Recovery mechanism of a microalgal species, Chlorella sp. from toxicity of doxylamine: Physiological and biochemical changes, and transcriptomics.

Ubiquitous distribution of pharmaceutical contaminants in environment has caused unexpected adverse effects on ecological organisms; however, how microorganisms recover from their toxicities remains largely unknown. In this study, we comprehensively investigated the effect of a representative pollutant, doxylamine (DOX) on a freshwater microalgal species, Chlorella sp. by analyzing the growth patterns, biochemical changes (total chlorophyll, carotenoid, carbohydrate, protein, and antioxidant enzymes), and transcriptomics. We found toxicity of DOX on Chlorella sp. was mainly caused by disrupting synthesis of ribosomes in nucleolus, and r/t RNA binding and processing. Intriguingly, additional bicarbonate enhanced the toxicity of DOX with decreasing the half-maximum effective concentrations from 15.34 mg L-1 to 4.63 mg L-1, which can be caused by inhibiting fatty acid oxidation and amino acid metabolism. Microalgal cells can recover from this stress via upregulating antioxidant enzymatic activities to neutralize oxidative stresses, and photosynthetic pathways and nitrogen metabolism to supply more energies and cellular signaling molecules. This study extended our understanding on how microalgae can recover from chemical toxicity, and also emphasized the effect of environmental factors on the toxicity of these contaminants on aquatic microorganisms.

Nausea and Vomiting of Pregnancy and its Management with the Dual-Release Formulation of Doxylamine and Pyridoxine.

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 max ) 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.

When Overdose of Doxylamine Leads to Severe Rhabdomyolysis and Renal Failure That Requires Hemodialysis: A Case Report and Literature Review.

A 52-year-old male with acute onset right-sided weakness, numbness, and buttock pain after consuming 30 tablets of doxylamine antihistamine the night prior. Laboratory tests showed elevated creatinine kinase, blood urea nitrogen, creatinine, troponins, liver transaminases, and phosphate. The patient was admitted to the medical intensive care unit for severe rhabdomyolysis, acute liver failure, and acute kidney injury secondary to doxylamine intoxication. Studies describe symptoms of severe doxylamine intoxication, such as impaired consciousness (coma), grand mal seizures, and cardiopulmonary arrest. Circulating myoglobin causes oxidative injury to the kidney through the formation of F2-isoprostanes leading to renal vasoconstriction. One study explained drug-induced rhabdomyolysis via two mechanisms: direct drug injury to the striated muscle and local muscle compression in seizure, coma, and metabolic abnormality. Treatment involves aggressive hydration with monitoring of serum electrolytes and renal function. Aggressive volume expansion via intravenous fluids remains critical in preventing rhabdomyolysis-associated nephrotoxicity and myoglobin-induced acute renal failure. Alkalinization of urine may prevent renal vasoconstriction resulting in enhanced excretion of the toxic metabolites of doxylamine and myoglobin via renal tubules, thereby reducing peak serum concentration time and preventing direct renal tissue damage.

[Insomnia in the context of affective disorders]. / Insomniya v kontekste affektivnykh rasstroistv.

The article analyzes the current literature on the relationship of insomnia with affective disorders, in particular with depression and anxiety. Research shows that there is a strong multi-channel relationship between insomnia, depression, and anxiety, with insomnia being considered a risk factor for mood disorders more often than vice versa. The so-called insomnia paradox of bipolar disorder is described, the essence of which is that in manic episodes the frequency of insomnia is higher than in depressive episodes. The data of a network meta-analysis, which found an evidence base for the use of a variety of drugs used for the pharmacological treatment of insomnia in adults, are presented. Efficiency and convenience in taking the drug Valocordin-Doxylamine are noted.

The simultaneous measurement of quaternary mixture in over-the-counter cold medications using sequential spectrophotometric resolution approach enhanced with in-lab sample enrichment.

