Dual hit lipopolysaccharide & oleic acid combination induced rat model of acute lung injury/acute respiratory distress syndrome.

Background & objectives: Despite advances in therapy and overall medical care, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) management remains a problem. Hence the objective of this study was to develop a rat model that mimics human ALI/ARDS. Methods: Four groups of Wistar rats, 48 per group were treated with (i) intratracheal (IT) lipopolysaccharide (LPS) (5 mg/kg) dissolved in normal saline (NS), (ii) intravenous (iv) oleic acid (OA) (250 μl/kg) suspension in bovine serum albumin (BSA), (iii) dual hit: IT LPS (2 mg/kg) dissolved in NS and iv OA (100 μl/kg) and (iv) control group: IT NS and iv BSA. From each group at set periods of time various investigations like chest X-rays, respiratory rate (RR), tidal volume (TV), total cell count, differential cell count, total protein count and cytokine levels in bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio and histopathological examination were done. Results: It was noted that the respiratory rate, and tumour necrosis factor-α (TNF-α) levels were significantly higher at 4 h in the dual hit group as compared to LPS, OA and control groups. Interleukin-6 (IL-6) levels were significantly higher in the dual hit group as compared to LPS at 8 and 24 h, OA at 8 h and control (at all time intervals) group. IL-1β levels were significantly higher in LPS and dual hit groups at all time intervals, but not in OA and control groups. The injury induced in dual hit group was earlier and more sustained as compared to LPS and OA alone. Interpretation & conclusions: The lung pathology and changes in respiration functions produced by the dual hit model were closer to the diagnostic criteria of ALI/ARDS in terms of clinical manifestations and pulmonary injury and the injury persisted longer as compared to LPS and OA single hit model. Therefore, the ARDS model produced by the dual hit method was closer to the diagnostic criteria of ARDS in terms of clinical manifestations and pulmonary injury.

A randomized comparative trial evaluating the safety and efficacy of liposomal amphotericin B (Fungisome TM ) versus conventional amphotericin B in the empirical treatment of febrile neutropenia in India.

Background: In patients with persistent fever and netropenia, amphotericin B is administered empirically for early treatment and prevention of systemic fungal infections. Despite this treatment, there are chances of breakthrough fungal infections and drug is also toxic. Materials and Methods: A multicentric, randomized, controlled clinical trial was conducted to compare liposomal amphotericin B two doses with conventional amphotericin B as empirical antifungal therapy. Results: The average body weight of patients was 26.4±14.8 (n=22), 32.9±19.4 (n=23) and 37.9±20.0 (n=20) kg in 1 mg, 3 mg Fungisome (liposomal amphotericin B) and 1 mg/kg/day conventional amphotericin B group, respectively. The mean age was 16.2±13.4, 16.0±10.9 and 22.7±16.2 yrs in 1 and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional AMP B group, respectively. The average duration of treatment with 1 mg and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional amphotericin B was 17±9.8, 16.2±8.3, and 14.7±10.7 days, respectively. The time to resolve fever was 13.3±10.2, 10.9±7.1, 10.1±6.7 days, and for absolute neutrophil count (ANC) to be above 500 cells per microliter, it took 13.4±9.6, 10.6±7.6 and 7.3±3.4 days, respectively. Liposomal formulations were well-tolerated compared to conventional amphotericin B. Conclusions: This small randomized study showed that the indigenous liposomal formulation Fungisome TM appears to be equally efficacious and safer than conventional amphotericin B. Also, the lower dose Fungisome (1 mg/kg/day) appears to be equally efficacious and was well-tolerated as compared to higher dose Fungisome (3 mg/kg/day). Treatment cost would be a major factor for limiting use of higher dose of Fungisome.

Tetany: Possible adverse effect of bevacizumab.

Background: Bevacizumab a recombinant humanized monoclonal antibody was approved in 2004 by US FDA for metastatic colorectal cancer. It is reported to cause potentially serious toxicities including severe hypertension, proteinuria, and congestive heart failure. Aim: To correlate adverse event tetany with the use of bevacizumab. Materials and Methods : World Health Organization's Uppsala Monitoring Centre, Sweden, for reporting of adverse drug reactions from all over the world, identified 7 cases with tetany-related symptoms to bevacizumab from four different countries. These 7 patients reported to UMC database developed adverse events described as musculoskeletal stiffness (1), muscle spasm (1), muscle cramps (1), lock jaw or jaw stiffness (4), and hypertonia (1), with hypocalcaemia. Results: After detailed study of the possible mechanism of actions of bevacizumab and factors causing tetany, it is proposed that there is a possibility of tetany by bevacizumab, which may occur by interfering with calcium metabolism. Resorption of bone through osteoclasts by affecting VEGF may interfere with calcium metabolism. Another possibility of tetany may be due to associated hypomagnesaemia, hypokalemia, or hyponatremia. Conclusions: Tetany should be considered as a one of the signs. Patient on bevacizumab should carefully watch for tetany-related symptoms and calcium and magnesium levels for their safety.

Malaria: anti malarial resistance and policy ramifications and challenges.

