Stroke and Ischemic Heart Disease With Enzyme-inducing Antiseizure Medications: Time to Change Prescribing Habits

Importance: Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease. Objective: To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use. Design, Setting, and Participants: This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4–15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021. Exposures: Receipt of 4 consecutive EI ASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age >/=18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model. Main Outcomes and Measures: Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models. Results: Of 10,916,166 adults, 50,888 (.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19–50] years; 16 584 [53%] female), of whom 31,479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06–1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from a median (IQR) of 1.54 (1.28–1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52–3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years' follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years. Conclusions and Relevance: The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.

Design of Oral Sustained-Release Pellets by Modeling and Simulation Approach to Improve Compliance for Repurposing Sobrerol

Sobrerol, an oral mucolytic agent, in a recent study showed promise for treating multiple sclerosis. A human equivalent dose of 486 mg of sobrerol administered thrice daily (i.e., 1459 mg of daily dose) demonstrated the highest therapeutic efficacy for repurposing use, which also points out the poor compliance of administration. In this study, oral sustained-release pellets of sobrerol were successfully developed with evaluated manufacturing conditions and drug release kinetics. For design of the target drug product, we used a modeling and simulation approach to establish a predictive model of oral pharmacokinetic profile, by exploring the characteristics and correlations corresponding to the pharmacokinetics and pharmacodynamics of sobrerol, such as absorption lag time (0.18 h), time-scaling in vitro–in vivo correlation (tin-vitro = 0.494 tin-vivo − 0.0904), gastrointestinal transit time (8 h), minimum effective concentration (1.61 μg/mL), and duration of action (12.8 h). Results showed that the frequency of administration and the daily dose remarkably reduced by 33.3% (i.e., from thrice to twice daily) and 22.8%, respectively, which indicates that this prototype approach can be adopted for rapidly developing a modified-release dosage form of sobrerol, with improvement of compliance of administration and therapeutic efficacy.

Cumulative Dietary Risk Assessment of Benzophenone-Type Photoinitiators from Packaged Foodstuffs

Photoinitiators used in ultraviolet-cured ink may migrate from food packaging materials into food products. Therefore, we conducted a dietary risk assessment of exposure to benzophenone (BP)-type photoinitiators by quantifying and reducing uncertainties associated with the risk characterization. A total of 362 food packaging samples including 180 cereals, 136 fruit and vegetable juices, and 46 milk samples were subjected to fast pesticides extraction to determine photoinitiator residues. The average daily dose (ADD) of BP was the highest in the age group of zero to three years, with a P97.5 ADD of 2.56 × 10−4 mg/kg bw/day. The ADD of 2-hydroxybenzophenone (2-OHBP) was the highest in the age group of three to six years, with a P97.5 UB ADD of 3.52 × 10−5 mg/kg bw/day. The estimated UB P97.5 ADD for each age group was below the toxicological concern threshold of 0.0015 mg/kg bw/day. The cumulative toxicity of all BPs, evaluated using the MOET value, was at an acceptable level. Although the MOET value of BPs was above the safety limit in the foodstuffs studied herein, this result may be different if Taiwan were to follow regulation guidelines for BP-type photoinitiators based on the specific migration limit for the unmeasured BP residues in other foodstuffs.

CYP2D6 Genotyping for Personalized Therapy of Tamoxifen in Indonesian Women with ER+ Breast Cancer

