An Expert Review and Recommendations on the Rational Use of Proton Pump Inhibitors: Indian Perspective.

BACKGROUND: Proton pump inhibitors (PPIs) are the mainstay of treatment for acid peptic diseases (APDs), but are often irrationally prescribed in clinical practice. Appropriate prescription of PPIs is needed to optimize outcomes, and minimize risks and cost burden on the healthcare system. OBJECTIVE: To review available literature on efficacy and safety of proton pump inhibitors (PPIs) and give recommendations for rational use of PPIs from an Indian perspective. METHODS: Twelve healthcare professionals (9 gastroenterologists, 1 cardiologist, 1 orthopedist, 1 clinical pharmacologist) comprised the expert group; members disclosed conflicts of interest. The creation of the expert review was through a process that included meetings (in-person, online, telephone) where each professional contributed their experiences with regards to efficacy and safety of PPIs. Articles published between the years 2000 and 2017 were reviewed for evaluation of safety and efficacy of PPIs in treatment of various APDs. CONCLUSION: This expert review provides key recommendations for decision making in order to minimize the irrational use of PPIs. Some significant recommendations include: patients with GERD and acid-related complications should take a PPI for minimum 12 weeks for healing of esophagitis, and for maximum up to 48 weeks for symptom control. Patients with Barrett's esophagus should take long-term PPI. Patients at high risk for ulcer-related bleeding from NSAIDs including aspirin should take a PPI if they continue to take NSAIDs. Best practice recommendations are meant to merely assist with decision making in conjunction with patients' clinical history, and are not intended to dictate mandatory rules.

Steady-state Pharmacokinetics of Vancomycin in Children Admitted to Pediatric Intensive Care Unit of a Tertiary Referral Center.

AIMS AND OBJECTIVES: Vancomycin is a drug of choice for various gram-positive bacterial (GPB) infections and is largely prescribed to pediatric intensive care unit (PICU) patients. Despite the different pathophysiology of these patients, limited data are available on pharmacokinetics of vancomycin. There are lack of data for critically ill Indian children; hence, study was conducted to assess the steady-state pharmacokinetics in children admitted to PICU. MATERIALS AND METHODS: Twelve subjects (seven males, five females) aged 1-12 years were enrolled. Vancomycin (dose of 20 mg/kg per 8 hours) was infused for over 1 hour and steady-state pharmacokinetics was performed on day 3. Vancomycin concentrations were measured by the validated liquid chromatography mass spectrometry method. Pharmacokinetic parameters were calculated using Winnonlin (Version 6.3; Pharsight, St. Louis, MO). RESULTS: The steady-state mean C ssmax was 40.94 µg/mL (±15.07), and mean AUC0-8 hours was 124.15 µg/mL (±51.27). The mean t 1/2 was 4.82 hours (±2.71), Vd was 12.48 L (±4.43), and Cl was 2.08 mL/minute (±0.89). The mean AUC0-24 among 12 subjects was 372.44 µg/mL (±153.82). Among 35 measured trough concentrations, 23 (65.71%) were below, 11 (31.43%) were within, and 1 (2.86%) was above the recommended range. CONCLUSION: The pharmacokinetic parameters of vancomycin were comparable with previously reported studies. However, recommended trough levels (10-20 µg/mL) were not achievable with current recommended dosing of 60 mg/kg/day. HOW TO CITE THIS ARTICLE: Mali NB, Tullu MS, Wandalkar PP, Deshpande SP, Ingale VC, Deshmukh CT, et al. Steady-state Pharmacokinetics of Vancomycin in Children Admitted to Pediatric Intensive Care Unit of a Tertiary Referral Center. IJCCM 2019;23(11):497-502.

Single-dose and Steady-state Pharmacokinetics of Vancomycin in Critically Ill Patients Admitted to Medical Intensive Care Unit of India.

