Redox Engineering of Myoglobin by Cofactor Substitution to Enhance Cyclopropanation Reactivity.

Design of metal cofactor ligands is essential for controlling the reactivity of metalloenzymes. We investigated a carbene transfer reaction catalyzed by myoglobins containing iron porphyrin cofactors with one and two trifluoromethyl groups at peripheral sites (FePorCF3 and FePor(CF3)2, respectively), native heme and iron porphycene (FePc). These four myoglobins show a wide range of Fe(II)/Fe(III) redox potentials in the protein of +147 mV, +87 mV, +42 mV and -198 mV vs NHE, respectively. Myoglobin reconstituted with FePor(CF3)2 has a more positive potential which enhances the reactivity of a carbene intermediate with alkenes and demonstrates superior cyclopropanation of inert alkenes such as aliphatic and internal alkenes. In contrast, engineered myoglobin reconstituted with FePc has a more negative redox potential, which accelerates the formation of the intermediate but has low reactivity for inert alkenes. Mechanistic studies indicate that myoglobin with FePor(CF3)2 generates an undetectable active intermediate with a radical character. In contrast, this reaction catalyzed by myoglobin with FePc includes a detectable iron-carbene species with electrophilic character. This finding highlights the importance of redox-focused design of the iron porphyrinoid cofactor in hemoproteins to tune the reactivity of the carbene transfer reaction.

Changes in Perampanel Pharmacokinetics and Cytochrome P450 3A4 Activity Before, During, and After Pregnancy.

ABSTRACT: This study evaluated perampanel pharmacokinetics and cytochrome P450 3A4 (CYP3A4) activity, assessed using the level of 4ß-hydroxycholesterol (4ß-OHC) as an endogenous biomarker of CYP3A4, before, during, and after pregnancy in a woman with epilepsy and compared these measurements with those from a control group of nonpregnant women with epilepsy. A 21-year-old pregnant woman was being treated with perampanel (serum concentration: 1120 ng/mL), lacosamide, and lamotrigine. After the first trimester, the lamotrigine concentration decreased markedly; however, the perampanel concentration remained almost unchanged (range, 1130-1320 ng/mL). Similarly, serum 4ß-OHC levels did not change during pregnancy (before pregnancy, 78.2 ng/mL; during pregnancy, 62.2-83.2 ng/mL). To compare these measurements with those in nonpregnant women, we enrolled 27 nonpregnant women with epilepsy (age range, 16-40 years). In the control patients, we found a strong negative correlation between the concentration-to-dose ratio of perampanel and the 4ß-OHC level (r = -0.78, P < 0.001). As there was no significant change in CYP3A4 activity, we concluded that the serum perampanel concentration did not change significantly before, during, or after pregnancy. More patients need to be studied to confirm these early results.

Population Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease.

KW-6356 is a selective antagonist and inverse agonist of the adenosine A2A receptor. The primary aim of the present analysis was to characterize the pharmacokinetics (PK) of KW-6356 and its active metabolite M6 in healthy subjects and patients with Parkinson's disease (PD). We pooled concentration-time data from healthy subjects and patients with PD who were administered KW-6356. Using these data, we developed a population PK model by sequentially fitting the KW-6356 parameters followed by the M6 parameters. A first-order absorption with a 1-compartment model for KW-6356 and a 1-compartment model for M6 best described the profiles. The covariates included in the final models were food status (fed/fasted/unknown) on first-order absorption rate constant, baseline serum albumin level on apparent clearance of KW-6356, and baseline body weight on apparent volume of distribution of KW-6356 and apparent clearance of M6. No covariate had a clinically meaningful impact on KW-6356 or M6 exposure.

Intramolecular C-H bond amination catalyzed by myoglobin reconstituted with iron porphycene.

C-H bond amination is an effective way to obtain nitrogen-containing products. In this work, we demonstrate that myoglobin reconstituted with iron porphycene (rMb(FePc)) catalyzes intramolecular C(sp3)-H bond amination of arylsulfonyl azides to yield corresponding sultam analogs. The total turnover number of rMb(FePc) is up to 5.7 × 104 for the C-H bond amination of 2,4,6-triisopropylbenzenesulfonyl azide. Moreover, rMb(FePc) exhibits higher selectivity for the desired C-H bond amination than the competing azide reduction compared to native myoglobin. Kinetic studies reveal that the kcat value of rMb(FePc) is 4-fold higher than that of native myoglobin. Furthermore, H64A, H64V and H64I mutants of rMb(FePc) enhance the turnover number (TON) and enantioselectivity for the C-H bond amination of 2,4,6-triethylbenzenesulfonyl azide. The present findings indicate that iron porphycene is an attractive artificial cofactor for myoglobin toward the C-H bond amination reaction.

