[Pitfalls in psychopharmacological drug use]. / Psyykenlääkkeiden käytön sudenkuopat.

Psychiatric drug therapy is based on diagnoses and controlled examinations Psychiatric illnesses or disorders are, however, heterogenous conditions in their nature and treatment response. It is not possible to know beforehand whether a drug is beneficial or actually harmful for an individual patient. In practice, the use of psychopharmacological drugs is actually experimental, and success will require critical monitoring of the response, flexibility and good pharmacotherapeutic rapport. The pitfall in the use of all psychopharmacological drugs is cessation of effective treatment and, on the other hand, unnecessary medication that sometimes involves even dangerous adverse effects.

Treatment of anxiety from musical obsessions with a cognitive behaviour therapy tool.

Musical obsessions and hallucinations are disturbing experiences of repeating internal music. Antipsychotic medication can sometimes reduce these symptoms but can also trigger or augment them. We report the case of a female patient with schizophrenia with drug-resistant obsessive musical hallucinations. The patient volunteered to participate in a 9-month pilot study to follow the development of the condition using an involuntary music and mood inventory. The patient perceived benefits from the intervention, including reduced anxiety, increased feeling of being in control and understanding the condition better. Findings from this case study suggest that cognitive therapy can be a useful complementary method of care for persons with musical obsessions. The presented tool requires further investigations among those with this rare condition.

[Drug-associated hyperthermic syndromes]. / Lääkkeisiin liittyvät hypertermiset oireyhtymät.

Drug-associated hyperthermic syndromes include the serotonin syndrome, neuroleptic malignant syndrome, neuroleptic-induced catatonia, anticholinergic syndrome, sympatomimetic syndrome and malignant hyperthermia. Discontinuation of medication is a sufficient treatment for mild serotonin syndrome. In a more severe situation the patient's spasticity and hyperthermia are treated with drugs. In neuroleptic malignant syndrome discontinuation of medication does not suffice, but the patient needs active therapy. Many of the drugs causing these syndromes are common in clinical use. Starting an effective treatment early enough is more important than a precise diagnosis.

[Smoking and drug interactions]. / Tupakointi ja lääkeinteraktiot.

Smoking causes certain clinically significant drug interactions. Polycyclic aromatic hydrocarbons induce CYP1A2 enzyme, which is important in metabolism of several drugs. This enzyme induction can lead todecreased efficacy of certain psychoactive drugs, teophylline, warfarin, certain antiarythmicsand anticancer drugs. In addition, nicotine may interfere with the action of beta-blockers and benzodiatsepines through pharmacodynamic mechanisms. After smoking cessation the induced metabolism begins to normalize increasing the risks related to elevated drug concentrations. The risk is highestwhen using drugs with narrow therapeutic ratio, such as clozapine and theophylline. Compared to enzyme inhibition, enzyme-induction takes significantly longer to develop and longer to normalize after abolition of the enzyme inductor. When planning smoking cessation or when a smoker is acutely hospitalized, the medication has to be screened and need for changes in dosages and measurements of drug concentrations to be evaluated.

Benzodiazepines and sedative-hypnotics in blood of drivers under the influence and their association with other common illegal drug use and national sales figures.

The authors examined benzodiazepine and sedative-hypnotic positive cases of drivers under the influence (DUI) in Finland from 1997 to 2008. Factors studied were the number of cases positive for the most commonly encountered of these pharmaceuticals, simultaneous use of amphetamine and/or cannabis, and the relationship between the number of DUI cases and overall sales in Finland for the individual pharmaceuticals. Data for 20037 cases positive for the relevant drugs were retrieved from the laboratory database of the Alcohol and Drug Analytics Unit, National Institute for Health and Welfare. Toxicological results were from blood analysis. Drug sales figures for each pharmaceutical were obtained from the Finnish Medicines Agency. An increase in DUI cases that were positive for the drugs studied was evident, which reflected the overall increase in positive DUI cases detected annually. The proportion of relevant cases was typically 75% or higher of all positive DUI cases up to 2003, the year that the Finnish zero tolerance law was introduced, and then decreased to 66.2% in 2008. Diazepam was consistently the most commonly detected nonmetabolite drug. The prevalence of clonazepam and alprazolam increased sharply from 2004 onward. Metabolites of diazepam, nordiazepam, temazepam, and oxazepam, were other common findings. Associated use of amphetamine and/or cannabis was also common in these DUI cases, typically between 56% and 66% of cases. An increase in the number of DUI cases showing combined use of benzodiazepines and sedative-hypnotics with amphetamines in particular was apparent after zero tolerance legislation and the introduction in 2005 of an effective on-site screening device for the stimulant. Ratios of DUI cases to sales figures showed an increase in detection of clonazepam-positive DUI cases from 2003. Diazepam, midazolam, and alprazolam also exhibited relatively high ratios, which increased from 1997 to 2008.

Effects of grapefruit juice on the pharmacokinetics of acebutolol.

