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Biomedical subjects

C P Thakur

Publications and source records attributed to C P Thakur.

At least 19 recordsLinked to original sources
PubMed2006

Oral miltefosine for the treatment of Indian visceral leishmaniasis.

Large-scale antimony resistance in the treatment of visceral leishmaniasis (VL) in north Bihar, India, has led to the development of miltefosine as an alternative therapy. In a pilot study and later in three Phase II studies involving 249 patients, oral miltefosine, 100-150 mg/day for 28 days, was shown to cure approximately 90% patients with reasonable safety. In the pivotal Phase III trial, 299 patients were treated at three centres with amphotericin B as the comparator drug (99 patients). In this trial 38% and 20% patients had mild to moderate vomiting and diarrhoea respectively, similar to previous studies. Asymptomatic transient elevation of hepatic transaminases and mild renal dysfunction were observed in 15% and 10% patients respectively. The final cure rate was 94% with miltefosine and 97% with amphotericin B; based on these results, the drug was approved in India. Subsequently in two paediatric studies involving 119 patients in the age group of 2-11 years, the safety and efficacy of miltefosine (2.5 mg/kg daily for 28 days) was established with a cure rate (94%) similar to that seen in adults. Miltefosine is the first oral antileishmanial drug with a high degree of safety and efficacy for the treatment of VL.

Administration, Oral↗
PubMed2004

A comparative evaluation of amphotericin B and sodium antimony gluconate, as first-line drugs in the treatment of Indian visceral leishmaniasis.

In a study to evaluate the relative efficacies of sodium antimony gluconate (SAG) and amphotericin B (AMB), each drug was used to treat 60 Indian cases of visceral leishmaniasis (VL). At the time of treatment, each case had recently been parasitologically confirmed. The patients received either 20 mg SAG/kg daily, by intramuscular injection, for 4 weeks, or 1 mg AMB/kg daily, infused slowly over 2 h, with no incremental dosage, for 20 days. The response of the patients was followed clinically and by the microscopical examination of bone-marrow aspirates (BMA). The infected macrophages in subsamples of the BMA collected pre-treatment were cultured so that the drug sensitivities of the parasites, to 20 microg SAG or 1 microg AMB/ml medium, could be determined in vitro. Other subsamples of the BMA were used to set up promastigote cultures that were then used to infect BALB/c mice. The responses of the mice to 5 days of treatment with SAG or AMB (at the same daily dosages as used in the clinical trials) were subsequently explored. SAG only cured 46.6% of the patients given the drug, only cleared amastigotes from 38.3% of the macrophage cultures, and only cured 53.3% of the infected mice. The corresponding values for AMB - 100%, 100% and 100% - were markedly higher (P <0.001 for each comparison). Although nine patients had to be withdrawn from the SAG group (all because of cardiac toxicity), all of the patients given AMB completed their treatment without any serious adverse effects (P <0.01). Two of the patients withdrawn from the SAG arm died shortly after their withdrawal; earlier withdrawal may have saved them. At least in the setting of the present study, AMB appears far superior to SAG as a first-line drug against VL and should replace it.

Adolescent↗
PubMed2004

Epidemiological, clinical & pharmacological study of antimony-resistant visceral leishmaniasis in Bihar, India.

