Liu, Jia; Dupree, Jeffrey L; Gacias, Mar; Frawley, Rebecca; Sikder, Tamjeed; Naik, Payal; Casaccia, Patrizia
Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior. Significance statement: Oligodendrocyte development and myelination are highly dynamic processes influenced by experience and neuronal activity. However, whether enhancing myelination and oligodendrocyte differentiation is beneficial to treat depressive-like behavior has been unexplored. Mice undergoing prolonged social isolation display impaired myelination in the prefrontal cortex. Clemastine, a Food and Drug Administration-approved antimuscarinic compound that has been shown to enhance myelination under
Li, Zhifang; He, Yangtao; Fan, Shuangyi; Sun, Binbin
Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia. But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia. To investigate this hypothesis, we used clemastine, an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination, on a cuprizone-induced mouse model of demyelination. The mice exposed to cuprizone (0.2% in chow) for 6 weeks displayed schizophrenia-like behavioral changes, including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze, as well as evident demyelination in the cortex and corpus callosum. Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for 3 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (APC-positive) and myelin basic protein. More importantly, the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle, suggesting a beneficial effect via promoting myelin repair. Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.
Phillips, M. J.; Meyrick Thomas, R H; I. Moodley; Davies, R J
The effect of ketotifen was compared with that of clemastine and chlorpheniramine, known antihistamines, and sodium cromoglycate, a drug considered to have mast cell "stabilizing' properties on histamine and allergen wealing reactions in human skin, in random order, double-blind, placebo controlled studies. Ketotifen was significantly more potent in the inhibition of both histamine (P less than 0.001) and allergen (P less than 0.001) skin wealing reactions than either clemastine or chlorpheni...
刘德胜; 徐玉文; 李玉梅
Objective:High performance liquid chromatography method was established to determine the related substances and the degradation substances in clemastine fumarate ant its tablets. Methods:An ODS -3 C18 column (250 mm x4. 6 mm,5 μm)with UV detection at 210 nm,and acetonitrile -sodium octanesulfonate solution (50:50) as the mobile phase were used in HPLC. The flow rate was 1. 0 mL·min-1 ,and the temperature of the column was 35 t. Results; An excellent separation was achieved for clemastine fumarate, excipient and its related substances. The reproducibility and precision of the method were good( RSD <0. 3% ). Conclusion:This method was accurate, simple, quick and effective for determination of related substances and the degradation substances in clemastine fumarate tablets. It was also suitable for the quality control for clemastine fumarate and its tablets.%目的:采用高效液相色谱法测定富马酸氯马斯汀及片剂中的有关物质和降解产物.方法:采用ODS -3 C18色谱柱(250mm ×4.6 mm,5μm)；柱温为35℃；流动相为乙腈-辛烷磺酸钠溶液(50∶50)；流速为1.0 mL·min-1；检测波长为210 nm;进样量为10μL.结果:各降解产物、辅料均可与富马酸氯马斯汀主峰良好分离,方法的精密度和重复性良好(RSD＜0.3％).结论:经方法学验证,该法灵敏、准确,适用于富马酸氯马斯汀及片剂中有关物质的测定.
