摘要:

Continuous long-term antipsychotic therapy is required for patients with schizophrenia to optimise treatment benefits. The use of long-acting antipsychotic preparations can help to ensure compliance with therapy and has been shown to improve efficacy in relapse prevention when compared with oral agents. How- ever, the use of long-acting agents has been limited, since this approach to patient care has only been available with conventional drugs. The atypical antipsychotic agents have provided a new option for the treatment of schizophrenia. However, entwined with health system limitations, partial or non-compliance remains a problem with oral atypical antipsychotic agents. Combining the attributes of the atypical antipsychotic class with the pharmacokinetic profile and compliance advantages of a long-acting formulation could potentially be an important advance in the management of patients requiring continuous anti- psychotic therapy. This review considers the available clinical data supporting possible advantages for the only long-acting atypical agent currently available, long-acting risperidone, as a microsphere formulation. The drug-delivery technology employed provides a sustained therapeutic plasma level, with administration once every 2 weeks, and this is translated into improved symptom control and improved quality of life, even in patients already deemed clinically stable on an oral agent or on a conventional depot antipsychotic.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveTriptans are highly effective in the treatment of migraine. Both central and peripheral mechanisms of action have been suggested. Until now, firm data about the passage of triptans into the CNS in humans have been lacking. The aim of the current study was to evaluate, using positron emission tomography (PET), the uptake and distribution of zolmitriptan into the CNS after intranasal administration.The PET images were analysed quantitatively for different areas of the brain, generating [11C]zolmitriptan time-activity data corrected for circulating tracer activity. The rate of uptake of intranasal zolmitriptan into the CNS was estimated by kinetic modelling using the PET data.Subjects and methods:Eight healthy volunteers, five males and three females (mean ages 23 and 26 years, respectively), were included. Radioactive [carbonyl-11C]zolmitriptan was infused intravenously for 5 minutes on two occasions: once alone, and once 30–40 minutes after intranasal administration of unlabelled zolmitriptan 5mg. PET was used to measure the concentration of labelled zolmitriptan in the brain, from the start of the tracer infusion for 90 minutes. Regional cerebral blood volume was determined with [15O]carbon monoxide. In addition, an MRI scan was performed to obtain anatomical information.The PET images were analysed quantitatively for different areas of the brain, generating [11C]zolmitriptan time-activity data corrected for circulating tracer activity. The rate of uptake of intranasal zolmitriptan into the CNS was estimated by kinetic modelling using the PET data.ResultsPET data from this study demonstrate a rapid dose-proportional uptake of [11C]zolmitriptan into the brain. Significant concentrations of [11C]zolmitriptan were found in all brain regions studied. Calculated CNS concentrations after intranasal zolmitriptan administration showed a gradual increase, reaching about 2nM (0.5 μg/L) 30 minutes after administration and 3.5nM (1.0 μg/L), or one-fifth of the plasma concentration, 1 hour after administration. Five minutes after zolmitriptan administration, the mean CNS concentration had already reached 0.5nM, which is higher thanin vitrovalues for initiation of the agonistic action on 5-HT1B/1Dreceptors.ConclusionThis study demonstrates by direct measurements that zolmitriptan enters the brain parenchyma in humans, achieving an uptake rate and concentration compatible with a central mode of action.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectivesTo the extent that current recombinant clotting factor concentrates contain even trace amounts of human or animal protein, there is continuing potential for transmission of nonenveloped viruses, including hepatitis A, and parvovirus, and the theoretical potential for transmission of relatively unknown agents, such as prions (Creutzfeldt-Jakob disease, or its variant). Full-length antihaemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM; Advate®), represents a novel pharmacotherapeutic option for the management of haemophilia A. This investigation was designed to discern: (i) the efficacy-based use pattern (International Units [IUs]) of rAHF-PFM versus B-domain deleted rFVIII (BDDrFVIII; ReFacto®) required to resolve a bleeding episode (event) among previously treated patients with haemophilia A employing on-demand treatment; (ii) the health service