Time-Course Changes in Lamotrigine Concentration after Addition of Valproate and the Safety and Long-Term Tolerability of Lamotrigine-Valproate Combination Therapy.

The aim of this study was to evaluate the time-course changes in lamotrigine (LTG) concentration after addition of valproate (VPA) and the safety and tolerability of the combination therapy. We reviewed our therapeutic drug monitoring (TDM) database and found 345 patients on LTG who received add-on therapy with VPA. VPA had been added at least 12 weeks after patients finished stepwise LTG titration. Also, we retrospectively evaluated the LTG concentration after addition of VPA and the safety and long-term tolerability of LTG-VPA combination therapy. Plasma LTG concentration increased more than 1.5-fold within 15 d of addition of VPA and reached a peak at 30 d. The rate of increase in LTG concentration occurred in a VPA concentration-dependent manner. During the first 120 d after addition of VPA, adverse events were reported by 58 patients (16.8%), but no patient developed cutaneous reactions. Kaplan-Meier analysis showed estimated retention rates for LTG-VPA combination therapy of 74.5% at 5 years. At 5 years, the mean concentration of LTG was 11.1 µg/mL (43.3 µmol/L). Because addition of VPA leads to a marked increase in LTG concentration over a short period, TDM for LTG should be performed at the earliest from 14 d after starting VPA. At 120 d after starting VPA therapy, the higher LTG concentration due to addition of VPA is not associated with an increased risk of cutaneous reactions. Although LTG-VPA combination therapy increases LTG concentration, it is well tolerated and has a high long-term retention rate.

Incidence trends and risk factors for hyponatremia in epilepsy patients: A large-scale real-world data study.

Objective: This study aimed to evaluate the annual incidence and risk factors of hyponatremia in pediatric, adult, and older adult patients with epilepsy. Methods: We enrolled 26,179 patients: 8598 pediatric patients (aged 0-15 years), 16,476 adults (aged 16-64 years), and 1105 older adults (aged ≥65 years). Patients were included if their serum sodium levels were measured between January 2006 and December 2020. Moderate-severe hyponatremia was defined as a serum sodium level of less than 130 mEq/L. Results: From 2006 to 2020, 677 patients (2.6%) developed moderate-severe hyponatremia. The incidence of hyponatremia per 1000 person-years was 3.1 in the pediatric group, 19.8 in the adult group, and 50.4 in the older adult group. The incidence increased markedly from 36.8 in 2007 to 58.5 in 2020 in the older adult group but remained unchanged in the adult group and tended to decrease in the pediatric group. In the multiple logistic regression model, use of carbamazepine, valproate, phenytoin, phenobarbital, benzodiazepines, and antipsychotics was found to be a significant risk factor for hyponatremia. In adult patients, carbamazepine, benzodiazepine, and antipsychotics induced hyponatremia in a dose-dependent manner. Concomitant use of zonisamide reduced the risk of hyponatremia. Significance: Hyponatremia will become an increasingly important concern in clinical settings because the population of epilepsy patients is aging. Serum sodium levels should be monitored carefully when patients are receiving first-generation antiseizure medications or antipsychotics or combinations of these drugs. Our findings may help to minimize the risk of hyponatremia in epilepsy patients.

Comparative analysis of intercellular lipid organization and composition between psoriatic and healthy stratum corneum.