A sequential spectrophotometric resolution technique (SSRT) was developed in this study without the use of systematic separation procedures to determine drug of a quaternary combination; caffeine (CAF), pseudoephedrine (PSE), doxylamine succinate (DOX), and paracetamol (PAR). Their presence in a tablet with a gap ratio of 3:3:1:150, respectively, and their overlapping spectra with low absorptivities make their resolution and determination impossible without prior separation. successive ratio subtraction technique (SRST) and constant multiplication method were used to solve these problems. Furthermore, an in-lab sample enrichment technique was applied to increase minor components concentration and consequently their absorbanses (CAF, PSE, and DOX). The D0 absorption spectra were generated by successive ratios followed by subtraction and multiplication of the constants. The maximum absorbances of the drugs tested, namely (CAF, PSE, DOX and PAR) were measured at wavelengths of 272.0, 257.0, 260.0, and 248.0 nm, respectively. The limits of detection (LOD) and limits of quantification (LOQ) were 0.021, 0.124, 0.186, 0.137 and 0.070, 0.414, 0.621, 0.456 (µg/mL), respectively. The linearitiy ranges (µg/mL) were 1.0-22.0, 1.0-24.0, 10.0-90.0 and 1.0-15.0 for CAF, PSE, DOX, and PAR, respectively. The International Conference on Harmonization (ICH) guidelines were applied for method validation, and the results obtained were within the limited parameters. The finding results were compared to official and/or published analytical methods to determine the procedure's reliability. It was noted that there was no actual difference in accuracy and precision between both meyhods. The proposed technique is sensitive, selective and economic;so it can be applied to the simultaneous analysis of these drugs in their commercial tablets and/or in quality-control laboratories.

Incorporation of doxylamine and N-doxylamine-oxide in human hair and the impact of a permanent oxidative hair dye.

Knowledge of the drug incorporation in hair and impact of cosmetic treatments remains essential to correctly interpret forensic cases. The study shows the analysis of doxylamine and doxylamine-N-oxide and the evaluation of the relationship between dose and hair concentration and the impact of hair treatment (oxidative dying). The study included (A) three subjects participated to the study: a regular user (Subject 1) and two single-dose users (Subject 2, 1 single dose; and Subject 3, 2 single doses spaced 5 months apart). Subject 3 applied a permanent oxidative hair dying monthly. (B) A permanent oxidative hair dying was applied twice to the hair collected from Subject 2. (A) The average concentrations in head hair for doxylamine and its N-doxylamine-oxide, respectively, were as follows: Subject 1, 1825 pg/mg and 16 pg/mg; Subject 2, 182 and

Identification of transformation products during Doxylamine chloramination for NDMA mitigation.

N-nitrosodimethylamine (NDMA) is a disinfection byproduct that forms at the presence of an organic nitrogen precursor. Doxylamine, an antihistaminic pharmaceutical, is a precursor of NDMA and has been shown to form NDMA in the presence of chloramine. In this study, the effect of Doxylamine as an NDMA precursor has been further studied during chloramination. The end product and byproducts during chloramination were investigated using a high-resolution mass spectrometer by taking samples at different time intervals. Results suggest that NDMA is not the only end product forming during chloramination of Doxylamine and several transformation products that do not end up as NDMA may form. A group of these transformation products have been selected based on their relative amounts during chloramination with time and notated as Focus Tentative Transformation Products (FTTPn). The identification of these byproducts will make it easier to study the conditions during chloramination that may favour these 'known' transformation products with the use of less sophisticated analytical instruments. Then, it might lead to the establishment of chloramination protocols that will minimise the formation of NDMA from its precursors.

A simple and sensitive LC-MS/MS method for determination of doxylamine in human plasma and its application in a bioequivalence study in healthy Chinese volunteers.

A simple, rapid, sensitive and specific LC-MS/MS method was developed and validated for the quantitative determination of doxylamine in human plasma, using isotope doxylamine-d5 as internal standard (IS). The detection was conducted on a QTRAP 5500 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive ion mode. Quantification was achieved by positive electrospray ionization containing multiple reaction monitoring (MRM) transitions of m/z 271.0→182.0 for doxylamine and m/z 276.2→187.3 for IS. The mobile phase A was methanol, and mobile phase B was 20 mM ammonium acetate (0.2 % formic acid) in water, using a gradient elution procedure at a flow rate of 0.6 mL/min. The method was validated with a sensitivity of 0.500 ng/mL and a linear concentration range of 0.500-200 ng/mL. The inter-batch precision (%CV) was less than 5.4 %, and the accuracy deviation (%RE) ranged from - 10.6 % to 3.7 %; the inter-batch precision (%CV) was less than 6.6 %, and the accuracy deviation (%RE) was ranged from - 2.7 % to 0.1 %. The selectivity, sensitivity, extraction recovery, matrix effect, carryover, dilution reliability, stability and other characteristics were within the acceptable range. This validated method was successfully applied to a bioequivalence study that orally administered 25 mg of doxylamine succinate tablets in 60 healthy Chinese volunteers.