BACKGROUND & OBJECTIVES: Sodium antimony gluconate (SAG) is reported to be losing its efficacy in Bihar as a first line drug for treatment of visceral leishmaniasis (VL). Concerned with the increasing incidence of antimony-resistant VL patients in Bihar, we undertook an epidemiological, clinical and pharmacological study to formulate a scientific basis for choosing a suitable first line drug for VL. METHODS: Consecutive, fresh and parasitologically confirmed patients of VL from different geographical areas of Bihar were considered for inclusion in the study. Parasites isolated from patients were tested in vitro to assess their response to sodium antimony gluconate (SAG) to 20 microg/ml, response to 20 mg/kg of SAG for 5 days in experimentally induced VL in BALB/c mice from those isolates, and response to SAG in patients treated with SAG for 28 days. Similarly response in culture (1 microg/ml) to amphotericin B (AMB) of all 282 isolates, (1 mg/kg body wt for 20 days) in patients and infected BALB/c mice (1 mg/kg body wt for 5 days) was determined. Antimony levels of plasma were determined at 2, 8 and 24 h after intramuscular injection of SAG. Patients unwilling for SAG treatment or relapsed after SAG treatment and withdrawn from SAG group because of toxicity were treated with AMB. Plasma antimony levels were estimated by atomic absorption spectrometer. RESULTS: Though antimony sensitive and resistant patient were distributed in all 14 districts of Bihar studied, there was a significant variation from district to district. Of the 123 patients included in the SAG treatment group, 19 were withdrawn due to development of toxicity and 2 died; 178 patients were treated with AMB. No patient in AMB group developed any toxicity or died. Only 47 (46%) of 102 patients, 106 (37.6%) of 282 infected macrophages, 90 (52.9%) of 170 experimental infections were cured with SAG. Mc Nemar's test on paired comparisons showed statistical significance difference (P<0.01) between infected macrophage and experimental infection. AMB cured all patients, infected mice and cleared parasites from all isolates. INTERPRETATION & CONCLUSION: Antimony resistant strains of L. donovani were wide spread over different geographical areas in Bihar. SAG cured lesser percentage of VL cases clinically compared to AMB and should be replaced by AMB as a first line drug.

Adult↗
PubMed2003

Efficacy and tolerability of miltefosine for childhood visceral leishmaniasis in India.

Miltefosine has previously been shown to cure 97% of cases of visceral leishmaniasis (VL) in Indian adults. Because approximately one-half of cases of VL occur in children, we evaluated use of the adult dosage of miltefosin (2.5 mg/kg per day for 28 days) in 80 Indian children (age, 2-11 years) with parasitologically confirmed infection in an open-label clinical trial. Clinical and parasitological parameters were reassessed at the end of treatment and 6 months later. One patient died of intercurrent pneumonia on day 6. The other 79 patients demonstrated no parasites after treatment, had marked clinical improvement, and were deemed initially cured. Three patients had relapse, and 1 patient was lost to follow-up. The final cure rate was 94% for all enrolled patients and 95% for evaluable patients. Side effects included mild-to-moderate vomiting or diarrhea (each in approximately 25% of patients) and mild-to-moderate, transient elevations in the aspartate aminotransferase level during the early treatment phase (in 55%). This trial indicates that miltefosine is as effective and well tolerated in Indian children with VL as in adults and that it can be recommended as the first choice for treatment of childhood VL in India.

Animals↗
PubMed2003

Single-dose liposomal amphotericin B in the treatment of visceral leishmaniasis in India: a multicenter study.

Widespread antimony resistance renders conventional amphotericin B the only option for the treatment of visceral leishmaniasis (VL) in North Bihar, India. Because of its excellent safety profile, a large dose (7.5 mg/kg) of liposomal amphotericin B (L-AmB) was given to each of 203 patients with VL at 4 treatment centers, and the patients were discharged the next day. At initial clinical and parasitological follow-up, performed on day 30 after treatment, evidence of a cure was seen in 195 (96%) of 203 patients (95% CI, 92-98); 4 patients experienced treatment failure. Two patients were lost to follow-up, 2 died (one due to progressive disease and another, 5 months after treatment, due to an unrelated illness), and 12 experienced relapses during follow-up. Thus, 183 patients (90%; 95% CI, 85-94) had obtained final cure 6 months after treatment. Very few adverse events (fever with rigor, in 9.8% of patients) were seen. Single-dose L-AmB (7.5 mg/kg) treatment is safe and effective, and it may be used for the mass treatment of VL in India.

Adolescent↗
PubMed2002

Oral miltefosine for Indian visceral leishmaniasis.