The lipid composition and organization of the stratum corneum (SC) in patients with psoriasis and healthy subjects were compared using X-ray diffraction, Fourier-transform infrared spectroscopy (FT-IR), and ultraperformance liquid chromatography, combined with time-of-flight mass spectrometry (UPLC-TOFMS). In healthy SC (HSC), SC lipids formed two lamellar phases (long and short periodicity phases). Hexagonal and orthorhombic hydrocarbon-chain packing were observed in the lateral lipid organization at 30 °C via X-ray diffraction. In HSC, the lamellar phases and the hydrocarbon-chain packing organizations changed with elevated temperatures and finally disappeared. In these behaviors, the high-temperature hexagonal hydrocarbon-chain packing organization, which appeared above the orthorhombic hydrocarbon-chain packing organization, transformed to the liquid phase at about 90 °C in HSC. In psoriatic SC (PSC), hexagonal hydrocarbon-chain packing organization disappeared at about 65 °C with elevated temperatures. No high-temperature hexagonal hydrocarbon-chain packing organization were observed in PSC during heating process. Disorder of the hydrocarbon-chain packing of SC lipids was observed in PSC via FT-IR. In UPLC-TOFMS, free fatty acid (FFA) and ceramide (CER) compositions differed between patients with PSC and HSC. Specifically, the levels of ultra-long chain fatty acids containing CER and phytosphingosine-containing CER were decreased, while those of sphingosine and dihydrosphingosine-containing CER and unsaturated FFA were increased in PSC. Furthermore, FFA and CER carbon chain lengths decreased in patients with PSC. These results suggest that the alteration of SC lipid composition and the reduction of carbon chain lengths in PSC lowered the structural transformation temperature, thereby reducing barrier function.

Remote template effect in the synthesis of bipyridine-strapped porphyrins.

A bipyridine-strapped porphyrin was prepared using a remote template effect of alkali or transition metal cations in the bipyridine subunit to enhance the yield 10-fold. The flexibility of the bipyridine-strap also allowed the synthesis of a doubly strapped porphyrin.

Effect of Equipment Parameters on Amount and Dispersion of Wetting Liquid in Planetary Centrifugal Granulation.

In planetary centrifugal wet granulation, the binder is often mixed into the formulation as a powder, followed by the addition of a wetting liquid, in a single step. Therefore, the amount and dispersion of the wetting liquid are important factors that determining granulation success and granules characteristics. In this study, granulation experiments, according to the Box-Behnken design, were performed. Further, the effects of equipment parameters, namely, processing speed, processing time, and vessel size, on the minimum amount of wetting liquid required to enable granulation and dispersion state in the vessel were statistically analyzed. Placebo granules were formulated with lactose hydrate and corn starch (7 : 3), using sodium carmellose as a binder. Results showed that the amount of wetting liquid decreased with increase in processing speed, processing time, and vessel size; however, the dispersion state of the wetting liquid was not significantly affected. Analysis of the effects of the equipment parameters on granule characteristics showed that a larger vessel size was proportional to a larger median diameter and smaller particle-size distribution width (span), and a faster processing speed was proportional to a smaller span. Furthermore, granules with the target properties could be prepared according to the parameters estimated from the model. In conclusion, the equipment parameters for controlling the amount of wetting liquid, which affected the granule properties, were clarified.

Effects of low-dose titration on the tolerability and safety of perampanel.

PURPOSE: To evaluate the effects of low-dose titration on the tolerability and safety of perampanel. METHODS: We retrospectively reviewed the records of 1065 patients who started perampanel therapy and compared the incidence of adverse events after standard titration (Group A: starting dose, 2 mg/day; titration speed, 2 mg/2 weeks or longer) and low-dose titration (Group B: starting dose, < 1 mg/day; titration speed, < 1 mg/2 weeks or longer). RESULTS: Adverse events were reported in 158 patients (14.8%) within the initial first 90 days of starting perampanel (mean concentration, 331 ng/mL). At 90 days, the cumulative incidence of adverse events was significantly higher in Group A than in Group B (24.5% vs. 16.3%, respectively; log-rank test p < 0.001). A Cox proportional hazards model also showed that low-dose titration decreased the incidence risk of adverse events (adjusted hazard ratio, 0.49; 95% confidence interval, 0.35-0.69). When the groups were stratified by use of enzyme-inducing antiseizure medications (inducers), Group A patients without inducers had a significantly higher cumulative incidence of adverse events than the other three subgroups (26.7%, p < 0.001). In patients taking 2 mg of perampanel, median concentrations in patients with or without inducers were 43 ng/mL and 204 ng/mL, respectively. CONCLUSION: Perampanel is generally initiated at 2 mg, but serum perampanel concentrations show substantial interindividual variation. Our study suggests that care must be taken when setting the starting dose of perampanel. In particular, low-dose titration is recommended in patients not taking inducers.