RATIONALE: Vancomycin remains the standard of care for gram-positive bacterial infections, though there are significant developments in newer antibacterial agents. Efficacy can be improved by linking pharmacokinetic with pharmacodynamic principles, thus leading to optimum antibiotic exposure. There is scarcity of pharmacokinetic data in Indian intensive care unit (ICU) population. MATERIALS AND METHODS: Fifteen subjects with suspected or proven gram-positive bacterial infection of either gender between 18 years and 65 years of age were enrolled. Vancomycin at the dose of 1 g every 12 hours was administered over 1-hour period and pharmacokinetic assessments performed on blood samples collected on days 1 and 3. Vancomycin concentrations were measured on validated liquid chromatography mass spectrometry method. Pharmacokinetic parameters were calculated using Winnonlin (Version 6.3; Pharsight, St. Louis, MO). RESULTS: The mean C max, elimination half-life, AUC0-12hours, volume of distribution, and clearance of single dose were 36.46 µg/mL (±14.87), 3.98 hours (±1.31), 113.51 µg/mL (±49.51), 52.01 L (±31.31), and 8.90 mL/minute (±3.29), respectively, and at steady state were 40.87 µg/mL (±19.29), 6.27 hours (±3.39), 147.94 µg/mL (±72.89), 56.39 L (±42.13), and 6.98 mL/minute (±4.48), respectively. The elimination half-life increased almost two-fold at steady state. The steady state mean AUC0-24 was 295.89 µg/mL (±153.82). Out of 45 trough levels, 32 (71.11%) concentrations were below recommended range. CONCLUSION: Recommended AUC0-24hours and trough concentrations were not achieved in majority of patients with current dosing, suggesting reevaluation of current vancomycin dosing. Individualized treatment based on close monitoring of vancomycin serum concentrations in critically ill patients is imperative. HOW TO CITE THIS ARTICLE: Mali NB, Deshpande SP, Wandalkar PP, Gupta VA, Karnik ND, Gogtay NJ, et al. Single-dose and Steady-state Pharmacokinetics of Vancomycin in Critically Ill Patients Admitted to Medical Intensive Care Unit of India. IJCCM 2019;23(11):513-517.

Vivax infection alters peripheral B-cell profile and induces persistent serum IgM.

B cell-mediated humoral responses are essential for controlling malarial infection. Studies have addressed the effects of Plasmodium falciparum infection on peripheral B-cell subsets but not much is known for P. vivax infection. Furthermore, majority of the studies investigate changes during acute infection, but not after parasite clearance. In this prospective study, we analysed peripheral B-cell profiles and antibody responses during acute P. vivax infection and upon recovery (30 days post-treatment) in a low-transmission area in India. Dengue patients were included as febrile-condition controls. Both dengue and malaria patients showed a transient increase in atypical memory B cells during acute infection. However, transient B cell-activating factor (BAFF)-independent increase in the percentage of total and activated immature B cells was observed in malaria patients. Naïve B cells from malaria patients also showed increased TLR4 expression. Total IgM levels remained unchanged during acute infection but increased significantly at recovery. Serum antibody profiling showed a parasite-specific IgM response that persisted at recovery. A persistent IgM autoantibody response was also observed in malaria but not dengue patients. Our data suggest that in hypoendemic regions acute P. vivax infection skews peripheral B-cell subsets and results in a persistent parasite-specific and autoreactive IgM response.

An assessment of the compliance of randomized controlled trials published in two high impact journals with the CONSORT statement.

Background: The Consolidated Standards of Reporting Trials (CONSORT) statement has been developed to improve the quality of reporting of clinical trials. There is possibly suboptimal adherence to the CONSORT statement in published trials. We evaluated the compliance of randomized controlled trials ( RCTs) published in the Journal of the American Medical Association (JAMA) and British Medical Journal (BMJ) in 2013 to the CONSORT statement 2010. Methods: A PubMed search for RCTs published in JAMA and BMJ for 2013 was done. Scores were assigned to each subitem of CONSORT by one of four authors and disputes were resolved by mutual consensus. The total score for each RCT was calculated and converted to a percentage total score (PTS). Scores were expressed as median (range). The median scores between journals and types of RCTs were compared using the Mann-Whitney U test. Results: There were 97 RCTs (69 in JAMA and 28 in the BMJ) comprising parallel (75), cluster (14) and non-inferiority (8) design studies. The overall median (range) of PTS of all RCTs was 82% (59.4%-97.1 %). JAMA had an overall median (range) PTS of 81.6% (59.4%-97.1 %) and the BMJ 84% (65.2%-92.2%). The difference was not statistically significant (p=0.25). Between trial designs, the highest PTS was seen with parallel (which included parallel, crossover and factorial designs) with a median (range) of 85.1% (68.4%-90.2%) followed by cluster randomized trials 82.8% (65.2%-92.2%) and non-inferiority trials 78.6% (72.7%-85.7%). There was no significant difference between the three trial designs (p=0.48). Conclusion: A wide range in PTS (59.4%-97.1 %) even in high impact journals indicates poor compliance of reported trials with CONSORT.