PurposeTamoxifen, common adjuvant therapy prescribed in estrogen receptor positive (ER+) breast cancer, is metabolized by CYP2D6 enzyme into endoxifen. The phenotypes of CYP2D6, a highly polymorphic gene, vary from ultrarapid (UM), normal (NM), intermediate (IM), and poor metabolizers (PM). Studies showed that reduced CYP2D6 activity in IMs and PMs resulted in lower endoxifen level, thereby reducing therapy efficacy. This study aims to observe the distribution of CYP2D6 profiles and their corresponding endoxifen levels in Indonesian ER+ breast cancer patients.Methods151 patients who have received tamoxifen therapy for ≥8 weeks were recruited prospectively. DNA and blood samples were collected with buccal swab and finger-prick methods, respectively. Genotyping was performed using the qPCR method while metabolites measurement was performed using HPLC-tandem MS. Patients with IM/PM CYP2D6 profile were advised to increase their tamoxifen dose or switch to aromatase inhibitor, while patients with UM or NM CYP2D6 profile remained on 20 mg daily dose. Tamoxifen metabolites levels of those given 40 mg/day of tamoxifen were measured eight weeks post dose adjustment.ResultsWe found that 40.7% of patients recruited were IM. CYP2D6*10 was the most abundant allele (28.8%) and *10/*36 was the most frequently observed diplotype (23.6%). Endoxifen levels between the NM-PM, NM-IM, and IM-PM were statistically significant, and dose increase of tamoxifen successfully increased endoxifen levels in IMs to a similar level with NMs at baseline.ConclusionIndonesian women have a relatively high proportion of IMs. The correlation between CYP2D6 genotype and phenotype was shown in the significant difference in endoxifen levels among NMs, IMs, and PMs. Dose adjustment of tamoxifen to 40 mg daily positively increased endoxifen levels in IMs to a similar level as NMs. Implementing pharmacogenomics testing of CYP2D6 on ER+ breast cancer women taking tamoxifen can potentially increase the likelihood of achieving better treatment efficacy.Trial RegistrationThe trial was retrospectively registered at ClinicalTrials.gov on 18 March 2020 with identifier NCT04312347 (accessible at: https://clinicaltrials.gov/ct2/show/NCT04312347).

Heavy Metals and Nutrients Loads in Water, Soil, and Crops Irrigated with Effluent from WWTPs in Blantyre City, Malawi

Heavy metals may cause acute and chronic toxic effects to humans and other organisms, hence the need to treat wastewater properly, as it contains these toxicants. This work aimed at assessing zinc, copper, cadmium, and chromium in water, soil, and plants that are irrigated with effluent from Manase and Soche Wastewater Treatment Plants (WWTPs) in Blantyre, Malawi. Atomic Absorption Spectrophotometry (AAS) was used to assess the heavy metals. Heavy Metal Health Risk Assessment (HMHRA) on plants (vegetables) around both WWTPs was also conducted. Average daily dose (ADD) and target hazard quotients (THQ) were used to assess HMHRA. Physicochemical parameters were determined using standard methods from American Public Health Association (APHA). The heavy metal ranges were below detection limit (BDL) to 6.94 mg/L in water, 0.0003 to 4.48 mg/kg in soil, and 3 to 32 mg/L in plants. The results revealed that plants irrigated with effluent from WWTP had high values of aforementioned metals exceeding the Malawi Standards and WHO permissible limits. Furthermore, the health risk assessment values showed that vegetables consumed for a long period of time from Manase WWTP were likely to cause adverse health effects as compared to those from Soche WWTP.

Antimicrobial usage in cattle and poultry production in Dar es Salaam, Tanzania: pattern and quantity

Background Antimicrobials are extensively used in cattle and poultry production in Tanzania. However, there is dearth of information on its quantitative use. A questionnaire-based cross-sectional study was conducted from August to September 2019 in randomly selected poultry and small-scale dairy farms, in three districts of Dar es Salaam City eastern, Tanzania, to assess the practice and quantify antimicrobial use. Descriptive and statistical analyses were performed at a confidence interval of 95%. The ratio of Used Daily Dose (UDD) and Defined Daily Dose (DDD) were used to determine whether the antimicrobial was overdosed or under dosed. Results A total of 51 poultry and 65 small-scale dairy farms were involved in the study. The route of antimicrobial administration was 98% orally via drinking water and 2% in feeds for poultry and for small-scale dairy farms, all through parenteral route. Seventeen types of antimicrobials comprising seven classes were recorded in poultry farms while nine belonging to six classes in the small dairy farms. Majority of the farms (poultry, 87.7% and small scale dairy, 84.3%) used antimicrobials for therapeutic purposes. About 41% of the poultry and one third (34%) of the dairy farmers’ were not compliant to the drug withdrawal periods. Beta-lactams, fluoroquinolones, sulphonamides, tetracyclines and macrolides were the commonly used antimicrobials on these farms. In the poultry farms both those with records and those which relied on recall, antimicrobials were overdosed whereas in the small dairy farms, sulfadimidine, oxytetracycline and neomycin were within the appropriate dosing range (0.8–1.2). The majority (58.6%) of farmers had adequate level of practices (favorable) regarding antimicrobial use in cattle and poultry production. This was associated with the age and level of education of the cattle and poultry farmers. Conclusion The study revealed a widespread misuse of antimicrobials of different types and classes in both poultry and small-scale dairy farming in Dar es Salaam, Tanzania. This result gives insight into the antimicrobial use practices and its quantification. The information obtained can guide and promote prudent use of antimicrobials among the farmers by developing mitigate strategies that reduce antimicrobial resistance risk potentials.

