Tom Mjörndal

HMG-CoA Reductase Inhibitors and Myotoxicity

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors specifically inhibit HMG-CoA reductase in the liver, thereby inhibiting the biosynthesis of cholesterol. These drugs significantly reduce plasma cholesterol level and long term treatment reduces morbidity and mortality associated with coronary heart disease.The tolerability of these drugs during long term administration is an important issue. Adverse reactions involving skeletal muscle are not uncommon, and sometimes serious adverse reactions involving skeletal muscle such as myopathy and rhabdomyolysis may occur, requiring discontinuation of the drug. Occasionally, arthralgia, alone or in association with myalgia, has been reported.In this article we review scientific data provided via Medline, adverse drug reaction case reports from the Swedish Drug Information System (SWEDIS) and the World Health Organization’s International Drug Information System (INTDIS) database, focusing on HMG-CoA reductase inhibitor-related musculoskeletal system events.Cytochrome P450 (CYP) 3A4 is the main isoenzyme involved in the metabolic transformation of HMG-CoA reductase inhibitors. Individuals with both low hepatic and low gastrointestinal tract levels of CYP3A4 expression may be at in increased risk of myotoxicity due to potentially higher HMG-CoA reductase inhibitor plasma concentrations. The reported incidence of myotoxic reactions in patients treated with this drug class varies from 1 to 7% and varies between different agents. The risk of these serious adverse reactions is dose-dependent and may increase when HMG-CoA reductase inhibitors are prescribed concomitantly with drugs that inhibit their metabolism, such as itraconazole, cyclosporin, erythromycin and nefazodone. Electrolyte disturbances, infections, major trauma, hypoxia as well as drugs of abuse may increase the risk of myotoxicity. It is important that the potentially serious adverse reactions are recognised and correctly diagnosed so that the HMG-CoA reductase inhibitor may at once be withdrawn to prevent further muscular damage.

Adverse drug reaction reporting by nurses in Sweden

AimTo investigate whether nurses could be a useful tool for improving the reporting rate of adverse drug reactions (ADRs). Furthermore, we wanted to study how physicians working at the study departments would respond to nurses as reporters of ADRs and if the reporting from the nurses affected the reporting rate from the physicians.MethodThree departments of internal medicine and one unit for orthopaedics were selected for the study. Nurses with special drug responsibilities were invited to participate. At the start of the study period, the nurses received an introduction with background, objective, method and other practical issues concerning the study. After this, an education programme about ADR reporting, definitions, and ADR classification according to mechanism and organ system was given. To study their knowledge about and attitude towards ADRs, a questionnaire was handed out to the nurses. A questionnaire was also handed out to all physicians at the participating departments in order to investigate their attitude towards nurses as reporters of ADRs.ResultsFifty-four nurses participated in the study. During the study period, a total number of 23 reports with 39 ADRs were sent to the regional centres by the nurses. Seventeen (74%) of the reports were assessed as serious. Eight of the 39 ADRs were unlabelled and all reports were considered appropriate. The reporting rate from the physicians during the study period was similar to the previous year, indicating that the nurses contributed with additional reports. At the end of the study, the nurses thought that they had enough knowledge to report ADRs. Sixty-eight percent of the physicians did not object to nurses being included as reporters of suspected ADRs.ConclusionAdverse drug reaction reporting by nurses could improve the overall safety of drugs.

1999 WHO/ISH Guidelines applied to a 1999 MONICA sample from northern Sweden.

Background Treating hypertension with drugs is so far the most cost-effective way to reduce this important risk factor for cardiovascular disease (CVD). It is, however, important to determine absolute risk, and thereby estimate indication for drug treatment, in order to maintain a cost-effective drug treatment. WHO/ISH Hypertension Guidelines from 1999 propose a risk stratification for estimating absolute risk for CVD based on blood pressure and additional risk factors, target organ damage (TOD) and CVD. Objectives We studied the consequences of applying the recent WHO/ISH risk stratification scheme to a MONICA sample of 6000 subjects from a geographically defined population in northern Sweden, regarding indications for treatment, target blood pressure and risk distribution. Methods We have risk-classified each of these patients using a computer program, according to the WHO/ISH scheme. Data on TOD were not available. Results In all, 917 (15%) had drug-treated hypertension. Three-quarters (n = 737) were inadequately treated, with blood pressure levels at or above 140 or 90 mmHg. 1773 (30% of 5997) untreated subjects had a blood pressure of 140/90 or above; 16% in the low-, 62% in the medium-, 8% in the high-, and 14% in the very-high-risk group. The corresponding risk-group pattern for the inadequately treated hypertensives (n = 737) was 5.5, 48.3, 11.1 and 35.2%, respectively. If we shifted the target blood pressure from below 140/90 to below 130/85 for drug-treated subjects under 60 (n = 278) the number of inadequately treated subjects increased by 34 (12.2% of 278); 14 in the low-risk group, 15 in the medium-risk group, and only five in the high- or very-high-risk groups. Conclusions Only one-fifth of the drug-treated hypertensives were well controlled. Moreover, the incidence of newly detected blood pressure elevation was high. The majority of younger subjects with high blood pressure had low risk, but in those aged 45–54 this had already risen to a medium risk. Changing the target blood pressure to below 130/85, for subjects aged below 60, as recommended by WHO/ISH, affects predominantly low- and medium-risk groups.

