Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

Evolution of Nervous Control from Primitive Organisms to Man A Symposium organized by the Section on Medical Sciences of the American Association for the Advancement of Science, and presented at the New York Meeting on December 29–30, 1956. Edited by Allan D. Bass. Pp. vii + 231. (Washington, D.C.: American Association for the Advancement of Science; London: Bailey Bros. and Swinfen, Ltd., 1959.) 52s.

The Central Nervous System

Understanding the molecular mechanisms underlying synergistic, potentiative and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations and multi-targeted agents. In this article, we describe an extensive investigation of the published literature on drug combinations for which the combination effect has been evaluated by rigorous analysis methods and for which relevant molecular interaction profiles of the drugs involved are available. Analysis of the 117 drug combinations identified reveals general and specific modes of action, and highlights the potential value of molecular interaction profiles in the discovery of novel multicomponent therapies.

Mechanisms of drug combinations: interaction and network perspectives.

Although a receptor exists for cannabinoid drugs, it is uncertain which pharmacological actions this receptor mediates. This structure-activity relationship investigation was initiated to determine which effects might correspond to binding affinity for the cannabinoid receptor, as well as to explore the binding requirements of this site. The ability of nearly 60 cannabinoids to displace [3H]CP-55,940 [(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-[3-hydroxy propyl] cyclohexan-1-ol] was determined before establishing correlations between receptor affinity and in vivo pharmacological potency. Analysis of [3H]CP-55,940 binding indicated a Hill coefficient of 0.97, a Bmax of 499 pM (3.3 pmol/mg of protein) and an apparent Kd of 924 pM. Closer inspection indicated the binding assay exhibited "zone B" characteristics, and use of correction equations indicated a true Kd for CP-55,940 of 675 pM. The structure-activity relationship indicated the importance of side chain structure to high-affinity binding, with the most potent analogs (K1 < 10 nM) possessing either a dimethylheptyl side-chain, a similarly complex branched side chain or a halogen substituent at the 5' position. Comparative analysis of K1 values to in vivo potency in a mouse model indicated a high degree of correlation between parameters for the depression of spontaneous locomotor activity (r = 0.91) and for the production of antinociception (r = 0.90), hypothermia (r = 0.89) and catalepsy (r = 0.85). Similarly high correlations were demonstrated between binding affinity and in vivo potency in both the rat drug discrimination model (r = 0.81) and for psychotomimetic activity in humans (r = 0.88).(ABSTRACT TRUNCATED AT 250 WORDS)

Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities.

Prostaglandins: effect of prostaglandin E1 on brain, stomach and intestinal serotonin in rat.

Previous studies showed that repeated ingestion of erythrosine B (artificial food color) developed behavioral hyperactivity, but nothing is known about its single administration effect as well as the neurochemical (s) involvement. The present study provides evidence that a single higher dosage (10, 100 or 200 mg/kg, p.o.) of erythrosine administration to young adult male rats reduced motor activity (MA) maximally at 2 h and brain regional (medulla-pons, hippocampus and hypothalamus) serotonergic activity (measuring steady-state levels of 5-HT and 5-HIAA, pargyline-induced 5-HT accumulation and 5-HIAA declination rate and 5-HT receptor binding) under similar experimental condition. The degree of erythrosine-induced inhibition of both MA and brain regional serotonergic activity was dosage dependent. Lower dosage (1 mg/kg, p.o.) did not affect either of the above. Erythrosine (100 or 200 mg/kg, p.o.)-induced MA suppression was also observed in the presence of specific MAO-A inhibitor, clorgyline (5 mg/kg, i.p.) or MAO-B inhibitor, deprenyl (5 mg/kg, i.p.); but their co-application (5 mg/kg, i.p., each) effectively prevented the erythrosine-induced motor suppression. Altogether these results suggest that a single higher dosage of erythrosine (10–200 mg/kg, p.o.) may reduce MA by reducing serotonergic activity with modulation of central dopaminergic activity depending on the brain regions.

Short-term erythrosine B-induced inhibition of the brain regional serotonergic activity suppresses motor activity (exploratory behavior) of young adult mammals

Caffeine (10–40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5–1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25–1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25–1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75–5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05–0.30 mg/kg, i.p.) or nicotine (0.5–1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeinetreated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75–150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa+carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.

Mrinal K. Poddar

Papers

Prostaglandins: effect of prostaglandin E1 on brain, stomach and intestinal serotonin in rat.

Short-term erythrosine B-induced inhibition of the brain regional serotonergic activity suppresses motor activity (exploratory behavior) of young adult mammals

Caffeine-induced locomotor activity: Possible involvement of GABAergic-dopaminergic-adenosinergic interaction

In vivo and in vitro effects of delta9-tetrahydrocannabinol on rats liver microsomal drug-metabolizing enzymes.

Carnosine: effect on aging-induced increase in brain regional monoamine oxidase-A activity.