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Biomedical subjects

B S Brown

Publications and source records attributed to B S Brown.

At least 19 recordsLinked to original sources
PubMed2001

An evaluation of drug treatments for adolescents in 4 US cities.

BACKGROUND: Little is known about outcomes of community-based treatment programs for adolescents with drug problems. METHODS: We studied 1167 adolescents (age range, 11-18 years; 368 females, 799 males) from 4 US cities (Pittsburgh, Pa; Minneapolis, Minn; Chicago, Ill; and Portland, Ore) using a naturalistic, nonexperimental evaluation design. These adolescents were consecutive admissions during the period from 1993 to 1995 at 23 community-based treatment programs in the Drug Abuse Treatment Outcome Studies for Adolescents. Included were 418 admissions to 8 residential programs, 292 admissions to 9 outpatient drug-free programs, and 457 admissions to 6 short-term inpatient programs. RESULTS: Adolescents in treatment typically had multiple problems (eg, 58.4% of them were involved in the legal system, and 63.0% met diagnostic criteria for a mental disorder). Nevertheless, less than half (43.8%) of all patients reported weekly marijuana use in the year following treatment (dropping from 80.4% in the year before admission). Similarly, there were decreases in heavy drinking (dropping from 33.8% to 20.3%), use of other illicit drugs (dropping from 48.0% to 42.2%), and criminal involvement (dropping from 75.6% to 52.8%). Additionally, patients reported better psychological adjustment and school performance after treatment. Longer stays in treatment were positively associated with several favorable outcomes, although length of time in treatment was generally short. CONCLUSIONS: Substance abuse treatment for adolescents is effective in achieving many important behavioral and psychological improvements. Strategies specific to adolescents to improve their treatment retention and completion are needed to maximize the therapeutic benefits of drug treatment.

Adolescent↗
PubMed2001

Effectiveness of a stand-alone aftercare program for drug-involved offenders.

A study was made of the effectiveness of an aftercare program operating in conjunction with area outpatient drug free treatment programs while organizationally independent of those programs. Parolees and probationers mandated to treatment were assigned to aftercare on the basis of residence in the catchment areas in which aftercare facilities were located (n = 32) and randomly to aftercare (n = 62) and control (n = 51) when not a resident in a catchment area. No outcome differences were found between aftercare groups based on proximity to facility. At 6 months postbaseline the combined aftercare group showed significantly lower levels of criminal activity and frequent drug use as compared to controls. At 12 months postbaseline there was an attenuation of group differences with only tendencies toward significance obtained for lower levels of frequent drug use by the aftercare group. The findings are discussed in terms of the relevance of community variables for programming and for understanding long-term treatment outcomes.

Adult↗
PubMed2001

Factors associated with frequency of 12-Step attendance by drug abuse clients.

Comparison was made of treatment clients attending Narcotics Anonymous and/or Alcoholics Anonymous meetings less than weekly (n = 41) with treatment clients attending meetings at least three times a week (n = 30). The frequent attenders (attending an average of 30.6 meetings monthly) differed from non- and infrequent attenders (attending an average of 0.4 meetings monthly) in terms of histories of greater lifetime drug use, more arrests and treatment experiences, and an earlier age of first use of alcohol. Although the frequent attender was also older, age was not found to influence the differences found between groups. Measures of religiosity, use of community services, and support from others for recovery and psychological functioning, other than ratings of the helpfulness of 12-Step, were not differentiated among groups. The findings suggest that 12-Step groups are more likely to be selected by clients with more severe histories of drug use and criminal activity, i.e., those most in need of the support to behavior change those groups provide. The role of treatment programs in facilitating the use of 12-Step groups is discussed.

Adult↗
PubMed2001

Factors associated with frequent and infrequent HIV testing.

Drug user treatment clients with 5 or more HIV tests (frequent testees N=43) and 0-2 HIV tests (infrequent testees-N = 56) were compared on demographic characteristics, risk behaviors, perceived risk of HIV infection to self, involvement with family members, and psychological functioning. Extreme groups of HIV testees did not differ on any variables other than an index of perceived vulnerability to HIV infection (e.g., " You think that you really could get AIDS"). That measure of felt vulnerability was not correlated significantly with needle or sexual risk behaviors, family involvement, psychological functioning or other measures of perceived risk. It was reasoned that, in a community in which both dangers and protective behaviors are widely understood, frequent testees experience a generalized and heightened concern unrelated to specific behaviors or characteristics.

