Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2.

COVID-19 pandemic has infected millions of people with mortality exceeding >1 million. There is an urgent need to find therapeutic agents that can help clear the virus to prevent severe disease and death. Identifying effective and safer drugs can provide more options to treat COVID-19 infections either alone or in combination. Here, we performed a high throughput screening of approximately 1,700 US FDA-approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 20 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, and thioridazine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating a wide therapeutic window compared to hydroxychloroquine which had a safety index of 22 in similar experiments. Mechanistically, five of the effective compounds (fendiline HCl, monensin sodium salt, vortioxetine, sertraline HCl, and salifungin) were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA-approved compounds can provide much needed therapeutic options that we urgently need during the midst of the pandemic.

Double-blind, randomized study of the anti-anginal and anti-ischaemic efficacy of fendiline and diltiazem in patients with coronary heart disease.

In a 6-week, randomized, double-blind trial, the drug effects of the calcium antagonists, fendiline (75 mg twice daily) and diltiazem (90 mg twice daily), as measured by subjective and objective parameters of coronary heart disease, were studied in 79 patients with stable angina pectoris. The statistical analysis included the data of 71 patients. The results of exercise-ECG tests showed that both medications were effective anti-ischaemic agents. Fendiline was found to be effective in reducing ST-segment depression at maximum comparable load (71 watts) as well as at the time of reaching the individual maximum tolerated load (discontinuation of exertion). Diltiazem, on the other hand, proved effective only at maximum comparable load (72 watts). There was no significant difference between the groups with regard to the reduction after 6 weeks. As regards work tolerance, the duration of exercise and time until appearance of a ST-segment depression of 0.1 mV, before and after treatment comparisons revealed significant changes only in the group receiving diltiazem and the differences between fendiline and diltiazem were statistically significant with regard to these three parameters. Reduction in the frequency of anginal attacks and the diminution of nitroglycerin consumption were comparable in both medication groups, and the changes from baseline were statistically significant. Assessment of the efficacy and tolerability of the medications by patients as well as by investigators revealed no statistically significant differences between the two groups. Blood pressure and heart rate were clearly lowered by diltiazem, whereas fendiline induced only a slight decrease in blood pressure. The results indicate that both medications are equally suited for the treatment of stable angina pectoris.

[Outpatient polyclinic observations on senzit in the treatment of ischemic heart disease]. / Ambulatorno-poliklinichni nabliudeniia vurkhu senzit pri lechenie na iskhemichna bolest na surtseto.

56 patients, aged from 28 up to 60 years, with ischemic heart disease II-III functional class according to the Canadian classification were treated with the original Hungarian drug Sensit in out-patient conditions. The number of patients with anginal pain fell from 56 to 12 and the overall effect of the Sensit treatment was 84% (47 patients improved). The physical load tolerance significantly increased--from 58.2 to 67.4 W. Sensit influences the pathological ECG changes--ST segment lowering after physical load. It must be emphasized that the effect of the Sensit treatment is seen after a 3 week course of treatment at least. The drug is suitable for an out-patient treatment.

[Calcium antagonists (finoptin and senzit) in the treatment of cerebrovascular disorders]. / Antagonisty kal'tsiia (finoptin i senzit) v lechenii tserebrovaskuliarnykh zabolevanii.

Finoptin and sensit produced a favourable effect in the treatment of 290 patients with initial manifestations of deficient blood supply to the brain, encephalopathy attended by circulatory disturbances and ischemic brain insult. Changes in the systemic and cerebral hemodynamics were more pronounced in middle-aged and elderly patients suffering from hypertension or its combination with atherosclerosis.

[Treatment of Raynaud's syndrome in systemic connective tissue diseases with calcium antagonists]. / Lechenie na sindrom na Raynaud pri sistemnite zaboliavaniia na suedinitelnata tukan s kaltsievi antagonisti.