宋冬梅; 张煊; 刘婷立; 郭智; 易志恒; 潘琳
目的:建立人血浆中氯马斯汀的LC-MS-MS测定法,评价酚麻氯汀胶囊中氯马斯汀在健康人体的相对生物利用度.方法:采用开放、随机、双周期、两制剂、双序列单次给药的交叉试验设计.19例健康志愿者分别口服相当于富马酸氯马斯汀0.67 mg剂量的受试制剂和参比制剂.以硝苯地平为内标,采用甲基叔丁基醚为提取溶剂,用LC-MS-MS法测定血浆中氯马斯汀的质量浓度,经WinNonlin 6.0软件处理血药质量浓度数据后得药动学数据.结果:氯马斯汀的线性范围为5.09～407.20 ng·L-1,定量下限为5.09ng·L-1,绝对回收率为79.7%～80.6%,绝对基质效应为101.0%～103.6%,批内和批间精密度与准确度均符合要求.受试制剂中氯马斯汀的t1/2为(20.67±3.56)h,Cmax为(142.07±65.69)ng·L-1,Tmax为(4.21±1.23)h,AUC0-t为(2 829±1 681)ng·h·L-1;参比制剂中氯马斯汀的的t1/2为(20.83±4.94)h,Cmax为(1 46.55±60.16)ng·L-1,Tmax为(4.13±1.27)h,AUC0-t为(2 839±1 560)ng·h·L-1.以AUC0-t计算,与参比制剂比较,受试制剂中氯马斯汀的平均相对生物利用度为(101.7±23.4)%.结论:本方法灵敏、准确,适于临床药动学研究;两种制剂中的氯马斯汀具有生物等效性.%Objective: To develop an HPLC-MS-MS assay for determination of clemastine in human plasma , and estimate the bioequivalence of clemastine in paracetamol, clemastine fumarate and pseudoephedrine hydro-chloride capsule in healthy volunteers. Methods; An open, randomized, two-periods, two-treatment, two-sequence, and crossover clinical trial was performed in 19 healthy male volunteers. They were orally administrated with a single dose of clemastine fumarate 0. 67 mg. The plasma concentration of clemastine was determined by LC-MS-MS using nifedipine as an internal standard and methyl tert-butyl ether as an extraction solvent. The plasma concentration-time curves as well as pharmacokinetics of both test and reference formulations were analyzed
Gjelstad, Astrid; Jensen, Henrik; Rasmussen, Knut Einar;
In this paper, extraction kinetics was investigated experimentally and theoretically in hollow fiber liquid-phase microextraction (HF-LPME) and electromembrane extraction (EME) with the basic drugs droperidol, haloperidol, nortriptyline, clomipramine, and clemastine as model analytes. In HF...
Desar, Ingrid M E; van Herpen, Carla M L; van Erp, Nielka P; Kaal, Suzanne E J; van de Kerkhof, Peter C M; van der Graaf, Winette T A
Since the introduction of tyrosine kinase inhibitors in gastrointestinal stromal tumor patients, the median survival of patients has increased from less than 1 to more than 5 years. The chronic use of a tyrosine kinase inhibitor has an impact on quality of life because of its toxicity. Adequate supportive therapy is therefore important. We describe a female patient with a metastatic gastrointestinal stromal tumor. During treatment with the c-KIT inhibitor imatinib, she developed severe therapy-limiting skin toxicity. After several different supportive attempts, the combination of doxycycline and clemastine proved to be the solution, enabling successful chronic treatment with imatinib. Chronic use of doxycycline and clemastine is useful in the management of skin toxicity caused by c-KIT inhibitors, enabling the needed long-term use of these kind of anticancer drugs without hampering the quality of life. PMID:26982239
Full Text Available Abstract Background The skin contains a system for producing serotonin as well as serotonin receptors. Serotonin can also cause pruritus when injected into the skin. SSRI-drugs increase serotonin concentrations and are known to have pruritus and other dermal side effects. Case presentation A 46-year-old man consulted his doctor due to symptoms of depression. He did not suffer from any allergy but drinking red wine caused vasomotor rhinitis. Antidepressive treatment with fluoxetine 20 mg daily was initiated which was successful. After three weeks of treatment an itching rash appeared. An adverse drug reaction (ADR induced by fluoxetine was suspected and fluoxetine treatment was discontinued. The symptoms disappeared with clemastine and betametasone treatment. Since the depressive symptoms returned sertraline medication was initiated. After approximately two weeks of sertraline treatment he noted an intense itching sensation in his scalp after eating a piece of chocolate cake. The itch spread to the arms, abdomen and legs and the patient treated himself with clemastine and the itch disappeared. He now realised that he had eaten a chocolate cake before this episode and remembered that before the first episode he had had a chocolate mousse dessert. He had never had any reaction from eating chocolate before and therefore reported this observation to his doctor. Conclusions This case report suggests that there may be individuals that are very sensitive to increases in serotonin concentrations. Dermal side reactions to SSRI-drugs in these patients may be due to high activity in the serotonergic system at the dermal and epidermo-dermal junctional area rather than a hypersensitivity to the drug molecule itself.
Joseph D Planer
Full Text Available An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 µM, a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 µM, and an antifolate drug (pyrimethamine, EC50 of 3.8 µM and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease.
Gregori-Puigjané, Elisabet; Setola, Vincent; Hert, Jérôme; Crews, Brenda A; Irwin, John J; Lounkine, Eugen; Marnett, Lawrence; Roth, Bryan L; Shoichet, Brian K
Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to "de-orphanize" drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration-approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest. PMID:22711801
De Rycker, Manu; Thomas, John; Riley, Jennifer; Brough, Stephen J; Miles, Tim J; Gray, David W
Chagas disease is a significant health problem in Latin America and the available treatments have significant issues in terms of toxicity and efficacy. There is thus an urgent need to develop new treatments either via a repurposing strategy or through the development of new chemical entities. A key first step is the identification of compounds with anti-Trypanosoma cruzi activity from compound libraries. Here we describe a hit discovery screening cascade designed to specifically identify hits that have the appropriate anti-parasitic properties to warrant further development. The cascade consists of a primary imaging-based assay followed by newly developed and appropriately scaled secondary assays to predict the cidality and rate-of-kill of the compounds. Finally, we incorporated a cytochrome P450 CYP51 biochemical assay to remove compounds that owe their phenotypic response to inhibition of this enzyme. We report the use of the cascade in profiling two small libraries containing clinically tested compounds and identify Clemastine, Azelastine, Ifenprodil, Ziprasidone and Clofibrate as molecules having appropriate profiles. Analysis of clinical derived pharmacokinetic and toxicity data indicates that none of these are appropriate for repurposing but they may represent suitable start points for further optimisation for the treatment of Chagas disease. PMID:27082760
Manu De Rycker
Full Text Available Chagas disease is a significant health problem in Latin America and the available treatments have significant issues in terms of toxicity and efficacy. There is thus an urgent need to develop new treatments either via a repurposing strategy or through the development of new chemical entities. A key first step is the identification of compounds with anti-Trypanosoma cruzi activity from compound libraries. Here we describe a hit discovery screening cascade designed to specifically identify hits that have the appropriate anti-parasitic properties to warrant further development. The cascade consists of a primary imaging-based assay followed by newly developed and appropriately scaled secondary assays to predict the cidality and rate-of-kill of the compounds. Finally, we incorporated a cytochrome P450 CYP51 biochemical assay to remove compounds that owe their phenotypic response to inhibition of this enzyme. We report the use of the cascade in profiling two small libraries containing clinically tested compounds and identify Clemastine, Azelastine, Ifenprodil, Ziprasidone and Clofibrate as molecules having appropriate profiles. Analysis of clinical derived pharmacokinetic and toxicity data indicates that none of these are appropriate for repurposing but they may represent suitable start points for further optimisation for the treatment of Chagas disease.
Full Text Available Serotonin syndrome is a potentially life-threatening drug effect. It may be misdiagnosed because it has mostly been reported in adults. Case Report. An 8-year-old girl with behavioral problems and medicated with risperidone and sertraline was admitted in the emergency department after she had taken voluntarily 1500 mg of sertraline (50 mg/kg. At admission, she had marked agitation, visual hallucinations, diaphoresis, flushing, and tremor. She had fever and periods of hypertension. She also showed generalized rigidity and involuntary movements. She was treated with fluids and iv diazepam, midazolam, clemastine, and biperiden. As the patient presented a severe insomnia and a progressive rhabdomyolysis, she was transferred to pediatric intensive care unit (ICU, where she was under treatment with cyproheptadine, mechanical ventilation, and muscular paralysis for 11 days. She was discharged from hospital a few days later with no neurological sequelae. Conclusions. Serotonin syndrome is still not well recognized by physicians. In our patient, the diagnosis was made early due to the history of overdose with serotonin reuptake inhibitors and the triad of mental, neurological, and autonomic signs. Parents must be educated to prevent children from having free access to drugs, avoiding self-medication or overdose.