A Prospective Antibacterial Utilization Study in Pediatric Intensive Care Unit of a Tertiary Referral Center.

PURPOSE: Antibacterials are commonly prescribed to Pediatric Intensive Care Unit (PICU) patients. However, inappropriate antibacterial prescriptions lead to increases in antibacterial resistance, treatment cost, duration of treatment, and poor clinical outcome. The antibacterial utilization study assesses the prescription patterns and if necessary recommends the interventions to improve antibacterial prescriptions. Hence, the present prospective groundwork was conducted. MATERIALS AND METHODS: The study was conducted over the period of 6 months (April 18 to October 20, 2014). The demographics and drug use details were captured daily from patients admitted to PICU to assess World Health Organization indicators. RESULTS: A total of 200 patients enrolled, among them 119 males and 81 females. There were 12.46 (±6.16) drugs prescribed per patient, of which 2.38 (±1.48) were antibacterials. Among the total drug prescribed, 18.49% were antibacterials and 97% patients received at least one antibacterial. Ceftriaxone (49.48%) was the most commonly prescribed antibacterial, while imipenem (2.58%) and colistin (2.06%) use was very low. A total of 80.95% antibacterials were prescribed by generic name, 94.88% were administered intravenously, and 80.76% were prescribed from hospital pharmacy. The average length of PICU stay was 6.15 days (±6.20), the average length of antibacterial treatment was 6.08 days (±6.27), and the average length of empirical antibacterial treatment was 5.50 days (±5.40). The cost of antibacterial therapy per patient was Indian rupees 824.64 (±235.35). In 27 patients, bacterial culture test was positive and of whom 21 received antibacterials as per sensitivity pattern. CONCLUSIONS: The use of antibacterials was not indiscriminately high but more prescriptions per sensitivity pattern are required.

A Multicentric, Prospective, Observational Antibacterial Utilization Study in Indian Tertiary Referral Centers.

RATIONALE: Antibacterials are largely prescribed to the intensive care unit (ICU) patients due to high prevalence of infections. However, appropriate use of antibacterials is imperative; since the misuse of antibacterials increases antibacterial resistance and ultimately, it has negative impact on health care and economic system. Hence, continuous antibacterials prescription assessments are very important to judge and improve prescription patterns. The present work was carried out at public and private hospitals to assess the differences in antibacterial prescribing pattern. METHODS: The present study was conducted at three public and two private hospitals over the period of 14 months. Demographic and drug use details were captured daily from patients admitted to medical ICUs to assess the World Health Organization indicators. RESULTS: A total of 700 patients were enrolled across the five centers (140 per center), among them 424 were male and 276 were female. Average number of drugs and antibacterials prescribed at public hospitals are significantly higher than the private hospital. However, percentage of antibacterial agents prescribed at public hospitals was significantly lower than the private hospitals (P = 0.0381). Private hospitals had significantly lower percentage of antibacterial agents prescribed by generic name (P < 0.0001). Differences in change of antibacterial agents required were not statistically significantly different (P = 0.1888); however, significant difference was observed in percentage of patients who received antibacterial treatment as per sensitivity pattern (P = 0.0385) between public and private hospitals. Significantly higher mortality was observed in public hospitals compared to private hospitals (<0.0001). CONCLUSIONS: More generic prescriptions and more number of prescriptions as per the sensitivity pattern are required at each public and private hospital.

An audit of colistin use in neonatal sepsis from a tertiary care centre of a resource-limited country.

