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Background: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine., Methods: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery., Results: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%., Conclusions: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Vicagrel, a novel acetate analogue of clopidogrel, exerts more potent antiplatelet effect than clopidogrel in rodents. Relevant evidence indicated that aspirin and vicagrel are the drug substrate for carboxylesterase 2. Accordingly, it is deduced that concomitant use of aspirin could attenuate the bioactivation of and platelet response to vicagrel. To clarify whether there could be such an important drug-drug interaction, the differences in both the formation of vicagrel active metabolite H4 and the inhibition of adenosine diphosphate-induced platelet aggregation by vicagrel were measured and compared between mice treated with vicagrel alone or in combination with aspirin. The plasma H4 concentration was determined by liquid chromatography-tandem mass spectrometry, and the inhibition of platelet aggregation by vicagrel was assessed by whole-blood platelet aggregation. Compared with vicagrel (2.5 mg·kg) alone, concurrent use of aspirin (5, 10, or 20 mg·kg) significantly decreased systemic exposure of H4, an average of 38% and 41% decrease in Cmax and AUC0-∞ in mice when in combination with aspirin at 10 mg·kg, respectively. Furthermore, concomitant use of aspirin (10 mg·kg) and vicagrel (2.5 mg·kg) resulted in an average of 66% reduction in the inhibition of adenosine diphosphate-induced platelet aggregation by vicagrel. We conclude that aspirin significantly attenuates the formation of vicagrel active metabolite H4 and platelet response to vicagrel in mice, and that such an important drug-drug interaction would appear in clinical settings if vicagrel is taken with aspirin concomitantly when marketed in the future.

Methiopropamine (1-(thiophen-2-yl)-2-methylaminopropane) is a synthetic methamphetamine analogue and is classified as a novel psychoactive substance. The use of novel psychoactive substance has been increasing substantially for recreational purpose in recent years. Methiopropamine was first detected in 2011 in Finland and was later detected in the United Kingdom. It can be purchased on the Internet and is currently poorly regulated. Reported adverse effects of methiopropamine use are mostly anecdotal user reports on Internet forums, and there are limited data on its pharmacodynamics and toxicity in the literature. Death as a direct result from methiopropamine toxicity has not been reported in Australia. We report here the first case of death caused by recreational use of methiopropamine in Australia. This same incident highlights the first ever death from isolated methiopropamine use. Being an analogue of methamphetamine, we hypothesize that the mechanism of death caused by methiopropamine would not be dissimilar to methamphetamine.

Background: This investigation was carried out with already available point-of-care testing (POCT) systems for coagulation parameters to evaluate the qualitative and semiquantitative determination of the time- and concentration-dependent anticoagulant effects of the direct oral anticoagulants rivaroxaban and dabigatran., Methods: The whole blood prothrombin time (PT), activated partial thromboplastin time (aPTT), and activated clotting time (ACT) were determined using the GEM PCL Plus coagulation system. Whole blood PT was also measured on the CoaguCheck XS instrument. In addition, PT and aPTT values were obtained in citrated plasma using the PT reagent Neoplastin Plus and the STA APTT reagent. Drug concentrations of rivaroxaban and dabigatran were determined with a chromogenic anti-Xa assay and the hemoclot assay, which are reported to have good agreement with liquid chromatography coupled with tandem mass spectrometry measurements. POCT was performed in 27 consecutive patients who received rivaroxaban 10, 15, or 20 mg once daily and in 15 patients receiving dabigatran 110 or 150 mg twice daily. Blood samples were collected predose and 2 hours after observed drug intake at steady state., Results: Two hours after observed rivaroxaban administration, the whole blood PT measured on the GEM PCL Plus was prolonged by an average of 64.5% in comparison with predose levels. Less differentiation was observed for rivaroxaban when the PT was measured on the CoaguCheck XS instrument or in plasma (prolongation of 24.1% and 36.8%, respectively). After 2 hours observed dabigatran administration, the whole blood aPTT was comparable with plasma values and was prolonged by 23.5% in comparison with trough values. Significant concentration-dependent prolongations of the activated clotting time were observed to different extents for both direct anticoagulants., Conclusions: Direct oral anticoagulants display variable ex vivo effects on different POCT-assays. POCT for aPTT is sensitive to increased concentrations of dabigatran, whereas the PT-POCT assessed with test systems such as the GEM PCL Plus may be helpful to measure the pharmacodynamic anticoagulant effects of rivaroxaban in emergency clinical situations.

