Brain Stimulation Reward: Effects of Ethanol

This paper briefly describes and compares the effects of ethanol with those of other abuse substances on brain stimulation reward. The most frequently observed effects of abuse substances on this phenomenon is an increase in sensitivity of the animal to the stimulation. This increased sensitivity to rewarding brain stimulation has been studied as a model of drug-induced euphoria. Although many studies have reported that ethanol does increase the sensitivity of animals to this stimulation, there is much less consistency in results between laboratories than observed with the abused opiates or psychomotor stimulants. Data is presented that suggests that associative factors, e.g., self- versus experimenter-administered ethanol, as well as route of administration and time of brain stimulation testing may all contribute to the variability in results obtained between laboratories. Further, the effects of ethanol on brain stimulation reward are more like those of other sedative-hypnotics than the opiates or psychomotor stimulants.     

Multidrug-Resistant <Emphasis Type="Italic">Pseudomonas</Emphasis> Infections: Hard to Treat,But Hope on the Horizon?

Purpose of Review

As the sixth most common nosocomial pathogen in the USA, Pseudomonas aeruginosa poses a significant threat to patients within the healthcare system. Its intrinsic and acquired resistance mechanisms also significantly limit the choices for antimicrobial therapy, prompting an increase in the research and development of antibacterial agents with enhanced activity against multidrug-resistant (MDR) P. aeruginosa. While many approved and pipeline antibiotics have activity against wild-type P. aeruginosa, only four new antibiotics have promising activity against MDR P. aeruginosa: ceftazidime-avibactam (Avycaz®), ceftolozane-tazobactam (Zerbaxa®), cefiderocol, and imipenem-cilastatin/relebactam. The goal of this paper is to review the epidemiology and mechanisms of resistance in P. aeruginosa as well as explore the newly approved and pipeline agents that overcome these mechanisms of resistance.

Recent Findings

Ceftazidime-avibactam and ceftolozane-tazobactam are currently FDA-approved and available for use, while cefiderocol and imipenem-cilastatin/relebactam are in development. Current evidence suggests ceftazidime-avibactam and ceftolozane-tazobactam both may have a role in treatment of MDR P. aeruginosa infections. Ceftolozane-tazobactam appears to be modestly more potent against P. aeruginosa, but emergence of resistance has been noted in various reported cases. Trials are ongoing for cefiderocol and imipenem-cilastatin/relebactam and early results appear promising.

Summary

The aforementioned agents fill important gaps in the antibiotic armamentarium, particularly for patients with MDR P. aeruginosa infections who otherwise have extremely limited and often toxic antibiotic options. However, resistance to all of these agents will likely emerge, and additional antibiotic development is warranted to provide sufficient options to successfully manage MDR P. aeruginosa infections.

     

Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.     

Esophageal duplication with pleural effusion in antenatal diagnosis

The authors report the case of a patient in whom an antenatal ultrasound showed a mediastinal tumor then a pleural effusion. At birth, the baby was intubated for adequate ventilation and pleural effusion was drained. Ultrasound, oesophagogram, CT scan permitted the diagnosis of tubular oesophageal duplication which was confirmed by surgery and pathologic examination. Review of the literature did not find such antenatal finding. The role of oral contraception during the first weeks of pregnancy is discussed.     

On the dissimilar effects of drugs on the digit symbol substitution and continuous performance tests

Summary A tentative hypothesis is presented to account for the dissociation of the effects of various centrally-acting drugs and other agents on performance of the Continuous Performance Test (C.P.T.) and the Digit Symbol Substitution Test (D.S.S.T.): L.S.D., secobarbital, pentobarbital meprobamate and phenobarbital produced significantly greater impairment of the D.S.S.T. than of the C.P.T., while chlorpromazine, sleep deprivation and centrencephalic epilepsy had the reverse effect. Psychological, neurophysiological, electroencephalographic and neuropharmacological data were cited which suggested that the tests were affected differently because they are dependent upon the functioning of somewhat different neural organizations which are, in turn, differentially sensitive to the action of various centrally-active agents.The studies referred to in this paper involving the Digit Symbol Substitution and Continuous Performance Tests were conducted in the Laboratory of Clinical Science, and in the Section on Neuropsychology, Laboratory of Psychology, National Institute of Mental Health, and in the Surgical Neurology Branch of the National Institute of Neurological Diseases and Blindness. The authors wish to express their appreciation to the numerous members of the staff of these laboratories who provided advice, assistance and facilities for these studies. Part of the costs of preparing this work for publication were borne by grant M-6015 from the National Science Foundation, grants GMK3-1759 and K3-14 915 from the National Institute of Mental Health and grant 61-241 from the Foundations Fund for Research in Psychiatry.     

Antimicrobial drug prescribing for pneumonia in ambulatory care

To determine patterns and predictors of antimicrobial drug use for outpatients with community-acquired pneumonia, we examined office visit and pharmacy claims data of 4 large third-party payer organizations from 2000 to 2002. After patients with coexisting conditions were excluded, 4,538 patients were studied. Despite lack of coexisting conditions, fluoroquinolone use was commonly observed and increased significantly (p < 0.001) from 2000 to 2002 (24%-39%), while macrolide use decreased (55%-44%). Increased age correlated with increased fluoroquinolone use: 18-44 years (22%), 45-64 years (33%), and > or =65 years (40%) (p < 0.001). Increased use of fluoroquinolones occurred in healthy young and old patients alike, which suggests a lack of selectivity in reserving fluoroquinolones for higher risk patients. Clear and consistent guidelines are needed to address the role of fluoroquinolones in treatment of outpatient community-acquired pneumonia.     

Effect of chlorpromazine on conditioned avoidance as a function of CS-US interval length

Three groups of four rats learned to avoid electric shock (US) by turning a wheel in response to a buzzer stimulus (CS). The CS-US intervals for each group were 5, 10, and 20 sec, respectively. After each animal had learned the avoidance procedure and had achieved a stable level of performance, the effect of several doses of chlorpromazine on percent avoidance, on latency time from CS onset to termination by a response, and on response rate was determined as a function of CS-US interval length. No consistent relationship between increasing interval length and response rate was observed. Neither lengthening the CS-US interval nor the interaction of this lengthening with chlorpromazine dose was found to exert a statistically significant effect on percent avoidance. Furthermore, although a statistically significant increase in response latency was found to be associated with increasing CS-US interval length, the increases in latency noted were not of sufficient magnitude to corroborate the hypothesis that lengthening the CS-US interval contributes importantly to increased avoidance responding in animals tested with chlorpromazine. Further, the results of this study do not support induction of a locomotor deficit as the mechanism by which chlorpromazine suppresses the avoidance response.This research was supported by USPHS NIMH Grant MH 12568.NIMH Research Scientist Award MH 1759.