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Background: Shirodhara is a classical and a well-established ayurvedic procedure of slowly and steadily dripping medicated oil or other liquids on the forehead. This procedure induces a relaxed state of awareness that results in a dynamic psycho-somatic balance., Objectives: The objective of the study is to evaluate the psychological and physiological effects of Shirodhara in healthy volunteers by monitoring the rating of mood and levels of stress, electrocardiogram (ECG), electroencephalogram (EEG), and selected biochemical markers of stress., Materials and Methods: The study was conducted in the human pharmacology laboratory. The study design was open labeled, comparing the baseline variables with values after Shirodhara. The subjects (n = 16) chosen were healthy human volunteers who gave an informed consent. Shirodhara was preceded by Abhyanga - whole body massage. The Shirodhara method was standardized for rate of dripping with peristaltic pump and temperature was controlled with a thermostat. Mood and stress levels were assessed by validated rating scales. The pre- and post-Shirodhara ECG and EEG records were evaluated., Results: Student's paired "t" test was applied to the means + SE of the variables to calculate statistical significance at P <0.05. There was a significant improvement in mood scores and the level of stress (P <0.001). These changes were accompanied by significant decrease in rate of breathing and reduction in diastolic blood pressure along with reduction in heart rate. The relaxed alert state, after Shirodhara, was co-related with an increase in alfa rhythm in EEG., Conclusion: A standardized Shirodhara leads to a state of alert calmness similar to the relaxation response observed in meditation. The clinical benefits observed with Shirodhara in anxiety neurosis, hypertension, and stress aggravation due to chronic degenerative diseases could be mediated through these adaptive physiological effects.

A liposomal amphotericin B preparation (L-AMP-LRC-1) has been developed and tested successfully in adults by us. This preparation was administered to 23 neonates with candidiasis in an open phase II study. All the 14 assessable patients responded completely to the L-AMP-LRC-1 therapy given at 1 mg/kg for 28 days. Compared to AmBisome, another liposomal formulation of amphotericin B, L-AMP-LRC-1 was effective at lower dose in neonatal candidiasis. Thus L-AMP-LRC-1 appears to be an effective and low cost drug for the treatment of candidiasis.

Amphotericin B (AmpB) incorporated into small unilamellar liposomes prepared from soya phosphatidylcholine and cholesterol (L-AMP-LRC-1) has been shown to be safe and effective in patients with systemic fungal infections. In this report, we compared the plasma levels of AmpB in adults, children and neonates following administration of L-AMP-LRC-1. A 1.0 mg/kg dose of L-AMP-LRC-1 in adult patients resulted in peak concentrations of 1.02+/-0.14 mg/l (mean+/-S.D.) on day 1, which increased to 1.66+/-0.19 mg/l on day 28 after continued therapy. The area under the plasma concentration-time curve also increased from 13.05+/-1.52 on day 1 to 19.85+/-5.41 mg h/l on day 28. In children, the peak plasma concentration following 1.0 mg/kg per day dose of L-AMP-LRC-1 increased from 0.63+/-0.20 on day 1 to 1.10+/-0.53 mg/l on day 28. While in neonates, the levels increased from 0.54+/-0.17 on day 1 to 0.73+/-0.29 mg/l on day 28. These levels of AmpB in children and neonates were found to be significantly lower than in adults. This may be due to higher volume of distribution, since 1.0 mg/kg per day dose of L-AMP-LRC-1 was found to be effective in neonates.

