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-1ß 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.

Quality check of spontaneous adverse drug reaction reporting forms of different countries.

Adverse drug reactions (ADRs) are considered as one of the leading causes of death among hospitalized patients. Thus reporting of adverse drug reactions become an important phenomenon. Spontaneous adverse drug reaction reporting form is an essential component and a major tool of the pharmacovigilance system of any country. This form is a tool to collect information of ADRs which helps in establishing the causal relationship between the suspected drug and the reaction. As different countries have different forms, our aim was to study, analyze the suspected adverse drug reaction reporting form of different countries, and assess if these forms can capture all the data regarding the adverse drug reaction. For this analysis we identified 18 points which are essential to make a good adverse drug reaction report, enabling proper causality assessment of adverse reaction to generate a safety signal. Adverse drug reaction reporting forms of 10 different countries were collected from the internet and compared for 18 points like patient information, information about dechallenge-rechallenge, adequacy of space and columns to capture necessary information required for its causality assessment, etc. Of the ADR forms that we analyzed, Malaysia was the highest scorer with 16 out of 18 points. This study reveals that there is a need to harmonize the ADR reporting forms of all the countries because there is a lot of discrepancy in data captured by the existing ADR reporting forms as the design of these forms is different for different countries. These incomplete data obtained result in inappropriate causality assessment.

Liposomal amphotericin B (Fungisome) for the treatment of cryptococcal meningitis in HIV/AIDS patients in India: a multicentric, randomized controlled trial.

BACKGROUND: There is need to investigate the use of liposomal amphotericin B in cryptococcal meningitis in India. AIMS: To compare the efficacy, safety, duration of treatment and cost of two doses of liposomal amphotericin B (Amp B) (Fungisome) in cryptococcal meningitis in HIV/AIDS patients. SETTINGS AND DESIGN: Prospective, randomized, multicenter study in tertiary care hospitals across India. MATERIALS AND METHODS: Adult patients with culture-proven cryptococcal meningitis with HIV/AIDS were randomized to receive either 1 (Group A) or 3 mg/kg/day of Fungisome (Group B). Clinical efficacy and tolerability, laboratory evaluations and mycological response were assessed daily, twice weekly and weekly respectively. The patients were assessed at four and eight-week follow-up. STATISTICS: We calculated average and standard deviation for the various parameters. RESULTS: The time to show clinical response was 13.66 days (1 mg) and 9.55 days (3 mg). In Group B (n=6 complete response), 50% patients responded within one week by microbial conversion, 83% in two weeks and 100% in three weeks. Patients with 1 mg dose (n=4 complete response), none showed microbial conversion within one week, 75% responded in two weeks, whereas one patient took four weeks. The average duration of treatment was 36.5+/-14.4 and 26.5+/-5.89 (S.D.) days in 1 and 3 mg/kg/day respectively. Drug was tolerated with little renal, hepatic or hematological toxicity. The cost was found to be 3.81 lacs and 1.74 lacs with 3mg/kg/day and 1mg/kg/day respectively. CONCLUSION: Higher dose showed better efficacy and quicker microbial conversion of Cerebrospinal fluid (CSF) (cerebrospinal fluid) than 1 mg/kg/day. It shortened the duration of treatment in days by 27% while drug cost almost doubled ( CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN 52812742).

Evaluation of the prevalence and economic burden of adverse drug reactions presenting to the medical emergency department of a tertiary referral centre: a prospective study.

