The Mechanisms of Zinc Action as a Potent Anti-Viral Agent: The Clinical Therapeutic Implication in COVID-19.

The pandemic of COVID-19 was caused by a novel coronavirus termed as SARS-CoV2 and is still ongoing with high morbidity and mortality rates in the whole world. The pathogenesis of COVID-19 is highly linked with over-active immune and inflammatory responses, leading to activated cytokine storm, which contribute to ARDS with worsen outcome. Currently, there is no effective therapeutic drug for the treatment of COVID-19. Zinc is known to act as an immune modulator, which plays an important role in immune defense system. Recently, zinc has been widely considered as an anti-inflammatory and anti-oxidant agent. Accumulating numbers of studies have revealed that zinc plays an important role in antiviral immunity in several viral infections. Several early clinical trials clearly indicate that zinc treatment remarkably decreased the severity of the upper respiratory infection of rhinovirus in humans. Currently, zinc has been used for the therapeutic intervention of COVID-19 in many different clinical trials. Several clinical studies reveal that zinc treatment using a combination of HCQ and zinc pronouncedly reduced symptom score and the rates of hospital admission and mortality in COVID-19 patients. These data support that zinc might act as an anti-viral agent in the addition to its anti-inflammatory and anti-oxidant properties for the adjuvant therapeutic intervention of COVID-19.

Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment.

The complex syndrome of cancer cachexia (CC) that occurs in 50% to 80% cancer patients has been identified as an independent predictor of shorter survival and increased risk of treatment failure and toxicity, contributing to the mortality and morbidity in this population. CC is a pathological state including a symptom cluster of loss of muscle (skeletal and visceral) and fat, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system, and metabolic dysfunction. The most prominent feature of CC is its non-responsiveness to traditional treatment approaches; randomized clinical trials with appetite stimulants, 5-HT3 antagonists, nutrient supplementation, and Cox-2 inhibitors all have failed to demonstrate success in reversing the metabolic abnormalities seen in CC. Interventions based on a clear understanding of the mechanism of CC, using validated markers relevant to the underlying metabolic abnormalities implicated in CC are much needed. Although the etiopathogenesis of CC is poorly understood, studies have proposed that NFkB is upregulated in CC, modulating immune and inflammatory responses induce the cellular breakdown of muscle, resulting in sarcopenia. Several recent laboratory studies have shown that n-3 fatty acid may attenuate protein degradation, potentially by preventing NFkB accumulation in the nucleus, preventing the degradation of muscle proteins. However, clinical trials to date have produced mixed results potentially attributed to timing of interventions (end stage) and utilizing outcome markers such as weight which is confounded by hydration, cytotoxic therapies, and serum cytokines. We propose that selective targeting of proteasome activity with a standardized dose of omega-3-acid ethyl esters, administered to cancer patients diagnosed with early stage CC, in addition to a standard intervention with nutritionally adequate diet and appetite stimulants, will alter metabolic abnormalities by downregulating NFkB, preventing the breakdown of myofibrillar proteins and resulting in increasing serum protein markers, lean body mass, and functional status.

Phase II, double-blinded, randomized study of enzastaurin plus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer.

INTRODUCTION: We examined the efficacy of enzastaurin plus pemetrexed as second-line therapy in patients with advanced (stage IIIA/B or IV) non-small cell lung cancer in a double-blinded, randomized, phase II study. METHODS: Patients received pemetrexed 500 mg/m intravenously on day 1 of 21-day cycles (day 8 in cycle 1) plus oral enzastaurin (250 mg two times per day; combination arm) or placebo (pemetrexed arm). Both arms received supplementation with vitamin B12, folic acid, and dexamethasone. An interim analysis was conducted to determine whether efficacy would warrant a phase III study. RESULTS: The interim analysis showed no evidence of improved progression-free survival with enzastaurin. At final analysis (N = 160, 80 in each arm), baseline characteristics were well balanced. There was no significant difference in progression-free survival (3.0 months, p = 0.544) or overall survival (9.6 months in combination arm and 7.4 months in pemetrexed arm, p = 0.171). Drug-related serious adverse events included cerebrovascular accident, palpitations, and renal failure (n = 1, each) in combination arm and neutropenic sepsis, thrombocytopenia, and panniculitis (n = 1, each) in pemetrexed arm. Nonhematologic drug-related grade 3/4 toxicities were similar in both arms. Grade 3/4 hematologic toxicities were higher with the combination, specifically leukopenia (6.3% versus 0%), neutropenia (15.2% versus 5.0%), and thrombocytopenia (8.9% versus 1.3%). Of the 26 deaths reported on-study or within 30 days of discontinuation (10 in combination arm and 16 in pemetrexed arm), none were drug related. CONCLUSION: The combination regimen of enzastaurin and pemetrexed is well tolerated but does not improve efficacy over pemetrexed and placebo as second-line treatment of unselected patients with advanced non-small cell lung cancer.

Beta-carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers: a meta-analysis and evaluation of national brands.

BACKGROUND: Some studies have suggested that beta-carotene supplementation may increase the risk of lung cancer, particularly among smokers or former smokers. Beta-carotene, a provitamin A, is available in multivitamins. In the current study, the authors investigated the risk of lung cancer associated with beta-carotene in smokers or former smokers and surveyed the beta-carotene content in national brand multivitamins. METHODS: The authors systemically reviewed the published literature using a search of the MEDLINE database and performed a meta-analysis of large randomized trials that reported on the effect of beta-carotene supplementation on the incidence of lung cancer among smokers or former smokers. A sample of multivitamins was evaluated for their beta-carotene content and the suggested daily dosage. RESULTS: Four studies contributing 109,394 subjects were available for analysis. The average daily beta-carotene dosage in these trials ranged from 20 to 30 mg daily. Among current smokers, beta-carotene supplementation was found to be significantly associated with an increased risk of lung cancer (odds ratio [OR], 1.24; 95% confidence interval [95% CI], 1.10-1.39). Among former smokers, there was no significant increase noted (OR, 1.10; 95% CI, 0.84-1.45). In a sample of 47 common multivitamins, beta-carotene was present in 70% of the identified formulas. The median dosage of beta-carotene was 0.3 mg (range, 0-17.2 mg) daily. The beta-carotene content was found to be significantly higher among multivitamins sold to improve visual health than among other multivitamins, with a median daily dosage of 3 mg (range, 0-24 mg). CONCLUSIONS: High-dose beta-carotene supplementation appears to increase the risk of lung cancer among current smokers. Although beta-carotene was prevalent in multivitamins, high-dose beta-carotene was observed among multivitamin formulas sold to promote visual health.