Ashish Kumar Kakkar

Bedaquiline for the treatment of resistant tuberculosis: Promises and pitfalls

Treatment of multidrug-resistant tuberculosis (MDR-TB) is hindered by limited efficacy and significant toxicity of second-line drugs. The need for new therapeutic options is critical to combat the global MDR-TB epidemic. Bedaquiline is a novel oral diarylquinoline approved by Food and Drug administration (FDA) for the treatment of adults with pulmonary MDR-TB on the basis of Phase IIb trial data under the provisions of the accelerated approval regulations for serious or life-threatening conditions. The FDA advisory committee members voted unanimously on efficacy data based on surrogate measures, however they were split on the issues of safety of bedaquiline. Main safety concerns include QT interval prolongation, hepatic related adverse events, and excess mortality in bedaquiline treated patients. While bedaquiline approval is a story of many firsts and certainly a welcome addition to the existing arsenal of anti-TB agents, a cautiously optimistic approach is required to assess the risk benefit profile of the drug. Acceleration of further Phase III trials and clinical studies is imperative, as is timely analysis of emerging data on the real world use of the drug. This mini review outlines the clinical pharmacology of bedaquiline highlighting the potential promises and challenges that implicate the risk benefit profile of drug.

The evolving drug development landscape: from blockbusters to niche busters in the orphan drug space.

Strategy, Management and Health Policy

Small gauge vitrectomy: Recent update

Small gauge vitrectomy, also known as minimally invasive vitreous surgery (MIVS), is a classic example of progress in biomedical engineering. Disparity in conjunctival and scleral wound location and reduction in wound diameter are its core principles. Fluidic changes include increased pressure head loss with consequent reduction in infusional flow rate and use of higher aspiration vacuum at the cutter port. Increase An increase in port open/port closed time maintains an adequate rate of vitreous removal. High Intensity Discharge (HID) lamps maintain adequate illumination in spite of a decrease in the number of fiberoptic fibers. The advantages of MIVS are, a shorter surgical time, minimal conjunctival damage, and early postoperative recovery. Most complications are centered on wound stability and risk of postoperative hypotony, endophthalmitis, and port site retinal break formation. MIVS is suited in most cases, however, it can cause dehiscence of recent cataract wounds. Retraction of the infusion cannula in the suprachoroidal space may occur in eyes with scleral thinning. As a lot has been published and discussed about sutureless vitrectomy a review of this subject is necessary. A PubMed search was performed in December 2011 with terms small gauge vitrectomy, 23-gauge vitrectomy, 25-gauge vitrectomy, and 27 gauge vitrectomy, which were revised in August 2012. There were no restrictions on the date of publication but it was restricted to articles in English or other languages, if there abstracts were available in English.

Endoilluminator-assisted scleral buckling: Our results

Aims: The aim was to evaluate the long-term surgical outcomes of endoillumination assisted scleral buckling (EASB) in primary rhegmatogenous retinal detachment (RRD). Methods: Twenty-five eyes of 25 patients with primary RRD and proliferative vitreoretinopathy ≤C2 where any preoperative break could not be localised, were included. All patients underwent 25 gauge endoilluminator assisted rhegma localisation. Successful break determination was followed by cryopexy and standard scleral buckling under surgical microscope. Anatomical and functional outcomes were evaluated at the end of 2 years. Results: At least one intraoperative break could be localized in 23 of 25 (92%) eyes. Median age of these patients was 46 years (range: 17-72). Thirteen eyes (56.52%) were phakic, 8 (34.78%) were pseudophakic and 2 (8.6%) were aphakic. Anatomical success (attachment of retina) was achieved in 22 (95.63%) of 23 eyes with EASB. All eyes remained attached at the end of 2 years. Significant improvement in mean visual acuity (VA) was achieved at the end of follow-up (1.09 ± 0.46 log of the minimum angle of resolution [logMAR]) compared with preoperative VA (1.77 ± 0.28 logMAR) (P < 0.001). Conclusion: EASB can be considered an effective alternative to vitreoretinal surgery in simple retinal detachment cases with the added advantage of enhanced microscopic magnification and wide field illumination.

