NEWER DRUGS IN LEPROSY

Presenter: Dr Anil Kumar

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

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

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

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

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

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

• 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

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

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

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

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

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

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

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

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

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

Side effects include abdominal discomfort joint pains pruritus and photosensitivity

Shortens other MDT regime and chances of drug resistance

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

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

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

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

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

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

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

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)

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 

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

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

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

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

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

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.

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

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

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

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

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

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)

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

Vaccine was well tolerated with no systemic side effects.

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.

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

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

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

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

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

 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.

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

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.

Thank you