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Journal of Clinical Pharmacology Sep 1985Sixteen healthy male volunteers received a single oral dose of 25 mg doxylamine succinate. Doxylamine concentrations in plasma were measured by a newly developed gas...
Sixteen healthy male volunteers received a single oral dose of 25 mg doxylamine succinate. Doxylamine concentrations in plasma were measured by a newly developed gas chromatographic methodology, utilizing direct alkaline extraction into hexane:isoamyl alcohol followed by concentration and autoinjection. Doxylamine kinetics were determined from multiple plasma doxylamine concentrations measured during the 24 hours postdose. Mean kinetic variables were: peak plasma level, 99 ng/mL; time of peak, 2.4 hours postdose; elimination half-life, 10.1 hours; and apparent oral clearance, 217 mL/min. Analogous analytic methodology can be used to study the pharmacokinetics of other drugs of this class.
Topics: Adult; Brompheniramine; Chromatography, Gas; Doxylamine; Half-Life; Humans; Kinetics; Male; Pyridines
PubMed: 4056080
DOI: 10.1002/j.1552-4604.1985.tb02875.x -
Southern Medical Journal Oct 2003Antihistamines, which are readily available over the counter in sleeping aids, are commonly found in intentional overdoses. We report three new cases of severe...
Antihistamines, which are readily available over the counter in sleeping aids, are commonly found in intentional overdoses. We report three new cases of severe rhabdomyolysis related to ingestion of these agents. This is a rarely reported but potentially overlooked complication among patients who present to the emergency center after intentional overdoses. We also describe the potential mechanism of muscle injury in antihistamine overdoses and comment on the potential for cross-reactivity of antihistamines with the urine screen for phencyclidine.
Topics: Adult; Diphenhydramine; Doxylamine; Drug Overdose; Histamine H1 Antagonists; Humans; Male; Rhabdomyolysis; Suicide, Attempted
PubMed: 14570348
DOI: 10.1097/01.SMJ.0000076461.67623.E4 -
Geburtshilfe Und Frauenheilkunde Feb 2024Nausea and vomiting of pregnancy (NVP) is among the most common conditions that pregnant women encounter in the early stages of pregnancy. It can affect up to 85% of...
Nausea and vomiting of pregnancy (NVP) is among the most common conditions that pregnant women encounter in the early stages of pregnancy. It can affect up to 85% of pregnant women, thus representing a significant public health concern. NVP results in substantial negative physical, emotional, and financial consequences. Despite its prevalence, the pathogenesis remains elusive. Few guidelines have been published; however, several interventions exist for the symptomatic treatment of NVP. The aim of this review is to provide an overview of modern treatment strategies of NVP with a special focus on the recently approved dual-release formulation of the doxylamine and pyridoxine combination. This combination was approved by the Food and Drug Administration (FDA) in November 2016 for the treatment of NVP when conservative management fails, and it has been introduced to the American market in April 2018. The maximum plasma concentration (T ) of doxylamine and pyridoxal-5-phosphate is reached 3.5 h and 15 h, respectively, after administration of one tablet twice daily, or 4.5 h and 0.5 h, respectively, when one tablet is administered just once daily. In addition, the delayed-release combination allows sufficient levels of doxylamine and the active metabolite pyridoxal-5-phosphate in the systemic circulation, providing symptoms relief in the subsequent morning. Hence, the dual-release formulation can improve the quality of life of pregnant women suffering from NVP. Additionally, large epidemiological trials have shown no increased risk of adverse effects to newborns, demonstrating that its use is not teratogenic.
PubMed: 38344043
DOI: 10.1055/a-2225-5883 -
Fundamental and Applied Toxicology :... Feb 1988Doxylamine succinate, a histamine (H1) antagonist (antihistamine), was administered as an admixture in the feed to male and female B6C3F1 mice for 14 or 90 days. Dose...
Doxylamine succinate, a histamine (H1) antagonist (antihistamine), was administered as an admixture in the feed to male and female B6C3F1 mice for 14 or 90 days. Dose levels of 0, 100, 250, 500, 1000, and 2000 ppm doxylamine were administered to males and females in the 14-day study while dose levels of 0, 80, 162, 325, 750, and 1500 ppm were administered to both sexes in the 90-day study. Little toxicity was seen in the 14-day study. Final body weights in the highest dose group were reduced 4.0 and 7.3% in males and females, respectively. Treatment-related histopathological changes in the 14-day study were limited to a very low incidence of hepatic necrosis in both sexes. There was little toxicity observed in the 90-day study and no clear dose response relative to weight gain was observed. Histologically, the liver was the only organ affected by doxylamine administration. The liver lesions consisted of hepatic cell cytomegaly and/or karyomegaly which varied from mild to severe and a possible dose-related hepatic necrosis.
