摘要:

ObjectiveTo assess the efficacy of propionyl-carnitine (PC) in patients with type 2 diabetes and peripheral arterial disease (PAD).Patients and methodsThis was an open pharmacodynamic study. Twenty-four obese patients with type 2 diabetes and PAD (stage IIb) were enrolled in the study. After an initial run-in period of 7 days on a low-calorie diet (1600 ± 150 kcal/day), patients received intravenous PC (600mg in 100mL saline solution Na/K 0.9%) twice daily for 10 days (T1).ResultsTreatment with PC produced statistically significant increases in maximal walking distance (30%; p < 0.05) and initial claudication distance (15%; p < 0.05) in 15 and eight patients, respectively. In addition, a decrease in dosage of oral antihyperglycaemic agents was observed in 21 patients at T1. No PC-related adverse effects were reported.ConclusionsThis study showed that acute intravenous administration of PC in patients with type 2 diabetes with PAD improved PAD-related symptoms as well as glycaemic control.

ISSN:1174-5886    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Background and objectiveCarnitine and its derivatives, namely propionyl-carnitine (PC), have been shown to protect cardiac metabolism and function in diabetes mellitus and ischaemic heart disease. Since diabetes is associated with abnormalities in mitochondrial metabolism of fuels, we examined the effects of PC on mitochondrial respiration in ischaemic hearts from streptozotocin-diabetic rats.MethodsDiabetes was induced in Sprague-Dawley rats by an intravenous injection of streptozotocin. Following the diagnosis of diabetes, oral PC treatment was initiated for a period of 6 weeks. After treatment, cardiac function was determined from working hearts perfused under aerobic conditions and in a separate group of hearts subjected to ischaemia and reperfusion. Mitochondrial respiration was determined under aerobic conditions and following low-flow ischaemia.ResultsRates of state 3 mitochondria respiration with pyruvate were significantly lower in diabetic (n = 4) hearts compared with control (n = 6) hearts (80 ± 5 vs 112 ± 5 nanoatoms O2/mg protein/min, respectively), but those with palmitoylcarnitine were similar (101 ± 11 vs 106 ± 6 nanoatoms O2/mg protein/min). Diabetic rat heart (n = 8) function, expressed as rate pressure product, was also significantly decreased compared with control (n = 8) hearts (21.5 ± 1.0 vs 29.5 ± 0.9 beats × mm Hg × 10−3/min, respectively). In PC-treated diabetic (n = 6) hearts, state 3 respiration with pyruvate was increased, and a marked improvement in left ventricular function from 21.5 ± 1.0 to 26.0 ± 0.6 beats × mm Hg × 10−3/min was observed. During low-flow ischaemia, state 3 respiration with pyruvate remained lower in diabetic (n = 5) hearts compared with control (n = 5) hearts (64 ± 3 vs 46 ± 5 nanoatoms O2/mg protein/min, respectively). Following treatment with PC (n = 4), however, respiration with this substrate was significantly increased to 57 ± 4 nanoatoms O2/mg protein/min. PC was also associated with a significant improvement in cardiac function in reperfused diabetic rat (n = 4) hearts (18.4 ± 0.2 beats × mm Hg × 10−3/min).ConclusionOur results showed that PC has a beneficial effect on cardiac function and increases ischaemic tolerance of the diabetic rat heart. This beneficial effect of PC can be explained, in part, as an improvement in mitochondrial metabolism of pyruvate during the actual ischaemic period.

ISSN:1174-5886    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

BackgroundAlterations in catalase (CAT) and superoxide dismutase (SOD) activity have been reported in diabetes mellitus. Glibenclamide (glyburide), a member of the second-generation sulphonylureas, provides effective treatment for patients with moderate diabetes. The action of the liver plays an important role in its glucose-lowering effect, suggesting that glibenclamide also exerts a direct effect on liver enzyme activities.ObjectiveTo evaluate the effect of glibenclamide on the activities of antioxidant enzymes (CAT and SOD) in liver and kidney tissue of diabetic rats.MethodsThirty-nine rats were included in this study. Moderate diabetes mellitus was induced with streptozocin (freshly dissolved in citrate buffer, ph 4.5) 55 mg/kg in 22 rats. Eight of these diabetic rats were left untreated, insulin was administered to six diabetic rats, and glibenclamide was administered to eight rats with moderate diabetes. Liver and kidney CAT and SOD activities were measured in all rats.ResultsHepatic CAT and SOD activities were significantly reduced in diabetic animals (p < 0.05 for both activities). Glibenclamide treatment of diabetic rats for 5 weeks reversed the changes observed in diabetic liver tissues (p < 0.05). However, renal CAT and SOD activities were unchanged. In addition, high blood glucose levels of diabetic rats were decreased following glibenclamide treatment.ConclusionAdministration of glibenclamide to diabetic rats reversed diabetes-induced changes, suggesting that glibenclamide may directly increase liver CAT and SOD activity.