Background: Direct oral anticoagulants (DOACs) are prescribed for systemic anticoagulation. Fixed doses are recommended, but dose individualization may be warranted. Functional coagulation assays may be available, but their use requires knowledge of the drug taken. To provide alternative methodology for guiding dosage, we have developed and validated a liquid chromatography-mass spectrometric assay for apixaban, dabigatran, edoxaban, and rivaroxaban at the concentrations attained during therapy., Methods: Samples, calibrators, and internal quality controls (100 μL) were mixed with internal standard solution (50 μg/L both dabigatran-13C6 and rivaroxaban-13C6 in acetonitrile) and, after centrifugation (16,400g, 4 minutes), supernatant (100 μL) was injected onto a Cyclone-C18-P-XL TurboFlow column. Analytes were focused onto an Accucore PhenylHexyl (2.1 × 100 mm, 2.6 μm) analytical column and eluted using a methanol + acetonitrile (1 + 1):aqueous ammonium acetate (10 mmol/L) gradient. Data were acquired using high-resolution mass spectrometry in full-scan mode (100-2000 m/z) with data-dependent fragmentation to confirm peak identity. Calibration was linear (1-500 μg/L all analytes)., Results: Total analysis time was 6 minutes. Intra-assay imprecision (% RSD) at 1 μg/L was 2.6%, 4.2%, 17.3%, and 9.5% for apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. Mean recovery was 96%-101%. No signal suppression or enhancement was observed. Apixaban, dabigatran, and rivaroxaban were stable over 3 freeze-thaw cycles, after storage at room temperature, and at 2-8°C for up to 2 weeks. Edoxaban was stable over 3 freeze-thaw cycles but showed a mean deterioration of 16% if stored at 2-8°C (2 weeks) and of 18% and 70% (1 day and 2 weeks, respectively) at room temperature., Conclusions: The method is suitable for high-throughput therapeutic drug monitoring of DOACs. The acquisition of full scan data allows for the retrospective identification of metabolites. The method can be used to identify a particular DOAC if information on the drug taken is lacking.

Objective: Rivaroxaban is an oral anticoagulant that directly targets both free factor Xa and factor Xa in complex with its protein cofactor, factor Va, in the prothrombinase complex. It is approved in the United States for the prophylaxis of deep vein thrombosis and stroke in patients with atrial fibrillation; however, it also carries a black box warning regarding the risk of thrombosis after discontinuation of treatment. The purpose of this study was to determine the degree to which rivaroxaban, over a range of physiologically relevant free plasma concentrations, inhibits preassembled prothrombinase at a typical venous shear rate (100 s(-1)) and to determine the dynamics of rivaroxaban washout., Methods and Results: Prothrombinase was assembled on phospholipid-coated glass capillaries. Its activity was characterized with respect to the activation of prothrombin (mean plasma concentration, 1.4 μmol/L) in the absence and presence of rivaroxaban (2, 5, and 10 nmol/L). The degree of inactivation of preassembled prothrombinase is sensitive to the solution-phase rivaroxaban concentration; however, prothrombinase unmasking upon removal of rivaroxaban is concentration independent., Conclusions: The model system presented suggests that when rivaroxaban plasma concentrations decrease after cessation of therapy, there will be an unmasking of thrombus-associated prothrombinase that may be related to the reported rebound phenomena.

