Psychosocial and pharmacologic interventions for methamphetamine addiction: protocol for a scoping review of the literature.

BACKGROUND: Methamphetamine use and harms are rising rapidly. Management of patients with methamphetamine use disorder (MUD) and problematic methamphetamine use (PMU) is challenging, with no clearly established best approach; both psychosocial and pharmacologic interventions have been described. Furthermore, given the diversity of individuals that use methamphetamines, there is a need to assess evidence for treatments for subgroups including youths; gay, bisexual, and other men who have sex with men; individuals with mental health comorbidities; and individuals in correction services. Establishing awareness of the messages regarding treatment from recent clinical practice guidelines (CPG) in the field is also of value. The first study objective will be to establish a greater understanding of the methods, populations, and findings of controlled studies for psychosocial and pharmacologic treatments for MUD and PMU. Investigation of this information can help establish the potential for advanced syntheses of the evidence (such as network meta-analysis) to compare therapies for this condition and to identify gaps related to key populations where more primary research is needed. Summarizing the recommendations regarding treatment of MUD/PMU from recent CPGs and systematic reviews will be an important secondary objective. METHODS: A scoping review will be performed. Using the OVID platform, MEDLINE, Embase, PsycINFO, and relevant Cochrane databases from EBM Reviews will be searched (from databases' inception onwards). Eligibility criteria will include individuals described as having MUD or PMU, with designs of interest including randomized trials, non-randomized trials, and controlled cohort studies with three or more months of follow-up; systematic reviews and CPGs will also be sought. Two reviewers (with support from automation tools) will independently screen all citations, full-text articles, and chart data. Different approaches to handling and summarizing the data will be implemented for each type of study design. Tables and graphics will be used to map evidence sources and identify evidence gaps. DISCUSSION: This research will enhance awareness of evidence addressing the effects of psychosocial and pharmacologic interventions for MUD/PMU overall and in sub-populations, both in terms of recent CPGs/reviews and primary studies; inspection of the latter will also help establish the feasibility of future syntheses to compare treatments, such as network meta-analysis. SYSTEMATIC REVIEW PROTOCOL REGISTRATION: Open Science Framework ( https://osf.io/9wy8p ).

Fuzzy logic pharmacokinetic modeling: application to lithium concentration prediction.

INTRODUCTION: We hypothesized that fuzzy logic could be used for pharmacokinetic modeling. Our objectives were to develop and evaluate a model for predicting serum lithium concentrations with fuzzy logic. METHODS: Steady-state pharmacokinetic data had been previously collected in 10 elderly patients (age range, 67 to 80 years) with depression who were receiving lithium once daily. Each patient had serial serum lithium concentration determinations over one 24-hour period. The resulting 137 data sets initially consisted of five input variables (age, weight, serum creatinine, lithium dose, and time since last dose) and one output variable (serum lithium concentration; range, 0.2 to 1.24 mmol/L). RESULTS: A fuzzy rulebase was created with 87 randomly chosen data sets, and predictions of serum lithium concentration were made on the basis of the remaining 50 data sets. All of the input variables except age and weight were identified as contributing to the fuzzy logic model. The average magnitude of the error in the predictions was 0.13 mmol/L (root mean squared error) with a bias (mean of the prediction errors) of 0.03 mmol/L. CONCLUSIONS: This study indicates that the use of fuzzy logic for pharmacokinetic modeling of lithium for serum concentration predictions is feasible.

Rapid onset of emphysema associated with diffuse parenchymal disease.

In experimental models pulmonary emphysema may be produced in hours to days; however, in human subjects emphysema commonly develops over a period of many years. In this report we document a case of severe emphysema which developed in less than six months in association with an unexplained illness characterized by dyspnea, hypoxemia and bilateral lung parenchymal disease. There was no hereditary predisposition. The diffuse alveolar injury syndrome must be considered as a potential cause of alveolar disruption.

Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence.

