Repurposing drugs in oncology (ReDO)—cimetidine as an anti-cancer agent

Cimetidine, the first H2 receptor antagonist in widespread clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical and clinical studies for a number of different cancer types. These data are summarised and discussed in relation to a number of distinct mechanisms of action. Based on the evidence presented, it is proposed that cimetidine would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of cimetidine as an anti-cancer therapeutic is warranted. Furthermore, there is compelling evidence that cimetidine administration during the peri-operative period may provide a survival benefit in some cancers. A number of possible combinations with other drugs are discussed in the supplementary material accompanying this paper

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research.

The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i) Muscarinic receptor antagonists-originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii) Histamine receptor antagonists-searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H1) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii) Phenothiazines and dopamine receptor antagonists-investigations of their pharmacology as "sedatives" (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D2) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv) Metoclopramide and selective 5-hydroxytryptamine3(5-HT3) receptor antagonists-metoclopramide was initially assumed to act only via D2 receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine4 receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT3 receptors. The latter led to identification of selective 5-HT3 receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) Neurokinin1receptor antagonists-antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years

A REVIEW ON THE ANTIPARASITIC DRUG IVERMECTIN FOR VARIOUS VIRAL INFECTIONS AND POSSIBILITIES OF USING IT FOR NOVEL SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2: NEW HOPE TO TREAT CORONAVIRUS DISEASE-2019

The novel coronavirus infection has spread all over the world. With no specific drug or vaccine, the process of “drug repurposing” becomes a feasible solution. As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has 80% sequence similarity with the SARS-CoV, the nuclear import inhibitor “Ivermectin” (IVM) has recently been studied as a possible treatment option for coronavirus disease-2019 (COVID-19). The article aims to provide a review on structure and immunogenicity of SARS-CoV-2, indications of IVM for viral diseases, its possible mechanism on COVID-19 with a brief discussion on IVM structure, pharmacokinetics, adverse drug reactions, drug interactions, and contraindications. Further, we made possible comparisons of IVM with solidarity trial drugs and analyzed its major advantages, limitations and gave necessary recommendations for its use in future in vivo studies in the treatment of COVID-19

Anti-cancer effects of disulfiram in head and neck squamous cell carcinoma via autophagic cell death

BACKGROUND: Disulfiram (DSF), which is used to treat alcohol dependence, has been reported to have anti-cancer effects in various malignant tumors. In this study, we investigated the anti-cancer effects and mechanism of DSF in HNSCC. METHODS: Head and neck squamous carcinoma cell lines (FaDu and Hep2) were used to analyze the anti-cancer effects of DSF. The anti-cancer effects of DSF were confirmed in vivo using a xenograft tumor model. RESULTS: The anti-cancer effects of DSF in HNSCC were found to be copper (Cu) dependent. Specifically, DSF/Cu markedly inhibited HNSCC at a concentration of 1 μM. After DSF/Cu administration, production of reactive oxygen species (ROS) was remarkable starting at 0.5 μM, suggesting that the inhibitory effects of DSF/Cu on HNSCC are mediated through the formation of ROS. The levels of phospho-JNK, phospho-cJun and phospho-p38 were increased after DSF/Cu treatment while levels of phospho-Akt were decreased. These results suggested that the inhibitory effects of DSF/Cu on HNSCC cells involve ROS formation and down-regulation of Akt-signaling. Through these molecular mechanisms, DSF ultimately induce the inhibitory effects on HNSCC cell lines mainly through autophagic cell death, not apoptotic cell death. Lastly, we investigated the clinical relevance of DSF/Cu using a HNSCC xenograft animal model, which showed that tumor growth was remarkably decreased by DSF (50 mg/kg injection). CONCLUSION: In treating patients with HNSCC, DSF may contribute to improved HNSCC patient's survival. The characteristic anti-cancer effects of DSF on HNSCC may suggest new therapeutic potential for this medication in HNSCC patients.ope

PATIENT, HOSPITAL AND STATE-LEVEL POLICY CHARACTERISTICS ASSOCIATED WITH PREVALENCE OF TREATING OPIOID USE DISORDER IN UNITED STATES EMERGENCY DEPARTMENTS