Harnessing of Doxylamine Succinate/Pyridoxine Hydrochloride-Dual Laden Bilosomes as a Novel Combinatorial Nanoparadigm for Intranasal Delivery: In Vitro Optimization and In Vivo Pharmacokinetic Appraisal.

The present work is concerned with tailoring and appraisal of a novel nano-cargo; bilosomes (BLS) dual laded with doxylamine succinate (DAS) and pyridoxine hydrochloride (PDH), the first treatment option against gestational nausea and vomiting, for intranasal delivery. This bifunctional horizon could surmount constraints of orally-commercialized platforms both in dosage regimen and pharmacokinetic profile. For accomplishing this purpose, DAS/PDH-BLS were elaborated integrating phospholipid, sodium cholate and cholesterol applying thin-film hydration method based on Box-Behnken design. Utilizing Design-Expert® software, the effect of formulation variables on BLS physicochemical features alongside the optimal formulation selection were investigated. Then, the optimum DAS/PDH-BLS formulation was incorporated into a thermally-triggered in situ gelling base. The in vivo pharmacokinetic studies were explored in rats for intranasal DAS/PDH-BLS in situ gel compared with analogous intranasal free in situ gel and oral solution. The optimized BLS disclosed vesicle size of 243.23 nm, ζ potential of -31.33 mV, entrapment efficiency of 59.18 and 41.63%, accumulative % release within 8 h of 63.30 and 85.52% and accumulative permeated amount over 24 h of 347.92 and 195.4 µg/cm2 for DAS/PDH, respectively. Following intranasal administration of the inspected BLS in situ gel, pharmacokinetic studies revealed a 1.64- and 2.3-fold increment in the relative bioavailability of DAS and a 1.7- and 3.73-fold increase for PDH compared to the intranasal free in situ gel and oral solution, respectively besides significantly extended mean residence times for both drugs. Thus, the intranasally exploited DAS/PDH-BLS could be deemed as a promising hybrid nanoplatform with fruitful pharmacokinetics and tolerability traits.

Prescription medications for use in pregnancy-perspective from the US Food and Drug Administration.

Obstetrical healthcare providers frequently field questions about the safety of medications recommended or prescribed to their pregnant patients. Most women use as least 1 medication during pregnancy; however, there is little information about the safety or appropriate dosing of many medications during this phase of life. In addition, the development of drugs for use in pregnant women trails behind the development of drugs intended for other sectors of the population. Our goal is to inform the obstetrics community about the US Food and Drug Administration authority and their role in approving drugs for marketing. We begin with the statutes that led to the creation of the Food and Drug Administration and its current organization. We then cover drug development and the Food and Drug Administration review process, including the role of the advisory committee. The different types of drug approvals are discussed, with some specific examples. Finally, we enumerate the drugs specifically approved for use in obstetrics and contrast them with drugs commonly used by pregnant women and drugs used "off-label" during pregnancy. The Food and Drug Administration is committed to protecting and advancing the public health of pregnant women by guiding the development and ensuring the availability of effective and safe therapeutics for obstetrical indications and for medical conditions during pregnancy. We hope this review will inspire more research addressing drug use during pregnancy.

Unravelling metabolism and microbial community of a phytobed co-planted with Typha angustifolia and Ipomoea aquatica for biodegradation of doxylamine from wastewater.

Pharmaceutical contaminants in environment induce unexpected effects on ecological systems and human; thus, development of efficient technologies for their removal is immensely necessary. In this study, biodegradation and metabolic fate of a frequently found pharmaceutical contaminant, doxylamine by Typha angustifolia and Ipomoea aquatica was investigated. Microbial community of the plant rhizosphere has been identified to understand the important roles of the functional microbes. The plants reduced 48-80.5 % of doxylamine through hydrolysis/dehydroxylation and carbonylation/decarbonylation. A constructed phytobed co-planted with T. angustifolia and I. aquatica removed 77.3 %, 100 %, 83.67 %, and 61.13 % of chemical oxygen demand, total nitrogen, total phosphorus, and doxylamine respectively from real wastewater. High-throughput sequencing of soil and rhizosphere indicated that the phyla Proteobacteria, Bacteroidetes, Firmicutes, Planctomycetes, Actinobacteria, and Cyanobacteria dominated the microbial communities of the phytobed. Current study has demonstrated the applicability of the developed phytobeds for the treatment of doxylamine from municipal wastewater and provide a comprehensive understanding of its metabolism through plant and its rhizospheric microbial communities.

