Merck & Co. · Small Molecule · Small Molecule
methyldopa is a small molecule developed by Merck & Co.. It is approved for therapeutic indications via oral (po).
| Company | Merck & Co. |
| Drug Class | Small Molecule |
| Route | Oral (PO) |
| Status | Approved |
methyldopa is developed for 1 unique indication across 1 therapeutic area.
| Therapeutic Area | Condition | Phase |
|---|---|---|
| Vascular disorders | Hypertension | ✓ Approved |
Sayer Ömer Naim ÖN, Baytar Gamze G, Kılıç Hülya H, Soytürk Koray K
Hup Rosalie J RJ, Vernooij Robin W M RWM, Ganzevoort Wessel W, Painter Rebecca C RC et al.
Hypertensive disorders of pregnancy (HDP) are associated with maternal and neonatal morbidity. Although delivery is the definitive treatment, antihypertensive agents are often prescribed to control blood pressure to facilitate safe prolongation of pregnancy. International guidelines vary in their treatment recommendations and preferences for methyldopa, labetalol and nifedipine. Within the field of HDP, randomised trials are often underpowered and observational studies are limited in causal inference due to confounding. Therefore, we propose a target trial emulation with hospital-based electronic health record (EHR) data to compare methyldopa, labetalol and nifedipine in pregnancies complicated by HDP, focusing on maternal and perinatal outcomes. We will emulate a target trial by using multicentre EHR data of four university and two non-university hospitals in the Netherlands covering the period from 2006 to 2025, although data availability varied across hospitals. With algorithm-based data extraction, we will collect EHR data from patients with an obstetric diagnosis-treatment code and a prescription of methyldopa, labetalol or nifedipine during pregnancy. Time zero between patients will be aligned to minimise the risk of immortal time bias. Therefore, patients will be stratified into gestational age groups at treatment initiation. Primary outcomes include severe hypertension and severe small for gestational age (SGA) below the third percentile. Secondary maternal outcomes include the development of pre-eclampsia, haemolysis, elevated liver enzymes and low platelets syndrome, acute kidney injury, maternal intensive care unit (ICU) admission, mortality and mode of delivery. Secondary perinatal outcomes include birth weight, SGA below the 10th percentile, fetal growth restriction (diagnosed based on ultrasound data), gestational age, preterm birth <37 and <34 weeks, Apgar score, neonatal ICU admission, neonatal hypoglycaemia and perinatal mortality. Weighted multivariable mixed-effects logistic or linear regression models will be used, depending on the outcome. The Medical Research Ethics Committee of the University Medical Centre Utrecht (NedMec, 23-092/DB) confirmed that formal ethical approval was not required. Study findings will be disseminated through publication in peer-reviewed scientific journals.
Taogoshi Takanori T, Kaneda Kohei K, Kobayashi Ryohei R, Kimura Yasuhiro Y et al.
Long-term l-3,4-dihydroxyphenylalanine (l-DOPA) therapy for Parkinson's disease increases plasma concentrations of 3-O-methyldopa (3-OMD), a major metabolite of l-DOPA. This study aimed to investigate the role of 3-OMD in the central nervous system (CNS)-mediated behavioral effects associated with chronic l-DOPA treatment in rats. The effects of 3-OMD on CNS function were examined using two rat models: repeated oral co-administration of l-DOPA/benserazide and single or repeated intraperitoneal (i.p.) administration of 3-OMD. Behavioral assessments included spontaneous locomotor activity, spontaneous alternation behavior (SAB), spatial learning, and depression-like behavior. Plasma and brain concentrations of 3-OMD were also measured. Repeated oral administration of l-DOPA/benserazide maintained plasma 3-OMD concentrations at 1.57-3.50 μg/mL and brain concentrations at 1.68-3.23 μg/g. This treatment reduced SAB by up to 30% and showed a trend toward reduced spatial learning, whereas locomotor activity was unaffected. Repeated i.p. administration of 3-OMD produced comparable plasma and brain concentrations of 3-OMD, reduced SAB, and showed a trend toward reduced spatial learning, without affecting other behaviors. The reduction in SAB was reversed after a 7-d washout period. In contrast, a single administration of 3-OMD had no detectable behavioral effects. In conclusion, sustained, but not transient, exposure to 3-OMD may contribute to reduced working memory performance during chronic l-DOPA therapy.