Topics: Animals; Body Weight; Doxylamine; Eating; Female; Male; Mice; Mice, Inbred Strains; Organ Size; Pyridines
PubMed: 3356311
DOI: 10.1016/0272-0590(88)90309-0 -
Forensic Science International Jan 2018Misuse of paracetamol, codeine and doxylamine combination analgesics may lead to addiction and mortality. This study aimed to (1) identify unintentional deaths in...
INTRODUCTION
Misuse of paracetamol, codeine and doxylamine combination analgesics may lead to addiction and mortality. This study aimed to (1) identify unintentional deaths in Australia associated with use of combination analgesic products containing paracetamol, codeine and doxylamine; (2) describe cases characteristics, including demographics and additional medication use; and (3) identify common factors associated with misuse and mortality of these medicines in Australia.
DESIGN
This retrospective case series analysed National Coronial Information System data to identify cases of unintentional death attributable to paracetamol, codeine and doxylamine products between 2002 and 2012.
SETTING
Three Eastern Australian states: New South Wales, Queensland, Victoria, comprising a population of approximately 18.6 million people.
RESULTS
441 unintentional deaths attributed to paracetamol/codeine products were identified; doxylamine was detected in 102 cases (23%). Overall unintentional death rates rose from 0.9-per-million in 2002 to 3.6-per-million in 2009, declining to 1.9-per-million in 2012. Median age at time of death was 48, half of all cases occurred between 35-54 years of age, and 57% were female. Concomitant medication use was detected in 79% of cases, including benzodiazepines, other opioids, psychiatric medications, alcohol and illicit drugs. Behaviours consistent with drug misuse including doctor/pharmacy shopping, excessive dosages and extended use, were identified in 24% of cases.
CONCLUSIONS
This study identified 441 deaths associated with codeine-combination analgesic products across three Australian states; with an average of 40 deaths per year. Death commonly involved multiple substance use and abuse behaviours indicative of misuse and dependence.
Topics: Accidents; Acetaminophen; Adolescent; Adult; Aged; Aged, 80 and over; Analgesics; Antiemetics; Australia; Bronchopneumonia; Codeine; Doxylamine; Drug Combinations; Drug Misuse; Female; Humans; Liver; Liver Failure; Male; Middle Aged; Multiple Organ Failure; Necrosis; Respiratory Insufficiency; Retrospective Studies; Substance-Related Disorders; Young Adult
PubMed: 29182956
DOI: 10.1016/j.forsciint.2017.11.026 -
American Journal of Perinatology Sep 2014Antihistamines are commonly used to treat nausea and vomiting of pregnancy (NVP). We re-analyzed the 24 primary studies cited in a 1997 meta-analysis that concluded... (Meta-Analysis)
Meta-Analysis
Antihistamines are commonly used to treat nausea and vomiting of pregnancy (NVP). We re-analyzed the 24 primary studies cited in a 1997 meta-analysis that concluded antihistamine use for NVP was safe as they had been studied in more than 200,000 participating women and the pooled odds ratio for congenital malformations was 0.76 (95% confidence interval [CI]: 0.60-0.94). Our analysis of this meta-analysis showed that 139,414 women were included in 22 original studies involving antihistamines, 129,108 of which were in studies involving doxylamine. In these studies, 23,485 women were exposed to antihistamines, 14,624 of which were exposed to doxylamine. The summary relative risk (cohort studies) and odds ratio (case-control studies) for congenital malformations from antihistamine exposure were 1.09 (95% CI: 1.01-1.18) and 1.04 (95% CI: 0.91-1.19), and for doxylamine exposure, the summary relative risk and odds ratio were 0.94 (95% CI: 0.80-1.10) and 1.07 (95% CI: 0.93-1.23), respectively. Although not a new systematic review, our re-analysis demonstrates that the safety data for antihistamines, and doxylamine in particular, are based on many fewer than 200,000 participating women and exposures, and that doxylamine use is not associated with a decreased risk of malformations as previously reported.
Topics: Antiemetics; Congenital Abnormalities; Doxylamine; Female; Humans; Morning Sickness; Odds Ratio; Pregnancy; Risk
PubMed: 24323370
DOI: 10.1055/s-0033-1358772 -
Journal of Analytical Toxicology 1990Elimination and metabolic profiles of the glucuronide products of doxylamine and its N-demethylated metabolites were determined after the oral administration of...