Effect of antiepileptic therapy on trace elements status in Indian population in a tertiary care hospital from northern India: A cross sectional study

AIM Conventional antiepileptics (AEDs) have been shown to alter the homeostasis of copper, zinc, and selenium in persons with epilepsy (PWE). The effects of newer AEDs on trace elements have not been addressed yet. This cross-sectional study evaluated trace elements and electrolytes status in PWE on conventional and newer AEDs treatment. METHODS A total of 307 adult persons with epilepsy and 42 healthy controls were recruited. Panels of ten trace elements estimated by inductively coupled plasma-atomic emission spectrometry, electrolytes, liver and renal function status were compared among subjects grouped according to the monotherapy of AEDs and type of conventional and newer AEDs. RESULTS Out of the total 307 PWE, 171 were on monotherapy [valproic acid (VPA) (n=50), carbamazepine (n=47), phenytoin (n=49), levetiracetam (n=21), lamotrigine (n=4)]. AEDs monotherapy groups had no significant difference in the trace element levels, except higher nickel level in levetiracetam group and low iron level in lamotrigine group compared to VPA group. Compared to control [zinc level 698.0 (367.8-3084.4)ng/ml], levetiracetam group had higher zinc [1293.1 (997.7-2419.7)ng/ml, p<0.0001], selenium, copper, iron, aluminium, cadmium, cobalt, and nickel levels; similar manganese and lead levels. Other monotherapy groups were having similar metal levels as that of levetiracetam group except nickel, iron, lead, and selenium levels. CONCLUSION Trace element status was significantly altered with both conventional and newer antiepileptic drugs as compared to control; however, there was not much difference in between conventional and new drug treated groups. Prospective studies will address its impact on treatment response and adverse effect profile. CTRI REGISTRATION NUMBER REF/2013/03/004819.

Obinutuzumab for chronic lymphocytic leukemia: promise of the first treatment approved with breakthrough therapy designation:

Obinutuzumab (also known as GA101, afutuzumab, Gazyva) is a humanized, glycoengineered type II monoclonal antibody targeted against CD20. The US Food and Drug Administration has approved obinutuzumab for use with chlorambucil in patients with previously untreated chronic lymphocytic leukemia. The drug is the first treatment to receive approval under the agencys breakthrough therapy designation, a program intended to facilitate and expedite the review and development of therapies for serious and life-threatening conditions. In preclinical studies, obinutuzumab has showed superior efficacy, as compared with rituximab, by inducing direct cell death and increased antibody-dependent cellular cytotoxicity activity with less complement-dependent cytotoxicity. Regulatory approval of obinutuzumab is based on a phase III (CLL11) study that demonstrated improved outcomes with a combination of obinutuzumab with chlorambucil in previously untreated patients with chronic lymphocytic leukemia and comorbidities. Obinutuzumab plus chlorambucil induced deeper and longer remissions than rituximab plus chlorambucil combination as evidenced by prolongation of progression-free survival and higher complete response and molecular response rates. Marketing applications for obinutuzumab have also been submitted to other regulatory authorities including the European Medicines Agency.

Current Issues With the Use of Bedaquiline

TO THE EDITOR: We read with interest the article by Chahine et al. The authors have reviewed the clinical pharmacology, safety, and efficacy of bedaquiline, a welcome addition to the existing arsenal of antitubercular drugs. However, we believe a cautiously optimistic approach is required to assess the risk benefit profile of this agent in the present scenario. Most of drug approvals are based on robust clinical trial data where thousands of patients have been exposed to test drug and actual clinical outcomes have been evaluated. However, Food and Drug Administration (FDA) approval of bedaquiline was based on sputum culture conversion, a surrogate endpoint evaluated in a small number of patients. The currently available clinical studies with bedaquiline have several other limitations, namely, low-quality evidence on background treatment regimens, use of modified intention to treat analysis, and low cure rates observed in the placebo group when compared with those reported by recent reviews. Also, FDA approval committee members may have been unanimous on efficacy data; however, they were split on the issues of drug safety and excess mortality. In the pivotal clinical study, the number of deaths in bedaquiline group was 5 times as compared with those in the control group. Concerns have been raised about evidence of QT prolongation and raised liver transaminase levels. Evidence base for the use of bedaquiline needs to be strengthened through well-designed large phase III clinical studies based on actual outcomes such as cure rates and studies investigating efficacy, safety, and pharmacokinetics in special populations, including children, the elderly, pregnant women, HIV patients, alcohol users, and patients with extrapulmonary tuberculosis. Because of its likelihood to be involved in drug interactions, dedicated studies exploring effects of its co-administration with other antitubercular and antiretroviral regimens and identification of optimal dose and duration of such therapies are needed. In addition, reliable drug susceptibility tests for bedaquiline need to be developed. Cost-effectiveness and patient acceptability also needs to be ascertained especially in settings where it is considered for inclusion in nationwide tuberculosis control programs. Another issue plaguing the usefulness of bedaquiline is its potential unregulated use in high multidrug-resistant tuberculosis burden countries. Such misuse in the absence of clear-cut national prescribing guidelines can rapidly limit its usefulness and promote emergence of resistance. Regimens containing bedaquiline need to be cautiously designed to avoid an extended period of exposure to low levels of bedaquiline as the sole drug. To address these concerns, both the World Health Organization and the Centers for Disease Control and Prevention have issued provisional guidelines on the use of bedaquiline in the treatment of multidrug-resistant tuberculosis. The possible benefits of using bedaquiline outweigh the potential risks in select group of patients. However, its precise role in various clinical settings will remain unclear until further efficacy and safety data are obtained through well-designed phase III studies and a timely analysis of data on its real-world use.