AIDS Serodiagnosis↗
PubMed2000

Modulation and genetic identification of the M channel.

Potassium channels constitute a superfamily of the most diversified ion channels, acting in delicate and accurate ways to control or modify many physiological and pathological functions including membrane excitability, transmitter release, cell proliferation and cell degeneration. The M-type channel is a unique ligand-regulated and voltage-gated K(+) channel showing distinct physiological and pharmacological characteristics. This review will cover some important progress in the study of M channel modulation, particularly focusing on membrane transduction mechanisms. The K(+) channel genes corresponding to the M channel have been identified and will be reviewed in detail. It has been a long journey since the discovery of M current in 1980 to our present understanding of the mysterious mechanisms for M channel modulation; a journey which exemplifies tremendous achievements in ion channel research and exciting discoveries of elaborate modulatory systems linked to these channels. While substantial evidence has accumulated, challenging questions remain to be answered.

Animals↗
PubMed2000

Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine.

Dexfenfluramine was approved in the United States for long-term use as an appetite suppressant until it was reported to be associated with valvular heart disease. The valvular changes (myofibroblast proliferation) are histopathologically indistinguishable from those observed in carcinoid disease or after long-term exposure to 5-hydroxytryptamine (5-HT)(2)-preferring ergot drugs (ergotamine, methysergide). 5-HT(2) receptor stimulation is known to cause fibroblast mitogenesis, which could contribute to this lesion. To elucidate the mechanism of "fen-phen"-associated valvular lesions, we examined the interaction of fenfluramine and its metabolite norfenfluramine with 5-HT(2) receptor subtypes and examined the expression of these receptors in human and porcine heart valves. Fenfluramine binds weakly to 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. In contrast, norfenfluramine exhibited high affinity for 5-HT(2B) and 5-HT(2C) receptors and more moderate affinity for 5-HT(2A) receptors. In cells expressing recombinant 5-HT(2B) receptors, norfenfluramine potently stimulated the hydrolysis of inositol phosphates, increased intracellular Ca(2+), and activated the mitogen-activated protein kinase cascade, the latter of which has been linked to mitogenic actions of the 5-HT(2B) receptor. The level of 5-HT(2B) and 5-HT(2A) receptor transcripts in heart valves was at least 300-fold higher than the levels of 5-HT(2C) receptor transcript, which were barely detectable. We propose that preferential stimulation of valvular 5-HT(2B) receptors by norfenfluramine, ergot drugs, or 5-HT released from carcinoid tumors (with or without accompanying 5-HT(2A) receptor activation) may contribute to valvular fibroplasia in humans.

Animals↗
PubMed2000

Molecular basis for differential sensitivity of KCNQ and I(Ks) channels to the cognitive enhancer XE991.

Channels formed by coassembly of the KCNQ1 (KvLQT1) subunit and the minK subunit underlie slowly activating cardiac delayed rectifier (I(Ks)) in the heart, whereas two other members of the KCNQ channel family, KCNQ2 and KCNQ3, coassemble to underlie the M current in the nervous system. Because of their important physiological function, KCNQ channels have potential as drug targets, and an understanding of possible mechanisms that would enable tissue-specific targeting of these channels will be of significant value to drug development. In this study, we examined the role of the minK subunit in determining the response of KCNQ1 channels to blockade by the cognitive enhancer XE991. Coexpression with minK markedly decreased the sensitivity of KCNQ1 to blockade by XE991. When measured at the end of a 500-ms step, XE991 blockade of the KCNQ1+minK current had a K(D) value of 11.1 +/- 1.8 microM, approximately 14-fold less sensitive than the block of the KCNQ1 current (K(D) = 0.78 +/- 0.05 microM). In addition, XE991 reduced activation and deactivation time constants and caused a rightward shift in the activation curve of KCNQ1+minK, but affected none of these parameters for KCNQ1 alone. Also, XE991 block of KCNQ1+minK, but not of KCNQ1, was time- and voltage-dependent. We conclude that the presence of minK in the I(Ks) channel complex gives rise to differential sensitivity of KCNQ and I(Ks) channels to blockade by XE991. Our results have implications for drug development by demonstrating the important potential role of accessory subunits in determining the pharmacological properties of KCNQ channels.