In vitro analytical dissolution profiling of antiemetic delayed release tablets in two different dissolution media: Validated spectrophotometric methods versus reported HPLC.

The combination of pyridoxine HCl (PYR) and doxylamine succinate (DOX) was proved to be effective and safe acting as the first line of pregnancy medication for vomiting and nausea under a trade name; Vomibreak® delayed release tablets. This combination has been available in the Egyptian market since 2016. Dissolution study is a meaningful tool that represents a predictor of output because the rate controlling steps in any drug's absorption is the rate of discharging from its medicinal formulation. Generally, the dissolution test of all delayed release tablets is operated at two stages: first the acid stage then the buffer stage. In our work, the acid stage was performed in 0.1 N hydrochloric acid (0.1 M HCl) and the buffer one was in 0.2 M sodium phosphate buffer (0.2 M Na-PB), pH = 6.8, according to FDA guidelines. In present work, for the first time, this binary mixture was quantitatively determined by applying four spectrophotometric methods. PYR was directly determined by zero order spectra method (D0) at 291.0 nm in the range 2.0-26.0 µg/mL in the acid stage and at 325.0 nm in the range 5.0-35.0 µg/mL in the buffer stage, where DOX show no interference in both cases. However, DOX was determined by three methods, namely, Dual wavelength (DW), Ratio difference (RD) and Derivative ratio (DD1). DD1 was the chosen method for determination of DOX in the two-phase dissolution study of Vomibreak® tablets at 249.0 nm in the range 2.0-44.0 µg/mL and 273.0 nm in the range 5.0-100.0 µg/mL in acid and buffer phases, respectively. All of the suggested methods were tested in compliance with ICH guidelines, where all methods were found to be reliable, reproducible, and selective. A statistical comparison was computed between two analytical techniques of critical importance in the development of two media dissolution profile: proposed UV- spectrophotometric and reported HPLC methods where no significant difference was found. Difference (ƒ1) and similarity (ƒ2) factors were calculated for PYR and DOX and shown that ƒ1 was 1.490 and 1.654 and ƒ2 was 94.431 and 92.396 for PYR and DOX, respectively.

Misleading meta-analyses of observational studies may generate unjustified alarms: The case of medications for nausea and vomiting in pregnancy.

OBJECTIVES: Because observational studies often use imperfect measurements, results are prone to misclassification errors. We used as a motivating example the possible teratogenic risks of antiemetic agents in pregnancy since a large observational study recently showed that first-trimester exposure to doxylamine-pyridoxine was associated with significantly increased risk of congenital malformations as a whole, as well as central nervous system defects, and previous observational studies did not show such associations. A meta-analysis on this issue was carried out with the aim to illustrate how differential exposure and outcome misclassifications may lead to uncertain conclusions. METHODS: Medline, searched to October 2019 for full text papers in English. Summary Odds Ratios (ORs) with confidence intervals (CIs) were calculated using random-effect models. Probabilistic sensitivity analyses were performed for evaluating the extension of differential misclassification required to account for the exposure-outcome association. RESULTS: Summary ORs were 1.02 (95 % CI, 0.92-1.15), 0.99 (0.82-1.19) and 1.25 (1.08-1.44) for overall congenital, cardiocirculatory, and central nervous system malformations respectively. By assuming exposure and outcome bias factor respectively of 0.95 (i.e., newborns with congenital defects had exposure specificity 5% lower than healthy newborns) and 1.12 (i.e., exposed newborns had outcome sensitivity 12 % higher than unexposed newborns), summary OR of central nervous system defects became 1.13 (95 % CI, 0.99-1.29) and 1.17 (95 % CI, 0.99-1.38). CONCLUSION: Observational investigations and meta-analyses of observational studies need cautious interpretations. Their susceptibility to several, often sneaky, sources of bias should be carefully evaluated.

Biodegradation of Doxylamine From Wastewater by a Green Microalga, Scenedesmus obliquus.