Handy Adrian A, Hira Rashmin R, Sheldon Robert S RS, Raj Satish R SR
To describe the therapeutic capability of methyldopa in patients with postural orthostatic tachycardia syndrome (POTS) and clinical features suggestive of a hyperadrenergic subtype. We conducted a retrospective chart review of five patients diagnosed with POTS at the Calgary Autonomic Investigation and Management Clinic that had hyperadrenergic features, such as episodes of tremors, diaphoresis, heat intolerance, irritability and/or increased anxiety, and were treated with methyldopa. Demographics, clinical features, autonomic function testing results, and treatment response were collected. Autonomic testing included head-up tilt table testing or active stand testing, and the Valsalva maneuver. Patients also completed an online survey assessing response to methyldopa via the Malmö POTS symptom score (MaPS). All five patients in this case series had POTS with hyperadrenergic features including episodes of tremors, diaphoresis, heat intolerance, irritability and/or increased anxiety often occurring at night. All five patients reported improvements in their orthostatic symptoms and sleep quality while taking methyldopa, with fewer episodes of nocturnal tachycardia, diaphoresis, and/or tremors. Overall, fatigue was improved in these patients. All patients lacked orthostatic hypertension on at least one visit, only one patient had orthostatic hypertension on formal active stand/head up tilt-table testing, and only two of the four patients had ∆DBPVM2 > 17 mmHg or a vigorous Phase 2 L SBP recovery on Valsalva (putative markers of a hyperadrenergic state in POTS). In patients with POTS and hyperadrenergic features, methyldopa is a safe central acting sympatholytic that can be used to treat their hyperadrenergic symptoms.
Manna Dina F DF, Lastuvkova Hana H, Schreiberova Jolana J, Jandova Lenka L et al.
Bile acids (BAs) are steroidal molecules with endocrine and exocrine functions, eliminated primarily via bile. Intrahepatic cholestasis of pregnancy (ICP) features elevated maternal BA concentrations linked to adverse perinatal outcomes. Hypertensive disorders of pregnancy, often managed with methyldopa, co-occur with BA dysregulation, yet the impact of methyldopa on BA homeostasis is unclear. We examined methyldopa in a murine model of estrogen-induced cholestasis. Female C57BL/6J mice received ethinylestradiol (10 mg/kg, s.c.) with or without methyldopa (250 mg/kg, p.o.) for 7 days. BA profiles were quantified by LC-MS across plasma, bile, liver, urine, intestine, and feces. Hepatic, ileal, and renal expression of BA-related enzymes/transporters was assessed by RT-qPCR and Western blotting. In estrogen-challenged mice, methyldopa selectively reduced total BA concentrations in plasma and liver without increasing fecal or urinary BA excretion. The lowering coincided with induction of CAR-responsive detoxification/export markers, particularly Cyp2b10 and Abcc3/Mrp3, together with partial restoration of nuclear CAR and reduced p-ERK1/2 normalized to total ERK1/2. Methyldopa also reduced hepatic free cholesterol in cholestatic mice, accompanied by reduced Hmgcr abundance and increased Acat2 expression, indicating altered cholesterol handling that may limit substrate availability for BA synthesis. In conclusion, methyldopa lowered BA plasma concentrations under estrogenic stress consistent with reduced substrate availability for BA synthesis and enhanced detoxification/export. In the context of pregnancy-related BA dysregulation, these findings suggest that methyldopa, when used for hypertensive disorders of pregnancy, does not exacerbate BA accumulation and may selectively attenuate it; this hypothesis warrants clinical evaluation.
Kharaghani Mohammad Amin MA, Kianipour Reza R, Ataei Seyed Mohammad-Navid SM, Ebrahimpour Sholeh S et al.
Potentially inappropriate prescribing (PIP) in the elderly is associated with adverse outcomes and increased healthcare use. We aimed to estimate its prevalence and pattern among the elderly population of Iran using the Screening Tool of Older Persons' Prescriptions (STOPP) criteria. Retrospective, population-based observational study. Nationwide data of Iran Health Insurance Organization (IHIO) prescription claims from 24 provinces (21 March 2014 to 19 March 2017). Adults aged ≥60 years with at least one prescription in the dataset were included. The study comprised 2 696 300 older adults who received 28 575 400 prescriptions. Not applicable. Using a two-stage curation process, we selected STOPP version 3 criteria that could be operationalised from dispensing data alone (age, Anatomical Therapeutic Chemical code, dose, duration and concurrent use). For each criterion, we calculated prescription and patient level PIP prevalence overall and among at-risk prescriptions. Across the curated STOPP criteria, 313 315 prescriptions issued to 131 012 patients met at least one PIP criterion. The most frequent PIPs were concurrent beta blocker and diltiazem use (99 027 prescriptions; 1.26% of patients), benzodiazepine therapy ≥4 weeks (89 240 prescriptions; 1.60% of patients), ≥2 anticholinergic drugs (47 079 prescriptions; 0.78% of patients) and concomitant non-steroidal anti-inflammatory drug plus anticoagulant (25 685 prescriptions; 0.38% of patients). PIPs involving acetylcholinesterase inhibitors, ticlopidine, clonidine and methyldopa were rare. In this nationwide claims-based study, about 5% of elderly Iranians were exposed to PIPs, particularly chronic benzodiazepine use, excessive anticholinergic burden and high-risk cardiovascular and antithrombotic combinations. Our findings provide concrete targets for claims-based surveillance and interventions to improve prescribing safety in Iran's ageing population.
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