Drug unresponsiveness & combination therapy for kala-azar.

Pentavalent antimonials (SbV) have been successfully used for treatment of kala-azar since last six decades. Since 1970s its conventional dosages have failed to achieve with 60 per cent unresponsiveness reported with WHO regimen in Bihar (India). Pentamidine initially used as a second line of drug, acquired resistance (25%) even with prolonged dosage. Newer oral drug miltefosine is a potent antileishmanial drug with longer half-life, a property likely to acquire resistance. Paromomycin has undergone extensive clinical trials in Indian kala-azar patients. Being an aminoglycoside, acquired resistance is likely to occur when used as a monotherapy. To encounter the problem of treatment failure in kala-azar and to reduce length of therapy, combination of at least two effective antileishmanial agents is a desirable option. In India sodium stibogluconate (SSG) in standard dose has been combined with other antileishmanial agents including paromomycin without encouraging result. Infection with Leishmania donovani depresses cell-mediated immunity. Immunological balance is tilted in favour of Th2 suppressive cytokines over Th1 producing protective cytokines. Interferon gamma (IFN-gamma) has been used in combination with SbV in Indian kala-azar patients with unexpectedly discouraging results. Combination of two most potent leishmanicidal drugs amphotericin B and miltefosine which are not dependent on host immune system, may shorten the course of therapy besides encountering unresponsiveness. A combination therapy should be preferred when treating kala-azar associated with HIV/AIDS. Immunotherapy with exogenous Th1 stimulating cytokines or use of antileishmanial vaccine in combination with a potent chemotherapeutic agent is a future option.

Quantitative structure activity relationship (QSAR) studies of some substituted benzenesulphonyl glutamines as tumour suppressors.

As a part of a composite programme of rational drug design (RDD), we had synthesized some substituted benzenesulphonyl glutamines and evaluated their inhibitory activities against Ehrlich Ascites Carcinoma (EAC) cell line in Swiss albino mice. Quantitative structure activity relationship (QSAR) studies of these inhibitory activities using Fujita-Ban model as well as Modified Hansch-Fujita model gave excellent correlations (correlation coefficient r = 0.89 and 0.82 respectively). These results could be useful in designing 'lead' compound with potent inhibitory activity on DNA and RNA synthesis and tumour development.

Direct agglutination test for early diagnosis of Indian visceral leishmaniasis.

In a prospective study, 80 cases of fever with hepatosplenomegaly, anemia and leucopaenia coming from the hyperendemic zones for visceral leishmaniasis of North-Bihar, India were screened and subjected to bone marrow or splenic puncture for demonstration of Leishman-donovan bodies (LDB) and DIRECT AGGLUTINATION TEST (DAT) with antigen prepared by Harith et al. 59 cases were confirmed for Visceral Leishmaniasis (VL) by demonstration of LDB in which DAT was also positive in different titres ranging from 1:1600 onwards. Out of 21 cases in which the bone marrow was negative for parasite, DAT was positive in 10 cases. 8 Out of 10 cases responded to WHO regimen of treatment with sodium stibogluconate (SSG). Remaining two cases who did not respond to this therapy became positive for parasites on subsequent splenic aspirate. They were treated with pentamidine isethionate and were cured. 11 out of 80 cases showing a titre of 1:400 or lower in DAT, 6 proved to be cases of enteric fever and 5 of malaria. Thus DAT using Harith's antigen was found to be 100% sensitive and specific in detection of early cases of Indian VL.

Combination therapy in Kala-azar.

128 untreated cases of Kala-azar were divided in 4 equal groups of 32, Group A was treated with Sodium Stibogluconate (SSG) in the dose of 20 mg/kg/body wt. for 30 days. Group B was treated SSG plus allopurinol in the dose of 20 mg/kg/body wt. orally in divided dosage for 30 days. Group C received SSG plus Ketoconazole 600 mg orally in divided dosage for 30 days. Group D in addition to SSG also received levamisole in single oral daily dose of 13 mg/kg/body wt. for 30 days. Response of Group B, C and D was compared to Group A. Results from this study revealed combination of allopurinol with SSG to be statistically not superior to SSG alone.

Lymphatic leishmaniasis associated with visceral leishmaniasis.

Lymphatic leishmaniasis associated with visceral leishmaniasis is rare in India. We are reporting one such case, which is the first case reported so far from Bihar.

Changing response to diamidine compounds in cases of kala-azar unresponsive to antimonial.

Two hundred and forty patients of kala-azar unresponsive to antimonial were treated with pentamidines in a dose of 4 mg/kg body weight on alternate days for 20 injections. Of these, 175 were treated with pentamidine isethionate and 65 with pentamidine methane sulphonate (Lomidine). Clinical and parasitological cure were significantly higher with lomidine as compared to pentamidine isethionate. However, cardiovascular, gastrointestinal and metabolic toxicity including hyperglycaemia were more marked with lomidine. Mortality rate was also significantly (P less than .05) higher with lomidine therapy. Significantly lower clinical and parasitological cure and higher relapse rate were observed in the present study compared with an earlier study in which pentamidine was used in the same doses for 10-12 injections only.

Kala-azar mortality in hospitalized cases in north Bihar, India.

The mortality in kala-azar was studied in 261 cases admitted in SKMCH during the years 1983-1987. 23 deaths (8.81%) were observed; 9 (39.1%) died due to complications of the disease, while 14 (60.9%) died of toxicity of Sodium Stibogluconate or Pentamidine.

Persistent hyperglycaemia requiring insulin therapy following the use of pentamidine in the treatment of kala-azar.

Five cases of persistent hyperglycaemia requiring insulin therapy following pentamidine treatment for Indian kala-azar are being reported.

Visceral kala-azar associated with post-kala-azar dermal leishmaniasis.

Visceral leishmaniasis associated with post-kala-azar dermal leishmaniasis (PKDL) is very rare. We are reporting one such case which incidentally is the seventh case so far reported from Indian sub-continent.