Clinical value of therapeutic drug monitoring for levetiracetam in pediatric patients with epilepsy.

PURPOSE: To identify pediatric patients who require therapeutic drug monitoring (TDM) of levetiracetam (LEV). METHODS: We retrospectively investigated 2413 routine therapeutic drug monitoring data on serum LEV concentration from 1398 pediatric patients (age, 0-15 years). Samples were grouped by age (infants, < 1 year; preschool children, 1-5 years; primary school children, 6-11 years; and adolescents, 12-15 years), and the LEV concentration-to-dose (CD) ratio was calculated. RESULTS: The mean CD ratio was highest in adolescents (analysis of variance, p < 0.001); 22.5 % and 15.7 % higher in adolescents than in preschool children and school children, respectively (Scheffé test, p < 0.001); and higher in infants than in preschool children. Preschool children had the lowest ratio and tended to show an increase in the ratio from age 2 to 5 years. Use of enzyme-inducing antiseizure medication reduced the CD ratio by 6.1 % in infants, 12.2 % in preschool children, 5.9 % in primary school children, and 9.4 % in adolescents. The mean CD ratio was 2.7 %, 26.9 %, and 39.3 % higher in preschool children, primary school children, and adolescents with defined chronic kidney disease (CKD) than in the respective age group of patients without CKD. The therapeutic concentration range for a long-term LEV therapy was 11 to 32 µg/mL. CONCLUSIONS: LEV pharmacokinetics are significantly different between infant and preschool children, so TDM of LEV is clinically useful in these patients. In pediatric patients at higher risk for CKD, glomerular filtration rate and LEV levels should be carefully monitored.

Safety, Tolerability, and Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 Following Single and Multiple Oral Administration in Healthy Volunteers.

KW-6356 is an adenosine A2A receptor-selective antagonist and inverse agonist. We conducted 2 studies: study 6356-001 (no NCT number), a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (1, 3, 10 mg) and multiple (6 mg once daily) oral doses of KW-6356 in healthy Japanese subjects; and study 6356-004 (NCT03830528), including a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (21, 42, 60 mg) and multiple (24 mg once daily) oral doses of KW-6356, and a phase 1 open-label trial of multiple oral doses (6 mg once daily) of KW-6356 in healthy Japanese and White subjects, to evaluate the safety, tolerability, and pharmacokinetics of KW-6356. KW-6356 was well tolerated after administration of single doses of up to 60 mg and multiple doses of up to 24 mg once daily for 14 days. The pharmacokinetics of KW-6356 were linear after a single dose of up to 60 mg KW-6356. The mean terminal elimination half-life of KW-6356 ranged from 18.4 to 43.1 hours following administration of single doses of 1-60 mg. There was no clear difference in the safety or pharmacokinetics of KW-6356 between healthy Japanese and White subjects.

Case of bullous pemphigoid refractory to corticosteroids by antiepileptic drug-induced CYP3A4.

The most common treatment option for patients with bullous pemphigoid is systemic corticosteroids. CYP3A4, a drug-metabolizing enzyme in the liver, metabolizes synthetic steroids to a varying degree. Although there are many CYP3A4-inducing drugs, several antiepileptic drugs, such as phenytoin and phenobarbital, strongly induce CYP3A4, thereby reducing the effects of corticosteroids. Here, we report a case of refractory bullous pemphigoid that rapidly improved after the discontinuation of phenytoin and phenobarbital. To achieve adequate pharmacological effects of corticosteroids, we must always ensure that patients who require corticosteroids for treatment are not medicated with CYP3A4-inducing agents.

Comprehensive Analyses of the Intracellular and in Vivo Disposition of Fab- Small Interfering RNA Conjugate to Identify Key Issues to Improve Its in Vivo Activity.