Influence of menstrual cycle on platelet serotonin uptake site and serotonin2A receptor binding

Depression and anxiety are common health problems affecting women, particularly during the reproductive years. Major depression is two to three times as common in women than in men. Neuroendocrine factors are likely to contribute to this overall increased risk for developing mood disorders in women, and the neuroendocrine influence is most obviously seen in women with premenstrual dysphoric disorder (PMDD) as these women experience depressed mood and anxiety premenstrually only during ovulatory cycles. Moreover, dysfunction of serotonergic transmission has been regarded as an important mechanism in several psychiatric disorders and ovarian steroids have been shown to profoundly influence the activity of the serotonergic system. Given these facts, the purpose of this study was to examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide ([3H]LSD) to the platelet 5-HT2A receptor are influenced by the cyclical changes in circulating estradiol and progesterone that occur during the menstrual cycle. We examined 28 healthy women, without oral contraceptives and with regular menstrual cycles. In the late follicular phase, Bmax for [3H]paroxetine binding was significantly higher than in the ovulatory (p<0.01), early luteal phase (p<0.05) and mid-luteal phase (p<0.01). Bmax for [3H]LSD binding was significantly higher in the early follicular phase and the early luteal phase compared to the mid-luteal phase (p<0.001 and p<0.05, respectively). In the early follicular phase and the ovulatory phase, significant correlations between estradiol serum concentrations and Kd for [3H]paroxetine were obtained (p<0.001, respectively). In the luteal phase, significant inverse correlations between progesterone as well as estradiol serum concentrations and Kd for [3H]LSD binding were found (p<0.05, respectively).

Evaluation of a computer-based decision support system for treatment of hypertension with drugs : retrospective, nonintervention testing of cost and guideline adherence

Abstract. Persson M, Mjörndal T, Carlberg B, Bohlin J, Lindholm LH (University of Umeå, Sweden). Evaluation of a computer‐based decision support system for treatment of hypertension with drugs: retrospective, nonintervention testing of cost and guideline adherence. J Intern Med 2000; 247: 87–93.

The effect of fluvoxamine on serum prolactin and serum sodium concentrations : Relation to platelet 5-HT2A receptor status

Hyperprolactinemia and hyponatremia are adverse drug reactions regularly reported for selective serotonin reuptake inhibitors. Results from animal studies suggest that serotonin receptors of different subtypes are involved in the mediation of these effects. We have investigated to what extent fluvoxamine alters serum prolactin and serum sodium levels and whether these effects are related to platelet 5-hydroxytryptamine 2A (5-HT2A) receptor status, as studied by [3H]lysergic acid diethylamide ([3H]LSD) binding. Eight healthy subjects were given fluvoxamine in increasing dosage from 25 mg/day to 200 mg/day during 4 weeks, and serum sodium and serum prolactin concentrations were obtained weekly. All subjects had normal prolactin and sodium levels before start of treatment. Two subjects had substantial increases in serum prolactin levels (up to 35 microg/L) during fluvoxamine treatment, and these two subjects had higher Bmax for platelet [3H]LSD binding before fluvoxamine treatment than the six other subjects (32.7 vs. 23.1 fmol/mg protein). There was a small, nonsignificant decrease (mean 1.0 mmol/L) in serum sodium levels after institution of fluvoxamine but a significant increase (mean 1.9 mmol/L) in serum sodium levels after discontinuation of the drug (p = 0.02). Bmax for [3H]LSD binding and change in serum sodium concentration after institution of fluvoxamine showed a significant positive correlation (r = 0.85;p = 0.007). The results indicate that fluvoxamine affects serum prolactin as well as serum sodium concentrations and lend indirect support to the suggestion that 5-HT2A receptors might be involved in the mediation of these effects.

Absence of interaction between erythromycin and a single dose of clozapine.