Several new oral anticoagulants such as rivaroxaban (which targets Factor Xa) and dabigatran etexilate (which targets thrombin) are in advanced stages of clinical development and are already available for clinical use in some countries. Although these agents do not require routine coagulation monitoring, assays to assess the level of anticoagulation may be of assistance in certain circumstances such as in case of overdose, in patients with a hemorrhagic or thromboembolic event during treatment, or to assess compliance. Moreover, the influence of the new oral anticoagulants on routine coagulation tests must be recognized. The prothrombin time is not suitable for rivaroxaban measurement for several reasons, and the routinely used international normalized ratio for monitoring the vitamin K antagonists cannot be applied to rivaroxaban. Development of universal assays is challenging because the new oral anticoagulants have different targets, and even those with the same target have variable effects on routine coagulation assays. Focusing on rivaroxaban, there is emerging evidence that an anti-Factor Xa assay that uses rivaroxaban-containing plasma calibrators may provide the optimal method for determining plasma rivaroxaban concentrations.

A method using high-performance liquid chromatography (HPLC) with column switching and ultraviolet (UV) spectroscopy was developed for the determination of duloxetine in human plasma. After centrifugation and addition of venlafaxine as internal standard, plasma samples were injected into the HPLC system and precleaned on a column (10 x 4.0 mm) filled with cyanopropyl (CN)-modified silica of 20 microm particle size, with use of 8% (vol/vol) acetonitrile in deionized water as eluent. Duloxetine was eluted and separated on a LiChrospher 100 CN (5-microm particle size; column size, 250 x 4.6 mm I.D.) using acetonitrile-water-potassium dihydrogenphosphate trihydrate buffer (pH, 6.4; 50:50 vol/vol) and detected at 218 nm. Duloxetine could be analyzed within 30 minutes. The limit of quantification was 5 ng/mL. At duloxetine concentrations up to 138 ng/mL that resulted from therapeutic doses of 30 to 120 mg per day, the interassay reproducibility of quality control samples was better than 12%. The method was found to be robust and stable. With the exception of chlorprothixene and desmethylclomipramine, other drugs that may be used as comedication were not found to exhibit retention times similar to duloxetine. In serum samples from 37 patients treated with 30 to 120 mg per day for at least 7 days, the mean steady state serum concentration of duloxetine was 40 ng/mL, the median was 37 ng/mL, and the 25th and 75th percentiles were 22 and 55 ng/mL, respectively. At 60, 90, and 120 mg/day, the mean +/- SD serum concentrations were 33+/-22.0, 43+/-22.2, and 48+/-17.0 ng/mL, respectively. There was a statistically significant correlation (P<0.05, r2=0.26) between prescribed daily doses and serum concentrations of duloxetine. In patients without or with comedication with other drugs, such as inhibitors of cytochrome P450 2D6 (eg, metoprolol or propranolol), serum concentrations of duloxetine were not significantly different. HPLC with column switching and ultraviolet detection as described here is suitable for pharmacokinetic studies and therapeutic drug monitoring of duloxetine.

The effects of supratherapeutic dosages of duloxetine, a serotonin and norepinephrine reuptake inhibitor, on blood pressure and pulse rate were assessed in a multicenter, double-blind, randomized, placebo-controlled, crossover study in 117 healthy women aged 19 to 74 years. Dosages were escalated from 60 mg twice daily (BID) to 200 mg BID over 16 days. Vital signs were monitored at baseline, before morning dosing, and sequentially at steady state. Duloxetine produced increases in supine systolic and diastolic blood pressures, which reached maximums of approximately 12 mm Hg and approximately 7 mm Hg above baseline, respectively, during dosing at 120 mg BID and then stabilized. Supine pulse rate increased gradually with dose, reaching 10 to 12 bpm above baseline after 4 days of dosing at 200 mg BID. Duloxetine caused changes in orthostatic blood pressures and pulse rate that reached plateau values after 3 to 4 days of dosing at 160 mg BID and were generally not associated with subjectively reported orthostatic-related adverse events. All vital signs normalized by 1 to 2 days after study drug discontinuation. Prehypertensive subjects may become hypertensive upon initial duloxetine dosing, but this can be predicted from predose blood pressure. Short-term supratherapeutic duloxetine dosages up to 200 mg BID are not well tolerated but are generally not associated with severe, clinically important adverse events. Overall, the types of adverse events reported in this study were similar to those in other studies of duloxetine in healthy subjects.