BACKGROUND & OBJECTIVES: Sepsis due to multidrug-resistant Gram-negative pathogens is a challenge for clinicians and microbiologists and has led to use of parenteral colistin. There is a paucity of data regarding safety and efficacy of intravenous colistin use in neonates. The objective of this retrospective analysis was to study the efficacy and safety of intravenous colistin in the treatment of neonatal sepsis. METHODS: An audit of the data from neonates, admitted to a neonatal intensive care unit of a tertiary care hospital during January 2012 to December 2012, and who received intravenous colistin was carried out. RESULTS: Sixty two neonates received intravenous colistin (52 preterm and 10 term) for the treatment of pneumonia, bloodstream infections and meningitis. The isolated pathogens in decreasing order of frequency were Acinetobacter baumannii, Klebsiella pneumonia and Pseudomonas aeruginosa. Of the total 62 neonates, 41 (66.12%) survived and 21 (33.87%) died. Significantly higher mortality was observed in neonates with lower body weights (P < 0.05). A significant association of mortality was found in those with sepsis due to Klebsiella species. Only one of seven with this infection survived as against 15 of the 23 who grew other organisms [P = 0.03; crude odds ratio = 11.25 (1.2, 110.5)]. None of the neonates developed neurotoxicity or nephrotoxicity. INTERPRETATION & CONCLUSIONS: This retrospective study in neonates with sepsis showed that intravenous colistin was safe and effective in the treatment of neonatal sepsis. Further, well-controlled, prospective clinical trials need to be done to corroborate these findings.

Immunological & metabolic responses to a therapeutic course of Basti in obesity.

BACKGROUND & OBJECTIVES: Basti (medicated enema) is a popular Ayurvedic intervention recommended for obesity. However, there are no data to show whether any physiological or biochemical changes occur following this treatment. This study was conducted to identify the immunological and metabolic changes in obese individuals after a therapeutic course of Basti. METHODS: Thirty two obese individuals (18 and 60 yr) with a body mass index (BMI) ≥30 kg/m [2] who received a therapeutic course of 16 enemas (Basti) followed by a specific diet and lifestyle regimen for a period of 32 days as their treatment for obesity, were enrolled in the study. Clinical examination, measurement of immune and metabolic markers were done before (S1), immediately after (S2) and 90 days after the completion of therapy (S3). RESULTS: A significant reduction ( P<0.001) in weight, BMI, upper arm and abdominal circumference was seen at S3, along with a decrease in serum interferon (IFN)-γ (P<0.02), interleukin (IL)-6 ( P<0.02) and ferritin (P<0.05) and increase in IgM levels ( P<0.02). Peripheral blood lymphocytes (PBLs) stimulated with anti-CD3 monoclonal antibodies showed significant increase in reactive oxygen species (ROS) generation and calcium flux after Basti. All organ function tests revealed no changes. INTERPRETATION & CONCLUSIONS: Our study documents that a therapeutic course of Basti modulates immune responses by regulating pro-inflammatory cytokines, immunoglobulins and functional properties of T-cells. These changes are associated with a reduction in the body weight which is maintained even after three months of treatment. The study also documents the safety of Basti procedure.

Use of computerized tests to evaluate psychomotor performance in children with specific learning disabilities in comparison to normal children.

BACKGROUND & OBJECTIVES: Children with specific learning disabilities (SpLD) have an unexplained difficulty in acquiring basic academic skills resulting in a significant discrepancy between their academic potential and achievements. This study was undertaken to compare the performance on a battery of six psychomotor tests of children with SpLD and those without any learning disabilities (controls) using computerized tests. METHODS: In this study, 25 children with SpLD and 25 controls (matched for age, socio-economic status and medium of instruction) were given three training sessions over one week. Then children were asked to perform on the six computerized psychomotor tests. RESULTS were compared between the two groups. RESULTS: Children with SpLD fared significantly worse on finger tapping test, choice reaction test, digit picture substitution test and card sorting test compared to the controls ( p <0.05). INTERPRETATION & CONCLUSIONS: Children with SpLD have impairment of psychomotor skills like attention, sensory-motor coordination and executive functioning. Further research is needed to evaluate if the remedial education plan results in improvement in psychomotor performance of children with SpLD on these selected tests.

