H1 Receptor

Absorption, Distribution and Excretion
Readily absorbed via the gastrointestinal tract.
H1 antagonists are eliminated more rapidly by children than by adults and more slowly in those with severe liver disease. /H1 Receptor Antagonists/
The H1 antagonists are well absorbed from the gastrointestinal tract. Following oral administration, peak plasma concentrations are achieved in 2 to 3 hours ... . /H1 Receptor Antagonists/
Elimination and metabolic profiles of the glucuronide products of doxylamine and its N-demethylated metabolites were determined after the oral admin of (14)C-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 metaboites at the 13.3 mg/kg dose were 44.4 + or - 4.2% and 47.3 + or - 8.1% of the total recoverd 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 + or - 2.6% and 47.9 + or - 2.5% of the total recovered dose for male and female rats, respectively. The conjugated doxylamine metabolites that were isolated, quantitiated, and identified are doxylamine O-glucuronide, N-desmethyl-doxylamine O-glucuronide, and N,N-didesmethyldoxylamine O-glucuronide.
The elimination of doxylamine and metabolites was determined after iv admin of (14)C-doxylamine succinate at 0.7 and 13.3 mg/kg to the adult female rhesus monkey. Although the total recovery of radioactivity was the same for the low- and high-dose studies (90.2%), the rate of plasma elimination of doxylamine and its demethylated metabolite (desmethyldoxylamine) was slower for the high dose group. The 24 hr urinary excretion of doxylamine metabolites, desmethyl- and didesmethyldoxylamine, was significantly incr and the polar doxylamine metabolites were significantly decr as the iv doxylamine succinate dose was incr. The plasma elimination of GC-detected doxylamine was determined after po admin of Bendectin (doxylamine succinate and pyridoxine hydrochloride) /also contains dicyclomine hydrochloride/ at 7, 13.3, and 27 mg/kg to adult female rhesus monkeys. As the dose incr, the clearance of doxylamine decr. A statistically evaluated fit of the po data to a single-compartment, parallel first-order elimination model and a single-compartment, parallel first- and second-order (Michaelis-Menten) elimination model indicated that the more complex model containing the second-order process was most consistent with the observed elimination data. /Doxylamine succinate/

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Metabolism / Metabolites
Hepatic.
The conjugated doxylamine metabolites that were isolated, quantitiated, and identified are doxylamine O-glucuronide, N-desmethyl-doxylamine O-glucuronide, and N,N-didesmethyldoxylamine O-glucuronide.
Analysis of doxylamine N-oxide and pyrilamine N-oxide as synthetic standards and biologically derived metabolites by thermospray mass spectrometry (TSP/MS) provided (M + H) + ions for each metabolite. ... In addition, TSP/MS and TSP/MS/MS analysis of ring-hydroxylated N-desmethyldoxylamine ... is also reported.
Hepatic.
Half Life: 10 hours

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Biological Half-Life
10 hours
The drug has an elimination half-life of about 10 hours in healthy adults.

Toxicity Summary
Like other antihistamines, doxylamine acts by competitively inhibiting histamine at H1 receptors. It also has substantial sedative and anticholinergic effects.

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Hepatotoxicity
Despite widespread use over many decades, doxylamine has not been linked to liver test abnormalities or to clinically apparent liver injury. The reason for its safety may relate its short half-life and limited duration of use.
Likelihood score: E (unlikely to be a cause of clinically apparent liver injury).
References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines.
Drug Class: Antihistamines

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Small occasional doses of doxylamine would not be expected to cause any adverse effects in breastfed infants. Larger doses or more prolonged use may cause drowsiness and other effects in the infant or decrease the milk supply, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established.
◉ Effects in Breastfed Infants
Relevant published information on doxylamine was not found as of the revision date. In one telephone follow-up study, mothers reported irritability and colicky symptoms 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention.
◉ Effects on Lactation and Breastmilk
Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. Whether lower oral doses of antihistamines have the same effect on serum prolactin or whether the effects on prolactin have any consequences on breastfeeding success have not been studied. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Interactions
Concurrent use may potentiate the CNS depressant effects of either these medications /alcohol or other CNS depression-producing medications/ or antihistamines; also, concurrent use of maprotiline or tricyclic antidepressants may potentiate the anticholinergic effects of either antihistamines or these medications. /Antihistamines/
Anticholinergic effects may be potentiated when these medications /anticholinergics or other medications with anticholinergic activity/ are used concurrently with antihistamines; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy. /Antihistamines/
Concurrent use of monoamine oxidase (MAO) inhibitors with antihistamines may prolong the intensify the anticholinergic and CNS depressant effects of antihistamines; concurrent use is not recommended. /Antihistamines/
Concurrent use /of ototoxic medications/ with antihistamines may mask the symptoms of ototoxicity such as tinnitus, dizziness, or vertigo. /Antihistamines/
For more Interactions (Complete) data for DOXYLAMINE (7 total), please visit the HSDB record page.

[1]. Sjöqvist F, Lasagna L. The hypnotic efficacy of doxylamine. Clin Pharmacol Ther. 1967;8(1):48-54.

[2]. Subcutaneous infiltration of doxylamine on cutaneous analgesia in rats. Pharmacol Rep. 2018;70(3):565-569.

[3]. Jackson CD, Blackwell BN. Subchronic studies of doxylamine in B6C3F1 mice. Fundam Appl Toxicol. 1988;10(2):254-261.

Doxylamine is a clear colorless liquid. (NTP, 1992)
Doxylamine is a member of pyridines and a tertiary amine. It has a role as a histamine antagonist, a cholinergic antagonist, a sedative, an antiemetic, a H1-receptor antagonist, an anti-allergic agent and an antitussive.
Histamine H1 antagonist with pronounced sedative properties. It is used in allergies and as an antitussive, antiemetic, and hypnotic. Doxylamine has also been administered in veterinary applications and was formerly used in parkinsonism.
Doxylamine is an Antihistamine. The mechanism of action of doxylamine is as a Histamine Receptor Antagonist.
Doxylamine is a first generation antihistamine that is used for symptoms of allergic rhinitis and the common cold and as a short acting sedative. Doxylamine has not been linked to instances of clinically apparent acute liver injury.
Doxylamine is a first generation ethanolamine with antiinflammatory, sedative and antihistamine properties. Doxylamine competitively inhibits the histamine 1 (H1) receptor, thereby preventing the action of endogenous histamine as well as the subsequent release of pro-inflammatory mediators from basophils and mast cells. This agent acts as an inverse agonist that combines with, and stabilizes the inactive form of the H1-receptor, shifting the H1 receptor equilibrium toward the inactive state. This results in downregulation of nuclear factor-kappaB (NF-kappaB) and NF-kappaB dependent antigen presentation, chemotaxis, as well as expression of cell-adhesion molecules and pro-inflammatory cytokines.
Histamine H1 antagonist with pronounced sedative properties. It is used in allergies and as an antitussive, antiemetic, and hypnotic. Doxylamine has also been administered in veterinary applications and was formerly used in parkinsonism. [PubChem]
Histamine H1 antagonist with pronounced sedative properties. It is used in allergies and as an antitussive, antiemetic, and hypnotic. Doxylamine has also been administered in veterinary applications and was formerly used in PARKINSONISM.
See also: Doxylamine Succinate (has salt form).

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Drug Indication
Used alone as a short-term sleep aid, in combination with other drugs as a night-time cold and allergy relief drug. Also used in combination with Vitamin B6 (pyridoxine) to prevent morning sickness in pregnant women.

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Mechanism of Action
Like other antihistamines, doxylamine acts by competitively inhibiting histamine at H1 receptors. It also has substantial sedative and anticholinergic effects.

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Therapeutic Uses
Anti-Allergic Agents; Antiemetics; Antitussive Agents; Histamine H1 Antagonists; Sedatives, Nonbarbiturate
ANTIHISTAMINIC AGENT PROBABLY EFFECTIVE FOR SYMPTOMATIC TREATMENT OF... ALLERGIC RHINITIS, VASOMOTOR RHINITIS, ALLERGIC CONJUNCTIVITIS DUE TO INHALANT ALLERGENS & FOODS, MILD, UNCOMPLICATED ALLERGIC SKIN MANIFESTATIONS OF URTICARIA & ANGIOEDEMA, AMELIORATION & PREVENTION OF...REACTIONS TO BLOOD OR PLASMA... /SUCCINATE/
VET USE: AS ARE OTHER ANTIHISTAMINES IN STOMATITIS, LAMINITIS, URTICARIA, RESPIRATORY DISORDERS, BLOAT, & INDIGESTION IN CATTLE; IN URTICARIA & LAMINITIS IN HORSES; IN DERMATITIS, URTICARIA, MOTION SICKNESS, & IN PREVENTION OF DEPIGMENTATION IN BLUE NOSED DOGS. /SUCCINATE/
Antihistamines are indicated in the prophylactic and symptomatic treatment of perennial and seasonal allergic rhinitis, vasomotor rhinitis, and allergic conjunctivitis due to inhalant allergens and foods. /Antihistamines; Included in US product labeling/
For more Therapeutic Uses (Complete) data for DOXYLAMINE (9 total), please visit the HSDB record page.

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Drug Warnings
PERSONS TAKING ANTIHISTAMINES SHOULD BE ALERTED TO THEIR SEDATIVE EFFECTS & SHOULD BE CAUTIONED NOT TO DRIVE AUTOMOBILE, FLY AIRPLANE, OR OPERATE HAZARDOUS MACHINERY... /ANTIHISTAMINES/
VET: USE OF ANTIHISTAMINES IN STOMATITIS, GANGRENOUS MASTITIS, METRITIS, & TOXIC ENGORGEMENTS HAVE BEEN QUESTIONED. /SUCCINATE/
Like other antihistamines, doxylamine should not be used in premature or full-term neonates. Safety and efficacy of doxylamine as a nighttime sleep aid in children younger than 12 years of age have not been established. In addition, children may be more prone than adults to paradoxically experience CNS stimulation rather than sedation when antihistamines are used as nighttime sleep aids. Because doxylamine may cause marked drowsiness that may be potentiated by other CNS depressants (e.g., sedatives, tranquilizers), the antihistamine should be used in children receiving one of these drugs only under the direction of a physician. As an antihistamine, doxylamine should be used in children 2 to younger than 6 years of age only under the direction of a physician; use of the drug in children younger than 2 years of age is not recommended.
Because of the potential for serious adverse reactions to antihistamines in nursing infants, a decision should be made whether to discontinue nursing or doxylamine, taking into account the importance of the drug to the woman.
For more Drug Warnings (Complete) data for DOXYLAMINE (11 total), please visit the HSDB record page.

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Pharmacodynamics
Doxylamine is an antihistamine commonly used as a sleep aid. This drug is also used to relieve symptoms of hay fever (allergic rhinitis), hives (rash or itching), and other allergic reactions. Doxylamine is a member of the ethanolamine class of antihistamines and has anti-allergy power far superior to virtually every other antihistamine on the market, with the exception of diphenhydramine (Benadryl). It is also the most powerful over-the-counter sedative available in the United States, and more sedating than many prescription hypnotics. In a study, it was found to be superior to even the barbiturate, phenobarbital for use as a sedative. Doxylamine is also a potent anticholinergic.

C17H22N2O

270.3695

270.173

469-21-6

Doxylamine succinate;562-10-7;Doxylamine-d5 succinate;1216840-94-6

3162

LIQ

1.043 g/cm3

364.9ºC at 760 mmHg

25°C

174.5ºC

1.5486 (estimate)

2.923

25.36

0

3

6

20

276

0

CC(C1=CC=CC=C1)(C2=CC=CC=N2)OCCN(C)C

HCFDWZZGGLSKEP-UHFFFAOYSA-N

InChI=1S/C17H22N2O/c1-17(20-14-13-19(2)3,15-9-5-4-6-10-15)16-11-7-8-12-18-16/h4-12H,13-14H2,1-3H3

N,N-dimethyl-2-(1-phenyl-1-pyridin-2-ylethoxy)ethanamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。