BACKGROUND: There are 500,000 cases per year of visceral leishmaniasis, which occurs primarily in the Indian subcontinent. Almost all untreated patients die, and all the effective agents have been parenteral. Miltefosine is an oral agent that has been shown in small numbers of patients to have a favorable therapeutic index for Indian visceral leishmaniasis. We performed a clinical trial in India comparing miltefosine with the most effective standard treatment, amphotericin B. METHODS: The study was a randomized, open-label comparison, in which 299 patients 12 years of age or older received orally administered miltefosine (50 or 100 mg [approximately 2.5 mg per kilogram of body weight] daily for 28 days) and 99 patients received intravenously administered amphotericin B (1 mg per kilogram every other day for a total of 15 injections). RESULTS: The groups were well matched in terms of age, weight, proportion with previous failure of treatment for leishmaniasis, parasitologic grade of splenic aspirate, and splenomegaly. At the end of treatment, splenic aspirates were obtained from 293 patients in the miltefosine group and 98 patients in the amphotericin B group. No parasites were identified, for an initial cure rate of 100 percent. By six months after the completion of treatment, 282 of the 299 patients in the miltefosine group (94 percent [95 percent confidence interval, 91 to 97]) and 96 of the 99 patients in the amphotericin B group (97 percent) had not had a relapse; these patients were classified as cured. Vomiting and diarrhea, generally lasting one to two days, occurred in 38 percent and 20 percent of the patients in the miltefosine group, respectively. CONCLUSIONS: Oral miltefosine is an effective and safe treatment for Indian visceral leishmaniasis. Miltefosine may be particularly advantageous because it can be administered orally. It may also be helpful in regions where parasites are resistant to current agents.

Administration, Oral↗
PubMed2002

Low-dose liposomal amphotericin B in refractory Indian visceral leishmaniasis: a multicenter study.

In this randomized, double-blind, dose-ranging, multicenter trial, 84 patients with visceral leishmaniasis refractory to antimony therapy were administered liposomal amphotericin B (AmBisome) at cumulative doses of 3.75, 7.5, and 15.0 mg/kg for 5 consecutive days. Posttreatment apparent cure and definite cure were assessed at 2 weeks and 6 months after the end of therapy, respectively. Mild to moderate infusion-related fever and rigors were seen in 29 and 44% of patients, respectively. One patient each in the 3.75- and 7.5-mg groups had detectable parasites on splenic smear at posttreatment evaluation. At 6 months' follow-up, however, 2, 1, and 1 patients relapsed in the 3.75-, 7.5-, and 15.0-mg groups, resulting in definite cure rates of 89, 93, and 97%, respectively. There was no significant difference in the cure rates of the 3 groups. Low-dose liposomal amphotericin B given for 5 days can cure most patients with Indian kala-azar.

Adolescent↗
PubMed2001

A single high dose treatment of kala-azar with Ambisome (amphotericin B lipid complex): a pilot study.

Thirty four patients with parasitologically confirmed visceral leishmaniasis were divided randomly into two groups of 17. Group A received Ambisome (amphotericin B lipid complex) at a dose of 15mg/kg body weight infused over 2h as a single dose; patients in group B received amphotericin B deoxycholate at a dose of 1mg/kg body infused for 2h for 20days. All 34 patients had a clinical, parasitological and ultimate cure. Ambisome was much better tolerated than amphotericin B, and adverse events were fewer in the Ambisome group. It was concluded that, if the cost of Ambisome were reduced, it would be a suitable first line drug. A longer study comparing three regimes of Ambisome: 15mg/kg body weight, 11mg/kg body weight and 7.5mg/kg body weight, should be undertaken.

Adolescent↗
PubMed2001

Observations on amphotericin B treatment of kala-azar given in a rural set up in Bihar, India.