Impact of the COVID pandemic on functioning of the institutional ethics committee: A comparison study.

Purpose and Aim: In COVID 19 pandemic, it was essential to document the functioning of the institutional ethics committee (IEC), how the organization adapted and faced challenges posed, thus forming the rationale behind this particular audit. The objectives were to assess the impact of the pandemic on the structure, review process, outcomes, and administration of IEC and to compare the same during its functioning in the prepandemic stage. Subject and Methods: The study was conducted as a retrospective audit. After exemption from ethics review, the data were collected from the IEC office situated in KEM Hospital and were segregated into four domains: structure, review process, outcomes, and administration. The data were analyzed using descriptive statistics. Mann-Whitney U-test was used to compare the turnover time for approval of projects between the two study periods at 5% level of significance. SPSS software version 22 was used to analyze the data. Results: Constitution changed , more protocols pertaining to COVID 19 studies were reviewed, meetings frequency doubled, and Standard Operating Procedures was amended to incorporate the changes faced during pandemic. Significant decrease in turnover time was noticed with respect to submission to query letter and study completion. There were more protocol deviations. Financial burden and expenditure decreased due to less paperwork and meetings being held online. Conclusion: The ethics committee infrastructure and functioning had to undergo a paradigm shift to adapt to the various changes and overcome the various hurdles occurring during the COVID-19 pandemic.

An audit of therapeutic drug monitoring services of anticonvulsants at a tertiary care hospital in India.

BACKGROUND: Therapeutic drug monitoring (TDM) is an important adjunct to the treatment of epilepsy. However, few studies have actually correlated plasma levels of antiepileptic drugs (AEDs) with treatment response. The present audit aimed to study (i) the association between seizure control and number of AEDs, plasma AED concentration, and concomitant use of antitubercular drugs; (ii) the pattern of indications for TDM requisitions; and (iii) the association between referral for toxicity and plasma AED concentration. METHODS: This observational and retrospective study was carried out to analyze the TDM data of patients referred between January 2008 and December 2011. As per the International League Against Epilepsy Task Force 2009, patients were categorized into responders and nonresponders. Plasma AED levels were interpreted as below, within, and above the reference range. RESULTS: Of 3206 TDM requisitions, 67% were monotherapy and 33% were 2 or more AEDs. Only 8% were responders as against 92% nonresponders. Of 95 patients on concomitant antituberculosis treatment, 72 were nonresponders, with odds ratio (95% confidence interval) 3.71 [2.19 to 6.23]. Breakthrough seizure (37%) was the most common indication followed by suspected toxicity and routine monitoring in 22% each and suspected nonadherence in 11% of the total requests. In 52% of patients, plasma levels were below the reference range, and they were equally distributed amongst responders and nonresponders. Among patients referred for suspected phenytoin toxicity, only 59% (50.6 to 67.8) had plasma concentrations above the reference range. CONCLUSIONS: TDM continues to remain an important tool to support dose individualization when the patient is receiving multiple AEDs or other drugs such as antitubercular medicines, to assess compliance, and to monitor and treat toxicity.

Pharmacokinetics of colistin in critically ill patients with multidrug-resistant Gram-negative bacilli infection.