BACKGROUND: Adverse drug reactions (ADRs) are now recognized as an important cause of hospital admissions, with a proportion ranging from 0.9-7.9%. They also constitute a significant economic burden. We thus aimed at determining the prevalence and the economic burden of ADRs presenting to Medical Emergency Department (ED) of a tertiary referral center in India METHODS: A prospective, observational study of adult patients carried out over a 6 week period in 2005. The prevalence of ADRs, their economic burden from the hospital perspective, severity, and preventability were assessed using standard criteria. RESULTS: A total 6899 patients presented during the study period. Of these, 2046 were admitted for various reasons. A total of 265/6899 patients had ADRs (3.84 %). A total of 141/265 was admitted due to ADsR, and thus ADRs as a cause of admissions were 6.89% of total admissions. A majority (74.71%) were found to be of moderate severity. The most common ADRs were anti-tubercular drug induced hepatotoxicity, warfarin toxicity and chloroquine induced gastritis. The median duration of hospitalization was 5 days [95% CI 5.37, 7.11], and the average hospitalization cost incurred per patient was INR 6197/- (USD 150). Of total ADRs, 59.62% (158/265) were found to be either definitely or potentially avoidable. CONCLUSION: The study shows that ADRs leading to hospitalization are frequent and constitute a significant economic burden. Training of patients and prescribers may lead to a reduction in hospitalization due to avoidable ADRs and thus lessen their economic burden.

Treatment outcome of extrapulmonary tuberculosis under Revised National Tuberculosis Control Programme.

BACKGROUND: Extrapulmonary tuberculosis (EPTB) constitutes 15-20% of tuberculosis cases in India. Earlier studies have evaluated treatment outcomes of EPTB with little information on outcomes of individual site of EPTB. AIMS: The objective was to study the outcome of Directly Observed Treatment Short course (DOTS) treatment of EPTB in different organ systems under Revised National Tuberculosis Control Programme. METHODS: Multi-centric retrospectives record review was carried out in three states in India. Data were collected from TB registers and analysed. RESULTS: Of the total 2219 patients studied, there were more males in age group 15-45. The commonest sites of EPTB were lymph node (34.4%) and pleural effusion (25.2%) followed by abdominal (12.8%) and central nervous system (CNS) (9.4%). Lymph node involvement was more common in females (58%) and pleural effusion in males (70%). Overall treatment completion rate was 84% in EPTB patients. Treatment completion was 86% in HIV negative EPTB patients compared to 66% in HIV positive patients. Individually, treatment completion rate observed as follows: lymph node 90.9%, genitourinary 92.6%, bone and joint 86%, pleural effusion 84.7%, abdominal 76% and CNS (tuberculoma and meningitis) 63.7%. The site of EPTB was not recorded in 173 (7.8%) patients. CONCLUSION: Treatment outcome of EPTB was poor in HIV infected patients and those with CNS tuberculosis. More efforts are needed to improve the treatment completion rates in these groups of patients.

A randomized, parallel study of the safety and efficacy of 45 mg primaquine versus 75 mg bulaquine as gametocytocidal agents in adults with blood schizonticide-responsive uncomplicated falciparum malaria [ISCRTN50134587].

BACKGROUND: The WHO recommends that adults with uncomplicated P. falciparum successfully treated with a blood schizonticide receive a single dose of primaquine (PQ) 45 mg as a gametocytocidal agent. An earlier pilot study suggested that 75 mg of bulaquine (BQ), of which PQ is a major metabolite, may be a useful alternate to PQ. METHODS: In a randomized, partial blind study, 90 hospitalized adults with Plasmodium falciparum malaria that was blood schizonticide-responsive and a gametocytemia of > 55/microl within 3 days of diagnosis were randomized to receive single doses of either PQ 45 mg or BQ 75 mg on day 4. We assessed gametocytemia on days 8, 15, 22 and 29 and gametocyte viability as determined by exflagellation (2 degrees end point) on day 8. RESULTS: On day 8, 20/31 (65%) primaquine recipients versus 19/59 (32%) bulaquine recipients showed persistence of gametocytes (P = 0.002). At day 15 and beyond, all patients were gametocyte free. On day 8, 16/31 PQ and 7/59 BQ volunteers showed gametocyte viability (p = 0.000065). CONCLUSION: BQ is a safe, useful alternate to PQ as a Plasmodium falciparum gametocytocidal agent and may clear gametocytemia faster than PQ.

Successful treatment of disseminated candidiasis resistant to amphotericin B by liposomal amphotericin B: a case report.

