trials in three different countries
however two of the trials have been terminated prematurely
Another combination of rifapentine-moxifloxacin-minocycline (PMM) is currently being used in a short-term clinical trial in lepromatous leprosy patients
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Common regimen for the treatment of both PB and MB leprosy is desirable
Recently, the WHO Technical Advisory Group (TAG) at its third meeting recommended that All leprosy patients, both PB and MB, be treated by
the MDT regimen for MB leprosy for a period of only 6 months
The question remains: is it justifiable to shorten the duration of a regimen even if it is effective and safe?
Before any recommendation to shorten further the duration of treatment for MB leprosy by the current MDT regimen is considered
this proposal must be studied by controlled trials, with relapse outcome
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slow bacterial clearance in high bacterial load cases which leads to increased risk of transmission and relapse
of the disease recurrent reactions drug resistance
To solve this problem Addition of immunomodulators as an adjunct
to MDT has been proposed Many vaccines such as
BCG BCG plus killed M. leprae Mycobacterium w M. phlei M. habana have been tried as immunomodulators
Mycobacterium w has been found to be antigenically closer to M. leprae and a vaccine derived from it has been used in multibacillary cases
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In a clinical trial on 20 untreated bacteriologically positive MB (BI >2) patients, who were administered 12 months WHO/MDT along with four doses each of 0.1 ml of Myco. w vaccine (injected intradermally at 3 months interval), significant improvement in all parameters Clinical Bacteriological Histopathological was reported except for lepromin conversion
(seen in 40% of study group, none in the control)
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Bacteriological index fell by 2.05 log in a year
The main draw back noticed with this vaccine-aided MDT was High incidence of type 1 lepra reaction (30% in
study group versus 10% in control) the incidence of type 2 reaction was more in
control group than in the study group (20% vs 10%)
Local ulceration of skin lesions of leprosy healed in 3-4 weeks
scar formation was seen in 60% of cases who were administered vaccine aided MDT
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Vaccine was well tolerated with no systemic side effects.
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Drugs for reactional episodes Besides the conventional drugs like
prednisolone, clofazimine and thalidomide for type 1 and type 2 lepra reactions certain other drugs and combination regimens are now available and some of these include
Zinc: Zinc given as zinc sulphate formulation (220mg/day0 for up to 4 months found to decrease incidence, duration and severity of reactions Due to its anti inflammatory function, inhibition of
complement-dependent immune-complex reaction T-cell activation and inhibition of neutrophil
chemotaxis Zinc resulted in marked reduction in the steroid
requirement.
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Levamisole At the dose of 150 mg twice weekly for up to six
weeks with dapsone found to decrease the incidence of reaction and results in
clinical improvement of lesions as compared to placebo Pentoxifylline Pentoxifylline (PTX), a methylxanthine derivative
given at the dose of 1200 mg per day in three divided doses is found to be Well-tolerated and effective in type 2 lepra reaction more
so in HIV positive cases In whom long term steroids therapy is contraindicated
The final impression regarding its use is that PTX is a well-tolerated drug
May be used for improving patient’s clinical condition during ENL reaction
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Pulse corticosteroid therapy Pulsed corticosteroid administration using
infusion of 40 mg betamethasone daily for 3 days in a month is well-tolerated
But did not offer any significant advantage over the conventional way of ENL management
Higher dose in combination with an immunosuppressant like cyclophosphamide pulse therapy could reduce steroid dependence and related problems
Other drugs like cyclosporine, chloroquine and azathioprine have been used recently for the management of reaction
Exact indication still need to be worked out
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Combination of newer anti - leprosy drugs During the recent years several
combinations of newer drugs among themselves and with already established drugs have been suggested and tried
Clinical trials of combination of OFLO with DDS and CLF and OFLO with RMP have been reported to be beneficial in treatment of lepromatous leprosy
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Because of greater bactericidal activity
the addition of OFLO, MINO, or CLARI or some combination of these drugs to WHO/ MDT or substituting one of these drugs might permit shortening of the treatment
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Intermittent therapy
For proper implimentation of control programmes intermittent regimens are more desirable
The first of these protocols involves the trial of a single dose of a combination of 600mg RMP, 100mg MINO and 400mg OFLO in the treatment of singlelesion PB patients
In another series PB patients will receive a combination of RMP with OFLO and MINO just prescribed once a month for 3 or 6 months
For MB patients the drugs will be administered once monthly for 12 or 24 months. The safety of these regimens will be examined by comparing the 6 and 24 month regimens with WHO/MDT
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Relapsed Patients
The study group on the chemotherapy of leprosy WHO 1994 has recommended the following treatment regimens for relapsed patients
Relapse with M leprae sensitive to all standard drugs: These cases essentially require retreatment with WHO-MDT for their type of disease
Relapse with dapsone resistant M leprae: The standard WHO-MDT is sufficient in such cases. Thus when relapses
occur among cases previously cured with dapsone monotherapy, only standard WHO-MDT is required
Relapses with rifampicin resistant M leprae: Such cases are recommended to be treated with clofazimine 50mg daily for 24 months plus two drugs out of the group: ofloxacin 400mg daily, minocycline 100mg daily and clarithromycin 500mg daily for 6 months, to be followed by either ofloxacin or minocycline daily for an additional 18 months
It is further recommended that such therapy be administered only under direct supervision of a referral centre.
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Conclusion
Purely in numerical terms leprosy represents an enormous challenge to global health
In order to develop a drug that is bactericidal against M. leprae researchers must try to exploit its particular idiosyncracics without affecting neighboring human cells
This is especially important for an intracellular bacteria like M. leprae which prefers to remain in Schwann cells and macrophages
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References Report of the International Leprosy Association Technical
Forum 25-28 February 2002, Paris, France: Chemotherapy. Lepr Rev 2002; 73:S27- S34.
Dhople AM. Search for newer antileprosy drugs. Ind J Lepr 2000; 72: 5-18.
Girdhar BK. Multi drug therapy in leprosy and its future components. Ind J Lepr 1994; 66:197-198.
Grosset JH. Newer drugs in lepros., Int J Lepr 2001; 69:S14-S18.
Grosset JH. Wurzburg symposium: Session IV: New Antileprosy drugs. Int J Lepr 1993; 61:312- 316.
Dhople AM. Comparative in vitro activities of rifampicin analogues against Mycobacterium leprae. Ind J Lepr 1997; 69:377-384.
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Thank you