PURPOSE: Colistin, which had not been used widely because of nephrotoxicity and neurotoxicity, has gained clinical importance in recent times due to the resurgence of multidrug-resistant Gram-negative bacilli. Very few studies, especially pharmacokinetic studies, have been performed with intravenous colistimethate sodium, and none in India. The aim of our study was to study the single-dose and steady-state pharmacokinetics of colistin in patients with multidrug-resistant Gram-negative bacilli infections. METHOD: This was a prospective open-label pharmacokinetic study done in an intensive care unit in a tertiary care hospital on 15 critically ill patients with proven multidrug-resistant Gram-negative bacilli infection. Colistimethate sodium was injected as intermittent intravenous infusions in accordance with the recommendations on the package insert. For patients weighing ≥ 60 kg with a normal renal function or with a creatinine clearance (CL(CR)) of between 20 and 50 ml/min, the drug was administered at 2 million international units (MIU) every 8 h; for those with a CL(CR) of 10-20 ml/min, the dose was 2 MIU every 12 h. Those patients who weighed <60 kg were administered 50,000 IU/kg/day in three divided doses at 8-h intervals. Both single-dose and steady-state pharmacokinetics of colistin were determined and correlated with clinical outcomes. RESULTS: A wide inter-individual variation was observed in pharmacokinetic parameters. The median (range) of the maximum plasma drug concentration/minimum inhibitory concentration (C(max)/MIC) ratio for Acinetobacter spp. was 13.4 (1.3-40.3) following the administration of a single dose of colistimethate sodium and 26.3 (0.9-64.9) at steady-state. For Pseudomonas spp., these values were 3.18 (1.6-23.1) following the single dose and 3.82 (2.3-10.9) at steady-state. For those patients whose cultures grew Acinetobacter spp., an optimum value of the C(max)/MIC ratio of >8 was achieved in seven of nine patients after the single dose and in seven of eight patients at steady-state. For those patients whose cultures grew Pseudomonas spp, only one patient after the single dose and one patient at steady-state achieved a C(max)/MIC ratio of >8. A significant association was noted between dose and survival, and a trend was observed with patients weighing ≤ 60 kg (who received 50,000 IU/kg/day instead of 6 MIU/day for those >60 kg) having an increased mortality. CONCLUSION: The pharmacokinetic parameters of colistin were comparable to those reported in previous studies in critically ill patients. However, the recommended dose may be inadequate to maintain the C(max)/MIC ratio to an optimal level-at least in patients infected with Pseudomonas spp. The dose recommendation should be based only on creatinine clearance and not body weight.

Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria.

BACKGROUND: Plasmodium vivax is an important cause of malaria in many parts of Asia and South America, and parasite resistance to the standard treatment (chloroquine) is now high in some parts of Oceania. This review aims to assess the current treatment options in the light of increasing chloroquine resistance. OBJECTIVES: To compare artemisinin-based combination therapies (ACTs) with alternative antimalarial regimens for treating acute uncomplicated P. vivax malaria. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; and the metaRegister of Controlled Trials (mRCT) up to 28 March 2013 using "vivax" and "arte* OR dihydroarte*" as search terms. SELECTION CRITERIA: Randomized controlled trials comparing ACTs versus standard therapy, or comparing alternative ACTs, in adults and children with uncomplicated P. vivax malaria. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We used recurrent parasitaemia prior to day 28 as a proxy for effective treatment of the blood stage parasite, and compared drug treatments using risk ratios (RR) and 95% confidence intervals (CIs). We used trials following patients for longer than 28 days to assess the duration of the post-treatment prophylactic effect of ACTs. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included 14 trials, that enrolled 2592 participants, and were all conducted in Asia and Oceania between 2002 and 2011. ACTs versus chloroquine: ACTs clear parasites from the peripheral blood quicker than chloroquine monotherapy (parasitaemia after 24 hours of treatment: RR 0.42, 95% CI 0.36 to 0.50, four trials, 1652 participants, high quality evidence).In settings where chloroquine remains effective, ACTs are as effective as chloroquine at preventing recurrent parasitaemias before day 28 (RR 0.58, 95% CI 0.18 to 1.90, five trials, 1622 participants, high quality evidence). In four of these trials, recurrent parasitaemias before day 28 were very low following treatment with both chloroquine and ACTs. The fifth trial, from Thailand in 2011, found increased recurrent parasitaemias following treatment with chloroquine (9%), while they remained low following ACT (2%) (RR 0.25, 95% CI 0.09 to 0.66, one trial, 437 participants).ACT combinations with long half-lives probably also provide a longer prophylactic effect after treatment, with significantly fewer recurrent parasitaemias between day 28 and day 42 or day 63 (RR 0.57, 95% CI 0.40 to 0.82, three trials, 1066 participants, moderate quality evidence). One trial, from Cambodia, Thailand, India and Indonesia, gave additional primaquine to both treatment groups to reduce the risk of spontaneous relapses. Recurrent parasitaemias after day 28 were lower than seen in the trials that did not give primaquine, but the ACT still appeared to have an advantage (RR 0.27, 95% CI 0.08 to 0.94, one trial, 376 participants, low quality evidence). ACTs versus alternative ACTs: In high transmission settings, dihydroartemisinin-piperaquine is probably superior to artemether-lumefantrine, artesunate plus sulphadoxine-pyrimethamine and artesunate plus amodiaquine at preventing recurrent parasitaemias before day 28 (RR 0.20, 95% CI 0.08 to 0.49, three trials, 334 participants, moderate quality evidence).Dihydroartemisinin-piperaquine may also have an improved post-treatment prophylactic effect lasting for up to six weeks, and this effect may be present even when primaquine is also given to achieve radical cure (RR 0.21, 95% CI 0.10 to 0.46, two trials, 179 participants, low quality evidence).The data available from low transmission settings is too limited to reliably assess the relative effectiveness of ACTs. AUTHORS' CONCLUSIONS: ACTs appear at least equivalent to chloroquine at effectively treating the blood stage of P. vivax infection. Even in areas where chloroquine remains effective, this finding may allow for simplified protocols for treating all forms of malaria with ACTs. In areas where chloroquine no longer cures the infection, ACTs offer an effective alternative.Dihydroartemisinin-piperaquine is the most studied ACT. It may provide a longer period of post-treatment prophylaxis than artemether-lumefantrine or artesunate plus amodiaquine. This effect may be clinically important in high transmission settings whether primaquine is also given or not.

