摘要:

Background and objectiveL-carnitine is an essential molecule involved in mitochondrial metabolism, controlling the transport of acetyl and acyl groups across the mitochondrial inner membrane. Carnitine and acetylated carnitine (L-acetylcarnitine) are found in high concentrations in the epididymis, where they also act as antioxidants, protecting spermatozoa against damage caused by reactive oxygen species. In this open study we investigated the correlation between seminal carnitine levels and spermatozoal function, and the effect of combined L-carnitine + L-acetylcarnitine therapy, in infertile men.Patients and methods170 infertile men were enrolled in this study. Patients were divided into those with a total sperm motility below the normal WHO range (<50% motility, group 1 [n = 102]) and those with total sperm motility within the normal range (≥50% motility, group 2 [n = 68]). Patients in group 1 were further divided into two groups: those with primary or secondary azoospermia (1B [n = 36]), and those without (1A [n = 66]). Patients in group 1A received L-carnitine 1 g/day and L-acetylcarnitine 500mg twice daily for 6 months. Seminal carnitine levels were measured and correlated with sperm count and motility, eosin test, hypo-osmotic swelling test, acridine orange test for sperm nuclear DNA integrity and sperm kinetics evaluated by computer-assisted sperm analysis in all patients.ResultsThere was a significant correlation between seminal carnitine concentration and sperm concentration, total sperm count, sperm total motility, rapid forward progression, live sperm count, membrane function, nuclear DNA inte-grity, capacity for cervical mucus penetration, linearity of spermatic movement, and amplitude of lateral sperm head movement (all p < 0.0001) in the entire study population. In group 1A, there was a significant increase in total motility, live sperm count, membrane integrity and linearity of spermatic movement after 3 and 6 months of L-carnitine/L-acetylcarnitine treatment, and in capacity for cervical mucus penetration after 6 months of treatment, compared with baseline.ConclusionSeminal carnitine concentration may be an appropriate marker of sperm and epididymal function. L-carnitine/L-acetylcarnitine treatment may be an effective therapy to improve mainly functional seminal parameters.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

BackgroundPolicosanol is a mixture of high-molecular-weight aliphatic pri-mary alcohols isolated from sugarcane wax with cholesterol-lowering and antiplatelet effects. Omega-3 fatty acids (FA) from fish oil can protect against coronary disease. An antiarrhythmic mechanism is emerging as the most convincing explanation for omega-3 FA cardiovascular protection, but triglyceride (TG)-lowering effects and inhibition of platelet function could play a role. In view of the effects of policosanol and omega-3 FA on lipid profile and platelet function, potential benefits of combined therapy were expected.ObjectiveTo investigate whether combined therapy with policosanol and omega-3 FA would offer some benefit, compared with policosanol or omega-3 FA alone, on serum lipid profile and platelet aggregation in rabbits.MethodsMale rabbits were randomly distributed in four groups (n = 9 per group). A control group received vehicle, one group was treated with policosanol 5 mg/kg and one with omega-3 FA (eicosapentaenoic acid; EPA [47.0%], docosahexaenoic acid; DHEA [41%]) 250 mg/kg, and the fourth received policosanol 5 mg/kg + omega-3 FA 250 mg/kg. Treatments were orally administered for 60 days. Bodyweight, food consumption and animal behaviour were recorded daily. Lipid profile, platelet aggregation and other blood tests were performed at baseline and study completion.ResultsPolicosanol significantly lowered low-density lipoprotein cholesterol (LDL-C) [42.7%; p < 0.01] and total cholesterol (TC) [29.4%; p < 0.05], increased high-density lipoprotein cholesterol (HDL-C) [15.4%; p < 0.05], but left TG levels unchanged. Omega-3 FA significantly lowered TG (47.1%; p < 0.05), but left TC, LDL-C and HDL-C unchanged. Combined therapy decreased LDL-C (38.7%; p < 0.05), TC (28.0%; p < 0.01) and TG (50.7%; p < 0.05), and increased HDL-C (15.4%; p < 0.05). Changes in TC, LDL-C and HDL-C obtained with combined therapy were greater (p < 0.05) than those with omega-3 FA, but similar to those with policosanol, whereas the opposite applied to TG reduction. No significant changes in lipid profile were observed in the control group. Policosanol and omega-3 FA significantly (p < 0.05) but moderately inhibited platelet aggregation induced with arachidonic acid (13.3% and 12.4%, respectively); combined therapy achieved greater inhibition (23.9%; p < 0.05). All groups showed similar food consumption and bodyweight gain. No toxic signs were observed in any animal.ConclusionsConcurrent therapy with policosanol 5 m/kg and omega-3 FA 250 mg/kg lowered LDL-C, TC and TG and increased HDL-C. All treatments inhibited platelet aggregation, but better effects were observed with policosanol + omega-3 FA compared with either treatment alone. Combined therapy was well tolerated. These results suggest that treatment with policosanol + omega-3 FA could be useful for regulating lipid profile and inhibiting platelet aggregation, but conclusive demonstration of such effects requires further experimental and clinical studies.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveThis study evaluated the utilisation of human pharmacology studies with biomarkers for either efficacy or safety estimation conducted for new drug applications (NDAs) submitted to the Japanese regulatory authority, the Ministry of Health, Labour and Welfare (MHLW).MethodsA total of 50 new chemical entities (NCEs) posted on the Websites, which were approved from June 2000 to November 2001, were evaluated by investigating their approval information. The utilisation of human pharmacology studies with biomarkers was evaluated by focusing on the classification referred to biomarkers for either efficacy or safety estimation and timing of studies.ResultsThe human pharmacology studies with biomarkers for either efficacy or safety estimation were conducted in 20 compounds classified by utilising measures of either efficacy (17 compounds) or safety (seven compounds). In 4 of 17 NCEs, some of the biomarkers in human pharmacology studies were similar to the clinical endpoints for efficacy assessment in therapeutic exploratory and/or therapeutic confirmatory studies. For safety assessment in therapeutic exploratory and/or therapeutic confirmatory studies, clinical endpoints rather than biomarkers in human pharmacology studies were used in all seven NCEs. The timing of each type of clinical study could only be obtained for 15 NCEs. Of these 15 NCEs, human pharmacology studies with biomarkers for either efficacy or safety estimation were conducted on six compounds. There were only two compounds for which human pharmacology studies with biomarkers for efficacy estimation were conducted before pivotal studies such as a therapeutic exploratory study or a bridging study.ConclusionOur survey suggests that with Japanese NDAs, human pharmacology studies with biomarkers for either efficacy or safety estimation do not play a key role in accelerating drug development and maximising the knowledge gained from confirmatory trials. The relationship between a biomarker and a clinical endpoint should be investigated appropriately for accelerating drug development. We think that the utilisation of human pharmacology studies with biomarkers for either efficacy or safety estimation in the regulatory review process for NDAs should be encouraged with the advancements of drug evaluation research using an appropriate biomarker based on clinical pharmacology.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Background and objectiveLithium, widely used in the prophylaxis of psychiatric patients with bipolar affective disorders, is well known to induce thyroid alterations. However, a possible metabolic linkage between blood thyroxine levels and its regulatory function on erythrocyte glutathione concentration has not yet been evaluated in lithium-treated patients. The aim of this study was to assess the antioxidative capacity of erythrocytes in lithium-induced hypothyroidism before and after thyroxine replacement.Patients and methodsThyroid ultrasound with clinical and laboratory evaluation of thyroid function and thyroid-stimulating hormone assay were performed prior to and at 6-month intervals during lithium prophylaxis in 76 patients with bipolar affective disorders. The daily lithium dosage was adjusted to 600–1200mg and the mean duration of treatment was 2.2 ± 0.4 years. Final assessment revealed that 12 patients had evidence of primary hypothyroidism, and these were assigned as the test group. Lithium prophylaxis was supplemented with thyroxine at a dosage of 100 mg/day within 6 months after thyroid dysfunction was diagnosed. Red blood cell superoxide dismutase activities and the glutathione contents were measured before and after thyroxine replacement. In order to assess the effect of long-term lithium administration on red blood cell glutathione and superoxide dismutase levels, 12 patients who had not developed hypothyroidism during the follow-up period were selected for the lithium-treated euthyroid group. Mann Whitney U-test and Wilcoxon rank sum W-test were used for comparison of data.ResultsA comparison of the lithium-treated test group with healthy volunteers and their own values after thyroxine replacement revealed a significant decrease in red blood cell glutathione concentrations (p = 0.000) in the hypothyroid state. However, no clinically significant changes were observed in red blood cell superoxide dismutase activities of the test group. A statistical survey also demonstrated that there was no significant difference in the thyroid-stimulating hormone values as well as the red blood cell glutathione contents or superoxide dismutase activities between healthy controls and lithium-treated euthyroid subjects.ConclusionsIt is most likely that lithium primarily inhibited hormone production in the thyroid and that this led to a compensatory increase in thyroid-stimulating hormone secretion with a significant decrease in the red blood cell glutathione content. While the red blood cell glutathione content of hypothyroid patients was reduced to 40% of the post-thyroxine level, unchanged superoxide dismutase activity might render the erythrocytes vulnerable to oxidative stress and ultimately haemolysis. Thyroxine replacement during lithium prophylaxis of psychiatric patients is advisable in order to prevent subclinical hypothyroidism and related defects of erythrocyte antioxidant capacity.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Glufosfamide [D 19575, β-D-Glc-IPM] is a next-generation glucose conjugate of ifosfamide that is under development with Threshold Pharmaceuticals for the treatment of cancer. It is an alkylating agent in which isophosphoramide mustard, the alkylating metabolite of ifosfamide, is glycosidically linked to β-D-glucose. Cellular uptake of glufosfamide is mediated by a sodium-dependent transmembrane transporter protein of glucose and possibly also by other transporter proteins. Threshold is using its Metabolic Targeting technology to exploit unique aspects of tumour metabolism, particularly the elevated glucose utilisation of tumour cells to selectively target glufosfamide to the tumour site.Glufosfamide was originally developed from a research collaboration between Asta Medica (Degussa) and the Cancer Research Centre (DKFZ) in Heidelberg, Germany. In October 2001, Baxter International acquired the oncology division of ASTA Medica, and renamed it Baxter Oncology GmbH. According to its 2002 Annual Report, Baxter announced that it was terminating development of glufosfamide.Subsequently, Baxter and Threshold Pharmaceuticals entered into an exclusive licensing and development agreement in August 2003. Threshold has responsibility for the development and commercialisation of glufosfamide, primarily for use as an antitumour agent. In addition, Baxter manufactures glufosfamide on Threshold's behalf.Threshold received fast-track status for glufosfamide from the US FDA in the treatment of metastatic pancreatic cancer refractory to gemcitabine in November 2004.[1]In December 2004, Threshold initiated a phase I/II trial (TH-CR-301 Study) investigating glufosfamide in combination with gemcitabine as a first-line treatment of pancreatic cancer or advanced solid tumours. The phase I portion of the study may enrol up to 15 patients. The maximum tolerable dose combination determined will then be used in the phase 2 portion of the study. Up to 42 patients with advanced pancreatic cancer will be enrolled at various sites in the US, Latin America and Brazil.[2]Previously, glufosfamide had been in phase II trials among patients with pancreatic carcinoma in Germany with Baxter Oncology and with the EORTC in the UK as well as Greece. However, development has been discontinued.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Valera Pharmaceuticals, formerly Hydro Med Sciences, is developing a once-yearly Histrelin Hydrogel Implant [Histrelin implant, LHRH-Hydrogel implant, RL 0903, SPD 424, Vantas™], a subcutaneous (SC) reservoir device capable of long-term delivery of histrelin at constant release rates for the treatment of prostate cancer. Histrelin is a luteinising hormone-releasing hormone agonist (LHRH). A different formulation of the LHRH implant is currently in development for the treatment of central precocious puberty (CPP).On 4 September 2003, Hydro Med Sciences announced that it had changed its name to Valera Pharmaceuticals.Shire Pharmaceuticals had an option to market and distribute the histrelin implant outside the US, but in a realigned agreement announced in January 2002, Shire stated that HydroMed (now Valera) would be responsible for concluding the phase III studies, filing for regulatory approval and producing the implant, while also gaining marketing rights in the US. Shire has no further involvement in development, but retains an option to market and distribute the product outside the US. The product is available for rest-of-the-world licensing through Valera Pharmaceuticals' business development division.Paladin Labs has received the exclusive rights for the sale and marketing of histrelin hydrogel implant in Canada. Valera Pharmaceuticals will have the responsibility for manufacturing and completing development of the product.In July 2004, Paladin announced it had filed for regulatory approval with Health Canada for the treatment of prostate cancer.Phase III trials have been conducted and initially involved two open-labelled, randomised, parallel studies that compared the hydrogel implant with the active comparators, leuprorelin acetate 22.5mg depot (TAP Pharmaceutical's Lupron Depot®) and a 3-month implant of goserelin acetate (Astra Zeneca's Zoladex®). However, because of financial constraints, HydroMed discontinued recruitment in a phase II European study and could not rationalise keeping the comparator arm of the phase III study. The US FDA then gave permission to continue the US part of the programme without the comparator arm, but with appropriate increases in the patient sample size. Patient enrolment in the phase III trial (US and Canada) was completed in July 2002. Valera Pharmaceuticals believes the product may have advantages over standard prostate cancer treatments including reduced costly surgical procedures, lower dosing, increased patient compliance and peace-of-mind, as well as potentially less cost to the patient. The phase III studies were completed in the second half of 2003.CPP arises from the increased release by the pituitary gland hormone gonadotropins and is characterised by an early onset of sexual development in pre-adolescents. Currently, the treatment of CPP involves injections of synthetic gonadotropic hormone-releasing factor agonists such as Supprelin®(histrelin acetate) and TAP Pharmaceutical's Lupron Depot-Red®(leuprolide acetate) every 28 days, a potentially painful procedure. This treatment inhibits pituitary release of gonadotropins. Valera's histrelin implant is a compact, removable subcutaneous implant that can be applied under a local anaesthetic in doctor's surgery.[1]

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Lasofoxifene [CP 336156] is a potent, nonsteroidal, tissue-selective estrogen receptor modulator (SERM). It has the bone-sparing and cardioprotective effects of estrogen, but lacks estrogen's uterine cancer risk. Lasofoxifene is under development with Ligand Pharmaceuticals and Pfizer (formerly Parke-Davis) for the prevention of postmenopausal osteoporosis and breast cancer.In June 2000, Parke-Davis' parent company, Warner-Lambert, merged with Pfizer. The resulting company retained the Pfizer name and Parke-Davis was integrated into Pfizer Global Research and Development.The discovery of lasofoxifene resulted from a research collaboration between Pfizer and Ligand Pharmaceuticals. There was a contract dispute between the two companies relating to their research agreement. Under a settlement of litigation, Ligand is entitled to milestone and royalty payments. If Pfizer is successful in developing the drug through to regulatory approval in the US, Ligand could receive royalty revenues from lasofoxifene as early as 2003–2004. The royalties will be equal to 6% of net sales and will be in addition to milestone payments for continuing development of the drug.However, on 6 March 2002, Ligand Pharmaceutical announced an agreement with Royalty Pharma in which the latter purchased the rights to a share of these future payments. Under the agreement, Ligand received $US6 million from Royalty Pharma in exchange for a 0.25% stake in net sales of three SERM products (lasofoxifene, bazedoxifene and bazedoxifene/Premarin®) for a period of 10 years. Royalty Pharma retains the option to purchase, at escalating prices, additional rights (subject to timing restrictions) to extend this stake up to 1.0%, for a total of $US56 million.In April 2002, Royalty Pharma exercised its first option to purchase an additional 0.125% of potential future sales of the three SERMS in exchange for $US3 million. Subsequently, in December 2002, Royalty Pharma exercised an expanded option and agreed to pay Ligand $US6.775 million for 0.1875% of potential future sales of SERM products.Royalty Pharma and Ligand Pharmaceutical amended their royalty agreement in October 2003 for the three SERM products. Under the amended agreement, Royalty Pharma exercised an option to pay Ligand $US12.5 million, plus cumulative milestones of up to $US2.5 million upon the launches of the three SERMs (provided they are approved by 30 September 2005), in exchange for 0.7% of potential future sales of the products for 10 years.In November 2004, Ligand Pharmaceuticals and Royalty Pharma further amended their existing royalty agreement for the three SERM products. Under the terms of the revised agreement, Royalty Pharma will purchase an additional 1.625% of the SERM products' net sales for $US32.5 million, which represents an acceleration of the previous option timetable and an increase in the royalty amount as well as aggregate purchase price. Consequently, Royalty Pharma increased its rights to a total of 3.0125% of net sales of each SERM product for 10 years following the first commercial sale of each product and has no further options. Ligand retains an approximately equal portion of lasofoxifene and other SERM's net sales going forward and for periods that could exceed 10 years. The royalty rates owed to Royalty Pharma for the royalties just purchased could be reduced by one-third if product sales exceed certain thresholds. Payments from the royalty purchase are non-refundable, regardless of whether the products ever become successfully launched or not. Milestone payments owed by Ligand's partners as products achieve development and regulatory targets will be paid to Ligand as earned and are not included in this amended agreement.[1]In September 2004, Ligand Pharmaceuticals earned a milestone payment of approximately $US2 million from Pfizer, payable in 181 818 shares of Ligand stock held by Pfizer. The payment was triggered by Pfizer's NDA submission for lasofoxifene in August 2004. Under the terms of the agreement between Ligand and Pfizer, Ligand is entitled to receive an additional milestone upon successful approval of lasofoxifene.On 19 August 2004, Pfizer filed an NDA with the US FDA for lasofoxifene for the prevention of osteoporosis in postmenopausal women.[2]Product launch is forecasted to occur in 2006–2007.Ligand reported in January 2004 at the 22nd Annual JP Morgan Healthcare Conference that it anticipated the availability of phase III data and NDA filing sometime in 2004. Lasofoxifene has undergone two phase III studies with Pfizer in the US as an orally administered therapy for postmenopausal osteoporosis. In June 2003, Pfizer reported that enrolment was completed in a trial evaluating lasofoxifene in the prevention of bone loss. The trial also evaluated lasofoxifene's effect on lipid levels. The trial enrolled ≊2000 postmenopausal women. Another trial was conducted among 8500 patients to investigate lasofoxifene in the treatment of fractures.In addition, Pfizer began a third worldwide phase III trial to evaluate whether lasofoxifene reduced the risk of vertebral fractures, breast cancer and cardiovascular disease.At the 10th Annual Meeting of the Biotechnology Industry Organization (BIO-2003), Ligand also confirmed that lasofoxifene was in phase III development for breast cancer.Lasofoxifene is under clinical evaluation as a treatment for vaginal atrophy.[3]According to Pfizer's pipeline in November 2004, the company anticipates regulatory submission for vaginal atrophy by the end of 2004.In June 2002, Ligand estimated that lasofoxifene has the potential to reach sales of $US1–2 billion, pending approval.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS