Systematic Evaluation of “Compliance” to Prescribed Treatment Medications and “Abstinence” from Psychoactive Drug Abuse in Chemical Dependence Programs: Data from the Comprehensive Analysis of Reported Drugs

This is the first quantitative analysis of data from urine drug tests for compliance to treatment medications and abstinence from drug abuse across “levels of care” in six eastern states of America. Comprehensive Analysis of Reported Drugs (CARD) data was used in this post-hoc retrospective observational study from 10,570 patients, filtered to include a total of 2,919 patients prescribed at least one treatment medication during 2010 and 2011. The first and last urine samples (5,838 specimens) were analyzed; compliance to treatment medications and abstinence from drugs of abuse supported treatment effectiveness for many. Compared to non-compliant patients, compliant patients were marginally less likely to abuse opioids, cannabinoids, and ethanol during treatment although more likely to abuse benzodiazepines. Almost 17% of the non-abstinent patients used benzodiazepines, 15% used opiates, and 10% used cocaine during treatment. Compliance was significantly higher in residential than in the non-residential treatment facilities. Independent of level of care, 67.2% of the patients (n = 1963; P<.001) had every treatment medication found in both first and last urine specimens (compliance). In addition, 39.2% of the patients (n = 1143; P<.001) had no substance of abuse detected in either the first or last urine samples (abstinence). Moreover, in 2010, 16.9% of the patients (n = 57) were abstinent at first but not at last urine (deteriorating abstinence), the percentage dropped to 13.3% (n = 174) in 2011; this improvement over years was statistically significant. A longitudinal analysis for abstinence and compliance was studied in a randomized subset from 2011, (n = 511) representing 17.5% of the total cohort. A statistically significant upward trend (p = 2.353×10⁻⁸) of abstinence rates as well as a similar but stronger trend for compliance ((p = 2.200×10⁻¹⁶) was found. Being cognizant of the trend toward drug urine testing being linked to medical necessity eliminating abusive screening, the interpretation of these valuable results require further intensive investigation.     

Treating Addictions: Harm Reduction in Clinical Care and Prevention

This paper examines the role of clinical practitioners and clinical researchers internationally in establishing the utility of harm-reduction approaches to substance use. It thus illustrates the potential for clinicians to play a pivotal role in health promoting structural interventions based on harm-reduction goals and public health models. Popular media images of drug use as uniformly damaging, and abstinence as the only acceptable goal of treatment, threaten to distort clinical care away from a basis in evidence, which shows that some ways of using drugs are far more harmful than others and that punitive approaches and insistence on total abstinence as the only goal of treatment often increases the harms of drug use rather than reducing drug use. Therefore the leadership and scientific authority of clinicians who understand the health impact of harm-reduction strategies is needed. Through a review of harm-reduction interventions in Canada, the United Kingdom, the United States, Australia, Switzerland, and the Netherlands, we identify three ways that clinicians have helped to achieve a paradigm shift from punitive approaches to harm-reduction principles in clinical care and in drug policy: (1) through clinical research to provide data establishing the effectiveness and feasibility of harm-reduction approaches, (2) by developing innovative clinical programmes that employ harm reduction, and thereby (3) changing the standard of care to include routine use of these evidence-based (but often misunderstood) approaches in their practices. We argue that through promotion of harm-reduction goals and methods, clinicians have unique opportunities to improve the health outcomes of vulnerable populations.     

Stereoselective and isozyme-selective drug interactions

A surprisingly large number of marketed drugs are racemic mixtures. The pharmacokinetic literature on racemic drugs contains a vast amount of information on drug–drug interactions derived from the measurement of total drug concentrations in plasma and urine. The appreciation of the role of stereochemistry in drug interactions with racemic warfarin resulted in a long-overdue scientific rigor being applied to the study of drug interactions. It also compelled us to recognize that much of the literature was uninterpretable. A better understanding of oxidative metabolism, particularly the complexity of the cytochrome P-450 family of enzymes, has also strengthened the scientific basis of drug interactions. We now recognize that investigators and clinicians must consider both stereoselectivity and isozyme selectivity in the study of drug interactions to understand the nature of the interaction so as to more effectively use new and potent drugs. © 1993 Wiley-Liss, Inc.     

Antifungal Dose Adjustment in Renal and Hepatic Dysfunction: Pharmacokinetic and Pharmacodynamic Considerations

Adjusting the dose of antifungal agents for renal and hepatic impairment can be challenging given that clinicians must rely on limited pharmacokinetic data to derive specific regimens. These pharmacokinetic studies are typically performed in a small number of patients without invasive fungal infection, and results are not often reported in concert with accepted pharmacodynamic indices. This article aims to review pertinent pharmacokinetic studies of antifungal drugs in patients with renal or hepatic dysfunction. The impact of novel continuous renal replacement therapy techniques on the pharmacokinetic disposition of antifungal agents will also be described where data are available. Subsequently, this review provides recommendations for antifungal drug dosing in patients with kidney or liver dysfunction after accounting for established or emerging pharmacokinetic-pharmacodynamic relationships as they relate to antifungal drug efficacy in vivo.     

Effect of glutaminic acid on the activity of the sympatho-adrenal system and the concentration of calcium in urine under conditions of development of the alcohol abstinence syndrome

The paper deals with the influence of glutaminic acid on the functional activity of the sympatho-adrenal system and the concentration of calcium in urine under conditions of the alcoholic abstinence syndrome development. Changes in the functional activity of sympatho-adrenal system and in the concentration of calcium in the process of the abstinence syndrome development are shown to be of the phase character. It is established that in the period of the developed abstinence syndrome glutaminic acid produces a normalizing action on the excretion of adrenaline and dopamine and also facilitates a decrease in the level of calcium in urine.     

Strategies for automated analysis of <Emphasis Type="Italic">C. elegans</Emphasis> locomotion

Automated analysis of C. elegans behaviour is a rapidly developing field, offering the possibility of behaviour-based, high-throughput drug screens and systematic phenotyping. Standard methods for parameterizing worm shapes and movements are emerging, and progress has been made towards overcoming the difficulties introduced by interactions between worms, as well as worm coiling and omega turning. Current methods have facilitated the identification of subtle phenotypes and the characterisation of roles of neurones in forward locomotion and chemotaxis, as well as the quantitative characterisation of behaviour choice and circadian patterns of activity. Given the speed with which C. elegans has been deployed in genetic screens and chemical screens, it is to be hoped that wormtrackers may eventually provide similar rapidity in assaying behavioural phenotypes. However, considerable progress must be made before this can be accomplished. In the case of genome-wide RNAi screens, for example, the presence in the worm genome of some 19,000 genes means that even the minimal user intervention in an automatic phenotyping system will be very costly. Nonetheless, recent advances have shown that drug actions on large numbers of worms can be tracked, raising hopes that high-throughput behavioural screens may soon be available.     

Chemical genetics and drug screening in Drosophila cancer models

Drug candidates often fail in preclinical and clinical testing because of reasons of efficacy and/or safety.It would be time- and cost-efficient to have screening models that reduce the rate of such false positive candidates that appear promising at first but fail later.In this regard,it would be particularly useful to have a rapid and inexpensive whole animal model that can pre-select hits from high-throughput screens but before testing in costly rodent assays.Drosophila melanogaster has emerged as a potential whole animal model for drug screening.Of particular interest have been drugs that must act in the context of multi-cellularity such as those for neurological disorders and cancer.A recent review provides a comprehensive summary of drug screening in Drosophila,but with an emphasis on neurodegenerative disorders.Here,we review Drosophila screens in the literature aimed at cancer therapeutics.     

Chemical genetics and drug screening in Drosophila cancer models

Drug candidates often fail in preclinical and clinical testing because of reasons of efficacy and/or safety.It would be time- and cost-efficient to have screening models that reduce the rate of such false positive candidates that appear promising at first but fail later.In this regard,it would be particularly useful to have a rapid and inexpensive whole animal model that can pre-select hits from high-throughput screens but before testing in costly rodent assays.Drosophila melanogaster has emerged as a potential whole animal model for drug screening.Of particular interest have been drugs that must act in the context of multi-cellularity such as those for neurological disorders and cancer.A recent review provides a comprehensive summary of drug screening in Drosophila,but with an emphasis on neurodegenerative disorders.Here,we review Drosophila screens in the literature aimed at cancer therapeutics.     

Machine-learning aided in situ drug sensitivity screening predicts treatment outcomes in ovarian PDX tumors

Long-term treatment outcomes for patients with high grade ovarian cancers have not changed despite innovations in therapies. There is no recommended assay for predicting patient response to second-line therapy, thus clinicians must make treatment decisions based on each individual patient. Patient-derived xenograft (PDX) tumors have been shown to predict drug sensitivity in ovarian cancer patients, but the time frame for intraperitoneal (IP) tumor generation, expansion, and drug screening is beyond that for tumor recurrence and platinum resistance to occur, thus results do not have clinical utility. We describe a drug sensitivity screening assay using a drug delivery microdevice implanted for 24 h in subcutaneous (SQ) ovarian PDX tumors to predict treatment outcomes in matched IP PDX tumors in a clinically relevant time frame. The SQ tumor response to local microdose drug exposure was found to be predictive of the growth of matched IP tumors after multi-week systemic therapy using significantly fewer animals (10 SQ vs 206 IP). Multiplexed immunofluorescence image analysis of phenotypic tumor response combined with a machine learning classifier could predict IP treatment outcomes against three second-line cytotoxic therapies with an average AUC of 0.91.     

Increased urinary F2-isoprostane excretion in alcoholic liver disease

Free radical-induced lipid peroxidation (LP) is thought to be important in alcoholic liver disease (ALD), however, direct demonstration of increased LP in patients with ALD has been difficult. Quantification of F2-isoprostanes (F2-isoP), prostanoids produced by peroxidation of arachidonic acid, in plasma and urine are sensitive and specific indices of LP in vivo. To determine if LP is increased in ALD, 24-h urinary excretion of F2-isoPs were measured in 10 patients hospitalized because of ALD. The mean urinary excretion of the F2-isoP in the ALD patients' urine was 9.6+/-3.5 ng/mg creatinine, which was significantly elevated compared to controls' urinary excretion, which was 1.7+/-0.2 ng/mg creatinine (p<.01). The urinary excretion of F2-isoP decreased to 3.6+/-1.1 ng/mg creatinine as the patients improved clinically with abstinence over the 1-month period. These data suggest that lipid peroxidation, as assessed by this noninvasive method, is increased in patients with acute ALD and decreases with time as the patients improve clinically with abstinence.     

Prenatal substance use in a Western urban community.

To assess the extent of prenatal substance use in a predominantly white population in an urban area of the western United States and to develop a risk profile for this population, a cross-sectional prevalence study was done. Prenatal clinics (10 public and 10 private) anonymously recorded demographic information about and collected aliquots of routinely obtained urine specimens from women during prenatal visits. Urine specimens were screened by enzyme immunoassay for amphetamines, marijuana, cocaine, opiates, and ethanol. Of the 935 women screened, 92 (9.8%) had urine specimens positive for one or more of these substances. Urine screens were positive in 56 (10.0%) of 562 women attending private clinics and 36 (9.6%) of 373 women attending public clinics. Only 7 of the 935 women (0.7%) had screens positive for cocaine. Ethanol was the most frequently detected substance in the private clinic group (6.4%), whereas marijuana was most common among women attending public clinics (5.1%). Although substance use in this group of pregnant women occurs at a lower rate and a different pattern from those found in other more densely populated areas, the rate is high enough to be of concern to all prenatal care professionals, who should incorporate substance use history taking and selective urine drug screening into their routine prenatal practices.     

Drugs, hERG and sudden death

Early recognition of potential QT/TdP liability is now an essential component of the drug discovery/drug development program. The hERG assay is an indispensable step and a high-quality assay must accompany any investigational new drug (IND) application. While it is the gold standard at present, the hERG assay is too labor-intensive and too low throughput to be used as a screen early in the discovery/development process. A variety of indirect high throughput screens have been used.     

慢性肾盂肾炎L型细菌感染及耐药分析

目的了解L型细菌在慢性肾盂肾炎的感染及耐药状况。方法对71例患者清洁中段尿做普通细菌培养(B型)、L型细菌培养(L型)及耐药分析。结果细菌阳性率为77.5%,其中单独L型阳性率为49.3%、B型与L型混合感染为15.5%,而B型阳性率仅为12.7%。主要是大肠埃希菌,其次是葡萄球菌;青霉素及头孢噻肟均有较高的耐药率(88.9%及73.6%)。结论L型细菌在慢性肾盂肾炎感染中占主导,β-内酰胺类药物有较高的耐药性,临床治疗应据药敏结果合理选择及时调整抗生素。     

Desensitization and coupled receptors: a model of drug dependence

It is assumed that certain drug receptors are so coupled with certain physiological receptors that stimulation of either receptor increases the sensitivity of the other. If the drug receptor suffers tolerance (i.e. slow desensitization) and if insensitivity of the drug receptor also makes the physiological receptor insensitive, then tolerance must be responsible for a physiological deficiency. This may be remedied by increased drug administration which will raise the sensitivity of the remaining physiological receptors so that a normal or near-normal physiological situation is achieved. Thus the organism is not only tolerant to the drug but also dependent on it. If such theoretical considerations apply to opiate receptors (as drug receptors) and to catecholamine receptors (as physiological receptors), then the theory predicts that acute morphine administration increases the sensitivity of dopamine receptors, that sympathetic stimulation decreases pain sensitivity, that opioid tolerance provokes increased catecholamine activity, that alpha-receptor stimulants attenuate and alpha-receptor antagonists exacerbate morphine abstinence, and that catecholaminergic inhibition results in increased morphine toxicity. All of these predictions have been verified experimentally.     

Treatment of idiopathic hypercalciuria with indapamide.

Twenty-six patients with idiopathic hypercalciuria (urine calcium level greater than 300 mg/24 h [7.5 mmol/d]) were treated with indapamide (a nonthiazide diuretic), 2.5 mg/d for 3 consecutive months. A mean decrease in urine calcium levels of 52% was noted (p less than 0.05). When therapy with indapamide was stopped, the calcium levels returned to pretherapy values. The effect of indapamide on urine calcium levels was similar to that of hydrochlorothiazide in 10 patients who were receiving the latter drug before therapy with indapamide. The results show that indapamide is an efficient drug for the treatment of idiopathic hypercalciuria.     

From Abstinence to Relapse: A Preliminary Qualitative Study of Drug Users in a Compulsory Drug Rehabilitation Center in Changsha,China

Background

Relapse among abstinent drug users is normal. Several factors are related to relapse, but it remains unclear what individuals’ actual life circumstances are during periods of abstinence, and how these circumstances facilitate or prevent relapse.

Objective

To illuminate drug users’ experiences during abstinence periods and explore the real-life catalysts and inhibitors contributing to drug use relapse.

Method

Qualitative in-depth interviews were conducted with 20 drug users recruited from a compulsory isolated drug rehabilitation center in Changsha. The interviews were guided by open-ended questions on individuals’ experiences in drug use initiation, getting addicted, treatment history, social environment, abstinence, and relapse. Participants were also encouraged to share their own stories. Interviews were digitally recorded and fully transcribed. The data of 18 participants who reported abstinence experiences before admission were included in the analyses. The data were analyzed using a thematic analysis with inductive hand coding to derive themes.

Results

Most drug users were able to successfully abstain from drugs. During abstinence, their lives were congested with challenges, such as adverse socioeconomic conditions, poor family/social support, interpersonal conflicts, and stigma and discrimination, all of which kept them excluded from mainstream society. Furthermore, the police’s system of ID card registration, which identifies individuals as drug users, worsened already grave situations. Relapse triggers reported by the participants focused mainly on negative feelings, interpersonal conflicts, and stressful events. Craving was experienced but not perceived as a relapse trigger by most participants.

Conclusions

This study of in-depth interview with drug users found evidence of situations and environments they live during abstinence appear rather disadvantaged, making it extremely difficult for them to remain abstinent. Comprehensive programs on relapse prevention that acknowledge these disadvantages are implicated.     

Dissociated Grey Matter Changes with Prolonged Addiction and Extended Abstinence in Cocaine Users

Extensive evidence indicates that current and recently abstinent cocaine abusers compared to drug-naïve controls have decreased grey matter in regions such as the anterior cingulate, lateral prefrontal and insular cortex. Relatively little is known, however, about the persistence of these deficits in long-term abstinence despite the implications this has for recovery and relapse. Optimized voxel based morphometry was used to assess how local grey matter volume varies with years of drug use and length of abstinence in a cross-sectional study of cocaine users with various durations of abstinence (1–102 weeks) and years of use (0.3–24 years). Lower grey matter volume associated with years of use was observed for several regions including anterior cingulate, inferior frontal gyrus and insular cortex. Conversely, higher grey matter volumes associated with abstinence duration were seen in non-overlapping regions that included the anterior and posterior cingulate, insular, right ventral and left dorsal prefrontal cortex. Grey matter volumes in cocaine dependent individuals crossed those of drug-naïve controls after 35 weeks of abstinence, with greater than normal volumes in users with longer abstinence. The brains of abstinent users are characterized by regional grey matter volumes, which on average, exceed drug-naïve volumes in those users who have maintained abstinence for more than 35 weeks. The asymmetry between the regions showing alterations with extended years of use and prolonged abstinence suggest that recovery involves distinct neurobiological processes rather than being a reversal of disease-related changes. Specifically, the results suggest that regions critical to behavioral control may be important to prolonged, successful, abstinence.     

New designer drug p-methoxymethamphetamine: studies on its metabolism and toxicological detection in urine using gas chromatography-mass spectrometry

Studies are described on the metabolism and the toxicological analysis of the new designer drug rac-p-methoxymethamphetamine (PMMA) in rat urine using gas chromatography-mass spectrometry (GC-MS). The identified metabolites indicated that PMMA was extensively metabolized mainly by O-demethylation to pholedrine and to a minor extent to p-methoxyamphetamine (PMA), 1-hydroxypholedrine diastereomers (one being oxilofrine), 4'-hydroxy-3'-methoxymethamphetamine and 4'-hydroxy-3'-methoxyamphetamine. The authors' systematic toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation allowed the detection of the main metabolites of PMMA in rat urine after a dose corresponding to that of drug users. Therefore, this procedure should be suitable for detection of PMMA intake in human urine via its metabolites. However, it must be considered that pholedrine and oxilofrine are also in therapeutic use. Differentiation of PMMA, PMA and/or pholedrine intake is discussed.     

Neurophysiological and Psychophysiological Effects of Sulpiride in the Norm and in Patients with Opiate Addiction

We studied characteristics of the EEG activity and psychophysiological indices in healthy persons and patients with opiate addiction (in the states of abstinence and remission) before and after peroral introduction of 200 mg sulpiride. In the initial state, spectral characteristics of EEG in patients with opiate addiction differed from those in the control (in healthy tested subjects) by higher relative powers of low- and high-frequency components (delta and beta waves) and a considerable depression of the alpha rhythm. Treatment with sulpiride evoked changes in the spectral characteristics of EEG, which showed a significant intergroup specificity; intensification of alpha oscillations was a general effect in all groups. We conclude that the effects of sulpiride on the EEG activity comprised components typical of both neuroleptics and antidepressants; in the group of patients in the abstinence state, the pattern of effects of sulpiride was close in its profile to the effect of anxiolytics. Dynamics of the indices of psychophysiological testing after sulpiride treatment demonstrated that the drug exerts mostly positive regulating effects on the state of higher nervous functions in patients with opiate addiction.