BACKGROUND & OBJECTIVES: In a kala-azar endemic area in rural Bihar with a large number of patients unresponsive to sodium antimony gluconate and pentamidine, treatment with amphotericin B was tried in a rural set-up with the objective to cure these patients, and to assess whether such a centre could be run successfully in a rural set-up. METHODS: After thorough clinical examination and biochemical investigations, parasitologically confirmed patients who had haemoglobin above 5 g/dl, electrolyte imbalance if any, corrected, and ECG changes suggestive of myocardial damage stabilised after 10 days of bed rest were treated. Amphotericin B deoxycholate was infused at a dose of 1 mg/kg body weight, daily for 20 days. The adverse events were closely monitored. RESULTS: All 7 (100%) untreated patients of kala-azar, 258 (97%) of the 266 antimony and pentamidine resistant patients, and 31 (86%) of the 36 patients who had relapsed after a low dose regimen of amphotericin B, were cured with 20 infusions of amphotericin B. Eight (3%) patients of the antimony and pentamidine resistant group and 5 (14%) patients who had relapsed after low dose amphotericin B regimen required 25 infusions of amphotericin B to achieve parasitological cure. INTERPRETATION & CONCLUSIONS: With some precautions and proper management, all patients of kala-azar could be cured with amphotericin B in a rural set-up. A significant (P < 0.05) percentage of patients of group C relapsing after a low dose amphotericin B regime requiring 25 infusions for cure suggests that an adequate dose regime of amphotericin B should be given during the first course of treatment to prevent emergence of drug resistance.

Adolescent↗
PubMed1999

Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis.

BACKGROUND: There is no effective orally administered medication for any leishmania infection. We investigated miltefosine, which can be taken orally, for the treatment of Indian visceral leishmaniasis. Miltefosine is a phosphocholine analogue that affects cell-signaling pathways and membrane synthesis. METHODS: The study was an open-label, multicenter, phase 2 trial in which four 30-person cohorts received 50, 100, or 150 mg of miltefosine per day for four or six weeks. The 120 patients, who ranged in age from 12 to 50 years, had anorexia, fever, and splenomegaly with at least moderate (2+) leishmania in a splenic aspirate. A parasitologic cure was defined by the absence of parasites in a splenic aspirate obtained two weeks after completion of treatment. The clinical response was assessed at six months. RESULTS: In all 120 patients there was an initial parasitologic cure. Six patients had clinical and parasitologic relapses; the remaining 114 patients had not relapsed by six months after treatment, for a cure rate of 95 percent (95 percent confidence interval, 89 to 98 percent). With the regimen of 100 mg of miltefosine per day (approximately 2.5 mg per kilogram of body weight per day) for four weeks, 29 of 30 patients (97 percent) were cured. Gastrointestinal side effects were frequent (occurring in 62 percent of patients) but mild to moderate in severity, and no patient discontinued therapy because of gastrointestinal side effects. In two patients, treatment was discontinued because of elevated levels of aspartate aminotransferase or creatinine; in both patients the levels rapidly returned to normal. In 12 other patients, the level of aspartate aminotransferase increased to 100 to 150 U per liter during treatment. CONCLUSIONS: Orally administered miltefosine appears to be an effective treatment for Indian visceral leishmaniasis.

Administration, Oral↗
PubMed1998

Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India.

OBJECTIVES: To assess the efficacy and tolerability of aminosidine compared with sodium stibogluconate for treating visceral leishmaniasis. DESIGN: Randomised, unblinded, controlled trial with 180 day follow up. SETTING: Kala-Azar Research Centre, Brahmpura, Muzaffarpur, Bihar, India. SUBJECTS: People of either sex aged 6-50 years with symptoms and signs suggestive of visceral leishmaniasis (fever, loss of appetite, enlarged spleen) with leishmania amastigotes detected in Giemsa stained aspirates of spleen or bone marrow. INTERVENTIONS: Aminosidine at three daily doses (12, 16, and 20 mg/kg) for 21 days and sodium stibogluconate 20 mg/kg/day for 30 days. MAIN OUTCOME MEASURES: Laboratory measures of efficacy: parasite count, haemoglobin concentration, white cell count, platelet count, serum albumin concentration. Clinical measures of efficacy: spleen size, fever, body weight, and liver size. Measures of safety: liver and renal function tests, reports of adverse events. RESULTS: Of the 120 patients enrolled (30 per treatment arm), 119 completed treatment and follow up. Cure at end of follow up was achieved in 23 (77%), 28 (93%), and 29 (97%) patients treated with 12, 16, and 20 mg aminosidine/kg/day respectively, and in 19 (63%) patients given sodium stibogluconate. At 16 and 20 mg/kg/day, aminosidine was significantly more active than sodium stibogluconate in both clinical and laboratory measures of efficacy. No significant clinical or laboratory toxicity occurred in any treatment group. CONCLUSIONS: A 21 day course of aminosidine 16 or 20 mg/kg/day should be considered as first line treatment for visceral leishmaniasis in Bihar.