expenditure pattern (percentage differential; payor’s perspective) associated with use of rAHF-PFM versus BDDrFVIII among previously treated patients with haemophilia A employing on-demand treatment; and (iii) the fiscal utility attributable to the plasma/albumin-free status of rAHF-PFM under the assumed emergence of a novel and infectious blood (plasma)-borne virus.Materials and methodsData stemming from phase II/phase III clinical trials of rAHF-PFM, together with published literature on BDDrFVIII, afforded calculation of the probability of occurrence for specific endpoints of interest (e.g. non-response to first infusion). Monte Carlo simulation, a decision-analytical framework parameterised with stochastic (random) and deterministic (fixed) components (10 000 iterations per month [or year] of age examined [3, 6, 9 months; years 1 through 19; and years 20, 30, 40, 50, 60, 70 and 80]) was used to compare: (i) the efficacy-based use pattern by treatment option; and (ii) the health service utilisation-based expenditure pattern by treatment option, accounting for the need for subsequent infusion(s), and potential complications (use of services) stemming from failure of the initial infusion (five scenarios). Theoretical and direct modelling methods for assessing the fiscal utility attributable to the plasma/albumin-free status of rAHF-PFM under the assumed emergence of a novel and infectious blood (plasma)-borne virus were developed. Assumptions included: (i) a low population infection rate (<5%); (ii) annual health service expenditures equivalent to 5% of that observed with HIV/AIDS; and (iii) the number of bleeding events experienced per year were 6, 9 or 12.ResultsMonte Carlo simulation-replicated simulations per year of age examined revealed: (i) use of rAHF-PFM resulted in a 12.20% median reduction in the number of IUs required to resolve a bleeding episode (event) relative to BDDrFVIII (p < 0.05); and (ii) a health service utilisation-based savings [primary care; hospital] (p < 0.05; range 13.74–39.34% [dependent on intensity (sequencing) of care required]) with rAHF-PFM relative to BDDrFVIII. The overall scenario-weighted health service utilisation-based savings was 16.94% (p < 0.05). Under the assumption of the emergence of a novel and infectious blood (plasma)-borne virus, deterministic models for persons weighing 20kg, 50kg and 80kg all revealed a savings potential ($US per IU) with use of rAHF-PFM relative to use of a non-plasma/albumin-free product.ConclusionUse of rAHF-PFM in on-demand management of haemophilia A offers enhanced patient safety and represents a fiscally prudent therapeutic strategy.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Background and aimStress as a cofactor has been reported to affect the progression and severity of several diseases. The influence of stress on the liver is of interest from the clinical point of view because stress plays a potential role in aggravating liver diseases in general and hepatic inflammation in particular, probably through generation of reactive oxygen species. The present study was undertaken to investigate the potential of the antioxidant vitamins A (retinol), E (tocopherol) and C (ascorbic acid) individually and in combination (vitamin E + C) to modulate restraint stress-induced oxidative changes. These effects were determined by measuring changes in hepatic levels of free radical scavenging enzymes such as superoxide dismutase (SOD), glutathione-S-transferase (GST) and catalase, as well as levels of total glutathione (GSH), malondialdehyde (MDA), aspartate aminotransferase (AST) and alanine aminotransferase (ALT).MethodsImmobilisation was achieved by placing the animals in wire mesh cages of their size. The rats were orally administered vitamins A, E and C individually and in combination (E + C) prior to and after 6 hours of immobilisation stress exposure. The hepatic levels of SOD, GST, catalase, GSH and MDA were determined by spectrophotometric methods. Liver SOD activity was assayed by monitoring the amount of enzyme required to inhibit autoxidation of pyrogallol by 50%. Hepatic GST was monitored by following the increase in absorbance at 340nm of CDNB-GSH conjugate generated due to GST catalysis between GSH and CDNB. Catalase activity in liver tissues was determined using peroxidase as the substrate. Lipid peroxidation was measured by determining the level of thiobarbituric acid reactive substances. ALT and AST were determined by commercial kits.ResultsSix hours of immobilisation stress caused a decrease in liver levels of SOD (p = 0.001), catalase (p = 0.031), GST (p = 0.021) and GSH (0.013), while levels of MDA (p = 0.0015), AST (p = 0.05) and ALT (p = 0.046) were increased compared with non-stressed control rats. Both pre-vitamin stress and post-vitamin stress treatments either alone or in combination were