Liposomal drug delivery system from laboratory to clinic.

The main objective of drug delivery systems is to deliver a drug effectively, specifically to the site of action and to achieve greater efficacy and minimise the toxic effects compared to conventional drugs. Amongst various carrier systems, liposomes have generated a great interest because of their versatility. Liposomes are vesicular concentric bilayered structures, which are biocompatible, biodegradable and nonimmumnogenic. They can control the delivery of drugs by targeting the drug to the site of action or by site avoidance drug delivery or by prolonged circulation of drugs. Amphotericin B (Amp B) remains the drug of choice in most systemic mycoses and also as a second line treatment for Kala azar. However, its toxic effects often limit its use. Although the liposome delivery system has been tried for several drugs, only a few have been used in patients due to the slow development of necessary large-scale pharmaceutical procedures. This paper reviews the development of the technique for liposomal Amphotericin B (L-Amp-LRC-1, Fungisome) drug delivery system in our laboratory in collaboration with the department of Biochemistry, Delhi University in India and proving the safety and efficacy of this preparation in clinical practice. It also attempts to compare the efficacy and benefits of our product for Indian patients with those of similar products and it includes facts from the publications that flowed from our work. As compared to conventional Amp B, Fungisome is infused over a much shorter period requiring a smaller volume and no premedication. It was found to be safe in patients who had developed serious unacceptable toxicity with conventional Amp B. In renal transplant patients, Fungisome did not produce any nephrotoxicity. Fungisome is effective in fungal infections resistant to fluconazole, conventional Amp B and in virgin and resistant cases of visceral leishmaniasis. The cost of any drug is of great significance, especially in India. We have therefore devoted a section of our review to the relative costs of our product and those of other commercially available products. This patient-worthy formulation is safe, efficacious and cheaper than the commercially available formulation of liposomal amphotericin B. The product has been patented and technology transferred to a pharmaceutical company for marketing. Results of postmarketing study also document safety and efficacy as observed in premarketing studies. A brief review of this work is provided here.

Medical ethics in the neurosciences.

Doctors in India are heirs to a long tradition of ethics from their own forebears and from those from the West. This paper discusses ethical aspects of topics of relevance to neurological scientists such as brain death, neural transplant and whole brain transplant. Many other topics such as ethics in research, patients with AIDS, patients in a persistent vegetative state and euthanasia deserve similar consideration and debate.

Open label, randomised, comparative phase III safety and efficacy study with conventional amphotericin B and liposomal amphotericin B in patients with systemic fungal infection.

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. RESULTS: 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.