The case of a female patient with acute lymphoblastic leukaemia and chronic disseminated candidiasis, who was refractory to 1.8 g conventional amphotericin B therapy, is reported. She experienced severe amphotericin-B-related side-effects in spite of pretreatment, but was subsequently successfully treated with 3 g of a small unilamellar liposome formulation of amphotericin B prepared from soya phosphatidylcholine and cholesterol in a 7:3 molar ratio at our institute. The patient experienced minimal side-effects with this preparation, although no pretreatment was given. Liposomal amphotericin B prepared in our institute appears to be a safe and effective therapy for systemic fungal infections. However, large controlled studies are required to determine more precisely the potential of liposomal amphotericin B in the treatment of severe systemic fungal infection.

A randomized, double-blind, parallel-group, comparative safety, and efficacy trial of oral co-artemether versus oral chloroquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in adults in India.

In India, treatment of acute, uncomplicated Plasmodium falciparum malaria is becoming increasingly difficult due to resistance to chloroquine, thus there is a need for new antimalarial drugs. CGP 56697 (co-artemether), a new drug, is a combination of artemether and lumefantrine in a single oral formulation (one tablet = 20 mg of artemether plus 120 mg of lumefantrine). In a double-blind study, 179 patients with acute uncomplicated P. falciparum malaria were randomly assigned to receive either CGP (n = 89) given as a short course of 4 x 4 tablets over a 48-hr period or chloroquine (n = 90) given as four tablets (one tablet = 150 mg of chloroquine base) initially, followed by two tablets each at 6-8, 24, and 48 hr. Due to a death in the chloroquine group and a decrease in the chloroquine cure rate to < 50% (based on the blinded overall cure rate at that time), recruitment was terminated prematurely. CGP 56697 showed a superior 28-day cure rate (95.4% versus 19.7%; P < 0.001), time to parasite clearance (median = 36 versus 60 hr; P < 0.001), and resolution of fever (median = 18 versus 27 hr; P = 0.0456). This drug provides a safe, effective, and rapid therapy for the treatment of acute uncomplicated P. falciparum malaria.

The use and safety of non-allopathic Indian medicines.

Non-allopathic Indian medicines, referred to elsewhere in the world as complementary and alternative medicine have gathered increasing recognition in recent years with regard to both treatment options and health hazards. Ayurveda, Siddha, Unani and homeopathy are practiced in India as non-allopathic systems. These systems comprise a wide range of therapeutic approaches that include diet, herbs, metals, minerals, precious stones and their combinations as well as non-drug therapies. Ayurveda is the oldest system of medicine in the world and by far the most commonly practiced form of non-allopathic medicine in India, particularly in rural India, where 70% of the population lives. The difference between modern medicine and these systems stems from the fact that the knowledge base of many of the above systems, unlike Western medicine, is based on years of experience, observations, empiricism and intuition and has been handed down generations both through word of mouth and treatises. The focus on non-allopathic systems of medicine in India can be attributed to various causes including a need to revive a rich tradition, the dependency of 80% of the country's population on these drugs, their easy availability, increasing worldwide use of these medicines, the lack of focused concerted scientific research and the abuse of these systems by quacks. Elsewhere, the increasing use of herbal products worldwide and the growth of the herbal product industry has led to increasing concern regarding their safety. The challenges in these non-allopathic systems relate to the patient, physician, regulatory authorities, the abuse/misuse of these medicines, quality and purity issues. Safety monitoring is mandated by a changing ecological environment, the use of insecticides, new manufacturing techniques, an as yet unregulated pharmaceutical industry, the availability of combinations of herbs over the counter and not mentioned in ancient Ayurvedic texts, and the need to look at the active principles of these medicines as potential chemotherapeutic agents. The Indian traditional medicine industry has come a long way from the times when it was considered unnecessary to test these formulations prior to use, to the introduction of Good Manufacturing Practice guidelines for the industry. However, we still have a long way to go. The conflict between the traditional practitioners and the purists demanding evidence of safety and efficacy needs to be addressed. There is an urgent need for the practitioners of the allopathic and non-allopathic systems to work together to optimise the risk-benefit profile of these medicines.

