Polymorphism, pseudopolymorphism, and amorphism of peracetylated alpha-, beta-, and gamma-cyclodextrins

Polymorphism, pseudopolymorphism, and amorphism of hexakis(2,3,6-tri-O-acetyl)-alpha-cyclodextrin (TAalphaCyD), heptakis(2,3,6-tri-O-acetyl)-beta-cyclodextrin (TAbetaCyD), and octakis(2,3,6-tri-O-acetyl)-gamma-cyclodextrin (TAgammaCyD) were investigated using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffractometry (XRPD), Fourier transform infrared spectroscopy (FTIR) and optical microscopy. An anhydrous and a bi-hydrate crystalline forms of TAalphaCyD, two monotropic anhydrous polymorphs and three pseudopolymorphs (i.e. methanolate, hydrate, and isopropanolate-hydrate) of TAbetaCyD, as well as two monotropic anhydrous polymorphs and isostructural pseudopolymorphs (e.g. hydrate and isopropanolate-hydrate) of TAgammaCyD were isolated and characterized. The amorphous forms of each TACyD were also obtained. Thermal data for desolvation of TAalphaCyD.2H2O and TAbetaCyD.CH3OH were reconciled with their crystal packing features. Melting temperatures and enthalpies of the crystalline forms of each TACyD can be referred to for possible solid-state interactions with drugs.     

Fibroblasts, myofibroblasts, and fibrosis: fact, fiction, and the future

Fibroblasts and their activated phenotype known as myofibroblasts are nonexcitable cells found in all organs of the body. In the heart, fibroblasts, along with the endothelial and smooth muscle cells of the blood vessels, make up approximately 30% of tissue mass. In vitro, myofibroblasts cocultured with cardiac myocytes can propagate electrical signals down cellular strands indicating that under these conditions myofibroblasts are capable of depolarizing enough to maintain electrical propagation. This has obvious implications for cardiac biology if heterocellular coupling between fibroblasts and myocytes were to occur in the intact heart either under normal conditions or during cellular stress. The purpose of this review series is to highlight the newest information on cardiac fibroblasts and myofibroblasts and to review the data on their interactions with cardiac myocytes.     

Alcohol,Age, and Piloting: Judgment,Mood, and Actual Performance

We have previously described acute and carry-over effects of alcohol on young and older pilots' performance. In the present paper we report the effects of alcohol and age on self-assessment of performance and mood in the same study. Young and older pilots flew in a simulator during an alcohol and placebo condition. In the alcohol condition, they flew after reaching. 04 g/dL (.04%) BAL, after. 10% BAL, and then 2,4, 8,24, and 48 h after. 10% BAL (they flew at the same times in the placebo condition). They rated confidence in ability to fly, mood, alertness, and intoxication before each flight, and perceived workload and performance after each flight. As reported in Morrow et al., alcohol had both acute and carry-over effects for 8 h on actual flight performance, with greater acute impairment for older pilots. The present study reports that these older pilots tended to be more aware than the young pilots of acute and carry-over alcohol impairment out to 4 h. By 8 h, however, all pilots were unaware of impairment. Alcohol also had a biphasic effect on mood, which increased on the ascending limb and decreased on the descending limb of the BAL curve.     

Lesbian,Gay, Bisexual,and Transgender Youth: Health Concerns,Services, and Care

Abstract

This paper was developed from a presentation made at the FDA/Industry Workshop held at Sandoz Research Institute, East Hanover, New Jersey on November 20, 1986.     

Smooth-pursuit eye movements,and diazepam,CPZ, and secobarbital

This study examined the effects on smooth-pursuit eye tracking of single doses of CPZ (0.667 and 1.334 mg/kg), diazepam (0.071, 0.142, and 0.284 mg/kg), and secobarbital (100 mg). Only the barbiturate significantly affected the ability to follow a moving target with smooth-pursuit eye movements. In repeated testing of a single subject, 130 mg of secobarbital disrupted smooth-pursuit movements at least until 24 hrs after ingestion.This study was supported in part by grant MH-19477, USPHS, and USFDA contract No. 72-42. Dr. Holzman is the recipient of Research Scientist Award No. K5-MH-70900, USPHS. We express our thanks to Dr. Alfred Heller for helpful comment.     

Temperature,pH, salinity,hardness, and particulates mediate nickel toxicity to eubacteria,an actinomycete,and yeasts in lake,simulated estuarine,and sea waters

The survival of some eubacteria, an actinomycete, and yeasts after acute and chronic exposures to nickel (Ni) in lake, simulated estuarine, and sea waters and the influence of environmental factors on Ni toxicity were determined. Nickel toxicity to microbes in marine systems was reduced by increasing the salinity, by decreasing the temperature, and by the incorporation of simulated sediment. The toxicity of Ni to microbes in fresh water was reduced by increasing the pH, by increasing the hardness, and by the incorporation of suspended particulates. Chronic toxicity studies indicated that fresh waters are more sensitive than marine waters to Ni pollution, as microbial survival was greater in marine than in fresh waters stressed with equivalent concentrations of Ni.     

Gradualism, identity, reinforcements, and change

This paper reflects the ongoing development of gradualism, a drug treatment perspective that seeks to make use of the full array of effective, creative, and innovative harm reduction and abstinence-oriented treatments available to help addicted individuals move along a continuum from active/chaotic use to abstinence or moderation, as appropriate. The essence of gradualism is an emphasis on positive change and transformation as therapeutic goals. The paper first looks at manifestations of gradualism in harm reduction treatment facilities. Following this is a discussion of the role of identity transformation in the change process. The final section explores how contingency management or motivational incentive interventions could be used in harm reduction settings to facilitate this kind of therapeutic movement.     