Animals↗
PubMed1999

Prior treatment experience related to process and outcomes in DATOS.

Using data collected from cocaine-abusing patients who participated in the Drug Abuse Treatment Outcome Studies (DATOS), we contrasted patients in treatment for the first time and patients having extensive histories of prior treatment to identify factors associated with better outcomes in each group. Compared with first-timers, treatment-experienced patients had less favorable post-treatment outcomes. Indicators of early engagement in DATOS treatment predicted post-treatment abstinence for both groups. Importantly, the interaction of treatment history and several process measures affected post-treatment abstinence. For example, individual counseling and program compliance had greater impacts on abstinence among treatment repeaters in outpatient drug-free programs than for first-timers. Social support and environmental context were significantly related to abstinence. These findings confirm the importance of considering treatment process and aftercare in developing and implementing strategies to optimize treatment for patients with different treatment histories.

Adult↗
PubMed1998

KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel.

The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current.

Adult↗
PubMed1998

Ion channel modulators that enhance acetylcholine release: potential therapies for Alzheimer's disease.

Enhancing the release of acetylcholine (ACh) in the brain is one approach to increasing neuronal activity, restoring central cholinergic tone and improving attention and cognition. ACh release is modulated by both ligand-gated (gamma-amino butyric acid A receptors/benzodiazepine [GABA(A)/BDZ], nicotinic-acetylcholine and serotonin, 5-HT3) and voltage-gated (calcium and potassium) ion channels. Of the ligand-gated channel modulators, the BDZ receptor (BDZR) inverse agonists (beta-CCM, ZK 93426) enhance activity-dependent release in animals, whereas S-8510, a partial inverse agonist, and the BDZR antagonist, flumazenil, show enhancement regardless of the behavioural state of the animal. Some of these agents have undergone limited clinical evaluation for Alzheimer's disease (AD) (ZK 93426, flumazenil, S-8510), but their potential anxiogenic liability makes their therapeutic use uncertain until more clinical data are available. Within the group of nicotinic agonists, ABT-418, though less potent than nicotine and epibatidine in promoting ACh release in vitro, was clinically evaluated based on its in vivo profile. Its lack of oral bioavailability has limited its acceptability, though transdermal administration has been used to circumvent this deficiency. Serotonin 5-HT3 receptor modulators have not been advanced for clinical evaluation for the treatment of AD. Among the voltage-gated ion channel modulators affecting L- or N-type calcium channels, nefiracetam, a nootropic agent, also increased ACh release in animal studies. It is currently undergoing clinical evaluation for AD, though a need for more potent and brain selective calcium channel blockers exists. Potassium channel modulators have been the most studied ACh release enhancing agents and several of these compounds (4-AP, 3,4-DAP, linopirdine) have been clinically evaluated. In AD patients, 4-AP, an A-type K+ channel blocker, elicited inconsistent and unremarkable effects. Linopirdine, whose enhancement of ACh release correlates with its ability to block M-type K+ channels, also produced disappointing clinical results, which may have been related to its suboptimal pharmacokinetic profile. Further work in this series has provided a compound (DMP 543) that should be a more reliable indicator of whether a blocker of this ion channel can activate the cholinergic system in man. This agent is currently undergoing clinical evaluation for AD.

Journal Article↗
PubMed1998

Drug use--chronic and relapsing or a treatable condition?

It is argued that the term "chronic relapsing disorder," which is used frequently to characterize drug use, does not capture the complexity of drug treatment evaluation findings and thereby limits an understanding and appreciation of the accomplishments of drug treatment. Specifically, it is noteworthy that a substantial minority (19%) of treated drug users have been found to maintain abstinence over a 6-year period posttreatment, and that the three major multisite treatment evaluations sponsored by NIDA have all found that overwhelming majorities of treated drug users do not revert to the levels of drug use (or criminal activity) shown pretreatment. Thus, the view of inevitable and continuing adoption of pretreatment behaviors, i.e., chronic relapse, gives undeserved comfort to those who deny the utility of drug treatment, and does so at a time when changes in the health care industry threaten the integrity of that treatment.

Attitude of Health Personnel↗
PubMed1998

Emergency physicians perceptions of drug screens at their own hospitals.

