Dimemorfan phosphate

Pharmacokinetics of dimemorfan phosphate tablets in healthy Chinese volunteers

Objective: Investigate the pharmacokinetic properties of the antitussive dimemorfan phosphate tablets in healthy male and female Chinese volunteers after single and multiple-dose administration; and to evaluate the food-effect on pharmacokinetics of dimemorfan. Methods: 12 subjects received a single dose of 10 mg and 40 mg dimemorfan phosphate tablets, respectively in study stage 1. Another 12 subjects received a single dose of 20 mg dimemorfan phosphate tablets under fed conditions, a single dose of 20 mg dimemorfan phosphate tablets under fasting conditions and multiple-dosing of 20 mg dimemorfan phosphate tablets 3 times per day, respectively in study stage 2. The washout between each treatment was 1 week. Plasma dimemorfan was quantified by a high pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Results: After single-dosing of 10 mg, 20 mg and 40 mg dimemorfan phosphate tablets, Cmax, AUC0-t and AUC0-∞ were dose proportional, which achievd 6.19 ± 7.61 ng·mL-1, 101 ± 171 and 117 ± 210 ng·mL-1·h, respectively after single-dosing of 40 mg dimemorfan phosphate tablets. Tmax ranged from 2.75 to 3.96 h and t1/2 ranged from 10.6 to 11.4 h. After multiple-dosing of 20 mg dimemorfan phosphate tablets, the Accumulation Index (AI) was 2.65 ± 1.11. The pharmacokinetic parameters after single-dosing of 20 mg dimemorfan phosphate tablets under fed conditions were similar with those under fasting conditions. Sex did not affect the pharmacokinetics of dimemorfan phosphate tablets. Conclusions: Single-dosing of dimemorfan phosphate tablets exhibited linear kinetic characteristics. Multiple-dosing of 20 mg dimemorfan phosphate tablets 3 times per day caused obvious accumulation. No food effect or sex effect on the pharmacokinetics of dimemorfan phosphate tablets was observed. Chictr.org identifier: ChiCTR-ONC-14004851.

Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2

Sigma-1 receptor (Sigmar1) is a specific chaperone located in the mitochondria-associated endoplasmic reticulum membrane (MAM) and plays a role in several physiological processes. However, the role of Sigmar1 in bone homeostasis remains unknown. Here, we show that mice lacking Sigmar1 exhibited severe osteoporosis in an ovariectomized model. In contrast, overexpression of Sigmar1 locally alleviated the osteoporosis phenotype. Treatment with Sigmar1 agonists impaired both human and mice osteoclast formation in vitro. Mechanistically, SERCA2 was identified to interact with Sigmar1 based on the immunoprecipitation-mass spectrum (IP-MS) and co-immunoprecipitation (co-IP) assays, and Q615 of SERCA2 was confirmed to be the critical residue for their binding. Furthermore, Sigmar1 promoted SERCA2 degradation through Hrd1/Sel1L-dependent ER-associated degradation (ERAD). Ubiquitination of SERCA2 at K460 and K541 was responsible for its proteasomal degradation. Consequently, inhibition of SERCA2 impeded Sigmar1 deficiency enhanced osteoclastogenesis. Moreover, we found that dimemorfan, an FDA-approved Sigmar1 agonist, effectively rescued bone mass in various established bone-loss models. In conclusion, Sigmar1 is a negative regulator of osteoclastogenesis, and activation of Sigmar1 by dimemorfan may be a potential treatment for osteoporosis in clinical practice.

The nonnarcotic antitussive drug dimemorfan: a review

The antitussive dimemorfan phosphate was discovered through extensive screening of morphinic derivatives and was introduced in Japan in 1975. The majority of studies on dimemorfan have been published in Japanese, and this review aims to make these data more generally available. The antitussive action of dimemorfan appears to be directly on the cough center in the medulla. Dimemorfan does not induce any significant physical or psychologic dependence, and its antitussive action is not affected by the opioid-receptor blocker levallorphan. Dimemorfan is therefore considered a nonnarcotic antitussive. Studies of antitussive effects in animal models indicate that dimemorfan is up to three times more potent than codeine and is equivalent to dextromethorphan. Three major comparative clinical trials and postmarketing surveillance studies showed that dimemorfan is equally or slightly more efficacious than dextromethorphan, benproperine phosphate, or placebo for the control of coughing. Several animal and clinical studies have confirmed the efficacy and safety of dimemorfan. Dimemorfan was effective in the majority of patients. In contrast to the narcotic antitussives, dimemorfan caused no serious problems with the digestive system, such as constipation and disorders of the bile duct, caused no dependence or tolerance, and was unlikely to have clinical analgesic effects. Minor side effects, such as loss of appetite, nausea, and drowsiness, were seen in less than 10% of patients. A syrup formulation of dimemorphan that retains its efficacy and safety is also available. Overall, these data indicate that dimemorfan is an effective nonnarcotic antitussive agent with a low incidence of adverse events.

Simple and sensitive LC-MS/MS-based assay for the quantification of dimemorfan in human plasma for use in a pharmacokinetic study

Dimemorfan phosphate has been widely used for 40 years throughout the world for the treatment of coughs. This is the first report on the use of an LC-MS/MS-based assay for the determination of dimemorfan in human plasma using estazolam as an internal standard after one-step protein precipitation with acetonitrile. Chromatographic separation was achieved on a Phenomenex Luna C18 column (3 ?m, 50 × 2.0 mm) using a fast gradient method, which involves water and methanol as the mobile phase (both containing 0.1% formic acid). Dimemorfan and estazolam were detected with proton adducts at m/z values of 255.8 → 155.1 and 295.0 → 267.0, respectively, in the selected reaction monitoring positive mode. The linear dynamic range of the assay was 0.04-5.00 ng/mL. The chromatographic run time for each plasma sample was <5 min. The method was proven to be accurate, precise, and repeatable. Finally, the developed method was successfully applied for the determination of dimemorfan in a pharmacokinetic study using healthy Chinese subjects.

Cytochrome P450 2D6*10 genotype affects the pharmacokinetics of dimemorfan in healthy Chinese subjects

This study aimed to investigate the effects of cytochrome P450 2D6*10 (100C > T, rs1065852) genotype on the pharmacokinetics of dimemorfan in healthy Chinese subjects. Data were evaluated from 24 subjects in two pharmacokinetic studies who received an oral dose of 40 mg of dimemorfan syrup (n = 12) or dimemorfan tablet (n = 12) after providing written informed consent and being divided into three groups: subjects with CYP2D6*10 CC (n = 5), CYP2D6*10 CT (n = 11) and CYP2D6*10 TT (n = 8). CC homozygotes and CT heterozygotes were defined to be C allele carriers. The CYP2D6*10 was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Dimemorfan was measured by LC-MS/MS. There was significant difference in C max, AUC0-t , AUC0-inf, V z , and CL values of dimemorfan observed among the three CYP2D6*10 genotype groups (GLM, (a) P < 0.05, co-dominant model). CYP2D6*10 under the recessive model (CC + TC vs TT) was significantly associated with pharmacokinetics of dimemorfan ((c) P < 0.05). The C max values were significantly higher in subjects with CYP2D6*10 TT (8.06 ± 4.43 ng/mL) than CYP2D6*10 CC (3.41 ± 2.79 ng/mL), CYP2D6*10 CT (3.11 ± 2.47 ng/mL), so was AUC0-inf. V z /F and CL/F of subjects with CYP2D6*10 TT homozygotes were the lowest. We demonstrated that cytochrome P450 2D6*10 (100C > T, rs1065852) polymorphism can affect the pharmacokinetics of dimemorfan in humans, not dosage forms.