Opiates,catecholamines, behavior,and mood

Indirect evidence has linked opioid reinforcement with changes in noradrenergic metabolism secondary to drug administration. Methodological precedents for biobehavioral correlations in depressive illness have suggested an important association between changes in mood and biogenic amine excretion patterns in the urines of patients during depression and recovery. This paper presents preliminary data on the possible relationship between changes in catecholamine excretion that were observed and the changes in behavior, mood, psychiatric status, and cardiorespiratory physiology secondary to heroin administration and methadone-assisted withdrawal. This study focuses on the urinary excretion of MHPG, since an appreciable fraction of this metabolite is probably derived from norepinephrine originating in the brain. The subjective changes in mood associated with heroin use, the decrease in respiratory rate, and the behavioral and mental status effects associated with opiate intoxication were observed only in the individuals whose MHPG excretion increased during the period of opiate administration.     

Brain,networks, depression,and more

Depression is a heterogeneous disorder with a highly variable course. Individual responses to treatment are inconsistent, and an established mechanism remains elusive. The classical hypothesis of depression posits that mood disorders are caused by a chemical imbalance in the brain that can be corrected with antidepressant drugs. However, recent evidence indicates that information-processing dysfunction within neural networks might underlie depression, and antidepressant drugs induce plastic changes in neuronal connectivity that gradually lead to improvements in neuronal information processing and recovery. This review presents the major current approaches to understanding the biological mechanisms of major depression, with a focus on complex brain networks.     

Chemistry,Manufacturing, and Controls Information in NDAs and ANDAs,Supplements, Annual Reports,and Other Regulatory Filings

Advice to the pharmaceutical industry regarding the chemistry, manufacturing, and controls and microbiology (sterility assurance) information to be included in regulatory submissions to the Center for Drug Evaluation and Research (CDER) can be found in the pertinent statutes, regulations, and guidances. The primary statute is the Federal Food, Drug and Cosmetic Act (the Act); applicable regulations appear in 21 CFR 312 and 314. Neither the Act nor the regulations provide sufficient detail on the information that should be included in these submissions. Over the past 14 years CDER has issued a series of guidelines and guidances that provide specific detail related to the recommended filing mechanisms and information that CDER expects applicants to provide. Some of these guidances are applicable to original submissions and some are applicable to post-approval changes. This article will provide an overview of The Act, the pertinent regulations, and the pre- and post-approval guidances.     

Synthesis,anti-inflammatory,analgesic, and antibacterial activities of some triazole,triazolothiadiazole, and triazolothiadiazine derivatives

This study is concerned with the synthesis of new 1,2,4-triazoles, 1,3,4-thiadiazoles, and 1,3,4-thiadiazines derivatives. Derivatives 3a–i were obtained by condensation of 4-amino-3-(4-pyridine)-5-mercapto-1,2,4-triazole 1 with the appropriate aldehyde. Compounds 4a–i were synthesized in a one pot reaction involving compounds 3a–i, formaldehyde, and morpholine. Condensation of compound 1 with the appropriate acids or 4-substituted phenacyl bromide gave compounds 6a–d and 8a–f respectively. The chemical structures of the newly synthesized derivatives were elucidated using different spectral and elemental methods of analysis. All compounds were evaluated for their anti-inflammatory activity and the most potent derivatives were tested for their analgesic activity using indomethacin as a reference drug. In addition, ulcerogenicity and LD₅₀ for the most active compounds were evaluated. Moreover, the antibacterial activities of the newly synthesized derivatives were investigated.     

Smoking, health behavior, and values: a replication, refinement, and extension

Within a larger study, 181 female undergraduates completed the Rokeach instrumental value survey and a version of the terminal value survey which included the value 'health', as well as measures of general preventive health behavior and social desirability. Analyses showed that nonsmokers reported better health behavior, and particularly direct rather than indirect-risk behavior, than smokers. While there was no difference in the value of 'health', smokers gave more priority to being 'broadminded' than nonsmokers gave. Smokers were also more concerned with 'freedom', being 'independent' and not being 'obedient', suggesting that smokers were more concerned with being 'flexible' or 'unconstrained'. Further, the value of being 'broadminded' was inversely related to the general health behavior and direct-risk behavior of smokers. Together with other research, these findings suggest that decreasing the extent to which smokers value 'broadmindedness' might not only reduce their smoking behavior but also affect their general preventive health behavior.     

Nirmatrelvir and COVID-19: development,pharmacokinetics, clinical efficacy,resistance, relapse,and pharmacoeconomics

Nirmatrelvir/ritonavir (N/R) is one of the most effective antiviral drugs against SARS-CoV-2. The preclinical development, pharmacodynamics and pharmacokinetics of N/R are reviewed herein. Randomized clinical trials have been conducted exclusively with pre-Omicron variants of concern, but in vitro studies show that efficacy against all Omicron sublineages is preserved, as confirmed by post-marketing observational studies. Nevertheless, investigations of large viral genome repositories have shown that mutation in the main protease causing resistance to N/R are increasingly frequent. In addition, virological and clinical rebounds after N/R discontinuation have been reported in immunocompetent patients. This finding is of concern when translated to immunocompromised patients, in whom N/R efficacy has not been formally investigated in clinical trials. Economical sustainability and perspectives for this therapeutic arena are discussed.