Previous studies evaluated the prudent use and potential over use of drug screens in clinical decision making. However, the percentage of emergency physicians who can correctly identify which drugs are found on their hospital's basic drug screens has not been established. Results of physician closed-ended questionnaires were compared to the results of a telephone survey with each physician's individual hospital laboratory. Eighty-one (35.7%) of 227 emergency physicians responded. Four (4.9%) correctly identified what was on their individual institution's urine drug screens and 17 (21%) correctly identified what was on serum screens. In other results, 74.3% erroneously relayed that all benzodiazepines can be found on urine drug screens and 46.3% incorrectly answered that acetaminophen would be found on basic quantitative serum screens. Drug screen results can be misinterpreted if the drugs the physician expects to be screened for, and what is actually screened for, are not the same. Pharmacy and laboratory personnel have a responsibility to keep the physician informed of drug screen issues. They should be proactive in advising physicians of changes in drug testing and new drug screening methods or by providing reports on the occurrence of false positive results.

Adult↗
PubMed1998

Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons.

Linopirdine [DuP 996, 3, 3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one], a putative cognition enhancing drug, increases acetylcholine release in rat brain tissue and improves performance in animal models of learning and memory. The mechanism whereby linopirdine enhances acetylcholine release has been proposed to involve inhibition of the M-type K+ current (IM). Our study examines the selectivity of linopirdine for IM by determining its effects on other ionic currents present in rat hippocampal CA1 neurons using patch clamp techniques. Linopirdine was found to block voltage-gated, calcium-activated and leak K+ currents in a dose-dependent manner. Of the seven currents measured, linopirdine was most selective for IM with an IC50 of 2.4 +/- 0.4 microM, followed by IC (measured as a medium afterhyperpolarization tail current, ImAHP) with an IC50 of 16.3 +/- 2.4 microM. Both IM and IC were completely suppressed by linopirdine. At a concentration of 100 microM, linopirdine weakly inhibited the K+ leak current, IL, the transient outward current, IA, the delayed rectifier, IK, and the slow component of IAHP, by 28 +/- 8, 37 +/- 10, 36 +/- 9 and 52 +/- 10 percent, respectively. The mixed Na+/K+ inward rectifying current, IQ, was essentially unaffected by linopirdine (IC50 >300 microM). These results indicate that linopirdine selectively blocks IM at concentrations </= 3 microM, the approximate EC50 for acetylcholine release enhancement. Inhibition of other voltage-gated and calcium-activated K+ currents could also contribute to enhanced neurotransmitter release by linopirdine at intermediate (IC) and high (IL, IA, IK, IsAHP) concentrations.

Acetylcholine↗
PubMed1997

Linopirdine reduces stimulus intensity threshold for induction of long-term potentiation in the Schaffer collateral/CA1 pathway in rat hippocampal slices.

Linopirdine, a putative cognition enhancing agent, increases neurotransmitter release and blocks M-current in rat brain. Its effects on long-term potentiation (LTP) in the Schaffer collateral/CA1 pathway were investigated using standard, extracellular recording techniques in rat hippocampal slice preparation. When using a half maximal stimulus intensity for tetanic stimulation, a 30 min exposure to 3 or 10 microM linopirdine exerted no significant effect on excitatory postsynaptic potential (EPSP) slope, post-tetanic potentiation or LTP. In contrast, when a weak stimulus was employed, linopirdine enhanced the incidence and amplitude of LTP in a dose-dependent manner. These results indicate that linopirdine reduced stimulus intensity threshold for induction of LTP, an effect which may be mediated by its ability to enhance presynaptic glutamate release and cause CA1 membrane depolarization.

Animals↗
PubMed1996

Psychological dysfunction and HIV/AIDS risk behavior.

The relationship between psychological problems and human immunodeficiency virus HIV/AIDS risk-taking behaviors was examined among 834 daily opioid users entering methadone treatment programs. A composite measure of psychological dysfunction was created using depression, anxiety, and hostility scales. This measure was found to be significantly related to needle risk in terms of injecting with used equipment, sharing of drug paraphernalia, and sharing with strangers. Psychological dysfunction was also related to sexual risk taking in terms of number of partners, unprotected sex with other injection drug users, and trading sex. Use of cocaine was significantly related to all measures of injection and sex-related risk taking; use of speedball (heroin and cocaine) was significantly related to use of dirty equipment and sharing of paraphernalia. The implications of study findings for AIDS prevention programming are discussed.

Acquired Immunodeficiency Syndrome↗