Dose-ranging studies on liposomal amphotericin B (L-AMP-LRC-1) in the treatment of visceral leishmaniasis.

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.

Efficacy of a 14-day primaquine regimen in preventing relapses in patients with Plasmodium vivax malaria in Mumbai, India.

We studied the antirelapse efficacy of a supervised 14-d 15 mg/d regimen of primaquine therapy (n = 131) compared with no antirelapse therapy (n = 142) in 273 patients with confirmed Plasmodium vivax malaria in Mumbai, India, between July 1998 and April 2000. There were 6/131 (4.6%) recurrences in patients given primaquine compared with 13/142 (9.2%) in those not given antirelapse therapy. In the 14-d primaquine group, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) genotyping analysis of pre- and post-treatment blood samples was done for the 6 patients who had a recurrence of parasitaemia and the results gave a true relapse rate of 2.29% (3/131), 2 samples were classified as reinfections and 1 sample did not amplify. Our results indicate probable resistance to the 14-d regimen of primaquine for the first time in India and illustrate the need to (i) monitor patients given this regimen and (ii) carry out comparative studies between primaquine and new drugs such as tafenoquine and bulaquine for preventing relapses.

Safety, tolerability, efficacy and plasma concentrations of diethylcarbamazine and albendazole co-administration in a field study in an area endemic for lymphatic filariasis in India.

Filariasis control programmes are moving towards a strategy of repeated single-dose mass treatment of endemic populations. Using a combination, such as albendazole (ALB) to diethylcarbamazine (DEC) gives both macrofilaricidal and anti-helmintic activity. However, the safety of the combination versus DEC alone should be established in field studies in large populations prior to incorporation into national programmes. The present study compared the safety, tolerability, and efficacy of single doses of DEC 6 mg/kg + ALB placebo with DEC 6 mg/kg + ALB 400 mg in populations living in two filariasis endemic villages in the district of Wardha in western India. The study was double blind, parallel group, and randomized. Safety and tolerability study were studied in males and females older than 5 years. Safety was assessed by monitoring if adverse events (AEs) over 5 days affected daily acivities. Subjects in the 2 treatment groups experienced insignificantly different effects on daily activities and the combination was shown to be safe. Efficacy was evaluated by microfilaraemia (Mf), immunochromatographic test (ICT) and ultrasonography (USG) at 0, 3, 6, and 12 months of follow up. The efficacy study enrolled 103 male patients (aged 18-50 years) in microfilariae positive, clinical disease and asymptomatic, amicrofilaremic groups. There was no significant difference in efficacy between groups at 12 months. Within the Mf positive group, significant differences were seen in microfilaraemia (P < 0.001) with both treatments, and in USG (P < 0.001 and P < 0.004 respectively), at 12 months. The present field study has shown the combination of DEC + ALB to be as safe as the single drug DEC and thus the combination can be put in use in the national filariasis control programmes. Both drugs were adequately absorbed. The study at present does not provide evidence for the greater efficacy of the combination at 12 months follow up. While the safety of the combination has been ascertained, the incorporation or otherwise of ALB into national programmes for greater efficacy must await results of studies with longer follow up.

Effect of antibiotics on polymorphonuclear function in iron deficiency anaemia patients & normal volunteers.

The effect of erythromycin and gentamicin on polymorphonuclear leukocyte (PMN) functions was assessed in normal individuals and in patients with iron deficiency anaemia (IDA) before and after treatment with iron. The PMN phagocytic function was investigated by the standard method. Erythromycin in vivo significantly increased the PMN phagocytic function from 44.18 +/- 2.08 to 57.0 +/- 1.5 at 8 h and the bactericidal activity from 48.33 +/- 1.97 to 56.7 +/- 0.89 at 8 h in the normal adult male volunteers. A significant increase in phagocytic and bactericidal function of PMNs from IDA patients was also observed after in vivo administration of erythromycin. Gentamicin in vitro reduced the bactericidal activity of PMN from normal volunteers (P less than 0.05) but increased the PMN phagocytic activity in normal volunteers and IDA patients.