Background: Serotonin (5-HT) and norepinephrine (NE) are involved in pain modulation via descending inhibitory pathways in the brain and spinal cord., Objective: To assess the efficacy of duloxetine, a dual reuptake inhibitor of 5-HT and NE, on the reduction of pain severity, as well as secondary outcome measures in patients with diabetic peripheral neuropathic pain (DPNP)., Methods: In this double-blind study, patients with DPNP and without comorbid depression were randomly assigned to treatment with duloxetine 60 mg once daily (QD), duloxetine 60 mg twice daily (BID), or placebo for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Secondary measures and health outcome measures were also assessed., Results: Duloxetine 60 mg QD and 60 mg BID demonstrated improvement in the management of DPNP and showed rapid onset of action, with separation from placebo beginning at week 1 on the 24-hour average pain severity score. For all secondary measures for pain (except allodynia), mean changes showed an advantage of duloxetine over placebo, with no significant difference between 60 mg QD and 60 mg BID. Clinical Global Impression of Severity and Patient's Global Impression of Improvement evaluation demonstrated greater improvement on duloxetine- vs placebo-treated patients. Duloxetine showed no notable interference on diabetic controls, and both doses were safely administered., Conclusions: This study confirms previous findings that duloxetine at 60 mg QD and 60 mg BID is effective and safe in the management of diabetic peripheral neuropathic pain.

The aim of this study was to examine the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain. Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/d (20 mg QD), 60 mg/d (60 mg QD), 120 mg/d (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score, which was rated on an 11-point (0-10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits. Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo on the 24-h Average Pain Score, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h Average Pain Score compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events. Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain.

Background: Arterial remodeling after balloon angioplasty has been recognized as a major determinant of restenosis. Perturbation of collagen metabolism might be important. After balloon injury, matrix metalloproteinase (MMP) expression is upregulated. We investigated the effect of Batimastat, a nonspecific MMP inhibitor, on late lumen loss, arterial remodeling, and neointima formation after balloon dilation., Methods and Results: In atherosclerotic iliac arteries of 12 Yucatan micropigs, balloon dilation was performed, with intravascular ultrasound and quantitative angiography used before and after balloon dilation and at 42-day follow-up. The animals were randomly divided into 2 groups, the Batimastat group (n=6) and the vehicle group (n=6). All animals were intraperitoneally injected with either Batimastat or a vehicle immediately after balloon dilation and at 2 weeks and 4 weeks after balloon dilation. Angiographic and echographic late lumen loss in the Batimastat group versus the vehicle group was 0.3+/-0.1 versus 0.8+/-0.1 mm (P=0.01) and 2.2+/-0.5 versus 4.9+/-0.7 mm(2) (P=0.004), respectively. Late media-bounded area loss was used as a measure of remodeling after balloon dilation and was 0.9+/-0.6 mm(2) in the Batimastat group compared with 3.8+/-0.8 mm(2) in the vehicle group (P=0.003, mixed model analysis P=0.01). Neointima formation was 1.3+/-0.3 mm(2) in the Batimastat group and 1.0+/-0.2 mm(2) in the vehicle group (P=0. 542)., Conclusions: Metalloproteinase inhibition by Batimastat significantly reduced late lumen loss after balloon angioplasty by inhibition of constrictive arterial remodeling, whereas neointima formation was not inhibited by MMP inhibition.