CNS drug reviews最新文献

{"title":"Ethosuximide: From Bench to Bedside","authors":"M. Zafer Gören,&nbsp;Filiz Onat","doi":"10.1111/j.1527-3458.2007.00009.x","DOIUrl":"10.1111/j.1527-3458.2007.00009.x","url":null,"abstract":"<p>Ethosuximide, 2-ethyl-2-methylsuccinimide, has been used extensively for “petit mal” seizures and it is a valuable agent in studies of absence epilepsy. In the treatment of epilepsy, ethosuximide has a narrow therapeutic profile. It is the drug of choice in the monotherapy or combination therapy of children with generalized absence (petit mal) epilepsy. Commonly observed side effects of ethosuximide are dose dependent and involve the gastrointestinal tract and central nervous system. Ethosuximide has been associated with a wide variety of idiosyncratic reactions and with hematopoietic adverse effects. Typical absence seizures are generated as a result of complex interactions between the thalamus and the cerebral cortex. This thalamocortical circuitry is under the control of several specific inhibitory and excitatory systems arising from the forebrain and brainstem. Corticothalamic rhythms are believed to be involved in the generation of spike-and-wave discharges that are the characteristic electroencephalographic signs of absence seizures. The spontaneous pacemaker oscillatory activity of thalamocortical circuitry involves low threshold T-type Ca²⁺ currents in the thalamus, and ethosuximide is presumed to reduce these low threshold T-type Ca²⁺ currents in thalamic neurons. Ethosuximide also decreases the persistent Na⁺ and Ca²⁺-activated K⁺ currents in thalamic and layer V cortical pyramidal neurons. In addition, there is evidence that in a genetic absence epilepsy rat model ethosuximide reduces cortical γ-aminobutyric acid (GABA) levels. Also, elevated glutamate levels in the primary motor cortex of rats with absence epilepsy (but not in normal animals) are reduced by ethosuximide.</p>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"13 2","pages":"224-239"},"PeriodicalIF":0.0,"publicationDate":"2007-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2007.00009.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26826152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ziprasidone for Schizophrenia and Bipolar Disorder: A Review of the Clinical Trials","authors":"William M. Greenberg,&nbsp;Leslie Citrome","doi":"10.1111/j.1527-3458.2007.00008.x","DOIUrl":"10.1111/j.1527-3458.2007.00008.x","url":null,"abstract":"<p>Ziprasidone is a newer “atypical” or “second-generation” antipsychotic. Oral ziprasidone (ziprasidone hydrochloride) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia, and acute manic or mixed episodes associated with bipolar disorder (with or without psychotic features). Ziprasidone intramuscular (ziprasidone mesylate) is FDA-approved for acute agitation in patients with schizophrenia. Oral ziprasidone appears efficacious, and has been shown to have some limited clinical advantages over chlorpromazine and haloperidol in ameliorating negative symptoms of schizophrenia. In Phase 2 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia, ziprasidone did not match the clinical performance of olanzapine and risperidone, appearing closer in overall effectiveness to quetiapine. The rate of dose titration and the dose achieved may have an important bearing on ziprasidone's efficacy profile. In studies of usage for acute agitation in individuals with schizophrenia, intramuscular ziprasidone has been shown to be efficacious and relatively well tolerated. Regarding tolerability, ziprasidone, has important advantages in that it is not associated with clinically significant weight gain or adverse changes in cholesterol, triglycerides, or glycemic control, and patients may experience moderate improvement in these measures when switching to ziprasidone from a different antipsychotic agent. It also lacks significant persistent effects on prolactin levels, is not anticholinergic, and only infrequently causes extrapyramidal side effects or postural hypotension, although it can be associated with somnolence. This tolerability profile may be quite valuable in the treatment of some patients. Ziprasidone may prolong the electrocardiogram (ECG) QTc interval (QT interval corrected for heart rate by a standard algorithm), but after 5 years' clinical availability ziprasidone (by itself) does not appear to pose a substantial clinical problem in this regard. Therefore, ziprasidone may be considered a first-line drug option in the treatment of schizophrenia or manic episodes, but, in view of the differences among antipsychotic medications, drug selection should be guided by the patient's individual characteristics and situation.