The results of a short and a prolonged treatment of Raynaud's syndrome with calcium antagonists are presented. The efficacy of Nifedipin, Verapamil and Fendiline was evaluated in a 14 day treatment of 61 patients with Raynaud's syndrome. Nifedipin and Fendiline was evaluated in a 14 day treatment of 61 patients with Raynaud's syndrome. Nifedipine and Fendiline were most efficient but Fendiline led to more untoward reactions. Verapamil was least efficient and exerted a weak vasoactive action. The influence of the hemocirculation indices on all drugs studied was insignificant. 20 patients with systemic sclerodermia were given 30-60 mg Nifedipin daily in the course of one year and the frequency, duration and expression of the attacks of Raynaud's syndrome decreased practically twice. The study allows the recommendation of Nifedipin as the drug of choice for the treatment of Raynaud's syndrome in the systemic connective tissue diseases.

[Treatment of Raynaud's syndrome with calcium entry blockers]. / Lechenie sindroma Reino blokatorami vkhoda kal'tsiia.

The authors have presented the results of a 14-day open randomized trial of the efficacy of 3 calcium inlet blocking agents: nifedipine, verapamil and phendilin in 61 patients with Raynaud's syndrome. In the group of patients receiving 30-80 mg of nifedipine (20) there was a significant decrease in the frequency and expression of Raynaud's syndrome attacks, a positive effect of varying degree was noted in 19 patients. The drug raised slightly the skin and muscular blood flow and skin temperature. The use of 120-360 mg of verapamil in 21 patients caused no significant inhibition of Raynaud's syndrome and rise of hemocirculation. Phendilin (150-300 mg) though being comparable with nifedipine in efficacy, often produced side-effects resulting in the drug cancellation (8 out of 20). The efficacy of the calcium inlet blocking agents, especially nifedipine, for therapy of Raynaud's syndrome was emphasized.

Fendiline: a review of its basic pharmacological and clinical properties.

Fendiline is an anti-anginal agent for the treatment of coronary heart disease. Together with other diphenylalkylamines it is sub-classified in the group of lipophilic calcium antagonists. It binds to the calcium channel and to calmodulin with rather similar affinities. Pharmaco-dynamically, it exerts the typical calcium as well as calmodulin antagonistic actions: inhibition of the transmembrane calcium current, smooth muscle relaxation, negative inotropism, cardioprotection, inhibition of calmodulin-activated myosin light-chain kinase and phosphodiesterase. Pharmacokinetics reveal slow onset of action and a long half-life. The anti-anginal and anti-ischaemic efficacy of fendiline has been proven in several placebo-controlled, double-blind trials. It does not interfere with digoxin therapy. Direct comparison with other calcium antagonists by means of controlled studies revealed that its potency is at least equal to that of nifedipine but, in contrast to nifedipine, verapamil, and diltiazem, its anti-anginal action increases during chronic therapy, reaching a steady state of action after 2 to 3 weeks. In addition, the anti-ischaemic and anti-anginal potency is about equal to that of isosorbide dinitrate but fendiline has the advantage of lacking tolerance development. Nevertheless, the data presented indicate that a combination of fendiline with low doses of ISDN may be beneficial. Adverse cardiac and haemodynamic actions, such as increase or decrease in heart rate, disturbance of AV nodal conduction, impairment of cardiac contractile performance or considerable decrease in arterial pressure in hypotensives and normotensives, are lacking.

[Experimental and clinical research on the effect of senzit on the cerebral blood flow and hemostatic function in cerebral ischemia]. / Eksperimental'no-klinicheskoe issledovanie vliianiia senzita na mozgovoi krovotok i sostoianie gemostaza pri tserebral'nykh ishemiiakh.

Senzit increased volume velocity of the cerebral blood flow and oxygen delivery to the brain tissues under normal conditions at the expense of a decrease of the cerebral vessels tone. In transient cerebral ischemia the drug prevents disorders of cerebral circulation and a lowering of oxygen tension in the brain tissue. A prophylactic administration of senzit in carotid arterial occlusion prevents the development of edema and death of animals. Oral senzit produced an increase of blood supply to the brain and hypocoagulation changes in hemostasis system in patients with chronic insufficiency of cerebral circulation.