Evaluation of factors that motivate participants to consent for non-therapeutic trials in India.

BACKGROUND AND RATIONALE: Several factors that motivate individuals to participate in non-therapeutic studies have been identified. This study was conducted as limited data is available regarding these motivations from developing countries. METHODS: This was a single-centre study conducted over 4 months in which a questionnaire was administered to 102 healthy participants and 16 patient participants who had earlier taken part in non-therapeutic studies at our centre. Descriptive statistics and univariate analysis were used to analyse data. RESULTS: The most common motivation among healthy participants was financial reward (65%) followed by altruism, free medical check up, curiosity and personal health benefit. Patient participants, however, most commonly said they consented to take part in the trial as they were 'invited to participate by the treating physician' (88%). In comparison with the patient participants, healthy participants were more likely to be satisfied with the financial reward (p=0.02), and recommend participation in studies to friends or relatives (p=0.0013). CONCLUSIONS: The most common motivating factor to participate in non-therapeutic studies appears to be different for healthy participants (financial reward) and patient participants (invitation to participate by the physician). Participants also felt that adequate information and care was given to them during the trial, and that they would participate in future clinical studies, and would also recommend such studies to their friends.

Do plants mediate their anti-diabetic effects through anti-oxidant and anti-apoptotic actions? an in vitro assay of 3 Indian medicinal plants.

BACKGROUND: Both experimental and clinical studies suggest that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. This oxidative stress leads to ß-cell destruction by apoptosis. Hence exploring agents modulating oxidative stress is an effective strategy in the treatment of both Type I and Type II diabetes. Plants are a major source of anti-oxidants and exert protective effects against oxidative stress in biological systems. Phyllanthus emblica, Curcuma longa and Tinospora cordifolia are three such plants widely used in Ayurveda for their anti-hyperglycemic activity. Additionally their anti-oxidant properties have been scientifically validated in various experimental in vitro and in vivo models. Hence the present in vitro study was planned to assess whether the anti-hyperglycemic effects of the hydro-alcoholic extracts of Phyllanthus emblica (Pe) and Curcuma longa (Cl) and aqueous extract of Tinospora cordifolia (Tc) are mediated through their antioxidant and/or anti-apoptotic property in a streptozotocin induced stress model. METHODS: RINm5F cell line was used as a model of pancreatic ß-cells against stress induced by streptozotocin (2 mM). Non-toxic concentrations of the plant extracts were identified using MTT assay. Lipid peroxidation through MDA release, modulation of apoptosis and insulin release were the variables measured to assess streptozotocin induced damage and protection afforded by the plant extracts. RESULTS: All 3 plants extracts significantly inhibited MDA release from RIN cells indicating protective effect against STZ induced oxidative damage. They also exhibited a dose dependent anti-apoptotic effect as seen by a decrease in the sub G0 population in response to STZ. None of the plant extracts affected insulin secretion from the cells to a great extent. CONCLUSION: The present study thus demonstrated that the protective effect of the selected medicinal plants against oxidative stress induced by STZ in vitro, which was exerted through their anti-oxidant and anti-apoptotic actions.

