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Serum Half-life (serum + half-life)
Selected AbstractsDevelopment of fluridil, a topical suppressor of the androgen receptor in androgenetic alopeciaDRUG DEVELOPMENT RESEARCH, Issue 3 2003Allen L Seligson Abstract Nonsteroidal antiandrogens (AA) cannot be topically used for androgenetic alopecia (AGA) because of systemic resorption. A new class of androgen receptor (AR) suppressors designed for safe topical treatment of AGA was synthesized from (3-amino-2-hydroxy-2-methyl- N -(4-nitro-3-trifluoromethyl)phenyl) propanamide (BP-34), to contain perfluoroalkyl moieties. The trifluoromethyl derivative (fluridil) at 10 ,M decreased expression of the AR in LNCaP human cells by 95%, its serum half-life was 6 h; it decomposes hydrolytically to BP-34 and trifluoroacetic acid. Acute intraperitoneal maximum tolerated dose (MTD) of fluridil in mice is 270,300 mg/kg/d and the subacute MTD is 450 mg/kg/d. The oral LD50 in mice was 2,872 mg/kg in males, 2,232 mg/kg in females, and >2,500 mg/kg in rats. Fluridil solution in isopropanol was not cutaneously absorbed in rabbits, did not sensitize or show any phototoxic or photoallergic effects on guinea pig skin, and demonstrated no skin irritation potential in rabbits and humans. Fluridil solid induced only slight and reversible eye irritancy in rabbits and displayed no cytotoxicity to rabbit corneal fibroblasts in vitro. Fluridil demonstrated no significant mutagenicity potential by Ames method. In a double-blind study, 43 males with AGA, Norwood grade II to Va, used topical 2% fluridil in isopropanol or the vehicle daily for 12 months. Anagens (growing hairs) increased in the fluridil group from 76% to 89%. All hematological and biochemistry values remained within normal range, including testosterone, which varied but seasonally. No fluridil or its decomposition product (BP-34) was detected in serum. No adverse side effects were reported. Drug Dev. Res. 59:292,306, 2003. © 2003 Wiley-Liss, Inc. [source] Increasing the sialylation of therapeutic glycoproteins: The potential of the sialic acid biosynthetic pathwayJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2009Kaya Bork Abstract The number of therapeutic proteins has increased dramatically over the past years and most of the therapeutic proteins in the market today are glycoproteins. Usually, recombinant glycoproteins are produced in mammalian cell lines, such as Chinese-hamster-ovary-cells to obtain mammalian-type of glycosylation. The terminal monosaccharide of N-linked complex glycans is typically occupied by sialic acid. Presence of this sialic acid affects absorption, serum half-life, and clearance from the serum, as well as the physical, chemical and immunogenic properties of the respective glycoprotein. From a manufacturing perspective, the degree of sialylation is crucial since sialylation varies the function of the product. In addition, insufficient or inconsistent sialylation is also a major problem for the process consistency. Sialylation of over-expressed glycoproteins in all mammalian cell lines commonly used in biotechnology for the production of therapeutic glycoproteins is incomplete and there is a need for strategies leading to homogenous, naturally sialylated glycoproteins. This review will shortly summarize the biosynthesis of sialic acids and describe some recent strategies to increase or modify sialylation of specific therapeutic glycoproteins. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3499,3508, 2009 [source] Glycoengineering: The effect of glycosylation on the properties of therapeutic proteinsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2005Angus M. Sinclair Abstract Therapeutic proteins have revolutionized the treatment of many diseases but low activity or rapid clearance limits their utility. New approaches have been taken to design drugs with enhanced in vivo activity and half-life to reduce injection frequency, increase convenience, and improve patient compliance. One recently used approach is glycoengineering, changing protein-associated carbohydrate to alter pharmacokinetic properties of proteins. This technology has been applied to erythropoietin and resulted in the discovery of darbepoetin alfa (DA), a hyperglycosylated analogue of erythropoietin that contains two additional N-linked carbohydrates, a threefold increase in serum half-life and increased in vivo activity compared to recombinant human erythropoietin (rHuEPO). The increased serum half-life allows for less frequent dosing to maintain target hemoglobin levels in anemic patients. Carbohydrates on DA and other molecules can also increase molecular stability, solubility, increase in vivo biological activity, and reduce immunogenicity. These properties are discussed. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1626,1635, 2005 [source] Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodiumJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2008G. LE TRAON Oral l -thyroxine (l -T4) supplementation is used to replace thyroid hormone concentrations in dogs with hypothyroidism. The pharmacokinetics of l -T4 following administration of a solution (Leventaź) was investigated in healthy dogs. l -T4 was absorbed fairly rapidly (tmax 3 h). A mean bioavailability of 22% was calculated following a single oral administration of 40 ,g l -T4/kg body weight. Repeated oral administration at the same dose for 14 consecutive days did not lead to any accumulation of T4 in serum. After intravenous administration of l -T4, a serum half-life of 11.6 h was calculated. Food intake concomitant with l -T4 oral administration