associated with increased normalisation of these parameters towards control values, with post-vitamin treatment being the more effective of the two. Vitamins E and C individually were found to be more effective in restoring the endogenous antioxidant system than vitamin A. The combined vitamin (E + C) post-stress treatment was found to be effective but not additive in combating hepatic oxidative stress. The beneficial effects of these vitamin treatments were also reflected in reversions of altered AST and ALT levels towards their control values.ConclusionVitamins E or C alone or in combination can be given as prophylactic/therapeutic supplements for combating scavenging free radicals generated in liver tissue. This approach may reduce oxidative stress caused by diseases such as cirrhosis.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Cilansetron [KC 9946] is a serotonin-3 receptor (5-HT3) antagonist under development with Solvay Pharmaceuticals for the treatment of irritable bowel syndrome with diarrhoea predominance (IBS-D), in both men and women.5-HT3antagonists inhibit the 5-HT3receptors, resulting in decreased GI motility, secretion and sensation, thereby improving symptoms of IBS-D. Current 5-HT3therapy indicated for IBS-D is approved for women only.IBS is one of the most common functional gastrointestinal disorders, affecting an estimated 10–20% of the population in developed countries. Approximately twice as many women as men are diagnosed with IBS; however, this discrepancy may be due to more women seeking medical care. IBS is a chronic and bothersome disorder, and its symptoms, although not life-threatening, have a negative impact on quality of life (QOL), interfering with social activities, relationships and work. The degree to which IBS reduces quality of life appears to be directly related to symptom severity and intensity.In July 2001, Solvay signed an agreement with Quintiles (CRO) in order to optimise clinical research for cilansetron.In April 2004, Solvay Pharmaceuticals submitted a new drug application (NDA) for cilansetron in the UK (for the European Union) for the treatment of irritable bowel syndrome with diarrhoea predominance, in both men and women.In April 2005, Solvay Pharmaceuticals received a ‘not-approvable’ action letter from the US FDA on its NDA for cilansetron for the treatment of irritable bowel syndrome with diarrhoea predominance (IBS-D), in both men and women. The letter requested additional clinical trials, and Solvay is currently examining its options and will discuss future steps with the FDA.[1]Solvay submitted the NDA for cilansetron in the US in June 2004 and included an extensive Appropriate Use Plan as part of its submission. The NDA submission was based on efficacy and safety studies in around 4000 patients worldwide with IBS-D. The FDA accepted for filing and granted priority review status for this NDA application in September 2004.[2]According to Solvay's first half 2004 results, cilansetron is due to begin phase II clinical trials in Japan for the treatment of irritable bowel syndrome with diarrhoea predominance.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Avanir Pharmaceuticals in the US is developing a fixed-dose combination of dextromethorphan (30mg), a weak NMDA antagonist/sigma 1 agonist, and quinidine (30mg), a cytochrome P450-2D6 (CYP2D6) enzyme inhibitor [AVP 923, Neurodex™]. Quinidine sustains therapeutic levels of dextromethorphan over a 12-hour dosing schedule by inhibiting oxidative first-pass metabolism of the drug, and is used in the combination product at 2.5–5.0% of its normal daily therapeutic dose. A rolling NDA for the treatment of emotional lability has been initiated, and phase II trials with dextromethorphan/quinidine for the treatment of neuropathic pain have been completed.Avanir is exploring partnering opportunities for dextromethorphan/quinidine in Europe and Japan. Prospective partners would carry out development and commercialisation in the licensed territory. Additionally, a co-promotion partner for the US is sought.Avanir Pharmaceuticals sublicensed this formulation of dextromethorphan from IriSys Research and Development. Avanir has exclusive rights to develop, manufacture and market dextromethorphan/quinidine for four potential indications: emotional lability, neuropathic pain, chronic cough and weaning drug-dependent patients from narcotics and antidepressants. Avanir will make milestone payments to Irisys upon US FDA acceptance of filing, marketing approval, and royalties based on product sales.Medison Pharma (Israel) has obtained development, marketing and distribution rights to the dextromethorphan/quinidine combination for the treatment of emotional lability in patients with multiple sclerosis in Israel.Avanir will fund all clinical development of the dextromethorphan/quinidine combination for the treatment of emotional lability.