'The National health Policy 2002 of India and the "Roll Back Malaria " policy makers have set up an ambitious goal of reducing malaria mortality and morbidity by 25% by 2007, and by 50% by 2010. To achieve these goals, problems should be identified, available evidence analyzed and policy should be changed early. Infection with drug resistant malarial parasites has a tremendous impact on health (prolonged recurrent illness, increased hospital admissions and death), health system (higher cost of treatment) and socioeconomics of the region. In view of the evidence of the economic burden of malaria, it has been suggested that second line treatment could be considered at 10% failure instead of 25%. Effective schizonticidal drugs will not only reduce morbidity and mortality but will also reduce transmission. Studies have shown that prevalence of viable (as tested by exflagellation test) gametocytes is considerably more after the Chloroquine or Chloroquine + Sulphadoxine-Pyrimethamine treatment compared to Quinine. Unfortunately, the only gametocytocidal drug for Plasmodium falciparum, primaquine, is also loosing its efficacy. 45 mg Primaquine reduces gametocyte prevalence by 50% while a new drug, 75 mg bulaquine or 60 mg primaquine reduces it by 90%. Plasmodium vivax forms 60-70% of malaria cases in India. Relapses which occur in 10-20% of cases adds to the burden. Efficacy, as confirmed by Polymerase Chain Reaction-Single Strand Conformational Polymorphism (PCRSSCP) to differentiate relapse and re-infection, of standard dose of primaquine (15 mg/day for 5 days, even 15 mg/day for 14 days) for vivax malaria is reducing. Fourteen day treatment is also impractical as compliance is poor. Newer drugs, newer drug delivery systems are thus needed. Slow release formulations with blood levels maintained for one week may be useful. Rationale of giving primaquine in higher doses and different timing need to be considered. The genome of Plasmodium falciparum and genome of Anopheles gambiae have been unraveled in last past 3 years. This has given us an opportunity to develop new tools. Whatever be the tool, educating health care workers as well as lay public and ensuring appropriate use of available drug are essential to achieve our goals of controlling malaria.

Post-marketing study to assess the safety, tolerability and effectiveness of Fungisome: an Indian liposomal amphotericin B preparation.

BACKGROUND: In May 2003, an indigenously developed liposomal amphotericin B (Fungisome) was introduced in the Indian market for the treatment of systemic fungal infections and visceral leishmaniasis. The present post marketing study assessed the safety and effectiveness of Fungisome in actual clinical practice. Setting and Design: Retrospective post marketing surveillance from four cities of India. METHODS: The present study was carried out for a period of 6 months (Jun-Nov 2004), a year after the introduction of the drug. A list of doctors who had prescribed and procured the drug was obtained from the distributor. Consent to participate and scrutinize the patients' source notes were obtained from the concerned doctors. All patients who had received Fungisome treatment were included. Data was collected from the patient's source notes on a predesigned proforma. They were then analyzed by descriptive statistics. Cost of Fungisome was calculated on the basis of dose used and number of days of treatment. RESULTS: Data were available for 109/144 patients from 35/40 physicians. Fungisome was administered at 1-3 mg/kg/day for 7-76 days. No serious adverse events related to the drug were observed in the study. Mild infusion-related adverse events were reported in 40 (36%), moderate in 11 (10%) of patients and severe in 2 (1.8%). None of the adverse events were certain to Fungisome exposure, 12 (11%) were probable, 28 (25 %) were possible, and 13 (11.9%) were unlikely. Of the 91 assessable patients (received at least eight doses of Fungisome) for efficacy complete response was observed in 67 (73.6%), 16 (17.5%) had partial responses, and 8 (8.7%) of patients had no response. The acquisition cost per day and per course treatment of different fungal infections ranged from (apprx) Rs 4500-8000 and 0.9-2.1 lakh respectively. CONCLUSION: This postmarketing study documents the safety, tolerability, effectiveness and cost advantage of indigenously developed liposomal amphotericin B in the treatment of systemic fungal infections and febrile neutropenia in actual clinical practice.

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.

A cost-effectiveness analysis of three antimalarial treatments for acute, uncomplicated Plasmodium falciparum malaria in Mumbai, India.

BACKGROUND: Malaria is a major public health problem representing 2.3% of the overall global disease burden. The cost of treatment of malaria continues to rise as older drugs and insecticides become less effective and are replaced by more effective, but also more expensive products. METHODS: A post-hoc pharmacoeconomic analysis (direct and indirect costs only) of three antimalarials, chloroquine, mefloquine and co-artemether, was carried out to address the problem of switch to a more expensive first-line antimalarial in the face of growing chloroquine resistance. RESULTS: From the perspective of a large public hospital, it was seen that in an area of high grade chloroquine resistance, the total expenditure on patients who fail chloroquine would exceed the excess expenditure on mefloquine when the RII + RIII resistance exceeded 9%. CONCLUSIONS: Switch to a more expensive drug like mefloquine as a first-line option would be cost-effective when the moderate-severe chloroquine resistance exceeded 9%.

Diagnostic and prognostic utility of rapid strip (OptiMal and Paracheck) versus conventional smear microscopy in adult patients of acute, uncomplicated P. falciparum malaria in Mumbai, India.

OBJECTIVES: The present study compared the diagnostic and prognostic utility of two rapid tests the (Paracheck and OptiMal) versus conventional smear microscopy. METHODS: Using two independent microscopists we carried out the three tests in 31 adult cases of smear positive, acute, uncomplicated Plasmodium falciparum malaria. All three tests were done pretreatment, and on Days 8, 15 and 29. RESULTS: Compared to microscopy, the Paracheck had a sensitivity of 100%, while the OptiMal had a sensitivity of 83.7%. The lower sensitivity of OptiMal resulted from misidentification by both microscopists of 6/31 cases as Plasmodium vivax. As a follow up tool, the OptiMal was better than Paracheck, due to the earlier disappearance of the parasite LDH. Also in the Paracheck, between microscopists, there was a significant difference in reading the tests, on Days 8 and 15. CONCLUSION: Our study reiterates, the continued utility of conventional smear microscopy.

Treatment of neonatal candidiasis with liposomal amphotericin B(L-AMP-LRC-1): phase II study.

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.

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.

Safety and efficacy of liposomal amphotericin B in patients with cryptococcal meningitis.

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.