AIMS: We aimed to investigate effects of grapefruit juice on acebutolol pharmacokinetics. METHODS: In a randomized cross-over study, 10 healthy subjects ingested 200 mL grapefruit juice or water three times daily for 3 days and twice on day 4. On day 3, each subject ingested 400 mg acebutolol with grapefruit juice or water. The concentrations of acebutolol and its metabolite diacetolol were measured in plasma and urine up to 33 h. RESULTS: Grapefruit juice decreased the peak plasma concentration (Cmax) of acebutolol by 19% from 872 +/- 207 ng mL(-1) to 706 +/- 140 ng mL(-1) (95% CI on the difference -306, -26.4; P < 0.05), and the area under the concentration time curve (AUC(0-33 h)) by 7%, from 4498 +/- 939 ng mL(-1) h to 4182 +/- 915 ng mL(-1) h (95% CI -609, -23.0; P < 0.05). The half-life (t1/2) of acebutolol prolonged from 4.0 to 5.1 h (P < 0.05). The time to peak concentration and the amount of acebutolol excreted into urine (Ae) were unchanged. The Cmax, AUC(0-33 h), and Ae of diacetolol were decreased by 24% (P < 0.05), 18% (P < 0.05), and 20% (P < 0.01), respectively, by grapefruit juice. CONCLUSION: Grapefruit juice caused a small decrease in the plasma concentrations of acebutolol and diacetolol by interfering with gastrointestinal absorption. The interaction between the grapefruit juice and acebutolol is unlikely to be of clinical significance in most of the patients.

Effect of caffeine-containing versus decaffeinated coffee on serum clozapine concentrations in hospitalised patients.

Clozapine and caffeine are metabolised mainly by the cytochrome P4501A2 (CYP1A2) enzyme. Studies suggest that caffeine in coffee inhibits clozapine metabolism and increases serum clozapine concentrations. Our objective was to study whether coffee in the amounts usually consumed has an effect on steady-state serum clozapine concentrations. A randomised placebo-controlled cross-over design with two phases was used. Twelve hospitalised clozapine-using patients volunteered in the study where, after one-week run-in period, either caffeine-containing or decaffeinated instant coffee was available ad libitum for seven days. Serum concentrations of clozapine, N-desmethylclozapine, clozapine-N-oxide, caffeine, paraxanthine and C-reactive protein were measured after run-in period and on days 4 and 8 of the following study phases. Two patients were excluded from the statistical analysis because of non-compliance based on serum caffeine and paraxanthine determinations. In six fully compliant patients caffeine-containing coffee increased the mean serum trough concentration of clozapine by 26% (non-significant (NS), 95% CI -3% to +54%, P=0.07), N-desmethylclozapine by 6% (95% CI 1% to 12%, P=0.03), and clozapine-N-oxide by 7% (NS, 95% CI -6% to +20%, P=0.22). The ratio of N-desmethylclozapine/clozapine decreased by 13% (NS, 95% CI -1% to +27%, P=0.06) and that of clozapine-N-oxide/clozapine by 7% (NS, 95% CI -5% to +17%, P=0.19). In the analysis of combined data (including day 4 data of the four patients compliant up to that point) serum trough concentration of clozapine was 20% (95% CI 3% to 37% to P=0.03) higher, and that of N-desmethylclozapine 7% (95% CI 2% to 13%, P=0.02) higher during the caffeine phase than during the decaffeinated phase. We conclude that the effect of instant coffee drinking on serum clozapine concentrations is of minor clinical relevance in most of the patients, but some individuals may be more sensitive to this interaction due e.g. to genetic factors. The increase in serum clozapine concentration was most likely due to the inhibition of the CYP1A2 enzyme by caffeine.

Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole.

OBJECTIVE: Our objective was to examine the effects of itraconazole on the pharmacokinetics and cortisol-suppressant activity of budesonide administered by inhalation. METHODS: In a randomized, double-blind, 2-phase crossover study, 10 healthy subjects took 200 mg itraconazole or placebo orally once a day for 5 days. On day 5, 1 hour after the last dose of itraconazole or placebo, 1000 microg budesonide was administered by inhalation. Plasma budesonide and cortisol concentrations were measured up to 23 hours. RESULTS: Itraconazole increased the mean total area under the plasma concentration-time curve of inhaled budesonide 4.2-fold (range, 1.7-fold to 9.8-fold; P <.01) and the peak plasma concentration 1.6-fold (P <.01) compared with placebo. The mean terminal half-life of budesonide was prolonged from 1.6 to 6.2 hours (ie, 3.7-fold; range, 1.5-fold to 9.3-fold; P <.001) by itraconazole. The suppression of cortisol production after inhalation of budesonide was significantly increased by itraconazole as compared with placebo, as shown by a 43% reduction in the area under the plasma cortisol concentration-time curve from 0.5 to 10 hours (P <.001) and a 12% decrease in the cortisol concentration measured 23 hours after administration of budesonide, at 8 am (P <.05). CONCLUSIONS: Itraconazole markedly increased systemic exposure to inhaled budesonide, probably by inhibiting the cytochrome P4503A4-mediated metabolism of budesonide during both the first-pass and the elimination phases. This interaction resulted in enhanced systemic effects of budesonide, as shown by suppression of cortisol production. Long-term coadministration of budesonide and a potent CYP3A4 inhibitor may be associated with an increased risk of adverse effects of budesonide.