The opioid crisis in the United States was declared a public health emergency due to escalating and untoward human, financial, and systemic consequences and effects on the nation. Opioid use disorder (OUD) comprising opioid abuse and dependence is devastating because of its associated chronic relapsing nature, overutilization of healthcare services, rising morbidity and mortality rates, and high cost of care. Efforts to address this have not made significant positive impacts. It is thus imperative to reassess the influence of factors associated with OUD. This study answered the question, what patient-, hospital-, and state-level policy factors were associated with prevalence of diagnosing and treating OUD in U.S. emergency departments (ED), since the ED which were usually first point-of-contact with the healthcare system by patients with OUD witnessed significantly increased visits related to nonmedical use of opioids. A retrospective secondary data analysis of the cross-sectional Nationwide Emergency Department Sample of patients 12 years and older from January 1 to December 31, 2016; ASAM state reports; SAMHSA Office of Policy, Planning and Innovation State Medicaid coverage reports; and KFF report on opioid epidemic was performed. Outcome variable was prevalence of diagnosing and treating OUD in the ED. Primary predictor variable was OUD condition, and covariates included, patient characteristics – primary payer, annual median income, patient location, and ED event; hospital characteristics – control/ownership, region, and designation; and state-level policy characteristics – medication-assisted treatment (MAT) policy, MAT medication coverage, Medicaid expansion, and Medicaid section 1115 behavioral health waiver statuses. Descriptive statistics was reported for all variables. Pearson’s chi-squared was test used to determine statistically significant differences between opioid abuse and opioid dependence diagnosis. Hierarchical linear regression model (HLM) was used to estimate association between outcome and predictor variables. In total, 32,680,232 ED visits in 953 hospitals across 35 states and District of Columbia which when generalized to the entire United States amounted to 144,842,742 visits to the ED in 4,639 hospitals across the 50 states including the District of Columbia were analyzed. The total number of opioid-related incidents to the ED was 1,623,490. The overall prevalence of any opioid-related incident was 1.12% while overall prevalence of diagnosis and treatment of uncomplicated OUD in U.S. ED was 0.5%. Significant regional disparities existed in state-level opioid policies, prevalence of uncomplicated OUD and other characteristics influencing treatment of OUD in U.S. ED. Opioid dependence patients (55.6%) were preponderantly of upper-lower income class, micropolitan residents, covered by Medicare; admitted to same hospital they presented, attended to largely in privately owned not-for-profit ED, in micropolitan areas, and in Southern and Western U.S. Opioid abuse patients (44.4%) were predominantly of lower-lower income status, metropolitan dwellers, Medicaid covered; presented commonly to privately-owned not-for-profit ED, in metropolitan locations, and in Northeastern and Midwestern U.S. Combined, patient and hospital-level policy characteristics accounted for 25.4% (R2=0.254, Adj. R2=0.254, F change (3,734618)=31937.906, p\u3c0.0001) of variance in prevalence of treating OUD in ED. Patient characteristics only accounted for 15.6% (R2=0.156, Adj. R2=0.156, F(5,734621)=27245.686, p\u3c0.0001) and hospital characteristics only for 9.7% (R2 change=0.097, F(3,734618)=31937.906, p\u3c0.0001) of the variance. Proportion of variance accounted for by each predictor variable was, control/ownership of hospital (9.67%), patient location (6.35%), annual median income (1.44%), hospital designation (1.21%), OUD diagnosis (0.20%), primary payer (0.04%), region of hospital (0.02%), and ED event (0.008%). Patient and hospital level characteristics significantly influenced prevalence of treating OUD in U.S. ED. Hospital-level characteristics contributed more that patient-level characteristics. A socioecological approach, which ensures an integrated and holistic method, is required to understand factors influencing OUD with the view to developing innovative policies and programs that can positively and significantly address the opioid crisis

False hope and fictitious patents: evaluating the intellectual property of OxyContin

In this article I evaluate the socio-legal process of transforming a scientific R&D output into a market commodity via the prism of a public health crisis, namely, the opioid epidemic in the United States (US). My jurisdictional focus on the US is justified by its position at the epicentre of the opioid crisis, as well as being the most prominent patent and regulatory jurisdiction for the global pharmaceutical market. I undertake the first substantive examination of OxyContin from an IP law perspective, exploring its trajectory from conception to market, considering what lessons can be learned for IP theory and practice. Overall, I contribute a novel theoretical approach, examining patented pharmaceuticals as products of industrialised hope, while evaluating a practical case study of one such commodity, OxyContin. I conclude that the case of OxyContin highlights several problems inherent to the current system, including misaligned incentives, inadequate patent examination, and insufficient regulation

Evaluation of Anti-Nociceptive and Analgesic Activities of Nizatidine in Mice

Previous research reports revealed that histamine H2 receptor blockers such as ranitidine and famotidine showed analgesic activity in rodent models. However, the analgesic or anti-nociceptive activity of nizatidine, a most widely used H2 receptor blocker, has not yet been reported. Hence, the present study was aimed to evaluate the probable anti-nociceptive and analgesic activities of nizatidine in valid animal models. The results obtained in this study revealed the anti-nociceptive and analgesic activities of nizatidine. However, further chronic studies are required to validate the analgesic and anti-nociceptive activities of nizatidine. In conclusion, nizatiine produces the anti-nociceptive and analgesic activities in valid animal models similar to that of other H2 receptor blockers