</p>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"13 2","pages":"137-177"},"PeriodicalIF":0.0,"publicationDate":"2007-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2007.00008.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26827869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Properties, Toxicology and Scientific Rationale for the use of Natalizumab (Tysabri®) in Inflammatory Diseases","authors":"Olaf Stüve,&nbsp;Jeffrey L. Bennett","doi":"10.1111/j.1527-3458.2007.00003.x","DOIUrl":"10.1111/j.1527-3458.2007.00003.x","url":null,"abstract":"<p>Natalizumab (Tysabri®) was the first adhesion molecule antagonist to make it into clinical trial for patients with multiple sclerosis (MS) and other inflammatory disorders. Natalizumab is a humanized recombinant monoclonal antibody (MAb) that binds to the alpha (α)₄ chain of the α₄ beta (β)₁ (very late activating antigen 4; VLA-4) and α₄β₇ integrins. The scientific rationale for natalizumab therapy is the reduction of leukocyte extravasation into peripheral tissues. Natalizumab, like other VLA-4 antagonists, may also interfere with the activation of T lymphocytes in secondary lymphoid organs and their reactivation in the central nervous system (CNS).</p><p>Shortly after its approval for the treatment of relapsing-remitting MS (RR-MS), three patients who were treated with natalizumab in the setting of clinical trials developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyoma virus JC. It remains to be elucidated why the use of this VLA-4 antagonist is associated with an increased incidence of PML. Natalizumab was recently reapproved for the treatment of relapsing forms of MS. In this review, we outline the scientific rationale for using natalizumab in MS and other inflammatory disorders. In addition, an overview of pharmacological properties, clinical efficacy, safety, and toxicology of natalizumab is provided.</p>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"13 1","pages":"79-95"},"PeriodicalIF":0.0,"publicationDate":"2007-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2007.00003.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26689690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MD-354: What is It Good For?","authors":"Małgorzata Dukat,&nbsp;Richard A. Glennon,&nbsp;Shawquia Young","doi":"10.1111/j.1527-3458.2007.00002.x","DOIUrl":"10.1111/j.1527-3458.2007.00002.x","url":null,"abstract":"<p>MD-354 (<i>meta</i>-chlorophenylguanidine) has been identified as a member of a novel class of 5-HT₃ serotonin receptor agonists. MD-354 is a 5-HT₃ receptor partial agonist that has been shown to behave as an agonist in some assays, and as an antagonist in others. MD-354 also binds at α-adrenoceptors (ARs) and displays an affinity for α_2B-ARs comparable to its affinity for 5-HT₃ receptors. Although devoid of antinociceptive actions following systemic administration alone, MD-354 markedly enhances the antinociceptive actions of clonidine in the mouse tail-flick assay without potentiating the sedative side effects of clonidine. Although studies with MD-354 are still in progress, some pharmacological findings are described here. MD-354-related agents may represent drug adjuvants for the relief of severe pain.</p>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"13 1","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2007-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2007.00002.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26689686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Levetiracetam: Part II, the Clinical Profile of a Novel Anticonvulsant Drug","authors":"Tim De Smedt,&nbsp;Robrecht Raedt,&nbsp;Kristl Vonck,&nbsp;Paul Boon","doi":"10.1111/j.1527-3458.2007.00005.x","DOIUrl":"10.1111/j.1527-3458.2007.00005.x","url":null,"abstract":"<p>The objective of this article was to review and summarize the available reports on the profile of the novel anticonvulsant drug levetiracetam (LEV) in a clinical setting. Therefore, a careful search was conducted in the MEDLINE database and combined with guidelines from regulatory agencies, proceedings of professional scientific meetings, and information provided by the manufacturers. This article is devoted to the clinical pharmacology and clinical trials of LEV investigating its efficacy and safety as add-on therapy or monotherapy for various seizure types. Finally, results from postmarketing surveillance of LEV are briefly discussed. In general, LEV is shown to be a safe, broad-spectrum anticonvulsant drug with highly beneficial pharmacokinetic properties, a favorable long-term retention rate, and a high responder rate, indicating that LEV is an efficient therapeutic option for the treatment of several types of epilepsy.</p>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"13 1","pages":"57-78"},"PeriodicalIF":0.0,"publicationDate":"2007-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2007.00005.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26689689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Pharmacology of Ro 64-6198, a Systemically Active, Nonpeptide NOP Receptor (Opiate Receptor-Like 1, ORL-1) Agonist with Diverse Preclinical Therapeutic Activity","authors":"James R. Shoblock","doi":"10.1111/j.1527-3458.2007.00007.x","DOIUrl":"10.1111/j.1527-3458.2007.00007.x","url":null,"abstract":"<p>The NOP receptor (formerly referred to as opiate receptor-like 1, ORL-1, LC132, OP₄, or NOP₁) is a G protein–coupled receptor that shares high homology to the classic opioid MOP, DOP, and KOP (mu, delta, and kappa, respectively) receptors and was first cloned in 1994 by several groups. The NOP receptor remained an orphan receptor until 1995, when the endogenous neuropeptide agonist, known as nociceptin or orphanin FQ (N/OFQ) was isolated. Five years later, a group at Hoffmann-La Roche reported on the selective, nonpeptide NOP agonist Ro 64-6198, which became the most extensively published nonpeptide NOP agonist and a valuable pharmacological tool in determining the potential of the NOP receptor as a therapeutic target. Ro 64-6198 is systemically active and achieves high brain penetration. It has subnanomolar affinity for the NOP receptor and is at least 100 times more selective for the NOP receptor over the classic opioid receptors. Ro 64-6198 ranges from partial to full agonist, depending on the assay. Preclinical data indicate that Ro 64-6198 may have broad clinical uses, such as in treating stress and anxiety, addiction, neuropathic pain, cough, and anorexia. This review summarizes the pharmacology and preclinical data of Ro 64-6198.</p>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"13 1","pages":"107-136"},"PeriodicalIF":0.0,"publicationDate":"2007-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2007.00007.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26689692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Levetiracetam: The Profile of a Novel Anticonvulsant Drug—Part I: Preclinical Data","authors":"Tim De Smedt,&nbsp;Robrecht Raedt,&nbsp;Kristl Vonck,&nbsp;Paul Boon","doi":"10.1111/j.1527-3458.2007.00004.x","DOIUrl":"10.1111/j.1527-3458.2007.00004.x","url":null,"abstract":"<p>The objective of this article was to review and summarize the available reports on the preclinical profile of the novel anticonvulsant drug levetiracetam (LEV). Therefore, a careful search was conducted in the MEDLINE database and combined with guidelines from regulatory agencies, proceedings of professional scientific meetings, and information provided by the manufacturers. This article provides detailed information on the anticonvulsant effects of LEV in various animal models of epilepsy and on its pharmacology in laboratory animals. The mechanism of action of LEV is reviewed, with special regard to its recently discovered binding site, the synaptic vesicle protein 2A. In general, LEV is shown to be a safe, broad-spectrum anticonvulsant drug with highly beneficial pharmacokinetic properties and a distinct mechanism of action. The clinical studies with LEV will be discussed in the second part of this review article to be published subsequently.</p>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"13 1","pages":"43-56"},"PeriodicalIF":0.0,"publicationDate":"2007-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2007.00004.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26689688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dextromethorphan: A Review of N-methyl-d-aspartate Receptor Antagonist in the Management of Pain","authors":"Anita Siu,&nbsp;Richard Drachtman","doi":"10.1111/j.1527-3458.2007.00006.x","DOIUrl":"10.1111/j.1527-3458.2007.00006.x","url":null,"abstract":"<p>Dextromethorphan (DM) is a noncompetitive <i>N</i>-methyl-<span>d</span>-aspartate (NMDA) receptor antagonist, which is widely used as an antitussive agent. DM also prevents neuronal damage and modulates pain sensation via noncompetitive antagonism of excitatory amino acids (EAAs). DM has been found to be useful in the treatment of pain in cancer patients and in the treatment of methotrexate-induced neurotoxicity. Clinical studies with DM in cancer patients are reviewed in this article.</p>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"13 1","pages":"96-106"},"PeriodicalIF":0.0,"publicationDate":"2007-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2007.00006.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26689691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lacosamide: A Review of Preclinical Properties","authors":"Bettina K. Beyreuther,&nbsp;Joachim Freitag,&nbsp;Cara Heers,&nbsp;Niels Krebsfänger,&nbsp;Ute Scharfenecker,&nbsp;Thomas Stöhr","doi":"10.1111/j.1527-3458.2007.00001.x","DOIUrl":"10.1111/j.1527-3458.2007.00001.x","url":null,"abstract":"<p>Lacosamide (LCM), (SPM 927, (R)-2-acetamido-<i>N</i>-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037) is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. LCM has demonstrated antiepileptic effectiveness in different rodent seizure models and antinociceptive potential in experimental animal models that reflect distinct types and symptoms of neuropathic as well as chronic inflammatory pain. Recent results suggest that LCM has a dual mode of action underlying its anticonvulsant and analgesic activity. It was found that LCM selectively enhances slow inactivation of voltage-gated sodium channels without affecting fast inactivation. Furthermore, employing proteomic affinity-labeling techniques, collapsin-response mediator protein 2 (CRMP-2 alias DRP-2) was identified as a binding partner. Follow-up experiments confirmed a functional interaction of LCM with CRMP-2 <i>in vitro</i>. LCM did not inhibit or induce a wide variety of cytochrome P450 enzymes at therapeutic concentrations. In safety pharmacology and toxicology studies conducted in mice, rats, rabbits, and dogs, LCM was well tolerated. Either none or only minor side effects were observed in safety studies involving the central nervous, respiratory, gastrointestinal, and renal systems and there is no indication of abuse liability. Repeated dose toxicity studies demonstrated that after either intravenous or oral administration of LCM the adverse events were reversible and consisted mostly of exaggerated pharmacodynamic effects on the CNS. No genotoxic or carcinogenic effects were observed <i>in vivo</i>, and LCM showed a favorable profile in reproductive and developmental animal studies. Currently, LCM is in a late stage of clinical development as an adjunctive treatment for patients with uncontrolled partial-onset seizures, and it is being assessed as monotherapy in patients with painful diabetic neuropathy. Further trials to identify LCM's potential in pain and for other indications have been initiated.</p>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"13 1","pages":"21-42"},"PeriodicalIF":0.0,"publicationDate":"2007-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2007.00001.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26689687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A New Look at the Respiratory Stimulant Doxapram","authors":"C. Spencer Yost","doi":"10.1111/j.1527-3458.2006.00236.x","DOIUrl":"10.1111/j.1527-3458.2006.00236.x","url":null,"abstract":"<div>\u0000 \u0000 <p>A number of life-threatening clinical disorders may be amenable to treatment with a drug that can stimulate respiratory drive. These include acute respiratory failure secondary to chronic obstructive pulmonary disease, post-anesthetic respiratory depression, and apnea of prematurity. Doxapram has been available for over forty years for the treatment of these conditions and it has a low side effect profile compared to other available agents. Generally though, the use of doxapram has been limited to these clinical niches involving patients in the intensive care, post-anesthesia care and neonatal intensive care units. Recent basic science studies have made considerable progress in understanding the molecular mechanism of doxapram's respiratory stimulant action. Although it is unlikely that doxapram will undergo a clinical renaissance based on this new understanding, it represents a significant advance in our knowledge of the control of breathing.</p>\u0000 </div>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"12 3-4","pages":"236-249"},"PeriodicalIF":0.0,"publicationDate":"2007-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2006.00236.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26492366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}