The potential for drug-drug interactions in psychiatric patients is very high as combination psychopharmacotherapy used to treat comorbid psychiatric disorders, to treat the adverse effects of a medication, to augment a medication effect or to treat concomitant medical illnesses. Interactions can be pharmacodynamic or pharmacokinetic in nature. This paper focuses on the metabolic kinetic interactions between selective serotonin reuptake inhibitors (SSRIs) and other central nervous system (CNS) drugs. The evidence for and clinical significance of these interactions are reviewed, with special emphasis on antipsychotics, tricyclic antidepressants and benzodiazepines. Many psychotropic medications have an affinity for the cytochrome P450 (CYP) enzymes which promote elimination by transforming lipid soluble substances into more polar compounds. SSRIs serve both as substrates and inhibitors of these enzymes. In vitro studies provide a screening method for evaluating drug affinities for substrates, inhibitors or inducers of CYP enzymes. Although in vitro data are important as a starting point for predicting these metabolic kinetic drug interactions, case reports and controlled experimental studies in humans are required to fully evaluate their clinical significance. Several factors must be considered when evaluating the clinical significance of a potential interaction including: (a) the nature of each drugs' activity at an enzyme site (substrate, inhibitor or inducer); (b) the potency estimations for the inhibitor/inducer; (c) the concentration of the inhibitor/inducer at the enzyme site; (d) the saturability of the enzyme; (e) the extent of metabolism of the substrate through this enzyme (versus alternative metabolic routes); (f) the presence of active metabolites of the substrate; (g) the therapeutic window of the substrate; (h) the inherent enzyme activity of the individual, phenotyping/genotyping information; (i) the level of risk of the individual experiencing adverse effects (e.g. the elderly) and (j) from an epidemiological perspective, the probability of concurrent use. This paper systematically reviews both the in vitro and in vivo evidence for drug interactions between SSRIs and other CNS drugs. As potent inhibitors of CYP2D6, both paroxetine and fluoxetine have the potential to increase the plasma concentrations of antipsychotic medications metabolised through this enzyme, including perphenazine, haloperidol, thioridazine and risperidone in patients who are CYP2D6 extensive metabolisers. Controlled studies have demonstrated this for perphenazine with paroxetine and haloperidol with fluoxetine. Fluvoxamine, as a potent inhibitor of CYP1A2, can inhibit the metabolism of clozapine, resulting in higher plasma concentrations. Drug interactions between the SSRIs and tricyclic antidepressants (TCAs) can occur. Fluoxetine and paroxetine, as potent inhibitors of CYP2D6, can increase the plasma concentrations of secondary and tertiary tricyclic antidepressants. Sertraline and citalopram are less likely to have this effect. Fluvoxamine can increase the plasma concentrations of tertiary TCAs. Fluvoxamine inhibits, via CYP3A. CYP2C19 and CYP1A2, the metabolism of several benzodiazepines, including alprazolam, bromazepam and diazepam. Fluoxetine increases the plasma concentrations of alprazolam and diazepam by inhibiting CYP3A and CYP2C19, respectively. The clinical importance of the interaction with diazepam is attenuated by the presence of its active metabolite. Sertraline inhibits these enzymes only mildely to moderately at usual therapeutic doses. Therefore the potential for interactions is less; however, the in vivo evidence is minimal. Paroxetine and citalopram are unlikely to cause interactions with benzodiazepines. The evidence is conflicting for an interaction between carbamazepine and the SSRIs fluoxetine and fluvoxamine. These combinations should be used cautiously, and be accompanied by monitoring for adverse events and carb

Effect of alprazolam on exercise and dyspnea in patients with chronic obstructive pulmonary disease.

To evaluate the efficacy of a mild anxiolytic, alprazolam, in relieving dyspnea, we conducted a randomized, placebo-controlled double-blind study on patients with chronic obstructive lung disease. Twenty-four patients had alprazolam (0.5 mg bid) or placebo administered for one week, followed by placebo for one week, then either placebo or alprazolam for the third week. Assessment tests were performed at the outset, end of the first and second weeks, and finally end of the third week. The parameters measured were: pulmonary function, exercise testing on a bicycle ergometer, and the distance covered in a 12 minute walk. Subjective sensations of dyspnea at rest and during guarded exercise, as well as subjective feelings of calmness or anxiety were also recorded. There was no difference in mechanical lung function, but the PO2 tended to decrease and PCO2 to increase after alprazolam administration. The maximum exercise level attained and the distance covered in the 12 minute walk was unchanged. The subjective perception of dyspnea was the same before and after alprazolam, at rest and during exercise. We conclude that alprazolam is not effective in relieving exercise dyspnea in patients with obstructive lung disease.

Endobronchial tuberculosis presenting as asthma.

Clinical deterioration with features suggestive of asthma was seen in three patients following two to six months of drug therapy of primary tuberculosis. There was a poor clinical response to administered bronchodilators. Bronchoscopy in all three revealed culture-negative mycobacterial caseating granulomas. Corticosteroid therapy resulted in good clinical response, with resolution of the asthmatic symptoms and improvement in the expiratory flow rates. In our opinion these patients are clinically compatible with a hypersensitivity response to mycobacteria following antituberculosis therapy and release of tuberculosis antigens. Corticosteroid therapy is appropriate in this form of tuberculous disease.

Cyclosporine and chronic sarcoidosis.

Two patients with progressive sarcoidosis who had poor responses and side effects from corticosteroid therapy were treated with cyclosporine. Cyclosporine suppressed conventional markers of inflammation and there was clinical improvement in one patient, but the disease recurred when therapy was discontinued. The second patient who had diabetes mellitus developed unstable glucose metabolism when given cyclosporine. This unstable diabetes mellitus together with side effects of nausea and vomiting resulted in weight loss and inadequate serum therapeutic levels that was associated with a poor therapeutic response to the cyclosporine. The major side effects in both patients were headache and gastrointestinal symptoms, but there was no renal dysfunction. We conclude that while corticosteroids remain the mainstay of sarcoid therapy, when these drugs have not been successful for the skin manifestations of the disease, a trial of cyclosporine may be justified.

Adrenocortical function in patients investigated for active tuberculosis.

Previous reports have identified adrenal insufficiency in groups of patients with active pulmonary tuberculosis. To investigate this possibility, serum cortisol levels were measured in consecutive patients admitted to the hospital for investigation of active tuberculosis. Blood was drawn for cortisol determination promptly at the time of hospital admission, in the morning and afternoon before commencing chemotherapy for the suspected tuberculosis, and before the diagnosis was confirmed. Thirty-seven patients were assessed; 19 of these patients were subsequently proven to have active pulmonary tuberculosis, six had pulmonary disease caused by mycobacteria other than tuberculosis, and 12 had radiologic appearance indicating tuberculosis, accompanied by a significant tuberculin skin reaction but with negative sputum cultures and no change in roentgenographic appearance during the course of treatment. In evaluating the adrenocortical function, the morning and afternoon serum cortisol level was measured and the diurnal change in serum cortisol level (the difference between afternoon and morning levels) was calculated. There was no association of either morning cortisol levels or diurnal change in cortisol levels with age, gender, or race. There was no difference among the three groups in either cortisol determination. Although difference in morning cortisol levels between those with extensive as compared with limited disease was not statistically significant (p = 0.349 from analysis of variance), there was a significantly decreased diurnal change in cortisol levels in those with extensive disease as compared with those with limited disease (+2.7 +/- 188.3 vs -259.1 +/- 177.1). We conclude that patients in our hospital with active pulmonary tuberculosis do not exhibit decreased adrenocortical function as compared with groups of patients without active pulmonary tuberculosis.

Hypothalamic-pituitary-adrenal function in extrinsic asthma.

Hypothalamic-pituitary-adrenal function in a well-defined, carefully selected group of 25 patients with extrinsic asthma was assessed by measuring plasma levels of adrenocorticotropic hormone (ACTH) and of 11-deoxycorticol after administration of metyrapone and by measuring the level of cortisol following stimulation with cosyntropin. No difference was demonstrated between asthmatic subjects and 20 normal age-matched controls. In addition, neither the response of the level of ACTH nor of 11-deoxycortisol correlated with the duration of asthma or the severity as assessed in 23 patients by tests of pulmonary function. We conclude that there is no abnormality in hypothalamic-pituitary-adrenal function in patients with extrinsic asthma, and we suggest that previous data suggesting such an abnormality may reflect heterogeneous groups of patients, inaccurate methods, and the variability of normal responses to ACTH and stimulation with metyrapone.

The effect of methacholine inhalation challenge on regional residual volume in patients with subclinical asthma.

Regional residual volume to total lung capacity (RVr/TLCr) was measured with xenon 133 before and after methacholine challenge in 26 nonsmoking subjects (mean age 34 years). Eleven were normal control subjects and 15 were patients referred for methacholine challenge because of previous asthma-like symptoms. All had normal pulmonary function and normal RVr/TLCr distribution. Following methacholine challenge, RVr/TLCr increased in two control subjects and ten patients who also had decreases in FEV1 of greater than 20 percent. The RVr/TLCr changes were patchy, suggesting that the degree of bronchospasm varied between individual lung regions. The other 14 subjects did not have a 20 percent decrease in FEV1, but two controls and four patients had generalized increases in RVr/TLCr, while seven controls and one patient had no significant changes in RVr/TLCr. In all subjects, FEV1 and RVr/TLCr returned to the baseline level after salbutamol administration. The results indicate that methacholine can cause localized or diffuse effects on lung emptying and that bronchodilator completely reverses the bronchoconstriction induced by methacholine.

Reversible ventilation and perfusion abnormalities in unilateral obstructed lung.

An intraluminal carcinoid tumor obstructing the left mainstem bronchus produced hypoxemia through alteration in ventilation/perfusion matching. Studies of regional lung function using 133-xenon (133Xe) and a multiprobe computerized instrumentation system documented a reduction of perfusion to 22 percent and ventilation to 6 percent of the total. There was negligible washout of intravenously injected 133Xe from the left lung consistent with air trapping. Four days after left mainstem bronchial sleeve resection, perfusion, ventilation and washout of injected xenon had significantly improved and by four months postresection, all measurements were virtually normal, although complete restoration of perfusion in relation to ventilation was delayed. Regional lung function studied with a multiprobe system in this patient provided a clinical model for the study of ventilation and perfusion inter-relationships in large airway obstruction and demonstrated that a prolonged time may be required for return of perfusion to normal.

Differential pharmacokinetics of lithium in elderly patients.

The pharmacotherapeutic use of lithium in the elderly as acute and maintenance therapy in bipolar disorder and augmentation therapy for major depression is well documented. Differences in the response to lithium are explained, in part, by the effect of age-related physiological changes, comorbid conditions, and concurrent medications on the pharmacokinetics of lithium in the elderly. The pharmacokinetic profile of lithium has been studied for many years, primarily in younger adult populations. Lithium pharmacokinetics may be influenced by a number of factors including age. It was first noted several years ago that elderly individuals required lower doses of lithium to achieve serum concentrations similar to those observed in younger adults. This is due to the combination of a reduced volume of distribution and reduced renal clearance. The composition of the human body changes with aging producing an increase in body fat, a decrease in fat-free mass and a decrease in total body water. Lithium clearance decreases as the glomerular filtration rate decreases with increasing age. The effects of other medical conditions in the elderly on the pharmacokinetics of lithium are less well delineated. Reduced lithium clearance is expected in patients with hypertension, congestive heart failure or renal dysfunction. Larger lithium maintenance doses are required in obese compared with non-obese patients. The most clinically significant pharmacokinetic drug interactions associated with lithium involve drugs which are commonly used in the elderly. Thiazide diuretics, ACE inhibitors, and nonsteroidal anti-inflammatory drugs can increase serum lithium concentrations. The tolerability of lithium is lower in the elderly. Neurotoxicity clearly occurs in the elderly at concentrations considered 'therapeutic' in general adult populations. There are no placebo-controlled randomised trials of lithium in old age and recommendations for clinical use are based on extrapolations from pharmacokinetic studies, anecdotal reports from mixed age populations and clinical experience in old age psychiatry. Serum concentrations of lithium need to be markedly reduced in the elderly population and particularly so in the very old and frail elderly.

Metabolic interactions of central nervous system medications and selective serotonin reuptake inhibitors.

Selective serotonin reuptake inhibitors (SSRIs) are prescribed alone and in combination with other psychotropic medications in the treatment of a variety of psychiatric disorders. Such combinations create the potential for pharmacokinetic interactions by affecting the activity of the cytochromes P450 (CYP450), drug metabolizing oxidative enzymes. SSRIs are not equivalent in their potential for interactions when combined with other central nervous system (CNS) medication. Generally citalopram and sertraline are characterized by weaker inhibition of CYP450 enzymes and, therefore, hold less potential for interaction than the other SSRIs. Paroxetine potently inhibits CYP2D6, which can result in increased neuroleptic serum concentrations, accompanied by increased CNS side-effects. Similarly, as a potent inhibitor of CYP2D6, fluoxetine can increase serum concentrations of neuroleptics and antidepressants and numerous case reports have documented concomitant adverse events. Fluoxetine also inhibits CYP3A and CYP2C19, increasing serum concentrations of some benzodiazepines. Fluvoxamine is a potent inhibitor of CYP1A2, a moderate inhibitor of CYP3A and a mild inhibitor of CYP2D6. Therefore, interactions with clozapine and benzodiazepines are evident.