Comprehensive analyses of intracellular disposition and in vivo pharmacokinetics were performed for small interfering RNA (siRNA) conjugated with the Fab fragment of panitumumab, a fully humanized monoclonal antibody against epidermal growth factor receptor (EGFR). The Fab-siRNA conjugate was internalized into EGFR-expressing cancer cells in an antigen-dependent manner. Intracellular disposition was quantitatively evaluated using fluorescent-labeled panitumumab and confocal microscopy. The majority of internalized panitumumab was suggested to be transferred into lysosomes. In vivo pharmacokinetics were evaluated in EGFR-expressing tumor-bearing mice. Intact Fab-siRNA was measured by immunoprecipitation using anti-Fab antibody followed by quantitative polymerase chain reaction. The Fab portion was measured by a ligand binding assay. Intact Fab-siRNA concentrations rapidly decreased in the plasma and tumor, although the Fab portion concentration remained high, suggesting extensive degradation in the linker-siRNA portion. After incubation of Fab-siRNA in mouse plasma, samples were digested with proteinase K, and extracted siRNA tagged with Fab-derived peptide was subjected to an ion-pair reversed-phase liquid chromatography with mass spectrometry analysis. Results suggested that hydrolysis from the 3' end of the antisense strand of siRNA is the major metabolizing pathway. Based on these findings, endosomal escape and stability in lysosomes, blood, and tumor are key factors to improve to achieve efficient target gene knockdown in tumors, and stabilizing the 3' end of the antisense strand was suggested to be most efficient. Our approaches clearly identified the key issues of Fab-siRNA from a pharmacokinetics aspect, which will be useful for improving the in vivo activity of siRNA conjugated with not only Fab but also other immunoproteins. SIGNIFICANCE STATEMENT: The intracellular and in vivo disposition of Fab-small interfering RNA (siRNA) conjugate was comprehensively investigated using various approaches, including newly developed analytical methods. This study clearly shows that improvements in siRNA stability in lysosomes, blood, and tumor are needed for target gene knockdown in tumors. The major metabolic pathway of Fab-siRNA is 3' exonuclease degradation, suggesting that optimization of the conjugation site to Fab might help improve stability.

Extemporaneous preparation of rifampicin granules from capsules to improve usability.

OBJECTIVES: Manipulation of tablets or capsules is frequently carried out in pharmacies to regulate doses for personalised therapy. We proposed the use of reconstructed granules as a suitable, flexible dosage form and developed an on-site granulation method using a compounding mixer. The aim of this study was to demonstrate the feasibility of small-scale preparation of granules in a pharmacy setting. Rifampicin capsules were used as a model medicine because of the associated need for drug desensitisation therapy. METHODS: The contents of a rifampicin capsule were granulated using a compounding mixer, and small ointment containers (12 mL) with filling rates of 4%, 8%, 12%, and 16% were used as granulation vessels. The obtained granules were examined for particle size distribution, yield, crystal transition, drug dissolution profile, storage stability, and weight loss during dosing. RESULTS: The yields increased by >95%, and the span of the particle size distribution decreased to 1.0, as the filling rate increased. The smallest batch size was found to be 0.8 g in a 12 mL vessel. Examination of the resultant granules revealed that granulation did not affect the crystal polymorphism, dissolution profile, or storage stability of rifampicin. Furthermore, the weight loss of the granules during the dosing process was significantly lower than that of the capsule powder content. CONCLUSIONS: We demonstrated that granules with sufficient quality for clinical use could be extemporaneously prepared using a compounding mixer in pharmacies. This improved the usability of the medicine, preventing weight loss, and making it a suitable alternative formulation for precise personalised pharmacotherapy.

Therapeutic Drug Monitoring for Rufinamide in Japanese Patients With Epilepsy: Focus on Drug Interactions, Tolerability, and Clinical Effectiveness.

BACKGROUND: The purposes of this study were to assess drug interactions between rufinamide and concomitant antiepileptic drugs (AEDs) and to identify the therapeutic window for rufinamide. METHODS: Serum samples (n = 1531) were obtained from 178 patients (aged 2-57 years), and clinical records were retrospectively reviewed to evaluate the safety and efficacy of rufinamide (mean observation time, 1073 ± 846 days). RESULTS: Rufinamide exhibited linear pharmacokinetics at doses of up to 60 mg/kg (range, 50-3200 mg/d). Concomitant use of the enzyme-inducing AEDs such as phenytoin, carbamazepine, and phenobarbital reduced rufinamide concentrations by 43.4%, 13.2%, and 30.3%, respectively. By contrast, concomitant use of valproate significantly elevated rufinamide concentrations. Clinical response was seen in 41 patients (23.0%), with a median therapeutic concentration (interquartile range) of 20.6 mcg/mL (13.3-27.0). There was no difference in the therapeutic concentrations between seizure types, but patients with tonic/atonic seizures tended to have higher rufinamide concentrations. During the study period, adverse events were reported in 64 patients (35.8%), including somnolence, gastrointestinal disorders, dizziness, and irritability/behavior disorders. Conditional logistic regression analysis showed that patients administered a concentration greater than 20 mcg/mL had an 8.6-fold higher incidence of adverse events. CONCLUSIONS: Therapeutic drug monitoring for rufinamide is clinically useful for predicting drug interactions between rufinamide and concomitant AEDs. When a patient has tonic/atonic seizures, careful titration is required for concentrations greater than 20 mcg/mL.