Effect of lamotrigine, levetiracetam & topiramate on neurobehavioural parameters & oxidative stress in comparison with valproate in rats.

Background & objectives: Though newer antiepileptic drugs are considered safer than conventional antiepileptics, the effects of lamotrigine, levetiracetam and topiramate on neurobehavioural functions are yet to be established. This study evaluated neurobehavioural parameters and oxidative stress markers in brain tissue of rats treated with lamotrigine, levetiracetam and topiramate compared to sodium valproate. Methods: Five groups of male Wistar rats were treated respectively with normal saline (control), sodium valproate (370 mg/kg), lamotrigine (50 mg/kg), levetiracetam (310 mg/kg) and topiramate (100 mg/kg) for 45 days. Neurobehavioural parameters were assessed using elevated plus maze (EPM), actophotometer, rotarod, passive avoidance and Morris water maze (MWM) at baseline and at the end of treatment. Oxidative stress parameters [malondialdehyde (MDA), reduced glutathione (GSH) and superoxide dismutase (SOD)] were estimated in rat brain at the end of treatment. Results: Valproate and lamotrigine showed no significant effect on learning and memory in passive avoidance and MWM tests. However, levetiracetam and topiramate reduced retention memory significantly as compared to control (P<0.01) and lamotrigine (P<0.05) groups. Performances on EPM, rotarod and actophotometer were not significantly different between the groups. In comparison to control group, MDA was higher in the levetiracetam and topiramate (360.9 and 345.9 nmol/g of homogenized brain tissue, respectively) groups. GSH and SOD activity were significantly reduced by valproate and levetiracetam treatment. Lamotrigine did not induce significant oxidative stress. Interpretation & conclusions: Long-term and therapeutic dose treatment with levetiracetam and topiramate significantly impaired learning and memory, which was not seen with valproate and lamotrigine in rats. Levetiracetam, topiramate and valproate augmented oxidative stress, whereas lamotrigine has little effect on it. These antiepileptic drugs are used in clinical practice, hence pharmacovigilance studies are required to evaluate their safety profile.

The Promise of Dolutegravir: A Novel Second Generation Integrase Strand Transfer Inhibitor

Dolutegravir (DTG), a novel integrase strand transfer inhibitor (INSTI), is one of the newest addition to the arsenal of anti-human immunodeficiency virus (HIV) therapeutics. Dolutegravir is the first member of the class of second generation integrase strand transfer inhibitors aimed primarily to address the current unmet need for novel unboosted integrase inhibitors with convenient once-daily dosing and a superior resistance profile. During its clinical development, DTG has demonstrated noninferior or superior efficacy in both treatment-naive as well as treatmentexperienced individuals including those who have previously failed first generation INSTIs. Other potential advantages include a favorable safety profile, low propensity for drug-drug interactions, and prolonged serum half-life permitting once-daily administration in treatment-naive or treatment-experienced INSTI naive HIV patients. Twice-daily administration is recommended in individuals with established or suspected resistance to first-generation INSTIs. This review outlines the need for new HIV therapeutics and summarizes the efficacy, safety, and pharmacokinetic profile of dolutegravir.

Resolution of Serous Retinal Detachment Following Partial Sclerectomy With Mitomycin C in Nanophthalmos

The authors report the results of partial-thickness sclerectomy combined with mitomycin C in a nanophthalmic eye with serous retinal detachment. Partial sclerectomy in two quadrants with adjuvant use of mitomycin C without drainage of subretinal fluid was performed. The patient was monitored with serial fundus photographs and spectral-domain optical coherence tomography (SD-OCT) for up to 16 weeks postoperatively. Best corrected visual acuity improved from counting fingers at 1 meter preoperatively to 6/60 at final follow-up. There was gradual but complete resolution of serous retinal detachment both clinically and on SD-OCT. Partial-thickness sclerectomy with mitomycin C is an effective and safe procedure in the management of nanophthalmic eyes with uveal effusion.