[1]The phase II clinical trials with dextromethorphan/quinidine for the treatment of neuropathic pain have been completed. Results indicated that the combination significantly improved pain scores in patients with diabetic neuropathy. Phase III trials in this indication are expected to begin in 2005.[2,3]Avanir has been issued with six patents in the US regarding dextromethorphan/quinidine and has a total of 14 pending applications, 12 of which are in Europe.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Efaproxiral [RSR 13, GSJ 61, JP 4, KDD 86, RS 4] is a synthetic, small-molecule, radiation-sensitising agent being developed by Allos Therapeutics primarily for the treatment of cancer. It works by binding and allosterically stabilising deoxyhaemoglobin in hypoxic regions of tumour tissue. This increases oxygen uptake of the tumour tissue and restores its sensitivity to radiation therapy, making therapy potentially more successful. This first-of-its-class compound is particularly applicable for the treatment of certain tumour types that lack oxygen, such as brain metastases. In contrast to conventional chemotherapeutic agents or radiation sensitisers, there is no requirement for efaproxiral to be administered directly into tumours or to cross the blood-brain barrier for it to display efficacy. Efaproxiral is under review for approval in the US and EU as an adjunct to whole-brain radiation therapy (WBRT) for the treatment of brain metastases originating from breast cancer. It is also under clinical evaluation for a variety of other cancers, including glioblastoma, non-small cell lung cancer (NSCLC) and cervical cancer.Allos is seeking partnership opportunities for efaproxiral's development and marketing. The company has indicated that the development of efaproxiral would be in cooperation with a corporate partner, according to its 2003 Annual Report.In 1994, Allos Therapeutics acquired exclusive worldwide rights to intellectual property relating to efaproxiral from the Center for Innovative Technology (CIT).Allos has entered into arrangements with two contract manufacturers for the supply of efaproxiral, and a third manufacturer for the supply of the formulated drug product. Hovione FarmaCiencia is the primary supplier of efaproxiral, and is contracted to manufacture sufficient quantities on a commercial scale. In addition, a second manufacturer, Raylo Chemicals, is also producing quantities of efaproxiral. In December 2003, Allos entered into a long-term development and supply agreement with Baxter Healthcare who will formulate the efaproxiral into an injection. Allos is also seeking to establish an alternate supplier of efaproxiral injection.Allos submitted a rolling NDA to the US FDA consisting of three data components. Submission began in the third quarter of 2003 and was completed by the fourth quarter of 2003.[1,2]The first part of the application containing non-clinical information was submitted on 5 August 2003. The second part of the NDA containing information about efaproxiral's chemistry, manufacture and controls (CMC) was submitted in October 2003.[3]Allos submitted its final component of the rolling NDA in December 2003. In February 2004, Allos announced that the FDA had accepted the company's NDA under priority review status.[4]The FDA granted efaproxiral orphan drug status in August 2004 as an adjunct to WBRT for the treatment of brain metastases among breast cancer patients.[5]Efaproxiral also received fast-track status in November 2000 for the same indication in the US.In February 2004, Allos initiated a phase III trial, called ENRICH (Enhancing Whole Brain Radiation Therapy In Patients with Breast Cancer and Hypoxic Brain Metastases) to investigate efaproxiral as an adjunct to WBRT for the treatment of brain metastases. Median survival time is the primary endpoint of the study. The National Breast Cancer Coalition (NBCC) is collaborating with the company to support trial enrolment and to gain additional insight about ways to improve radiation treatment in this patient population. The ENRICH trial protocol was approved by the FDA under a Special Protocol Assessment process; as part of the protocol, two interim analyses for safety and efficacy will be performed.[6]This multicentre, randomised, open-label study has a target enrolment of approximately 360 patients at >100 medical centres across the US, Canada, Europe and South America. Allos announced in September 2004 that recruitment of clinical sites for the trial is ongoing across the US and Canada.[7,8]Completion of trial enrolment in North America is anticipated in December 2005. Subsequently, Allos announced in January 2005 that recruitment into the ENRICH trial has commenced and is ongoing in Europe; enrolment at European sites is expected to conclude by the third quarter of 2006.