ISSN:1174-5886    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Bertek Pharmaceuticals, a subsidiary of Mylan Laboratories Inc., is developing an intermittent subcutaneous formulation of apomorphine hydrochloride as a treatment for Parkinson's disease. Apomorphine injection (APO-go®) for the treatment of Parkinson's disease was launched in the UK in May 2002.Bertek licensed the formulation from Britannia Pharmaceuticals in the UK for development and marketing in the US.In April 2004, apomorphine injection was approved as the first and only therapy in the US for the acute, intermittent treatment of hypomobility, ‘off’ episodes associated with advanced Parkinson's disease. This approval follows the fast-track status designation given by the US FDA in January 2003, and an approvable letter issued in July 2003. The product is expected to be available by July 2004.[1]

ISSN:1174-5886    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Clofarabine [Clofarex™] is a purine nucleoside in development with Bio-envision, the Southern Research Institute and ILEX Oncology as an anticancer agent. Clofarabine's nucleoside structure is such that both the purine and ribose rings are halogenated, which allows it to inhibit DNA synthesis at two critical junctures: DNA polymerase I and RNA reductase. An intravenous infusion and an oral formulation are undergoing clinical development. Clofarabine was originated by the Southern Research Institute.In August 1998 Bioenvision signed a co-development agreement with the Southern Research Institute, under which it obtained the right to manufacture, market and distribute clofarabine worldwide, except Japan and Southeast Asia. In addition, the company appears to have licensed rights from the Institute that cover the development and marketing of other purine nucleoside analogues that have relevance in the treatment of leukaemia and lymphoma. Bioenvision will pay royalties to the Southern Research Institute for sales of clofarabine.Bioenvision extended its option in May 2004 to manufacture, market and distribute clofarabine in Japan and Southeast Asia, and is seeking a co-marketing partner to convert the option into a license agreement following the terms agreed upon between Bioenvision and the Southern Research Institute.[1]Bioenvision and ILEX Products (a wholly owned subsidiary of ILEX Oncology) signed an agreement in February 2004 that converted ILEX's option (agreed in March 2001) to market and distribute clofarabine in the US and Canada. As part of the deal, Bioenvision received a $US3.5 million payment from ILEX in December 2003.[2]In March 2004, Genzyme Corporation announced that it had signed a merger agreement with ILEX Oncology under which ILEX shareholders will receive shares of Genzyme common stock valued at approximately $US1 billion in equity value. Genzyme's business combination with ILEX is expected to be completed by the middle of 2004, Genzyme will, therefore, acquire a considerable boost to its product portfolio.[3]Bioenvision obtained the exclusive option from the Southern Research Institute in September 2003 to manufacture, market and distribute clofarabine in Japan and Southeast Asia. Bioenvision stated it was actively seeking a co-marketing partner to convert this option into a license.[4]Bioenvision announced in June 2003 that it had formed two separate agreements with Ferro Pfanstiehl Laboratories. The agreements cover worldwide development and supply of clofarabine, excluding the US and Canada. Ferro Pfanstiehl has more than 25 years of experience in potent compound manufacturing.The US FDA granted clofarabine fast-track designation for the treatment of refractory or relapsed acute lymphoblastic leukaemia in children in September 2003. Clofarabine has also been granted orphan drug status by the US FDA for the treatment of adult and paediatric patients with acute lymphocytic leukaemia (ALL) or acute myeloid leukaemia (AML).[5]In December 2001, clofarabine was granted orphan drug status in the EU for the treatment of adult and paediatric patients with ALL.A single-agent phase II study has been completed in patients with acute leukaemia and myelodysplastic syndromes. Results of a phase II study of clofarabine in the treatment of acute myelogenous leukaemia in older adults who are not considered suitable for intensive chemotherapy have been very positive, with a 64% response rate in these patients being reported.[6]In May 2004, Bioenvision announced that it had decided to stop enrolment at 25 evaluable patients (initially anticipated to be approximately 37 patients) because of the encouraging interim results. It said the trial would conclude earlier than expected and be completed by the end of June 2004. The pivotal trial will enrol approximately 65 patients with AML considered unsuitable for intensive chemotherapy.[7]Bioenvision currently has phase II trials ongoing in adult and paediatric patients with acute leukaemia and chronic lymphocytic leukaemia (CLL). In addition, Bioenvision-sponsored phase I/II clinical trials of clofarabine in patients with CLL and non-Hodgkin's lymphoma are underway in Europe.In July 2002, ILEX began two US multicentre, open-label, phase II trials in children with relapsed or refractory AML or ALL. Children enrolled in the studies receive an intravenous infusion of clofarabine over 2 hours for five consecutive days every 2–6 weeks. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), an overall response rate of 28% was reported for clofarabine therapy in heavily pretreated children with acute leukaemia.[8]In September 2003, a multicentre European phase II trial (BIOV-111) was initiated in children with relapsed/refractory ALL. In December 2003, the first of 65 patients received treatment.[9,10]As part of the global development programme, Bioenvision and ILEX are also conducting a phase II study in adult patients with AML. The companies are planning to investigate the potential use of clofarabine in combination with DNA-damaging agents, because clofarabine has been shown to inhibit DNA repair and may, therefore, potentiate the effects of DNA damaging drugs. A phase I/II trial of clofarabine in combination with cytarabine (Ara-C) in adult patients with first relapse AML, ALL, CML blast crisis and myelodysplastic syndrome was initiated at the University of Texas MD Anderson Cancer Centre in October 2002.Clofarabine has completed US phase I trials, and has reported favourable results in patients with leukaemia and solid tumours, including breast, colorectal and prostate cancers.A phase I/II trial in patients with solid tumours was initiated in July 2002. In addition, ILEX said it intended to develop an oral formulation of clofarabine for the treatment of colorectal cancer.