Adolescent↗
PubMed1998

Do the diminishing efficacy and increasing toxicity of sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar, India, justify its continued use as a first-line drug? An observational study of 80 cases.

Eighty parasitologically confirmed cases of visceral leishmaniasis (kala-azar) in Bihar, India, were treated daily with 20 mg sodium stibogluconate/kg for 30 days, to assess the current efficacy and toxicity of this 30-day regimen. Clinical and parasitological cure was obtained in 48 (60%) of the patients. However, 26 (33%) patients did not respond to the first course of treatment (primary unresponsiveness), two relapsed after initial clinical and parasitological cure, and two were withdrawn from the study (one on day 6 of treatment because of cardiotoxicity in the form of supraventricular tachycardia and the other on day 24 because of severe loss of appetite). All 30 patients who were not entirely cured with sodium stibogluconate were successfully treated with amphotericin B. Electrocardiographic changes occurred in many of the patients as the result of treatment with sodium stibogluconate. Diminution in the height of the T wave was seen in 32 (40%), inversion of the T wave (Minnesota code 5-1, 5-2) in seven (9%), elevation of the ST segment (Minnesota code 4-1) in three (4%), prolonged QT interval (compared with baseline findings) in six (8%), and diminution in the height of the P, R and T waves in two (3%). Cardiac arrhythmia occurred in five patients (6%), supraventricular arrhythmia (coarse atrial fibrillation) occurred in one patient and ventricular tachycardia, ventricular fibrillation, torsade de pointes and multifocal ventricular ectopics occurred in the four patients (5%) who died of cardiotoxicity. Minor side-effects, such as pain at the site of injection (two cases), mild diminution in appetite (12 cases), metallic taste in mouth (six cases), and joint pain (two cases), were also observed. It was concluded that the efficacy of sodium stibogluconate in the study area has declined over the years and that its toxicity has increased. A more efficacious, safer and cheaper, alternative drug is required as the first line of treatment of kala-azar.

Adolescent↗
PubMed1998

A randomized comparison of classical mode of administration of amphotericin B with its newer modes of administration in kala-azar.

UNLABELLED: One hundred thirty parasitologically confirmed cases of kala-azar were randomly divided in two equal treatment groups. Patients in group A were treated by infusion with amphotericin B deoxycholate (ABD), 1 mg/kg day on days 1-20 and the infusion was given in two hours. Patients in group B were treated by an escalating dose of ABD 0.05 mg/kg, 0.1 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg on days 1-5, respectively and then in the same dosage on alternate days. The infusion was completed in 6 hours. Total dose of 20 mg/kg remaining the same in both the groups, the treatment was completed in 20 days in group A and 43 days in group B. Clinical cure (subsidence of fever, improvement in general well being and regression in the size of the spleen) and parasitological cure (absence of parasites in splenic aspirates at the end of treatment) occurred in all patients in both the groups. Sixty four (99%) patients in each group had not relapsed clinically and parasitologically within 6 months of follow up and were ultimately cured. The two relapsed patients, one in each group were treated with a 20-day course of ABD and were cured. Leukocyte count, haemoglobin, serum albumin increased (P < 0.05) and ESR, spleen and liver size decreased (P < 0.05) at the end of treatment and follow up. Adverse events were similar in both the groups. The minimum cost of treatment estimated was Rs. 14,500 in group B and Rs. 10,000 in Group A. Thus the newer mode of administration was more cost effective. CONCLUSION: It was concluded that newer mode of administration of amphotericin B was as effective and tolerable as the classical mode of administration and was no more toxic. The newer mode of administration of amphotericin B is more cost effective and puts lesser burden on hospital staff and is recommended for use in kala-azar.

Adolescent↗
PubMed1998

Efficacy and safety of liposomal amphotericin B (AmBisome) for visceral leishmaniasis in endemic developing countries.