delayed l -T4 absorption and decreased its rate and extent by about 45%. The relative bioavailability of l -T4 following administration of a tablet formulation was about 50% of that of the l -T4 solution. The pharmacokinetic properties of liquid l -T4 after oral administration support the use of a dose rate of 20 ,g/kg once daily, as a starting dose for replacement therapy in dogs with hypothyroidism. [source] Immunotoxic activity of ochratoxin AJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2006L. AL-ANATI Ochratoxin A (OTA) is an immunosuppressant fungal compound, produced by toxigenic species of Aspergillus and Penicillium fungi in a wide variety of climates and geographical regions. The contamination of food by this mycotoxin takes place primarily during preharvest periods. Almost all types of food can be contaminated. In addition, its chemical stability against heat and during industrial food processing makes OTA one of the most abundant food contaminating mycotoxins. Due in part to its long serum half-life in man, almost 100% of all human blood samples from some geographic regions may be positive for OTA. The immunosuppressant activity of OTA is characterized by size reduction of vital immune organs, such as thymus, spleen, and lymph nodes, depression of antibody responses, alterations in the number and functions of immune cells, and modulation of cytokine production. The immunotoxic activity of OTA probably results from degenerative changes and cell death following necrosis and apoptosis, in combination with slow replacement of affected immune cells, due to inhibition of protein synthesis. [source] Darbepoetin alfa administered monthly maintains haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis: A multicentre, open-label, Australian studyNEPHROLOGY, Issue 1 2007ALEX DISNEY SUMMARY: Aim: Darbepoetin alfa, an erythropoiesis-stimulating protein, has a longer serum half-life than recombinant human erythropoietin, allowing less-frequent administration. This study aimed to demonstrate that once-monthly (QM) darbepoetin alfa administration would maintain haemoglobin (Hb) concentrations in subjects with chronic kidney disease (CKD) not receiving dialysis who had previously been administered darbepoetin alfa every 2 weeks (Q2W). Methods: This was a multicentre study in which subjects with CKD receiving stable Q2W darbepoetin alfa doses and with stable Hb (100,130 g/L) were started on QM darbepoetin alfa dosing. The initial QM darbepoetin alfa dose was equivalent to the cumulative darbepoetin alfa dose administered during the month preceding enrolment. Darbepoetin alfa doses were titrated to maintain Hb concentrations between 100 and 130 g/L. The primary endpoint was the proportion of subjects maintaining mean Hb 0e; 100 g/L during the evaluation period (weeks 21,33). Results: Sixty-six subjects were enrolled in the study and all received at least one dose of darbepoetin alfa; 55 (83%) had mean Hb 0e; 100 g/L during evaluation. Mean (SD) Hb concentrations at baseline and during the evaluation period were 119 (8.7) g/L and 114 (9.8) g/L, respectively. The median QM darbepoetin alfa dose at baseline and during the evaluation period was 80 ,g. Darbepoetin alfa was considered to be well-tolerated. Conclusion: Patients with CKD not receiving dialysis who are receiving darbepoetin alfa Q2W can be safely and effectively extended to darbepoetin alfa QM. Dosing QM may simplify anaemia management for patients and health-care providers. [source] Formatted anti,tumor necrosis factor , VHH proteins derived from camelids show superior potency and targeting to inflamed joints in a murine model of collagen-induced arthritisARTHRITIS & RHEUMATISM, Issue 6 2006Ken Coppieters Objective The advent of tumor necrosis factor (TNF),blocking drugs has provided rheumatologists with an effective, but highly expensive, treatment for the management of established rheumatoid arthritis (RA). Our aim was to explore preclinically the application of camelid anti-TNF VHH proteins, which are single-domain antigen binding (VHH) proteins homologous to human immunoglobulin VH domains, as TNF antagonists in a mouse model of RA. Methods Llamas were immunized with human and mouse TNF, and antagonistic anti-TNF VHH proteins were isolated and cloned for bacterial production. The resulting anti-TNF VHH proteins were recombinantly linked to yield bivalent mouse and human TNF-specific molecules. To increase the serum half-life and targeting properties, an anti,serum albumin anti-TNF VHH domain was incorporated into the bivalent molecules. The TNF-neutralizing potential was analyzed in vitro. Mouse TNF-specific molecules were tested in a therapeutic protocol in murine collagen-induced arthritis (CIA). Disease progression was evaluated by clinical scoring and histologic evaluation. Targeting properties were evaluated by 99mTc labeling and gamma camera imaging. Results The bivalent molecules were up to 500 times more potent than the monovalent molecules. The antagonistic potency of the anti-human TNF VHH proteins exceeded even that of the anti-TNF antibodies infliximab and adalimumab that are used clinically in RA. Incorporation of binding affinity for albumin into the anti-TNF VHH protein significantly prolonged its serum half-life and promoted its targeting to inflamed joints in the murine CIA model of RA. This might explain the excellent therapeutic efficacy observed in vivo. Conclusion These data suggest that because of the flexibility of their format, camelid anti-TNF VHH proteins can be converted into potent therapeutic agents that can be produced and purified cost-effectively. [source] | ||||||||||