Advances in CGRP Monoclonal Antibodies as Migraine Therapy: A Narrative Review.

Migraine is a potentially disabling disorder, yet it remains underdiagnosed and undertreated. The release of the neuropeptide calcitonin gene-related peptide (CGRP) in the trigemino-cerebrovascular system plays a vital role in the evolution of migraine. It enhances peripheral sensitization by mediating neurogenic inflammation and also influences central sensitization. The majority of the drug classes available for migraine prophylaxis are nonspecific and associated with numerous side effects and drug interactions. Anti-CGRP monoclonal antibodies (mAb) are an innovative therapeutic class that fulfills the need for more efficacious and tolerable preventive therapy. While erenumab is a mAb to the CGRP receptor, eptinezumab, fremanezumab, and galcanezumab bind to the CGRP molecule. They decrease the number of headache days and improve disability. Upper respiratory tract infection, nausea, constipation, pain at the site of injection, and fatigue are the associated side effects. CGRP mAbs are an excellent advancement in translational research and are a promising addition in migraine therapy. This article discusses the recent advances in the development of the CGRP mAbs.

Sclerostin Inhibition: A Novel Target for the Treatment of Postmenopausal Osteoporosis.

Osteoporosis, a widespread skeletal disorder with a substantial economic load, is characterized by increased porosity of the bones resulting in vulnerability to fractures. When activated, the canonical Wnt signaling pathway results in osteoblastogenesis and bone formation. A Wnt ligand forms a complex with low-density lipoprotein receptor-related proteins 5 and 6 (Lrp5/6) and stimulates intracellular signaling cascades, leading to nuclear translocation of ß-catenin and transcription of downstream molecules involved in osteoblast differentiation, maturation, and survival. Sclerostin (SOST), a glycoprotein produced by osteocytes, is an extracellular Wnt antagonist that blocks the binding of Wnt ligands to Lrp5/6, preventing the activation of the pathway and osteoblast-mediated bone formation subsequently. Inhibition of SOST represents a new therapeutic paradigm for the treatment of osteoporosis. Monoclonal antibodies to SOST include romosozumab, blosozumab, and setrusumab. With its unique dual effect of increasing bone formation (anabolic action) and decreasing bone resorption, the Food and Drug Administration approved romosozumab, a promising new treatment for postmenopausal osteoporosis. Its efficacy and safety have been established in trials. However, patients at high risk of cardiovascular or cerebrovascular events should not be prescribed romosozumab.

Cardiometabolic vigilance in COVID-19 and resource husbandry in resource-challenged times: Clinical practice- based expert opinion.

BACKGROUND AND AIMS: The ongoing pandemic of coronavirus disease 2019 (COVID-19) is rapidly evolving, thereby posing a profound challenge to the global healthcare system. Cardiometabolic disorders are associated with poor clinical outcomes in persons with COVID-19. Healthcare challenges during the COVID-19 pandemic are linked to resource constraints including shortage of Personal Protective Equipment's (PPE), laboratory tests and medication. In this context, a group of clinical experts discussed the endocrine and cardiology vigilance required in times of COVID-19. Further, the group proposed certain resource husbandry recommendations to be followed during the pandemic to overcome the constraints. METHOD: The clinical experts discussed and provided their inputs virtually. The expert panel included clinical experts comprising endocrinologists, Consultant Physicians and cardiologists from India. The panel thoroughly reviewed existing literature on the subject and proposed expert opinion. RESULTS: The expert panel put forward clinical practice-based opinion for the management of cardiometabolic conditions including diabetes mellitus and hypertension. As these conditions are associated with poor clinical outcomes, the expert panel recommends that these persons be extra-cautious and take necessary precautions during the ongoing pandemic. Further, experts also provided appropriate, affordable, available and accessible solution to the resource constraint situations in times of COVID-19 pandemic. CONCLUSION: The clinical expert opinion put forward in this article will serve as a reference for clinicians treating diabetes and cardiovascular disease during the COVID-19 pandemic.

Vismodegib: A smoothened inhibitor for the treatment of advanced basal cell carcinoma.

Incidence of basal cell carcinoma (BCC), the most common skin cancer in humans, is rising. Surgery is the mainstay of treatment but there is no standard of care for locally advanced or metastatic disease. Hedgehog signaling proteins are critical for cell growth and differentiation during embryogenesis; Hh pathway is silenced in adults. Dysregulated or aberrant Hh signaling has been implicated in the pathogenesis of BCC. This hyperactive pathway can be inhibited by use of smoothened inhibitors such as vismodegib. Food and drug administration approved this oral, once-daily medication in 2012 to treat adults with metastatic BCC or locally advanced, recurrent BCC after surgery and also for patients with locally advanced BCC who are not candidates for surgery or radiation treatment. Clinical studies have shown it to be highly efficacious and the most common adverse effects include, muscle spasms, alopecia and dysgeusia. Use of targeted biologic modifiers, exemplified by Hh directed therapeutics offer a new hope to patients with high-surgical morbidity or inoperable tumors.

Istaroxime: A rising star in acute heart failure.

Heart failure in India is a growing epidemic. Around 30 to 40% of patients die from heart failure within one year of receiving the diagnosis. Currently available inotropes have not only failed to show consistent results but are also associated with adverse outcomes. Istaroxime is a novel intravenous agent with luso-inotropic properties that acts by inhibition of Na(+)/K(+) adenosine triphosphatase and stimulation of sarco/ endoplasmic reticulum calcium ATPase isoform 2. In clinical studies, it significantly decreased left ventricular end diastolic pressure, pulmonary capillary wedge pressure, heart rate and increased systolic blood pressure and cardiac index with no change in neurohormones, renal function or troponin I. Istaroxime is a promising alternative for patients presenting with acute heart failure syndrome for whom the therapeutic options are currently limited.

Spinosad: An effective and safe pediculicide.

Although head lice are not a major health hazard, they have been a source of irritation and disgust for thousands of years. Despite the use of over-the-counter (OTC) treatments, it has high prevalence, and epidemics occur regularly. Permethrin 1% is currently recommended as a drug of choice, but many areas have shown resistance to this insecticide. A 0.9% suspension of spinosad, a naturally occurring pest control product, has recently been approved by the USFDA for treatment of pediculosis capitis. It acts by enhancing the action of nicotinic acetylcholine, resulting in paralysis of the parasite. Clinical trials show that spinosad is more effective and safe than current drugs of treatment. Additionally, it does not require nit combing. Spinosad appears as a powerful recruit in the battle against head lice.

Vaptans: A new option in the management of hyponatremia.

Arginine vasopressin (AVP) plays an important role in water and sodium homeostasis. It acts via three receptor subtypes-V1a, V1b, and V2-distributed widely throughout the body. Vaptans are nonpeptide vasopressin receptor antagonists (VRA). By property of aquaresis, VRAs offer a novel therapy of water retention. Conivaptan is a V1a/V2 nonselective VRA approved for euvolemic and hypervolemic hyponatremia. Tolvaptan is the first oral VRA. Other potential uses of this new class of drugs include congestive heart failure (CHF), cirrhosis of liver, syndrome of inappropriate secretion of antidiuretic hormone, polycystic kidney disease, and so on. These novel drugs score over diuretics as they are not associated with electrolyte abnormalities. Though much remains to be elucidated before the VRAs are applied clinically, the future holds much promise.