[9]Allos Therapeutics announced in June 2004 that it had filed an MAA with the EMEA for marketing of exaproxiral as an adjunct to WBRT for treatment of patients with brain metastases originating from breast cancer. The application is based on positive data from a pivotal phase III (REACH, RT-009) trial in this indication.[10]The completed REACH trial investigated efaproxiral among patients with brain metastases undergoing WBRT. The trial was conducted at multiple sites in 11 countries, including the US, Canada, Europe and Australia. In August 2002 Allos completed the enrolment of 538 patients in the study. Initially only 408 patients were to be enrolled, but the company increased the size of the trial to conduct an appropriately powered subgroup analysis in patients with brain metastases from breast and NSCLC. The study was designed to demonstrate a 35% increase in median survival in the subgroup of patients compared with standard WBRT alone. The primary endpoint was survival.[11]Allos began screening US patients for a phase III trial in NSCLC in early 2003. However, in May 2003, the company announced that as part of its revised operating plan it had suspended the screening of patients for this trial. The trial, which was known as ELITE (Enhanced Lung cancer treatment with Induction chemotherapy and Thoracic radiation and Efaproxiral), was comparing induction chemotherapy followed by thoracic radiation therapy with supplemental oxygen, with or without efaproxiral. The trial was enrolling patients with locally advanced, unresectable NSCLC. ELITE was planned to enrol up to 600 patients across North America and Western and Eastern Europe.[12]Phase II trials in patients with inoperable NSCLC have been conducted in the US and Canada. Patient enrolment in one of these studies was completed in August 2000, with a total of 52 patients enrolled. This was an open-label, multicentre study of induction therapy with paclitaxel plus carboplatin followed by chest irradiation and efaproxiral in patients with locally advanced NSCLC. Positive results from this study were reported at the annual meeting of the European Society for Therapeutics Radiology and Oncology in September 2002.Efaproxiral has completed phase I trials as a treatment of surgical hypoxia in elective surgery patients receiving general anaesthesia. However, no recent development has been reported for these indications.In 1994, Allos signed an agreement with CIT for the exclusive worldwide rights to 17 US patents, a European patent covering the UK, France, Italy and Germany plus two pending patents in these territories, two issued patents in Japan, and a pending patent in Canada. These patents cover methods of allosterically modifying haemoglobin with efaproxiral and other compounds, the binding site of efaproxiral and therapy in certain indications including cancer, ischaemia and hypoxia.In addition to the licensed patents from CIT, Allos exclusively owns two patent families with pending applications directed to a formulation of efaproxiral and to methods of its use in BLOD MRI (blood oxygenation level-dependent magnetic resonance imaging) applications. These patents are pending in the US, Canada and Europe, and include an international patent application.In a May 2002 interview with theWall Street Transcript, the CEO of Allos estimated the overall market for radiation therapy to be approximately 750 000 patients/year. Of this, brain metastases, NSCLC and glioblastoma therapy accounts for about 170 000, 140 000 and 6000 patients, respectively. Allos intend to use a speciality sales force to market efaproxiral directly to radiation therapists in North America. To penetrate the non-oncology market in the US, the company will seek partnership with one or more pharmaceutical companies with direct sales forces and with established distribution systems. Allos is also hoping to secure an oncology marketing partner for non-North American territories. At the time, the company had been issued 21 patents in the US, Canada, Europe and Japan.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Ramelteon [TAK 375] is a melatonin (MT1/MT2) receptor agonist that is being developed by Takeda as a treatment for sleep disorders. It is undergoing regulatory review in the US, phase III trials in Europe, and phase II trials in Japan for the treatment of insomnia. Phase II trials are also being conducted in the US for the treatment of circadian rhythm sleep disordersIn September 2004, Takeda submitted an NDA to the US FDA for ramelteon for the treatment of insomnia.[1]In May 2003, data presented at the 156th Annual Meeting of the American Psychiatric Association report that ramelteon is highly selective for the MT1receptor, and has greater affinity, selectivity and potency than melatonin.[2]

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS