Plasma concentrations of antipsychotics and QTc prolongation: a pilot study.

Background: Certain antipsychotics are known to cause QTc interval prolongation, which has been associated with increased risk of arrhythmia and sudden death. Previous studies have investigated whether there is an association between oral antipsychotic dose and QTc interval prolongation, however only few have examined the association between antipsychotic plasma concentrations and QTc interval.Material and methods: We performed a cross-sectional study with 22 forensic psychiatric in-patients. We measured the plasma concentration of the prescribed antipsychotics and performed an ECG simultaneously. We used Bazett's formula to calculate QTc and defined QTc as prolonged when: >460 ms for women and >450 ms for men.Results: Seventy-seven percent (n = 17) of the subjects were men (mean age = 40 years) and 91% (n = 20) were diagnosed with schizophrenia. QTc's ranged from 369 to 437 ms. Patients receiving QTc prolonging drugs had significantly greater QTc interval compared to patients receiving non-prolonging drugs. Weak to moderate negative correlations were found between QTc interval and both defined daily dose (DDD) and antipsychotic plasma concentration. There was no statistical difference between the correlations for DDD and plasma concentration versus QTc interval.Conclusion: We did not find a stronger association between antipsychotic plasma concentration and QTc than between antipsychotic dose and QTc. We suggest close monitoring with regular electroencephalogram's until the development of a better marker for predicting the risk of cardiac arrhythmia.

[Sparse evidence of antipsychotic drugs for the treatment of delirium].

Traditionally, haloperidol has been the recommended antipsychotic drug for pharmacological treatment of delirium, which is a frequent complication in the critical care setting. Due to a less frequent occurrence of extrapyramidal adverse effects, second-generation antipsychotic drugs have been evaluated. In the present paper we review the current randomized prospective studies of second-generation antipsychotics as treatment for delirium in hospitalized patients and conclude that so far the evidence in favour of these drugs compared with haloperidol is still sparse.

[Sparse evidence of antipsychotic drugs for the treatment of delirium].

Traditionally, haloperidol has been the recommended antipsychotic drug for pharmacological treatment of delirium, which is a frequent complication in the critical care setting. Due to a less frequent occurrence of extrapyramidal adverse effects, second-generation antipsychotic drugs have been evaluated. In the present paper we review the current randomized prospective studies of second-generation antipsychotics as treatment for delirium in hospitalized patients and conclude that so far the evidence in favour of these drugs compared with haloperidol is still sparse.

Potential role of linagliptin as an oral once-daily treatment for patients with type 2 diabetes.

BACKGROUND: Linagliptin is an oral antihyperglycemic agent that selectively inhibits the enzyme dipeptidyl peptidase-4 (DPP-4). Inhibition of DPP-4 increases the levels of the incretin hormones glucagon-like peptide and glucose-dependent insulinotropic polypeptide by preventing their degradation. OBJECTIVE: We reviewed the role of linagliptin as an oral once-daily treatment for patients with type 2 diabetes. METHODS: A comprehensive literature search was performed using the term "linagliptin." Original research articles and review articles were included in our examination. RESULTS: Linagliptin has a similar mode of action as other gliptins, with comparable efficacy, safety profile, and tolerability. Differences in pharmacokinetic parameters that distinguish linagliptin from other gliptins include that linagliptin is not renally excreted and does not require dose reduction with renal impairment. CONCLUSION: Linagliptin is an oral, once-daily, antihyperglycemic agent that significantly reduces glycated hemoglobin (HbA(1c)) when used alone or in combination with other antidiabetic drugs in people with type 2 diabetes. Pharmacokinetics, such as the lack of renal excretion, distinguishes linagliptin from other gliptins.

Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: results from the ONSET-OFFSET and RESPOND studies.

BACKGROUND AND OBJECTIVES: Ticagrelor, the first reversibly binding oral P2Y(12) receptor antagonist, improves outcomes in patients with acute coronary syndromes (ACS) compared with clopidogrel. In the ONSET-OFFSET study (parallel group trial) and the RESPOND study (crossover trial), the pharmacodynamic effects of ticagrelor were compared with clopidogrel in patients with coronary artery disease (CAD). We now report the pharmacokinetic analyses of ticagrelor, and the exposure-inhibition of platelet aggregation (IPA) relationships from these studies. PATIENTS AND METHODS: Patients were treated with ticagrelor (180 mg loading dose, 90 mg twice daily maintenance dose) or clopidogrel (600 mg loading dose, 75 mg once daily maintenance dose) in addition to aspirin (acetylsalicylic acid) [75-100 mg once daily]. Ticagrelor administration was for 6 weeks in ONSET-OFFSET. In RESPOND, ticagrelor was given for 14 days before or after 2 weeks of clopidogrel in patients classified as clopidogrel responders or non-responders. Pharmacokinetics and IPA were evaluated following the loading and last maintenance doses. Exposure-IPA relationships were evaluated using a sigmoid maximum effect (E(max)) model. OUTCOME MEASURES: The outcome measures were ticagrelor and AR-C124910XX (active metabolite) pharmacokinetics and exposure-IPA relationships in both trials, including the effect of prior clopidogrel exposure, and effects in clopidogrel responders and non-responders in RESPOND. RESULTS: In ONSET-OFFSET, maximum (peak) plasma concentration (C(max)), time to C(max) (t(max)) and area under the plasma concentration-time curve from time 0 to 8 hours (AUC(8)) for ticagrelor were 733 ng/mL, 2.0 hours and 4130 ng · h/mL, respectively; and for AR-C124910XX were 210 ng/mL, 2.1 hours and 1325 ng · h/mL, respectively. E(max) estimates were IPA >97%. Trough plasma ticagrelor (305 ng/mL) and AR-C124910XX (121 ng/mL) concentrations were 5.2 and 7.7 times higher than respective concentration producing 50% of maximum effect (EC(50)) estimates. In RESPOND, ticagrelor mean C(max) and AUC(8) following 2-week dosing were comparable between clopidogrel responders (724 ng/mL and 3983 ng · h/mL, respectively) and non-responders (764 ng/mL and 3986 ng · h/mL, respectively). Pharmacokinetics of ticagrelor were unaffected by prior clopidogrel dosing. E(max) estimates were IPA >96% for both responders and non-responders. Trough plasma concentrations were sufficient to achieve high IPA. CONCLUSIONS: Ticagrelor pharmacokinetics in stable CAD patients were comparable to previous findings in stable atherosclerotic and ACS patients, and were not affected by prior clopidogrel exposure or clopidogrel responsiveness. Ticagrelor effectively inhibited platelet aggregation, and trough plasma concentrations of ticagrelor and AR-C124910XX were sufficient to result in high IPA in stable CAD patients.

[Eosinophilic myocarditis and sudden unexpected death in a younger patient treated with antipsychotics]. / Eosinofil myokarditis og pludselig uventet død hos en yngre patient behandlet med psykofarmaka.

A 36 year-old man suffering from schizophrenia was found dead in his apartment. Forensic autopsy was performed due to sudden unexpected death but did not yield the cause of death. Histological examination of the heart showed eosinophilic myocarditis (EM) while forensic chemistry showed a raised level of aripripazol. We discuss the risk of sudden cardiac death in patients receiving antipsychotic drugs and the possible connection between raised drug levels and EM, and we emphasise the importance of autopsy and hope for better means in the future of finding patients at risk.