Efficacy of Oxcarbazepine for Sleep-Related Leg Cramps: A Retrospective Study

Objectives: Sleep-related leg cramps (SRLC) are common among older people. Severe clinical symptoms of SRLC usually cause great discomfort to patients. To date, many treatment drugs have been tried; however, there are currently no drugs approved for treating this condition. We aimed to assess the efficacy of a new drug, oxcarbazepine (OXC), in the treatment of SRLC.Methods: We retrospectively analyzed clinical outcomes following OXC administration. A daily dose of 150 mg OXC was prescribed to control nocturnal leg cramps. Clinical outcomes were measured using the Clinical Global Impression Scale to confirm the effectiveness of OXC.Results: A total of 88.9% (16/18) of patients clinically improved four weeks after OXC prescription, and 94% (15/16) of patients continued to improve at the last follow-up (3–6 months). None of the patients complained of side effects related to 150 mg OXC.Conclusions: OXC may be a new medical option for treatment of SRLC.

Treatment of thyroid dysfunction in a medical specialist’s office – the role of levothyroxine

Synthetic levothyroxine is the first line treatment for hypothyroidism, one of the most common endocrine disorders, independently its cause, in all age groups. The Polish Endocrinological Society, together with European Thyroid Association, American Thyroid Association and American Association of Clinical Endocrinologists, do not recommend the use of dried thyroid preparations, triiodothyronine or combined preparations of thyroxine with triiodothyronine. The objective of treatment is to achieve biochemical and clinical euthyroidism monitored by TSH and/or FT4 levels. The daily dose of levothyroxine depends on many factors, including the etiology and severity of hypothyroidism, age, body weight, pregnancy and comorbidities. Routinely, levothyroxine is administered on an empty stomach at least 30 minutes before breakfast (ATA 2014 recommend up to 60 minutes interval between meal and taking the drug). Levothyroxine can also be used in combination therapy in Graves’ disease. Currently, the routine use of synthetic sodium levothyroxine in patients with multinodular goiter is not recommended because it increases the risk of osteoporosis in postmenopausal women and atrial fibrillation in patients after 60 year of life.

Model-based efficacy and toxicity comparisons of moxifloxacin for multi-drug-resistant tuberculosis

Background Moxifloxacin (MOX) is used as a first-choice drug to treat multi-drug-resistant tuberculosis (MDR-TB), however, evidence-based dosing optimization should be strengthened by integrative analysis. The primary goal of this study was to evaluate MOX efficacy and toxicity using integratvie model-based approaches in MDR-TB patients. Methods In total, 113 MDR-TB patients from five different clinical trials were analyzed for the development of a population pharmacokinetics (PK) model. A final population PK model was merged with a previously developed lung-lesion distribution and QT prolongation model. Monte Carlo simulation was used to calculate the probability target attainment (PTA) value based on concentration. An area under the concentration-time curve (AUC)-based target was identified as the minimum inhibitory concentration (MIC) of MOX isolated from MDR-TB patients. Results The presence of human immunodeficiency virus (HIV) increased clearance by 32.7% and decreased the AUC by 27.4%, compared with HIV-negative MDR-TB patients. A daily dose of 800 mg or a 400 mg twice daily dose of MOX is expected to be effective in MDR-TB patients with an MIC of ≤ 0.25 µg/mL, regardless of PK differences resulting from the presence of HIV. The effect of MOX in HIV-positive MDR-TB patients tended to be decreased dramatically from 0.5 µg/mL, in contrast to the findings in HIV-negative patients. A regimen of twice-daily doses of 400 mg should be considered safer than an 800 mg once-daily dosing regimen, because of the narrow fluctuation of concentrations. Conclusions Our results suggest that a 400 mg twice-daily dose of MOX is an optimal dosing regimen for MDR-TB patients because it provides superior efficacy and safety.