Use of prescription and nonprescription hypnotics in a Canadian elderly population.

BACKGROUND: Hypnotics are commonly used by older adults, yet little is known about the patterns of their use and effectiveness in this population. METHODS: Three thousand eight hundred sixty anonymous, self-report surveys were distributed to community pharmacies (n=356) across Canada to obtain information on the patterns of use of hypnotics from elderly volunteers. RESULTS: The mean age of respondents was 72+/-7 years (range 60 to 95 years) and 66% were women. In the past year, 53% of respondents used hypnotics. Prescription products accounted for 83% of the past year's use (66% benzodiazepines, 11% zopiclone, 4% antidepressants, 2% opioids), and 17% of the products used were over-the-counter (5% herbal, 5% antihistamines, 3% analgesics). Use was regular (50% daily) and chronic (mean duration six years: range two weeks to 30 years). Hypnotics significantly (P<0.001) improved subjective sleep latency (mean 32 min compared with 93 min), number of nocturnal awakenings (mean two compared with four) and total hours of sleep (mean 7 h compared with 4 h). Effectiveness was highly rated: at the most recent use of the product, mean 7.6 (SD+/-2.2) of 10; initially, 7.9 (SD+/-2.3) with a significance of P=0.02. Most respondents (59%) reported side effects, mainly dry mouth (30%), memory problems (22%) and daytime sleepiness (22%), although 60% rated the side effects as mild. The mean number of other medications used was five (range zero to 17). Of the 54 subjects who used nonprescription sleep products, only half (52%) indicated that their physician was aware of this use. CONCLUSIONS: Prescription drugs were primarily used for sleep and were perceived to be effective even with long term use, despite mild side effects.

Effects of venesection on cerebral function in chronic lung disease.

Regional cerebral blood flow measurements and neuropsychological testing were conducted before and after venesection on 6 patients with polycythemia secondary to chronic obstructive pulmonary disease. Venesection resulted in lowered viscosity and hematocrit, and an accompanying improvement in cerebral perfusion and mental function. Blood flow was significantly increased in the left cerebral hemisphere following phlebotomy, and there was significant improvement in sensory/mental function. Cerebral function would appear to be related to blood flow alterations influenced by the viscosity of the blood.

Idiopathic pulmonary hemosiderosis, complete heart block and celiac disease.

A 24-year-old male with recurrent hemoptysis due to idiopathic pulmonary hemosiderosis and celiac sprue developed infranodal heart block necessitating implantation of a pacemaker. A possible common underlying mechanism is discussed.

The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol - a randomized study.

BACKGROUND: Retrospective accounts suggest that therapeutic doses of paracetamol can produce severe hepatic injury in patients with putative high-risk conditions, including alcoholism and infectious hepatitis. Metabolism of paracetamol to its hepatotoxic metabolite is enhanced in patients who abuse alcohol, who also have compromised liver defences from depressed hepatic glutathione. AIM: To determine the effect of paracetamol on serum liver tests of newly abstinent subjects who abuse alcohol, including subjects with hepatitis C infection. METHODS: A randomized, double-blind, placebo-controlled study. Adult alcohol abusers with a current drinking episode longer than 7 days received either placebo or paracetamol 4 g/day for 5 days. RESULTS: Of 142 subjects enrolled, 74 received paracetamol and 68 received placebo. Mean ALT activity during treatment increased from 48 to 62 IU/L in the paracetamol group and from 47 to 49 IU/L in the placebo group. Maximum ALT was 238 and 249 IU/L in the paracetamol and control groups respectively. The INR remained unchanged and serum bilirubin decreased in both groups. Subgroup analyses for subjects with alcoholic hepatitis, hepatitis C virus antibody and other subgroups showed no statistical difference between groups. CONCLUSION: Administration of paracetamol 4 g/day appears safe in newly abstinent patients who abuse alcohol.