AbstractObjective: To study the suggested pharmacokinetic interaction between erythromycin, a strong inhibitor of CYP3A4, and clozapine. Methods: Twelve healthy male volunteers received a single dose of 12.5 mg of clozapine alone or in combination with a daily dose of 1500 mg erythromycin in a randomised crossover study. Clozapine and its metabolites clozapine-N-oxide and desmethyl-clozapine were measured in serum samples which were collected during a 48 h period and in a sample of the urine secreted over the interval 0–12 h. Results: There were no significant differences in mean area under the serum concentration time curves (1348 (633) nmol h · 1−1 in the control phase and 1180 (659) nmol h · 1−1 in the erythromycin phase), terminal half-lives (19 (13) h and 15 (6) h, respectively), peak serum concentrations (92 (53) nmol · 1−1 and 77 (40) nmol · 1−1, respectively), time to peak serum concentrations (1.4 (0.7) h and 1.5 (1.0) h, respectively) or apparent oral clearances of clozapine (34 (15) l · h−1 and 46 (37) l · h−1, respectively). There were no significant differences in partial metabolic clearances to clozapine-N-oxide (5.1 (3.6) l · h−1 and 7.8 (9.4) l · h−1, respectively) or to desmethyl-clozapine (1.5 (1.3) l · h−1 and 1.8 (1.7) l · h−1, respectively) or in renal clearances of clozapine (0.8 (0.5) l · h−1 and 1.0 (0.7) l · h−1, respectively) between the two phases. Conclusion: These results demonstrate that erythromycin at a clinically relevant dosage does not inhibit the metabolism of clozapine. Hence, CYP3A4 seems to be of minor importance in the disposition of clozapine in humans at least when clozapine is taken at a low single dose.

Serotonin 5-HT2A Receptor Binding in Platelets from Healthy Subjects as Studied by [3H]-Lysergic Acid Diethylamide ([3H]-LSD): Intra- and Interindividual Variability

In studies on platelet 5-HT2A receptor binding in patients with neuropsychiatric disorders, there has been a marked variability and a considerable overlap of values between patients and controls. The causes of the large variability in 5-HT2A receptor parameters is still unsettled. In the present study, we have quantified the intra- and interindividual variability of platelet 5-HT2A receptor binding in 112 healthy subjects and explored factors that may influence 5-HT2A receptor binding, using [3H]-lysergic acid diethylamide as radioligand. Age, gender, blood pressure, and metabolic capacity of the liver enzymes CYP2D6 and CYP2C19 did not influence Bmax and Kd values. Body weight and body mass index (BMI) showed a negative correlation with Kd (p =. 04 and. 03, respectively), but not with Bmax. Bmax was significantly lower in the light half of the year than in the dark half of the year (p =. 001), and Kd was significantly lower in the fall than in the summer and winter (p <. 001). In females, there was a significant increase in Bmax from week 1 to week 2 of the menstrual cycle (p =. 03). Females taking contraceptive pills had significantly higher Kd than drug-free females in weeks 1 and 4 of the menstrual cycle (p =. 04). This study shows that a number of factors should be taken into account when using platelet 5-HT2A receptor binding in studies of neuropsychiatric disorders.

Plasma Levels and Clinical Effects of Thioridazine and Thiothixene

The effects of thioridazine and thiothixene were studied by a double-blind technique on 40 schizophrenic patients. The doses were adjusted for optimal clinical and therapeutic effects and side effects were rated after three and eight weeks of treatment. No statistically significant differences were observed between the two drugs or between either of the two drugs and the previous medication. Plasma levels were estimated by a fluorometric technique after three and eight weeks of treatment. No correlation was found between plasma levels and clinical effects for either thioridazine or thiothixene. Plasma levels of both drugs were clearly correlated to dosage after three weeks of treatment. After eight weeks this correlation persisted for thioridazine but not for thiothixene. By that time plasma levels of thiothixene had decreased to about 30 per cent of the initial value, indicating strong enzyme induction.

Circannual variations in the binding of [3H]lysergic acid diethylamide to serotonin2A receptors and of [3H]paroxetine to serotonin uptake sites in platelets from healthy volunteers.

BACKGROUND Circannual variations occur in several serotonergic parameters, including platelet serotonin uptake and platelet [3H]imipramine binding. METHODS Binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors and binding of [3H]paroxetine to platelet serotonin uptake sites were studied longitudinally for 1 year in 12 healthy volunteers. RESULTS For [3H]LSD, the number of binding sites (Bmax) showed no significant seasonal variation (two-way analysis of variance), although Bmax was significantly higher during the months October through February than during the months April through August (32.6 vs. 29.8 fmol/mg protein; p = .015). For [3H]paroxetine, Bmax showed a significant seasonal variation (p = .003) with maximum in August (1322 fmol/mg protein) and minimum in February (1168 fmol/mg protein). The affinity constant (Kd) showed a significant seasonal variation for [3H]LSD binding (p = .046), but not for [3H]paroxetine binding. The seasonal fluctuations in [3H]LSD binding and in paroxetine binding tended to be inversely correlated for Bmax (r = -.70; p = .08) and were significantly negatively correlated for Kd (r = -.88; p = .009). CONCLUSIONS The present study demonstrates a seasonal effect on platelet serotonin uptake site binding and indicates a possible seasonal effect on 5-HT2A receptor binding. The results imply that circannual fluctuations should be taken into account when these platelet serotonin markers are studied.