Reported are the results of a study to determine the efficacy and safety of liposomal amphotericin B (AmBisome) for treating visceral leishmaniasis (kala-azar) in several developing countries where the disease is endemic (Brazil, India, and Kenya). At each study site, sequential cohorts of 10 patients each were treated with AmBisome at a dose of 2 mg.kg-1.day-1 (2 MKD). The first cohort received regimen 1:2 MKD on days 1-6 and day 10 (total dose: 14 mg/kg). If the efficacy with this regimen was satisfactory, a second cohort received regimen 2:2 MKD on days 1-4 and 10 (total dose: 10 mg/kg); and a third cohort received regimen 3:2 MKD on days 1, 5, and 10 (total dose: 6 mg/kg). In India, regimens 1, 2, and 3 (which were studied concurrently) each cured 100% of 10 patients. In Kenya, regimen 1 cured all 10 patients, regimen 2 cured 90% of 10 patients, but regimen 3 cured only 20% of 5 patients. In Brazil, regimen 1 was only partially curative: 5 of 13 patients (62%). Therefore, 15 patients were administered regimen 4 (2 MKD for 10 consecutive days; total dose, 20 mg/kg) and 13 patients were cured (83%). These results suggest that for the treatment of kala-azar the following doses of AmBisome should be administered: in India and Kenya, 2 mg/kg on days 1-4 and day 10; and in Brazil, 2 mg/kg on days 1-10.

Adolescent↗
PubMed1997

Amphotericin B is superior to sodium antimony gluconate in the treatment of Indian post-kala-azar dermal leishmaniasis.

Parasitologically confirmed cases of post-kala-azar dermal leishmaniasis (PKDL) were treated by infusion with amphotericin B deoxycholate (ABD; 1 mg/kg.day on days 1-20, 21-40 and 61-80) or by intramuscular injection with sodium antimony gluconate (SAG; 20-day courses at 20 mg/kg day, with 20-day, drug-free intervals). Of the 11 patients given ABD, all were cured with the three courses, none relapsed in 12 months of follow-up, all developed mild adverse effects (shivering and fever) because of the infusion, five lost their appetites, and three showed increases in their serum creatinine concentrations (although none exceeded 'normal' limits). In contrast, only seven (63%) of the 11 patients given SAG were considered treatment successes (improvement in lesions by the end of the third course) and these took six courses (two cases), nine courses (four cases) or 10 courses (one case) to cure completely. Two of the patients given SAG developed arthralgia and two others developed non-specific ST changes in their electrocardiograms (ECG), although their ECG were normal between courses. The better cure rate with ABD was not statistically significant, probably because of the small sample size. However, ABD appears to be a superior to SAG in terms of the speed of response and cure, although it is more expensive and has some nephrotoxicity. As the effectiveness of SAG against PKDL is apparently declining over time and the cost of ABD is prohibitive in poor countries such as India, a safe, cheap and more effective drug for the treatment of PKDL is needed.

Adolescent↗
PubMed1996

Comparison of regimens of amphotericin B deoxycholate in kala-azar.

A total of 288 parasitologically proved patients of kala-azar were randomly allocated to three treatment groups. Patients in groups A, B and C received amphotericin B (AMB) in a dose of 1 mg/kg body weight (bw)/day, 0.75 mg/kg bw/day and 0.5 mg/kg bw/day for 20 days respectively. Apparent cure (afebrile at the end of therapy) occurred in all patients and parasitological cure in 96 (100%), 92 (96%) and 84 (88%) patients respectively in groups A, B and C. Ultimate cure (no relapse in six months of follow up) occurred in 95 (99%), 87 (91%) and 79 (82%) patients in groups A, B and C respectively. The difference between the ultimate cure in the three groups was significant (P < 0.05). The incidence of adverse events (rise in serum creatinine and fall in serum potassium, loss of appetite and shivering, rigor and fever during infusion indicative of renal, GIT and infusion related toxicities respectively) was similar in the three groups. This study showed that amphotericin B should be given at a dosage of 1 mg/kg bw/day for 20 days for Indian kala-azar patients to minimise relapses and prevent development of drug unresponsiveness.

Adolescent↗