A prospective study to assess the role of paraoxonase 1 genotype and phenotype on the lipid-lowering and antioxidant activity of statins.

Human paraoxonase 1 (PON1) enzyme protects against atherosclerosis by preventing low-density lipoprotein from oxidative modification. Upregulation of PON1 enzymatic activity is suggested to contribute to atheroprotective potential of statins. Glutamine (Q) to arginine (R) at site 192 and leucine (L) to methionine (M) substitution at site 55 polymorphisms influence the PON1 activity. The study assessed the role of PON1 polymorphisms on lipid-lowering and PON1-modulating activity of statins in a Western Indian cohort of patients with dyslipidemia. Lipid profile and PON1 activity were determined at baseline and 3 months after initiation of statin treatment. PON1 genotypes (QQ, QR, RR; LL, LM, and MM) were determined by PCR-RFLP. Paraoxon was used as a substrate for assessing PON1 activity by spectrophotometry. A total of 140 statin-naïve patients were enrolled; of them, 116 were available for final analysis. Fifty-seven (50%) had QQ, 39 (35%) had QR, and 17 (15%) had RR genotypes. Seventy-six (67%) patients had LL, 35 (31%) had LM, and 2 (2%) had MM genotypes. We observed no impact of PON1 polymorphisms on lipid parameters posttreatment. A significant increase was observed in the serum PON1 activity from a median (range) of 47.92 U/L (9.03-181.25) to 72.22 U/L (7.64-244.44) (P < 0.05) following statin treatment, which was independent from high-density lipoprotein (HDL) concentration. This increase was significantly greater in QQ compared to QR and RR genotypes (P = 0.01). To conclude, the important antioxidant properties of statins are exerted via the rise in serum PON1 activity, independent of HDL cholesterol concentrations. The increase was greater in individuals with QQ genotype. Future large-scale studies will validate the premise that QQ homozygotes see added benefits from statin treatment compared to R carriers. In the meantime, PON1 enzymatic activity remains an important marker to be measured while assessing pleotropic effects of statins in CAD.

Evaluation of clinical trials done for orphan drugs versus nonorphan drugs in infectious diseasesan eleven year analysis [2010-2020].

Background: The 1983 US Orphan Drug Act provided impetus for the development of new therapies for rare diseases. Several studies focused on the number of orphan designations over time. However, very few focused on clinical trials that lead to their approval, particularly for infectious diseases. Materials and Methods: All new drug approvals (orphan and non-orphan) by the US Food and Drug Administration (FDA) from January 2010 to December 31, 2020, were identified and details of approvals were taken from the US-FDA labels and summary reports for each drug. The pivotal trials for each were characterized based on their design. We tested the association of the type of drug approval with respect to the characteristics of trial using Chi-square test and generated crude odds ratios with 95% confidence intervals. Results: From the total 1122 drugs approved, 84 were for infectious diseases, of which 18 were orphan drugs and 66 were nonorphan. A total of 35 pivotal trials supported 18 orphan drug approvals, while 115 pivotal trials supported 66 nonorphan drugs. The median number of participants enrolled/trial for orphan drugs was 89, while for nonorphan drugs, it was 452 (P < 0.0001). Blinding was done for 13/35 (37%) orphan drugs versus 69/115 (60%) nonorphan drugs (P = 0.029); randomization was done for 15/35 (42%) orphan drugs versus 100/115 (87%) nonorphan drugs (P < 0.0001) and 20/35 (57%) of the orphan drugs got approval in phase II versus 8/115 (6%) of nonorphan drugs (P < 0.00001). Conclusion: A significant number of orphan drugs get approval based on early phase, nonrandomized, and unblinded with a smaller sample size as compared to nonorphan drugs.