Elimination and metabolic profiles of the glucuronide products of doxylamine and its N-demethylated metabolites were determined after the oral administration of (14C)-doxylamine succinate (13.3 and 133 mg/kg doses) to male and female Fischer 344 rats. The cumulative urinary and fecal eliminations of these conjugated doxylamine metabolites at the 13.3 mg/kg dose were 44.4 +/- 4.2% and 47.3 +/- 8.1% of the total recovered dose for male and female rats, respectively. The cumulative urinary and fecal eliminations of conjugated doxylamine metabolites at the 133 mg/kg dose were 55.2 +/- 2.6% and 47.9 +/- 2.5% of the total recovered dose for male and female rats, respectively. The conjugated doxylamine metabolites that were isolated, quantitated, and identified are doxylamine O-glucuronide, N-desmethyl-doxylamine O-glucuronide, and N,N-didesmethyldoxylamine O-glucuronide.
Topics: Administration, Oral; Animals; Chromatography, High Pressure Liquid; Doxylamine; Feces; Female; Histamine H1 Antagonists; Male; Mass Spectrometry; Molecular Structure; Pyridines; Rats; Rats, Inbred F344; Sex Factors
PubMed: 1975634
DOI: 10.1093/jat/14.4.247 -
Toxicology Letters Oct 1989Doxylamine succinate (DA), a compound which was formerly used as an antinauseant during pregnancy, showed no substantial mutagenicity in mouse embryos following...
Doxylamine succinate (DA), a compound which was formerly used as an antinauseant during pregnancy, showed no substantial mutagenicity in mouse embryos following transplacental exposure. A small dose-dependent induction of chromosomal aberrations was found in mouse embryos on day 11 of gestation. No induction of sister chromatid exchanges (SCE) was found in embryos on day 11 of gestation. A micronucleus test with fetal blood on day 17 of gestation was negative. Additionally, DA was negative in Chinese hamster bone marrow in vivo (micronuclei) and in human lymphocyte cultures in vitro (SCE).
Topics: Animals; Antiemetics; Bone Marrow; Chromosome Aberrations; Cricetinae; Cricetulus; Doxylamine; Embryo, Mammalian; Female; Fetal Blood; Humans; Lymphocytes; Male; Maternal-Fetal Exchange; Mice; Micronucleus Tests; Mutagens; Pregnancy; Pyridines; Sister Chromatid Exchange
PubMed: 2815116
DOI: 10.1016/0378-4274(89)90104-5 -
Clinical Pharmacokinetics May 1989A single oral dose of doxylamine succinate 25 mg was administered to 21 young (20 to 43 years) and 22 elderly (60 to 87 years) volunteers. Multiple plasma doxylamine...
A single oral dose of doxylamine succinate 25 mg was administered to 21 young (20 to 43 years) and 22 elderly (60 to 87 years) volunteers. Multiple plasma doxylamine concentrations were determined during a 30-hour period after each dose. Elderly and young women did not differ significantly in peak plasma doxylamine concentration (Cmax) [116 vs 103 micrograms/L], time to Cmax (tmax) [2.4 vs 2.4 h], elimination half-life (12.2 vs 10.1 h), volume of distribution (179 vs 176 L) or clearance (191 vs 218 ml/min). Cmax (107 vs 108 micrograms/L) and tmax (2.1 vs 1.6 h) also did not differ between elderly and young men. However, elderly men had reduced doxylamine clearance (174 vs 240 ml/min, p less than 0.02; 2.5 vs 3.2 ml/min/kg, p less than 0.07) and prolonged half-life (15.5 vs 10.2 h, p less than 0.05). The reduced doxylamine clearance and prolonged half-life in elderly men, but not in elderly women, is similar to results for many other drugs which are transformed by oxidation.
Topics: Adult; Aged; Aged, 80 and over; Aging; Doxylamine; Female; Half-Life; Humans; Male; Pyridines; Sex Factors
PubMed: 2743704
DOI: 10.2165/00003088-198916050-00003 -
Drugs in R&D Jun 2023Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its...
BACKGROUND
Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules.
OBJECTIVES
In the present study, we aimed to characterize the bioavailability performance of Cariban in vitro and in vivo.
METHODS
An in vitro dissolution test was performed to evaluate the release profile of Cariban, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug.
RESULTS
Cariban capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h.
CONCLUSION
Cariban behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.
Topics: Adult; Female; Humans; Pregnancy; Antiemetics; Biological Availability; Capsules; Delayed-Action Preparations; Doxylamine; Drug Combinations; Nausea; Pregnancy Complications; Pyridoxine; Vomiting
PubMed: 37318714
DOI: 10.1007/s40268-023-00425-7