ISSN:1174-5886    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Neurobiological Technologies in the US is clinically developing corticorelin [ACTH RF, corticoliberin, corticotrophin-releasing hormone, corticotropin-releasing factor, human corticotropin-releasing hormone; Xerecept®], a synthetic preparation of the peptide hormone Corticotropin-Releasing Factor (CRF), as a potential treatment for the reduction of cerebral oedema associated with brain cancer (peritumoral brain oedema).Corticorelin may be a safer alternative than the use of current treatments such as synthetic corticosteroids. In addition, the company believe the agent may enhance radiation therapy for brain tumours.Neurobiological Technologies licensed human corticorelin from the Salk Institute in the US.Various phase I/II trials have shown improvement in neurological function with corticorelin, which was well tolerated. In 1998, corticorelin received orphan drug status from the US FDA for the treatment of peritumoral brain oedema.

ISSN:1174-5886    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Exisulind [Aptosyn™, FGN 1™, Prevatac™, sulindac sulfone], the sulfone derivative of sulindac, is the lead compound in a series of selective apoptotic antineoplastic drugs (SAANDs) being developed by OSI Pharmaceuticals. The compounds were originally developed by Cell Pathways, which was acquired by, and integrated into, OSI Pharmaceuticals in June 2003. Exisulind inhibits the enzyme cyclic GMP phosphodiesterase (GMP-PDE), overexpressed in precancerous and cancerous colorectal cells, and induces apoptosis in such cells with minimal effects on normal cells. This apoptotic effect is independent of COX I or COX II inhibition, p53, Bcl-2, or cell-cycle arrest. Preclinical evidence suggests that exisulind also inhibits angiogenesis.Cell Pathways has formed sales and distribution agreements with three healthcare-related companies in the US for its future marketing and support campaign for exisulind. Innovex will hire and train sales representatives for Cell Pathways to launch and promote exisulind, Livingston Healthcare Services will be responsible for customer service, order and distribution administration, and Lash Group will be respons-ible for the development and implementation of reimbursement support services for exisulind.Cell Pathways has issued an exclusive licence for exisulind to Paladin Labs of Montreal, Canada. The agreement allows Paladin exclusive rights to commercialise the drug in Canada.In August 1999 Cell Pathways submitted an NDA application to the US FDA for exisulind (Aptosyn™) for the treatment of familial adenomatous polyposis (FAP). However, in September 2000, the FDA announced that it had found deficiencies in the safety and efficacy data of Cell Pathways' NDA, and returned a non-approvable letter to the company. Cell Pathways then initiated another phase III study of the agent in combination with Aventis' docetaxel and comparing combination therapy with docetaxel alone. Exisulind has fast-track designation for FAP in the US.Phase I and II paediatric trials are also underway in the US. Cell Pathways announced in April 2000 that it had completed enrolment in an open-label phase II study in children with familial adenomatous polyposis (FAP). Patients will be evaluated to determine whether polyp numbers have been reduced after 1 year relative to baseline. In June 2000, Cell Pathways announced the results of a 1-year extension of a 1997–1999 phase III trial that showed that exisulind significantly reduced polyp formation in patients with FAP.Enrolment of 282 patients in a multicentre, placebo-controlled phase III trial for the treatment of sporadic colonic polyps was completed in the US in May 1999.In its 2003 Annual Report, Paladin Labs announced that it is conducting a phase III study of exisulind in patients with prostate cancer in Canada.Exisulind has completed a pivotal phase II/III trial for preventing the recurrence of prostate cancer in the US. Two phase II prostate cancer trials were initiated in June 1999. The first study assessed the efficacy of exisulind in 15 patients who had undergone prostatectomy, were receiving LHRH-agonist hormone therapy and had increasing PSA levels (study EX1001). The second trial was to enrol 20 hormone-refractory patients scheduled for radical prostatectomy within 2–8 weeks of diagnosis (study EX1004). This study compared the effect of exisulind + docetaxel on the rate of apoptosis and GMP-PDE expression in premalignant or malignant and normal prostate tissue.Cell Pathways and Rhône-Poulenc Rorer (now Aventis) agreed to collaborate on clinical trials of exisulind in combination with docetaxel in the treatment of various solid tumours. The first phase I/II trial (study 026) was to enrol previously untreated patients with non-small cell lung cancer (NSCLC).OSI Pharmaceuticals and Bristol-Myers Squibb are conducting a phase I/II trial (study EX 2002) of exisulind in combination with paclitaxel and carboplatin as first-line treatment for patients with NSCLC. Both companies will share costs and information gathered from the trial. A phase I/II trial (study EX 2006) of weekly paclitaxel and carboplatin combined with exisulind is also underway in patients with advanced NSCLC.Cell Pathways and Glaxo Wellcome are cooperating in supporting a clinical trial (study EX 2004) of exisulind in combination with vinorelbine as first-line treatment for elderly patients with advanced NSCLC. The study will be conducted at the University of Wisconsin, and the two companies will share the costs of the trial while maintaining the rights to their respective compounds.Cell Pathways and Eli Lilly have a phase I/II trial (study EX 2005) of exisulind in combination with gemcitabine underway in patients with NSCLC. This study will investigate the efficacy and tolerability of escalating doses of exisulind in combination with a standard gemcitabine regimen.The Cancer and Leukaemia Group B (CALGB) initiated a phase II study of exisulind in combination with etoposide and carboplatin in patients with small cell lung cancer in the US in September 2002. The Eastern Cooperative Oncology Group (ECOG) initiated a phase II study in NSCLC patients in September 2002 that will investigate the effects of exisulind in combination with gemcitabine and carboplatin. The objectives of the two studies are to determine the 12-month survival rate and response rates following treatment with the combination regimens.Patents covering the mechanism of action of exisulind have been allowed in Europe and Japan, and extend to the methods of identifying compounds that selectively stimulate apoptosis in precancerous and cancerous cells.

ISSN:1174-5886    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Gadoxate disodium [gadolinium EOB DTPA, Gd-EOB-DTPA, gadoxetic acid, Eovist®injection, Primovist™] is a hydrophilic paramagnetic contrast agent being developed by Schering AG for hepatobiliary magnetic resonance imaging.In April 2004, gadoxate disodium (Primovist™) was approved in Sweden, the reference member state for the EU registration. Following the Swedish approval, Schering will initiate a mutual recognition procedure for the EU with approvals expected in most countries during 2004.[1]Gadoxate disodium is in phase III clinical trials in the US and has completed phase III studies in Japan. Submisions for approval in Japan and other Asian countries are planned for 2004. Schering AG plans to launch Eovist®in Japan in 2005.Schering AG acquired a worldwide, royalty-bearing licence to EPIX Medical's patents covering liver-enhancing agents such as Eovist®injection. These included a European patent (222886) and the US patents (4,899,755 and 4,888,008) that EPIX Medical exclusively licensed from the Massachusetts General Hospital (MGH). The MGH patents, a part of EPIX's extensive intellectual property, also covered albumin-targeted agents such as MS 325 (AngioMARK™). Schering AG formally withdrew from the opposition proceedings against EPIX's EU patent 222886 following its acquisition of EPIX's intellectual property.These EU and US patents were also non-exclusively licensed by EPIX Medical to Bracco in September 2001. Apart from covering Eovist®(Schering AG), the EU patent also covered gadobenate dimeglumine (MultiHance®Bracco). Following the licensing agreement, Bracco withdrew its opposition to the patents in Europe and Japan, and both EPIX Medical and Bracco settled their European patent dispute.In its 2002 Annual Report, Schering predicted that Eovist®has the potential to reach peak sales of euro50 million, three years after launch – at the time, launch in Europe was anticipated in 2004, followed by launch in Japan in 2005. This is down from earlier predictions, made at an analyst presentation in Berlin in March 2002, when the company forecast the product to reach peak sales of euro100 million.

ISSN:1174-5886    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Metformin extended release [Glumetza™,metformin hydrochloride, metformin gastric retention, metformin GR™] is a proprietary once-a-day formulation of metformin hydrochloride under development with DepoMed for the treatment of diabetes.In May 2002, DepoMed licensed manufacturing and marketing rights for its proprietary formulation of metformin extended release (500mg dose) to Biovail Corporation for the US (including Puerto Rico) and Canada. Under the terms of the agreement, Biovail would pay a $25 million milestone fee upon approval and also customary royalties on the net sales in the US and Canada. Biovail also agreed to acquire approximately 2.4 million of additionally issued DepoMed shares for $12.3 million. Biovail has subsequently developed a 1000mg dose of metformin extended release. In April 2004, Depomed and Biovail amended their original license agreement of May 2002. Under the terms of the amended agreement, Depomed will receive royalties on sales of Biovail's 1000mg tablet in the US and Canada. In turn, Biovail acquired access to Depomed's clinical data for the metformin 500mg tablet that will be used to accelerate regulatory filings for Biovail's 1000mg tablet and establish equivalence between the two dosages.[1]Metformin GR™ is available for partnership in Europe and Asia (Bio-Square-2004, Basel, Switzerland).In April 2004, Depomed and Biovail filed an NDA with the US FDA for the once-daily, extended-release formulation of metformin extended release (Glumetza™), 500mg and 1000mg tablets. The 500mg dosage was developed by Depomed using its patented drug delivery GR™ technology, while Biovail developed the metformin 1000mg dose using its proprietary Smartcoat delivery technology.[1]Depomed completed two double-blind, pivotal, phase III clinical trials with metformin extended release 500mg at 60 sites in the US in more than 1000 patients with type 2 diabetes. In three different dosing regimens, metformin extended release significantly decreased the glycosylated haemoglobin level similarly to that of metformin immediate release. Biovail successfully compared the metformin extended release 1000mg dose with Depomed's 500mg dose in multiple equivalence studies. In these studies, metformin extended release was well tolerated and demonstrated an excellent safety profile in terms of gastrointestinal adverse events.The licensee, Biovail, has submitted an application for metformin extended release with Health Canada.[2]Bristol-Myers Squibb is marketing a proprietary, once-daily extended-release formulation of metformin (Glucophage®XR).Several companies are developing controlled-release and extended release formulations of metformin.

ISSN:1174-5886    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Santarus Inc., is developing an immediate-release formulation of omeprazole in combination with an antacid (sodium bicarbonate) as a powder for suspension, known as Acitrel™ [SAN 05], and also as Rapinex powder for oral suspension.Acitrel™ is based on technology licensed from the University of Missouri. Santarus have also licensed technology from Tulane and North Carolina Universities relating to potential treatments for GI diseases.Santarus have licensed exclusive, worldwide rights to patent applications covering specific combination-formulations of proton pump inhibitors and antacids for treating various upper GI diseases and disorders.Santarus plans to license development, distribution and marketing rights of Rapinex®Powder for oral suspension 20mg outside the US, to one or more well established pharmaceutical companies.The US FDA has requested that Santarus pursue a name other than Rapinex®for the product. Santarus is currently discussing potential alternative names for the product with the FDA.Santarus announced positive results, in August 2003, from a phase III trial comparing oral Acitrel™ (Rapinex®40mg) to intravenous cimetidine in preventing upper GI bleeding in 359 critically ill adult patients. Santarus has also completed an open-label clinical trial in 243 patients, including 97 patients with gastric ulcers, evaluating the safety of Rapinex®40mg for an 8-week period.In connection with the NDA for Rapinex®40mg, Santarus provided notice to the NDA holder for Prilosec®delayed-release capsules and related patent owners that Rapinex®40mg does not infringe currently listed patents for Prilosec®or that those patents are invalid.[1]

ISSN:1174-5886    

出版商:ADIS    

年代:2004

数据来源: ADIS