Antagonists For Treatment Research Articles

Serotonin 2A receptor antagonists for treatment of schizophrenia

Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia.Areas covered: Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia.Expert opinion: 5-HT2A receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT2A receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia.

Perspectives of CB1 Antagonist in Treatment of Obesity: Experience of RIO-Asia

Rimonabant, a selective cannabinoid-1 (CB1) receptor antagonist, has been shown to reduce weight and enhance improvements in cardiometabolic risk parameters in Western populations. This study assessed these effects of rimonabant in Asian population. A total of 643 patients (BMI 25 kg/m2 or greater without diabetes) from China, Republic of Korea, and Taiwan were prescribed a hypocaloric diet (600 kcal/day deficit) and randomized to rimonabant 20 mg (n = 318) or placebo (n = 325) for 9months. The primary efficacy variable was weight change from baseline after 9 months of treatment. Results showed that rimonabant group lost more weight than placebo, (LSM ± SEM of −4.7 ± 0.3 kg vs. −1.7 ± 0.3 kg, P < .0001). The 5% and 10% responders were 2 or 3 folds more in the rimonabant group (53.0% vs. 20.0% and 21.5% vs. 5.7%, resp.) (P < .0001). Rimonabant also significantly increased HDL-cholesterol, decreased triglycerides and waist circumference,by 7.1%, 10.6%, and 2.8 cm, respectively (P < .0001). This study confirmed the comparable efficacy and safety profile of rimonabant in Asian population to Caucasians. Owing to the recent suspension of all the CB1 antagonists off the pharmaceutical market for weight reduction in Europe and USA, a perspective in drug discovery for intervening peripheral CB1 receptor in the management of obesity is discussed.

Management of hyponatremia: Providing treatment and avoiding harm

Hyponatremia, in its most severe form, requires urgent infusion of hypertonic saline to correct cerebral edema. However, overly rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome. The authors review the treatment of hyponatremia in order to provide clinicians with a sound approach in a variety of settings in which severity, symptoms, and underlying disease states influence therapy. Also discussed is the current role of vasopressin antagonists in treatment.

Rimonabant attenuates sensitization, cross-sensitization and cross-reinstatement of place preference induced by nicotine and ethanol

The present study focused on the evaluation of behavioral sensitization, cross-sensitization, and cross-reinstatement processes induced by nicotine and ethanol in rodents. First, we showed that nicotine (0.175mg/kg, base, intraperitoneally, ip) produced a conditioned place preference in rats. When the nicotine place preference was extinguished, nicotine-experienced animals were challenged with nicotine (0.175mg/kg, ip) or ethanol (0.5g/kg, ip), which reinstated a preference for the compartment previously paired with nicotine. In the second series of experiments, we demonstrated that after 9 days of nicotine administration (0.175mg/kg, subcutaneously, sc) every other day and following its 7-day withdrawal, challenge doses of nicotine (0.175mg/kg, sc) and ethanol (2g/kg, ip) induced locomotor sensitization in mice. Finally, when we examined the influence of rimonabant (0.5, 1 and 2mg/kg, ip), we found that this cannabinoid CB1 receptor antagonist attenuated reinstatement effect of ethanol priming as well as nicotine sensitization and locomotor cross-sensitization between nicotine and ethanol. Our results indicate that similar endocannabinoid-dependent mechanisms are involved in the locomotor stimulant and reinforcing effects of nicotine and ethanol in rodents, and as such these data may provide further evidence for the use of cannabinoid CB1 receptor antagonists in treatment of tobacco addiction with or without concomitant ethanol dependence.

Inhibition of Endothelin-1 and Hypoxia-induced Pulmonary Pressor Responses in the Rat by a Novel Selective Endothelin-A Receptor Antagonist, Di-n-butylaminocarbamyl-l-leucyl-d-tryptophanyl-d-4-chloro-Phe

Pulmonary hypertension is a kind of disease associated with a very high rate of mortality, and there are not many effective drugs for the treatment. Today, endothelin (ET)-1 receptor antagonists were proved to be effective in the treatment of pulmonary hypertension. Aiming at developing new endothelin-A receptor (ETA) antagonist for treatment of pulmonary hypertension, di-n-butylaminocarbamyl-L-leucyl-D-tryptophanyl-D-4-chloro-Phe, named GF063, was synthesized at base of selective ETA receptor antagonist BQ485 and selected for the further pharmacological characterization. The preliminary pharmacodynamics of GF063 was evaluated by radioligand receptor binding assay and test of antivasoconstriction effects in vitro and in vivo. The integrative pharmacodynamics was evaluated in hypoxia-induced rat pulmonary hypertension. In vitro, GF063 bound to ETA receptor with 100,000-fold higher affinity than to ETB receptor. GF063 concentration dependently inhibited contraction of isolated rat aortic ring induced by ET-1 and shifted the cumulative concentration-contraction response curve to right with no change in the maximal response. In vivo, GF063 inhibited the increase of mean systemic arterial pressure induced by ET-1 in anesthetized rat. In hypoxia-induced rat pulmonary hypertension model, pretreatment with GF063 (40 mg/kg, s.c.) significantly decreased pulmonary artery pressure and right ventricular hypertrophy, also significantly inhibited the increase of ET-1 level in lung, improved hemodynamics, and alleviated the wall thickness of pulmonary vessels. This study indicated that GF063, as a selective ETA receptor antagonist, could inhibit vasoconstriction effects in vivo and in vitro, could prevent pulmonary hypertension induced by hypoxia, and may have great potential to be developed as a new drug of antipulmonary hypertension.

Histamine and histamine receptors in pathogenesis and treatment of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease associated with chronic inflammatory demyelination of the central nervous system (CNS). Due to disease complexity and heterogeneity, its pathogenesis remains unknown and despite extensive studies, specific effective treatments have not yet been developed. The factors behind the initiation of the inflammatory reactions in CNS have not been identified until now. MS is considered as a complex disease depending on genetic as well as environmental factors. Experimental autoimmune encephalomyelitis (EAE) is the preferential experimental rodent model for MS. Histamine [2-(4-imidazole) ethylamine] is a ubiquitous inflammatory mediator of diverse physiological processes including neurotransmission, secretion of pituitary hormones, and regulation of the gastrointestinal and circulatory systems which can modulate immune responses. Histamine functions are mediated through four G-protein coupled receptors that are named H1-H4 receptor. Histamine is implicated as an important factor in pathophysiology of MS and EAE. It has been shown that histamine can change the permeability of blood brain barrier, which leads to elevation of infiltrated cells in CNS and neuroinflammation. In contrast, there are evidence that show the protective role of histamine in MS and its animal model, EAE. In this review, we try to clarify the role of histamine in pathogenesis of MS, as well as we evaluate the efficacy of histamine receptors agonists and antagonists in treatment of this disease.

Galanin Mediates the Pathogenesis of Cerulein-Induced Acute Pancreatitis in the Mouse

Acute pancreatitis (AP) is characterized by pancreatic microcirculatory and secretory disturbances. As galanin can modulate pancreatic vascular perfusion, we sought to determine if galanin plays a role in AP. Acute pancreatitis was induced in wild-type and galanin gene knockout mice by intraperitoneal injections of cerulein. The severity of AP was evaluated (plasma amylase and lipase, myeloperoxidase activity, and acinar cell necrosis) with and without treatment with galanin or the antagonist galantide. Galanin receptor messenger RNA expression in mouse pancreas was measured by reverse transcription-polymerase chain reaction and Western blot analysis. Galantide ameliorated AP, reducing all indices by 25% to 40%, whereas galanin was without effect. In galanin knockout mice, all indices of AP were reduced 25% to 50% compared with wild-type littermates. Galanin administration to the knockout mice exacerbated AP such that it was comparable with the AP induced in the wild-type mice. Conversely, administration of galantide to the galanin knockout mice did not affect the AP, whereas AP was ameliorated in the wild-type mice. The 3 galanin receptor subtypes are expressed in mouse pancreas, with receptor subtype 3 expression predominating. These data implicate a role for galanin in AP and suggest a potential clinical application for galanin antagonists in treatment.

Early and effective use of ketamine for treatment of phantom limb pain

Treatment for phantom limb pain is difficult and challenging. There is often suboptimum treatment with fewer than 10% receiving lasting relief. Treatments based broadly on other neuropathic pains may not be appropriate for a clinical success. We report a case of phantom limb pain, which proved resistant to multiple analgesics, including opioids and continuous epidural blockade. Treatment with intravenous (IV) ketamine as an alternate day infusion, gave complete remission of phantom limb pain. This demonstrates an early and effective use of a potent NMDA antagonist for treatment of phantom limb pain. Mechanisms underlying phantom limb pain are briefly discussed.

Is there a need for Degarelix as LH/RH Antagonist in treatment of advanced PCa: Comparative Review of Literartue

Is there a need for Degarelix as LH/RH Antagonist in treatment of advanced PCa: Comparative Review of Literartue

The role of angiotensin receptor antagonists in treatment of arterial hypertension: focus on losartan

The role of angiotensin receptor antagonists in treatment of arterial hypertension: focus on losartan

Table of Contents

AbstractPatients Choosing Second‐Generation Antipsychotics and Combination TherapyCombination CBT Plus Therapy Superior for Reducing Anxiety in ChildrenSerotonin Syndrome Associated With Use of SSRI/SNRI Drugs With TriptansOpiate Antagonists in Treatment of Pathological GamblingEditor's Commentary: Bad to the BoneSSRI Use and Risk of Gestational HypertensionPsychotropic Drugs and Corrected QT Interval ProlongationOropharyngeal and Facial Dyskinesia After Discontinuation of QuetiapineFDA Requires Epilepsy Drugs to Carry Suicide WarningFDA Creates New Drug Safety Webpage

HIV entry: new insights and implications for patient management

The discovery of the chemokine coreceptors CCR5 and CXCR4, essential for HIV entry, provoked over a decade of research into the mechanism of HIV entry and potential targets for treatment and prevention of HIV. This review article reports the recent published data regarding licensed and investigational HIV entry inhibitors including CCR5 and CXCR4 antagonists, fusion inhibitors and attachment inhibitors. The results from the maraviroc and vicriviroc clinical trials are reported, showing the efficacy and safety of CCR5 antagonists in treatment of multidrug resistant HIV. The poor sensitivity of the original screening tropism assay is associated with virological failure in individuals mislabelled R5 tropic who receive CCR5 antagonists. Reanalyses of clinical trials using a superior screening assay are in progress. Superior immunological restoration is seen with CCR5 antagonists that may be of benefit to individuals with discordant CD4 cell response with antiretroviral therapy and to those with severe immunosuppression. Research and development of HIV entry inhibitors is ongoing and provides new classes of drug that can be used in the treatment of HIV. Clinical trials will soon commence to assess the benefit of CCR5 antagonists in immune reconstitution and other therapeutic uses.

Vasopressin antagonists in treatment of hyponatremia

Hyponatremia is the most frequently encountered electrolyte disturbance in hospitalized patients. It is usually caused by dysregulation of arginine vasopressin (AVP) homeostasis which accompanies disorders associated with water retention such as congestive heart failure and cirrhosis, or follows euvolemic states such as syndrome of inapprioprate secretion of antidiuretic hormone. Available therapy, i.e. restriction of fluid intake, saline and diuretics, is often ineffective with unpredictable results and potentially serious side effects. Recent clinical trials with non-peptide AVP receptor antagonists (vaptans) have indicated that these drugs are effective in the treatment of hyponatremia. Vaptans lead to aquaresis, an electrolyte-sparing excretion of free water, that results in the correction of serum sodium concentration. Until now the Food and Drug Administration in the USA has approved the use of intravenous conivaptan for treatment of euvolemic hyponatremia. In this article, we review results from recent clinical trials on vaptans (lixivaptan, tolvaptan, conivaptan and satavaptan) which showed their efficacy in the treatment of hyponatremia.

Molecular modeling of histamine H3 receptor and QSAR studies on arylbenzofuran derived H3 antagonists

Histamine H3 receptors are presynaptic autoreceptors found in both central and peripheral nervous systems of many species. The central effects of these receptors suggest a potential therapeutic role for their antagonists in treatment of several neurological disorders such as epilepsy, schizophrenia, Alzheimer's and Parkinson's diseases. The purpose of this study was to identify the structural requirements for H3 antagonistic activity via quantitative structure–activity relationship (QSAR) studies and receptor modeling/docking techniques. A combination of partial least squares (PLS) and genetic algorithm (GA) was used in the QSAR approach to select the structural descriptors relevant to the receptor binding affinity of a series of 58 H3 antagonists. The descriptors were selected out of a pool of >1000 descriptors calculated by DRAGON, Hyperchem and ACD labs suite of programs. The resulting QSAR models for rat and human H3 binding affinities were validated using different strategies. QSAR models generated in the current work suggested the role of charge transfer interactions in the ligand–receptor interaction verified using the molecular modeling of the receptor and docking two antagonists to the binding site. The 3D model of human H3 receptor was built based on bovine rhodopsin structure and evaluated by molecular dynamics (MD) simulation in a mixed water–vacuum–water environment. The results were indicative of the stability of the model relating the observed structural changes during the MD simulation to the suggested ligand–receptor interactions. The results of this investigation are expected to be useful in the process of design and development of new potent H3 receptor antagonists.

Handbeteiligungen im Rahmen der progressiven systemischen Sklerodermie - Möglichkeiten der Handchirurgie im interdisziplinären Konzept

Clinical manifestations of scleroderma at the hand include Raynaud's phenomenon, calcinosis cutis, sclerodactylia and teleangiectasia. With the progression of the disease, cutaneous and joint contractions, acro-osteolysis, necrosis of the finger tips, and even extensive digital ulceration are likely to occur. These painful and often rapidly advancing lesions cause loss of function and disfigurement and, untreated, often lead to mutilation of the affected hand. Only an interdisciplinary management including the hand surgeon, the rheumatologist, and the physiotherapist can guarantee optimal treatment. Drug therapy should be included as well as physical therapy. Both should be made use of before and accompanying surgical treatment. Surgical therapy consists of treatment of the infections, excision of calcinosis, arthrodesis, in particular of the proximal interphalangeal joints, and sympathectomy. Amputation remains a final option, whereas with timely and sufficient treatment, amputations can be avoided and an improvement of function and an alleviation of the symptoms can be achieved. Among the non-operative treatment options, behavioural training, calcium antagonists, prostacyclin derivatives, topical nitrates as well as plexus anesthesia and stellatum blocks have proved to be effective. Recent drug therapies include endothelin-receptor antagonists for the prevention of digital ulceration and phosphodiesterase-V antagonists in treatment of Raynaud's phenomenon and induction of ulcer healing. With reference to several cases seen at our institution, we propose an interdisciplinary treatment concept for acral manifestations of scleroderma.

218 Efficacy of angiotensin II antagonists in treatment of essential hypertension associated with ischemic heart disease

218 Efficacy of angiotensin II antagonists in treatment of essential hypertension associated with ischemic heart disease

SPC2968—A novel Hif-1α antagonist for treatment of clear cell renal cell carcinoma

14581 Background: SPC2968 is a short (16-mer), oligonucleotide antagonist of Hif-1α mRNA in which potency has been enhanced through incorporation of Locked Nucleic Acid. Over-expression of Hif-1α has been correlated with increased vascularisation, metastatic potential and poor clinical outcome in a variety of malignancies, including Renal Cell Carcinoma (RCC) of clear cell aetiology, where Hif-1α dysregulation, brought about by mutations in the von Hippel Lindau gene, appears to play a major pathogenic role. Methods: In vitro, human cancer and endothelial cells grown under hypoxic conditions were used to evaluate the effect of SPC2968 on mRNA and protein to Hif-1α as well as phenotypic effects, measured by quantitative polymerase chain reaction (QPCR), Western blotting and biochemical/cellular assays. QPCR was also used to measure mRNA levels in SPC2968-treated mice, while the effects of the drug on tumour growth and vascularisation were evaluated in xenografts. To assess biodistribution in vivo, tritium-labelled SPC2968 was injected intravenously. Results: In vitro, SPC2968 at 1nM reduced both mRNA and protein levels of Hif-1α in cancer cell lines and downregulated two downstream targets of Hif-1, VEGF and MMP-2.Treatment also induced apoptosis in tumour cells and prevented tube formation by endothelial cells in vitro. Parenteral administration of SPC2968 in mice yielded potent inhibition of Hif-1α and VEGF mRNA in several tissues, including kidney, liver, and colon. Radioactively labelled SPC2968 distributed to kidney, liver, colon, bone marrow, lymph nodes and skin. Preclinical studies investigating acute and sub-acute toxicity and safety pharmacology of SPC2968 are completed, and SPC2968 was well tolerated. Conclusions: SPC2968 is an effective suppressor of Hif-1α mRNA and Hif-1α-regulated genes in vitro and in vivo and has shown good tissue biostability and biodistribution in rodents. Preclinical safety studies have been completed, and SPC2968 is ready for clinical testing. A phase I/II, dose-escalating study of SPC2968 in clear cell RCC in the US and the EU is planned to be submitted by mid 2006. [Table: see text]

Endothelin Receptor Antagonists in Treatment of Pulmonary Arterial Hypertension

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DOUBLE-BLIND PLACEBO CONTROLLED STUDY OF α-ADRENERGIC RECEPTOR ANTAGONISTS (DOXAZOSIN) FOR TREATMENT OF VOIDING DYSFUNCTION IN THE PEDIATRIC POPULATION

We sought to determine whether the alpha-adrenergic antagonist doxazosin could be used as primary therapy in children with voiding dysfunction. Children were assigned to maintain a voiding diary and then randomly divided into a double-blind placebo controlled protocol (0.5 mg doxazosin or placebo). Duplicate uroflow studies with post-void residual evaluations and assessment of dysfunctional voiding scores were performed on initiation and completion of the study. At the conclusion parents were asked to rank the perceived improvement of the urinary incontinence (ie parental subjective perception of improvement). No significant differences between doxazosin (18) and placebo (20) treated patients were found in the number of incontinent days per week, severity of incontinent episodes or alterations in uroflow patterns. Although not significant, 2 findings suggested a beneficial effect of doxazosin over placebo. Specifically, doxazosin decreased the number of incontinent episodes weekly from a median of 18 to 4, while the number of incontinent episodes weekly in the placebo group remained essentially unchanged, decreasing from 15 to 14 (p = 0.13). Doxazosin also improved the dysfunctional voiding scores over placebo, for an improvement of -3 vs 0 points. Further substantiating a doxazosin effect over placebo was the subjective perception of the parents that doxazosin significantly improved urinary continence (p <0.02). Compared to placebo, doxazosin did not demonstrate a significant objective benefit, but produced a significant subjective benefit in the treatment of urinary incontinence secondary to voiding dysfunction.

Lack of cataleptogenic potentiation with non-imidazole H 3 receptor antagonists reveals potential drug–drug interactions between imidazole-based H 3 receptor antagonists and antipsychotic drugs

Since H 3 receptor (H 3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H 3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H 3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H 3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272–80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H 3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H 3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H 3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug–drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug–drug interactions and support the potential utility of non-imidazole H 3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.