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

Cumulative Effect of Risk factors on Short-term Surgical Success of Mitomycin Augmented Trabeculectomy

Context: Risk factors for failure of trabeculectomy may have a cumulative effect on the outcome. Aims: To study the effect of preoperative ocular risk factors on the surgical outcome of trabeculectomy augmented with 2 commonly used doses of Mitomycin C. Settings and Design: In a prospective cohort study, cases were recruited over an 18 month period. 92 eyes of 83 patients with one to three known risk factors for failure of trabeculectomy underwent Mitomycin-C (MMC) augmented trabeculectomy. Methods and Material: Trabeculectomy was done with a randomly chosen MMC dose of 0.2 mg/ml or 0.4 mg/ml. All cases were followed up for a period of at least 3 months. Surgical success was defined as the lowering of intraocular pressure (IOP) below 21 mmHg during the follow up period. Statistical analysis used: Chi square test, paired t test, odds ratio, effect size. Results: Eyes with two or three risk factors (out of aphakic glaucoma, failed trabeculectomy, neovascular glaucoma, post uveitic glaucoma, traumatic glaucoma, adherent leucoma, juvenile glaucoma, prolonged medical therapy, steroid induced glaucoma, post penetrating keratoplasty glaucoma and developmental glaucoma) had a significantly poorer surgical success rate (88% and 78%) than eyes with one risk factor (100%). 0.4 mg/ml MMC used sub-sclerally had a statistically similar effect on lowering the IOP as 0.2 mg/ml in all groups. The rate of complications was significantly higher in the 0.4 mg/ml subgroup. Conclusions: The presence of more than one preoperative ocular risk factor, affects the surgical success of MMC augmented trabeculectomy in high-risk cases. Because of the significantly higher rate of complications with the higher dose of MMC, this should be used sparingly, only in cases with more than two risk factors

Editorial - Do All Projects Require Ethics Committee Clearance?

When a manuscript is submitted to a journal for publication, one of the first things a referee will look at is whether an Ethics Committee has approved the study (be it a study in humans or now even animals) and whether written informed consent has been taken from the subjects participating in the study or their guardians (of course only relevant for human studies!). The dilemma comes when these have not been done

Ethics Committees in India: Past, present and future

Following watershed amendments in Schedule Y India's star rose rather rapidly on the clinical research (especially clinical trials) horizon. Just as dramatic was the fall of this empire. At the centre of these events has been the participant and indirectly, the Ethics Committee (EC) that is established primarily to protect this individual. This paper traces the evolution of the concept of ECs in India, examines the current state of these committees in the country and suggests the way forward. The Past: The requirement for an EC to oversee clinical research was first made in the ICMR Policy Statement for Ethics published in 1980 and then again in the Schedule Y (1988). Later, both the Amended Schedule Y (2005) assigned regulatory responsibility on the EC and the ICMR Guidelines (2006) described the functioning of ECs. Several challenges including inadequate formal training, contribution from non-technical members, administrative support as well no SOPs and a heavy workload were identified. In the absence of regulatory oversight of ECs, the introduction of the Clinical Trial Registry - India (CTRI) and self-regulation through voluntary accreditation programs brought a measure of accountability and transparency. The Present: A slew of regulatory reforms led to more than 1000 ECs to be registered with CDSCO although the actual impact on participants' protection and safety of these new regulations still remains to be seen. Way Forward: A method to oversee all ECs, improved functioning of ECs including on site monitoring, central ECs for multicentric studies, the development of metrics to assess the ability of ECs to protect the participant are other ideas for the future. Conclusions: Although ECs in India have evolved from being mere rubber stamps for approval of protocols to efficiently functioning accredited ECs, yet there is much to be done for and by Ethics Committees

Valbenazine: Drug review

Valbenazine is the first drug approved by the US Food and Drug Administration for the treatment of adults with tardive dyskinesia (TD) on April 11, 2017. It acts as a reversible inhibitor of vesicular monoamine transporter 2. It is available orally with a starting dose of 40 mg once daily which can be increased after 1 week to the recommended dose of 80 mg. Clinical trials showed positive outcomes in Abnormal Involuntary Movement Scale and Clinical Global Impression - Global Improvement of TD score with respect to placebo. Valbenazine has an acceptable safety and tolerability profile, the most common side effect observed is somnolence. However, long-term study is lacking, and more data are required to establish its full benefits and concomitant risks which can be missed in the recent trials

Regulatory requirements for clinical trials in India: What academicians need to know

The academician forms the backbone of any medical college, hospital or university and shoulders the quadruple responsibilities of patient care, teaching, administration and research. Of these, research, though long and difficult, is extremely fulfilling. Academicians often carry out research that is based on observations in practice or in response to their patient's needs. These are called as “Investigator- initiated studies” and these may not have the funding support of the pharmaceutical industry. Hence, the investigator must make sure that he/she complies with the country's regulatory requirements. In the past decade, several changes have dotted the regulatory landscape in the country and have changed the way in which academic research is carried out. The present article outlines regulatory requirements for academic research giving their historical evolution, the key bodies in India that govern or oversee research, along with “must know” and “good to know” facets for the conduct of clinical research in the country