Objective: To compare conventional amphotericin B (c-amp B) and liposomal amphotericin B (L-AMP-LRC-1-India) in patients with systemic fungal infection in open, randomized, comparative, laboratory blind, phase III safety and efficacy study., Material and Methods: Formulation of liposomal amphotericin B - L-AMP-LRC-1, containing natural phospholipids, was prepared and tested at the Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, India. Patients suffering from proven systemic fungal infection, were treated with c-amp B or L-AMP-LRC-1 with 17 patients in each group. Data was compared for the safety and efficacy., Safety: L-AMP-LRC-1 was better tolerated than c-amp B. Out of the 695 infusions of c-amp B fever occurred on 25.04% occasions in 68.42% patients, while it occurred on 2.09% occasions out of 767 infusions (in 30.43% patients of L-AMP-LRC-1. Chills occurred on 16.83% and 1.17% occasions after c-amp B and liposomal amphotericin B respectively. Other adverse effects observed on 0.2-5% of occasions were: headache, nausea, vomiting, palpitation and dizziness occurring more frequently in c-amp B group. The L-AMP-LRC-1 did not cause bronchospasm at 1 mg/kg dose in a patient who developed bronchospasm to 0.1 mg/kg dose of c-amp B. The L-AMP-LRC-1 was found to be less nephrotoxic than c-amp B and could be administered to patients who had renal problems or had undergone renal transplant. L-AMP-LRC-1 caused less hypokalemia than c-amp B. Effficacy: 17/17 patients in L-AMP-LRC-1 group and 14/17 in c-amp B group had complete response (100% and 82.35% response rate). The number of infusions and dose of amphotericin B and L-AMP-LRC-1 used were similar and required individualization of duration of treatment (in cases where response to fixed duration was not observed). All the patients were treated with 0.5 to 1.0 mg/kg/day dose of L-AMP-LRC-1 (except one patient required 2 mg/kg dose). This is markedly different from other marketed liposome and lipid formulations, which are recommended at higher (3-5 mg/kg) doses every day. At the same time L-AMP-LRC-1 being prepared from naturally occurring lipids is expected to cost at least one-third of the marketed formulation. Thus cost of every day treatment would be very much less compared to other delivery systems. Thus L-AMP-LRC-1 will be an economical and safe treatment option available to the physicians for the treatment of systemic fungal infection.

Four patients with cryptococcal meningitis were successfully treated with liposomal amphotericin B prepared at our institute using Soya phosphatidylcholine and cholesterol. In one patient, response with 1 mg/kg/day treatment was poor. However, on increasing the dose to 2 mg/kg/day, a good response was observed with CSF becoming negative for Cryptococcus neoformans after seven days of this enhanced dose. L-AMP-LRC-1 was found to be well tolerated and a major advantage was observed in two renal transplant patients in whom it could be given safely.

Efficacy and tolerability of liposomal amphotericin B (L-AMP-LRC-1; developed in India by the Liposome Clinical Pharmacology Centre, Mumbai, and the Liposome Research Centre, New Delhi) were assessed in 63 patients suffering from visceral leishmaniasis at centres in Mumbai and Patna. Patients were treated with different daily dose schedules ranging from 1 mg/kg for 21 days to 3.0 mg/kg for 7 days. L-AMP-LRC-1 was well tolerated by all 63 patients. Two patients on the 3.0 mg/kg dose developed bronchospasm on 4 occasions which reversed with standard treatment and could be prevented by increasing the duration of infusion to 3 h. Forty-three patients were freshly diagnosed cases while 20 were unresponsive to standard treatment. All 42 assessable freshly diagnosed cases responded completely to L-AMP-LRC-1 (1 patient died owing to pulmonary infection before completion of treatment), but 5 patients required additional doses for parasitological cure. All 20 patients unresponsive to standard therapy responded completely, but 3 patients required additional doses. The regimen of 2 mg/kg daily for 10 days was 100% effective; 3 mg/kg daily for 5 days was efficacious in 90.9% freshly diagnosed patients, and 3 mg/kg daily for 7 days was effective in 100% of the unresponsive cases of visceral leishmaniasis. L-AMP-LRC-1 is thus found to be safe and effective in freshly diagnosed as well as unresponsive cases of visceral leishmaniasis at dose schedules of shorter duration than used for conventional amphotericin B.

Objectives: Given the steep increase in the incidence of malaria in the city of Mumbai in the nineties, we decided to study the causes for the same as well as analyse the resistance pattern of P. falciparum in the city., Methods: Smear positive cases of acute uncomplicated P. falciparum malaria who presented to us in 1994, 1995 and 1996 were analysed for their response to full dose chloroquine (25 mg/kg over 3 days). Samples of those patients who satisfied criteria for in vitro resistance testing to chloroquine and other antimalarials, were also studied. Chloroquine level in all patients was studied on Day 3 by HPLC. In vivo response to chloroquine was studied in 30, 71 and 78 patients while in vitro response was studied in 17, 35 and 30 patients respectively in the above years., Results: We found in vivo chloroquine resistance figures of 36.78%, 45% and 53.8% in the years '94, '95 and '96 and the in vitro resistance figures of 41.17%, 54.28% and 66.6% in the same years., Conclusions: Our previous studies documenting 15% chloroquine resistance in 1993 and the increasing incidence in subsequent years suggests resistance to chloroquine as one of the causes of resurgence and maintenance of malaria in the city. If patients of uncomplicated P. falciparum malaria are to be treated with chloroquine, rigorous monitoring for nonresponse and timely rescue medication is necessary. Alternative antimalarial drugs such as mefloquine, artemisinin derivatives and sulfadoxine-pyrimethamine should be used in patients where this is not possible.