A case of complete atrioventricular block with extremely high blood concentration of azelnidipine.

BACKGROUND: Azelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported. CASE PRESENTATION: In the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient's physician that the patient's serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient's serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment. CONCLUSIONS: Azelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.

Impact of Cilostazol Pharmacokinetics on the Development of Cardiovascular Side Effects in Patients with Cerebral Infarction.

This study investigated the impact of polymorphisms of metabolic enzymes on plasma concentrations of cilostazol and its metabolites, and the influence of the plasma concentrations and polymorphisms on the cardiovascular side effects in 30 patients with cerebral infarction. Plasma concentrations of cilostazol and its active metabolites, and CYP3A5*3 and CYP2C19*2 and *3 genotypes were determined. The median plasma concentration/dose ratio of OPC-13213, an active metabolite by CYP3A5 and CYP2C19, was slightly higher and the median plasma concentration rate of cilostazol to OPC-13015, another active metabolite by CYP3A4, was significantly lower in CYP3A5*1 carriers than in *1 non-carriers (p = 0.082 and p = 0.002, respectively). The CYP2C19 genotype did not affect the pharmacokinetics of cilostazol. A correlation was observed between changes in pulse rate from the baseline and plasma concentrations of cilostazol (R = 0.539, p = 0.002), OPC-13015 (R = 0.396, p = 0.030) and OPC-13213 (R = 0.383, p = 0.037). A multiple regression model, consisting of factors of the plasma concentration of OPC-13015, levels of blood urea nitrogen, and pulse rate at the start of the therapy explained 55.5% of the interindividual variability of the changes in pulse rate. These results suggest that plasma concentrations of cilostazol and its metabolites are affected by CYP3A5 genotypes, and plasma concentration of OPC-13015, blood urea nitrogen, and pulse rate at the start of therapy may be predictive markers of cardiovascular side effects of cilostazol in patients with cerebral infarction.

Risk factors for psychiatric adverse effects associated with perampanel therapy.

PURPOSE: To identify the risk factors for psychiatric adverse effects associated with perampanel therapy. METHODS: We retrospectively evaluated the adverse effects of perampanel by reviewing clinical records from 895 Japanese patients with epilepsy (aged 1-86 years) who started perampanel therapy at National Epilepsy Center, Shizuoka, Japan, between June 2016 and December 2019. Patients were classified into 3 groups: those without adverse effects (Group I), those with psychiatric adverse effects (Group II), and those with common adverse effects (Group III). RESULTS: The number of patients assigned to each group was as follows: Group I, n = 641; Group II, n = 93; and Group III, n = 161. The mean follow-up period was 458 ±â€¯265 days (median, 511 days). Kaplan-Meier survival estimates showed that the median time to treatment failure was shorter in Group II than in Group III (294 vs. 392 days, respectively; log-rank test, p < 0.001). According to polytomous logistic regression, younger age (<16 years) was associated with a lower risk of common and psychiatric adverse effects. The risk factors for psychiatric adverse effects (Group II) were intellectual disability (adjusted odds ratio [AOR], 2.6; 95% confidence interval (CI), 1.5-4.5) and psychiatric comorbidity (AOR, 3.8; 95% CI, 2.3-6.3); in patients with intellectual disability, the occurrence of psychiatric adverse effects was concentration dependent. Patients with lamotrigine use had a 0.54-fold lower risk of psychiatric adverse effects. In Group III, concomitant use of inducers was associated with a decreased risk of common adverse effects (AOR, 0.68; 95% CI, 0.46-0.99). SIGNIFICANCE: We found clear differences in the risk factors for psychiatric adverse effects. In patients with intellectual disability, care must be taken when titrating perampanel, and therapeutic drug monitoring should be performed.