Ajay Kumar Gupta

Naloxegol: First oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation

Opioid-induced constipation (OIC) is one of the most troublesome and the most common effects of opioid use leading to deterioration in quality of life of the patients and also has potentially deleterious repercussions on adherence and compliance to opioid therapy. With the current guidelines advocating liberal use of opioids by physicians even for non-cancer chronic pain, the situation is further complicated as these individuals are not undergoing palliative care and hence there cannot be any justification to subject these patients to the severe constipation brought on by opioid therapy which is no less debilitating than the chronic pain. The aim in these patients is to prevent the opioid-induced constipation but at the same time allow the analgesic activity of opioids. Many drugs have been used with limited success but the most specific among them were the peripherally acting mu opioid receptor antagonists (PAMORA). Methylnaltrexone and alvimopan were the early drugs in this group but were not approved for oral use in OIC. However naloxegol, the latest PAMORA has been very recently approved as the first oral drug for OIC. This article gives an overview of OIC, its current management and more specifically the development and approval of naloxegol, including pharmacokinetics, details of various clinical trials, adverse effects and its current status for the management of OIC.

A review of the current anti-HCV therapy: Are we finally ready for interferon-free regimens

Hepatitis C virus (HCV) continues to be a global problem but with the arrival of new drugs it is expected to move towards exile. The health care community has finally woken up to the need to tackle this infection especially because HCV-induced hepatitis in combination with HIV has turned out to be a formidable foe. So far the management of HCV has concentrated mainly on interferon-based therapies. The focus is now increasingly on drugs targeting various other components of hepatitis C, which are essential for its survival in the host like HCV non-structural (NS) 3/4A serine protease inhibitors: Boceprevir, telaprevir, simeprevir; NS5A inhibitors (daclatasvir, ledipasvir); NS5B polymerase inhibitors (sofosbuvir), cyclophilin inhibitors and many others in the pipeline like the NS4B inhibitors and the micro-RNA122 inhibitors. These new drugs have shown excellent sustained virological response (SVR) compared to the presently available drugs and their combinations. Adding to this is the new HCV vaccine which although facing various hurdles is making good inroads and expected to meet its endpoints in the near future. This review gives a brief overview of epidemiology, pathogenesis, followed by the description of current regimens in the treatment of hepatitis C and the much eagerly awaited future all new oral anti-hepatitis C regimen, which can potentially eliminate the use of painful injections of interferon.

Inhaled insulin: A “puff” than a “shot” before meals

Diabetes is a metabolic disorder characterized by relative or absolute deficiency of insulin, resulting in hyperglycemia. The main treatment of diabetes relies on subcutaneous insulin administration by injection or continuous infusion to control glucose levels, besides oral hypoglycemic agents for type 2 diabetes. Novel routes of insulin administration are an area of research in the diabetes field as insulin injection therapy is burdensome and painful for many patients. Inhalational insulin is a potential alternative to subcutaneous insulin in the management of diabetes. The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium facilitates systemic delivery of insulin via pulmonary administration. Inhaled insulin has been recently approved by Food and Drug Administration (FDA). It is a novel, rapid-acting inhaled insulin with a pharmacokinetic profile that is different from all other insulin products and comparatively safer than the previous failed inhaled insulin (Exubera).

Palbociclib: A breakthrough in breast carcinoma in women.

Breast cancer (BC) is the most common cancer and leading cause of death in women worldwide. Cellular proliferation, growth, and division are tightly controlled by the cell-cycle regulatory machinery. An important pathway is cyclin-dependent kinases (CDKs) which regulate cell cycle and thus control transcriptional processes. In human cancer, multiple CDK family members are commonly deregulated. The cyclin D-CDK4/6-retinoblastoma (RB) protein-INK4 axis is particularly affected in many solid tumors which leads to cancer cell proliferation. This has led to long-standing interest in targeting CDK4/6 as an anticancer strategy. Different investigational agents that have been tested which inhibit multiple cell cycle and transcriptional CDKs but have carried excessive toxicity thus failed to stand the rational of human use. Amongst several selective and potent inhibitors of CDK4/6, palbociclib is the first to be accessed suitable for human use having explicit selectivity toward CDK4/6. Its mechanism is to arrest cells in G1 phase by blocking RB phosphorylation at CDK4/6-specfic sites without affecting the growth of cells which are RB-deficient. Studies conducted in patients of BC having cells with advanced RB-expression demonstrated acceptable side effects but dose-limiting toxicities primarily neutropenia and thrombocytopenia, with prolonged stable disease in patients.

Evaluation of the protective effects of naproxen and celecoxib on naphthalene-induced cataract in albino rats

Background: Cataract is an age-related disorder. The role of non-steroidal anti-inflammatory drugs (NSAIDs) in cataract formation is still unclear. Previous data have indicated a cataractogenic as well as a potential protective effect of NSAIDs against cataract formation. Anti-cataract efficacy of NSAIDs has been studied extensively in different experimental settings. Use of aspirin in the prevention of cataract came from its use in elderly patients with osteoarthritis, rheumatoid arthritis, cardiovascular diseases and diabetes. Subsequently, a number of NSAIDs with diverse chemical structures like paracetamol, Ibuprofen, naproxen were reported to have anti-cataract potential as they delayed the onset and progression of cataract development. In view of this, naproxen is used as standard and celecoxib, a (cyclooxygenase II) COX II inhibitor, is used as drug for comparison to evaluate the protective effects on naphthalene-induced cataract in albino rats. Objective: The objective of the present study was to evaluate the effects of naproxen and celecoxib on naphthalene-induced cataract in albino rats. Materials and Methods: Thirty-six adult albino rats were divided into six groups containing six animals each. Group I (control) received normal saline orally. Group II (control) received normal saline eye drops. Group III received naproxen (4 mg/kg) orally. Group IV received naproxen eye drops (2%). Group V received celecoxib (3 mg/kg) orally. Group VI received celecoxib eye drops (2%). Oral dose and eye drops were given daily for 10 days prior to induction of cataract. Cataract was induced by oral administration of naphthalene 1 gm/kg in albino rats. Rats were examined daily for the appearance of lenticular capacity by indirect illumination, direct ophthalmoscopy, slit lamp examination, and observed for any mortality for period of 30 days. Results: Oral naproxen significantly retarded the appearance and progression of cataract, whereas less significant improvement was seen with oral celecoxib. Although, naproxen eye drops were just marginally effective, celecoxib eye drops was not at all effective in preventing cataract. Conclusion: Oral naproxen being a nonselective COX inhibitor was more efficacious than celecoxib, a COX II selective inhibitor, in retarding the progress of cataract induced by naphthalene. Similarly, naproxen eye drops also showed a marginal effect in prevention of progression of cataract, whereas celecoxib eye drops had no effect at all.