Preclinical & pharmaceutical testing of liposomal amphotericin B.

Various liposomal amphotericin-B formulations prepared from soya phosphatidylcholine and cholesterol were tested for toxicity, therapeutic efficacy and stability in mice infected with Aspergillus fumigatus. No advantage was noted by removing the unencapsulated drug from that bound to liposomes, as evident by the LD50 and efficacy being similar with both dialyzed and undialyzed formulations. Small unilamellar liposomes were more effective and less toxic, but also less stable, as compared to multilamellar vesicles. In view of these results, multilamellar liposomes were prepared without removing the unencapsulated drug and converted to unilamellar vesicles just prior to administration. The LD50 and efficacy of this formulation was similar to freshly prepared small unilamellar liposomes. These liposomes were prepared under aseptic conditions and were found to be sterile and pyrogen-free. The batch-to-batch variation was also found to be quite low, and therefore liposomal amphotericin B formulation suitable for administration in patients suffering with systemic fungal infection has been developed.

In vitro effect of intravenous immunoglobulin supplementation on serum opsonic activity in tracheostomised patients.

An in vitro study of the effect of immunoglobulins (mainly IgG) on opsonophagocytic activity of polymorphs was carried out in 17 tracheostomised patients admitted in medical intensive care unit of our hospital. The opsonic and phagocytic activities were tested against Staphylococcus aureus by modified polymorphonuclear leucocyte overlay method; and serum IgG and serum IgM levels were estimated by single radial immunodiffusion technique. As compared to healthy volunteers, opsonophagocytic activity was significantly lower in tracheostomised patients. However, this activity improved markedly after immunoglobulin supplementation (P less than 0.01). The same degree of enhancement was also observed in normal controls.

In vitro effect of intravenous immunoglobulin on serum opsonic activity in normal & intrauterine growth retarded neonates.

In vitro effect of intravenous immunoglobulin (IVIG), Intraglobin F, on serum opsonic activity against Staphylococcus aureus was studied in 26 full term normal healthy neonates and 18 intrauterine growth retarded (IUGR) neonates by the polymorphonuclear leucocyte overlay method (requiring only a few drops of blood). Cord IgG and IgM levels were determined by single radial immunodiffusion. Serum opsonic activity against Staph. aureus was significantly lower in the IUGR neonates (49.1 +/- 0.89), as compared to that in normal neonates (61.96 +/- 0.73; P less than 0.001). Immunoglobulin supplementation in vitro at a concentration of 5 g/dl significantly enhanced the opsonic activity of IUGR neonate sera. Cord IgG levels of IUGR neonates were significantly lower (P less than 0.01) than IgG levels of normal neonates. No significant difference was observed in cord IgM levels between the normal and IUGR neonates.

Analysis of a clinically important interaction between phenytoin and Shankhapushpi, an Ayurvedic preparation.

During the course of routine plasma drug level monitoring an unexpected loss of seizure control and reduction in plasma phenytoin levels was noticed in two patients who were also taking 'Shankhapushpi' (SRC), an Ayurvedic preparation. Therefore, the present study was undertaken in rats to investigate any SRC-phenytoin interaction from both pharmacokinetic (serum levels) and pharmacodynamic (electroshock seizure prevention) aspects. Single dose SRC and phenytoin (oral/i.p.) coadministration did not have any effect on plasma phenytoin levels but decreased the antiepileptic activity of phenytoin significantly. On multiple-dose coadministration, SRC reduced not only the antiepileptic activity of phenytoin but also lowered plasma phenytoin levels. SRC itself showed significant antiepileptic activity compared to placebo and is worth further investigation. However, the clinical combination of SRC with phenytoin is not advised.

A prospective survey of drug induced hepatotoxicity in a large hospital.

A prospective survey of laboratory records was carried out to identify the extent of drug induced hepatotoxicity in a hospital population. Eleven of 1000 (1.1%) abnormal liver function tests were due to drug induced hepatotoxicity. Anti-tubercular drugs, viz isoniazid, rifampicin and pyrazinamide were responsible for all cases of serious hepatotoxicity.