Pharmaceutical contaminants (PCs) have been recognized as emerging contaminants causing unexpected consequences to environment and humans. There is an urgent need for development of efficient technologies to treat these PCs from water. The current study has investigated the removal capacity of a green microalgal species, Scenedesmus obliquus, for doxylamine, chemical oxygen demand (COD), and nutrients from real wastewater. Results have indicated that S. obliquus can grow well in the doxylamine-polluted wastewater with the achievement of 56, 78.5, 100, and 89% removal of doxylamine, COD, total nitrogen (TN), and total phosphorus (TP). Addition of 2 g L-1 bicarbonate enhanced the removal of doxylamine up to 63% and slightly inhibited the removal of COD. Decreased carbohydrate (28-26%) and increased protein content (30-33%) of the harvested biomass have been observed after cultivation in the wastewater. The current study has shown the feasibility of using microalgae-based biotechnologies for PC-contaminated wastewater.

[The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin]. / Les effets anti-H1 intéressants dans les insomnies de maintien : réflexion sur les intérêts comparés de la doxylamine et de la doxépine.

Doxylamine (Donormyl®, Lidene®, Generics) is commonly proposed by pharmacists as a sleeping pill which does not require a prescription. In France, today it is only prescribed for occasional insomnia in adults. In light of knowledge about the role of the histamine H1 inverse agonist drugs in the treatment of insomnia, and specifically the low dose doxepin (3 mg and 6 mg) marketed in the US and Canada (Silenor®), we suggest that the use of doxylamine may be appropriate for treating insomnia in the last third of the night. Better information to the pharmacist on the prescription of this anti-H1 hypnotic would be beneficial to the patient.

[Acute insomnia: natural course and correction modalities]. / Ostraia insomniia: estestvennoe techenie i vozmozhnosti korrektsii.

The review describes general patterns of the development of acute (short-term) insomnia, its occurrence and course with the risk of transition to chronic insomnia. Main approaches for pharmacological and psychotherapeutic correction of acute insomnia needed to prevent chronification are indicated. The author suggests an algorithm for the treatment of acute insomnia taking into account its staging.

[Modern concepts about insomnia in mental disorders: clinical aspects]. / Sovremennye predstavleniia ob insomnii pri psikhicheskikh rasstroistvakh (klinicheskie aspekty).

Insomnia is one of the most common symptoms of mental pathology (affective, anxious, hypochondriac, asthenic, psychotic) and reveals a number of characteristic features depending on the structure of the mental disorder. Psychopharmacotherapy for insomnia in mental disorders is an important aspect of patient supervision. Doxylamine (donormil) is one of the promising drugs for the correction of insomnia, both in combination with other psychotropic drugs and in monotherapy.

New evidence for concern over the risk of birth defects from medications for nausea and vomitting of pregnancy.

OBJECTIVES: The aim of the study was to quantify the risk of major congenital malformations (MCM) associated with first-trimester exposure to antiemetics. STUDY DESIGN AND SETTING: Using the Quebec Pregnancy Cohort (1998-2015), first-trimester doxylamine-pyridoxine, metoclopramide, and ondansetron exposures were assessed for their association with MCM. Generalized estimating equations were used to estimate odds ratios (OR), adjusting for potential confounders (aOR). RESULTS: Within 17 years of follow-up, the prevalence of antiemetic use during pregnancy increased by 76%. Within our cohort, 45,623 pregnancies were exposed to doxylamine-pyridoxine, 958 to metoclopramide, and 31 to ondansetron. Doxylamine-pyridoxine and metoclopramide use were associated with an increased risk of overall MCM (aOR 1.07, 95% confidence interval [CI]: 1.03-1.11; 3,945 exposed cases) and (aOR 1.27, 95% CI: 1.03-1.57; 105 exposed cases), respectively. Doxylamine-pyridoxine exposure was associated with increased risks of spina bifida (aOR 1.87, 95% CI: 1.11-3.14; 23 exposed cases), nervous system (aOR 1.25, 95% CI: 1.06-1.47; 225 exposed cases), and musculoskeletal system defects (aOR 1.08, 95% CI: 1.02-1.14; 1,735 exposed cases). Metoclopramide exposure was associated with an increased risk of genital organ defects (aOR 2.26, 95% CI: 1.14-4.48; 10 exposed cases). No statistically significant association was found between ondansetron exposure and the risk of overall MCM. CONCLUSION: First-trimester doxylamine-pyridoxine and metoclopramide exposure was associated with a significantly increased risk of overall and specific MCM.