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Clinical Doses (clinical + dose)
Selected AbstractsRapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent parathyroid hormone treatmentJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2009P.J. Niziolek The osteo-anabolic effects of intermittent parathyroid hormone (PTH) treatment require insulin-like growth factor (IGF) signaling through the IGF-I receptor. A major downstream target of the IGF-I receptor (via Akt) is the mammalian target of rapamycin (mTOR), a kinase involved in protein synthesis. We investigated whether the bone-building effects of intermittent PTH require functional mTOR signaling. Mice were treated with daily PTH 1,34 (0, 10, 30, or 90,µg/kg) for 6 weeks in the presence or absence of rapamycin, a selective inhibitor of mTOR. We found that all PTH doses were effective in enhancing bone mass, whether rapamycin was present or not. Rapamycin had little to no effect on the anabolic response at low (10,µg) PTH doses, small effects in a minority of anabolic measures at moderate doses (30,µg), but the anabolic effects of high-dose PTH (90,µg) were consistently and significantly suppressed by rapamycin (,4,36% reduction). Serum levels of Trap5b, a marker of resorption, were significantly enhanced by rapamycin, but these effects were observed whether PTH was absent or present. Our data suggest that intermittent PTH, particularly at lower doses, is effective in building bone mass in the presence of rapamycin. However, the full anabolic effects of higher doses of PTH are significantly suppressed by rapamycin, suggesting that PTH might normally activate additional pathways (including mTOR) for its enhanced high-dose anabolic effects. Clinical doses of intermittent PTH could be an effective treatment for maintaining or increasing bone mass among patients taking rapamycin analogs for unrelated health issues. J. Cell. Physiol. 221: 579,585, 2009. © 2009 Wiley-Liss, Inc. [source] Topical tacrolimus in the management of atopic dermatitis in JapanDERMATOLOGIC THERAPY, Issue 2 2006Masutaka Furue ABSTRACT:, Atopic dermatitis (AD) is a common, chronic, relapsing, severely pruritic, eczematous skin disease. Topical steroids are the mainstay of treatment. However, the adverse effects of steroids on hormonal function are the major obstacle for their use as long-term topical therapy. Topical calcineurin inhibitors, such as tacrolimus, not only complement existing treatment options but also overcome some of the drawbacks of topical steroid therapy and fulfill the long-term needs of patients in preventing disease progression. Short- and long-term efficacy and safety of topical tacrolimus has been widely recognized and it is also accepted as a first-line treatment for the inflammation of AD. In order to reduce the possible long-term adverse effects, it is important to monitor the clinical dose in daily clinics. [source] Design, Synthesis and Evaluation of N -Basic Substituted 3-Hydroxypyridin-4-ones: Orally Active Iron Chelators with Lysosomotrophic PotentialJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2000ZU D. LIU To investigate the possibility of targeting chelators into the lysosomal iron pool, nine bidentate 3-hydroxypyridin-4-ones with basic chains have been synthesized. As the turnover of ferritin iron is centred in the lysosome, such strategy is predicted to increase chelator efficacy of bidentate ligands. The pKa values of the ligands together with their distribution coefficients between 1-octanol and 4-morpholinepropane sulphonic acid (MOPS) buffer pH 7.4 have been determined. The in-vivo iron mobilization efficacy of these basic 3-hydroxypyridin-4-ones has been investigated in a 59Fe-ferritin-loaded rat model. No obvious correlation was observed between efficacy and the pKa value of the side chain, although those with pKa > 7.0 tended to be more efficient than those with pKa < 7.0. The imidazole-containing molecules are much less effective than the tertiary amine derivatives. A dose-response study suggested that basic pyridinones are relatively more effective at lower doses when compared with N -alkyl hydroxypyridinones. Optimal effects were observed with the piperidine derivatives 4h and 4i. The derivative 4i at a dose of 150 ,mol kg,1 was more effective than 450 ,mol kg,1 deferiprone, the widely adopted clinical dose. [source] Clenbuterol in the horse: urinary concentrations determined by ELISA and GC/MS after clinical dosesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2001J. D. Harkins Clenbuterol is a ,2 agonist/antagonist bronchodilator marketed as Ventipulmin® and is the only member of this group of drugs approved by the US Food and Drug Administration (FDA) for use in horses. Clenbuterol is a class 3 drug in the Association of Racing Commissioners International (ARCI) classification system; therefore, its identification in postrace samples may lead to sanctions. Recently, the sensitivity of postrace testing for clenbuterol has been substantially increased. The objective of this study was to determine the ,detection times' for clenbuterol after administration of an oral clinical dose (0.8 g/kg, b.i.d.) of Ventipulmin syrup. Five horses received oral clenbuterol (0.8 g/kg, b.i.d.) for 10 days, and urine concentrations of clenbuterol were determined by an enhanced enzyme-linked immunoabsorbent assay (ELISA) test and gas chromatography/mass spectrometric (GC/MS) analysis by two different methods for 30 days after administration. Twenty-four hours after the last administration, urine concentrations of apparent clenbuterol, as measured by ELISA, averaged about 500 ng/mL, dropping to about 1 ng/mL by day 5 posttreatment. However, there was a later transient increase in the mean concentrations of apparent clenbuterol in urine, peaking at 7 ng/mL on day 10 postadministration. The urine samples were also analysed using mass spectral quantification of both the trimethylsilyl (TMS) and methane boronic acid (MBA) derivatives of clenbuterol. Analysis using the TMS method showed that, at 24 h after the last administration, the mean concentration of recovered clenbuterol was about 22 ng/mL. Thereafter, clenbuterol concentrations fell below the limit of detection of the TMS-method by day 5 after administration but became transiently detectable again at day 10, with a mean concentration of about 1 ng/mL. Derivatization with MBA offers significant advantages over TMS for the mass spectral detection of clenbuterol, primarily because MBA derivatization yields a high molecular weight base peak of 243 m/z, which is ideal for quantitative purposes. Therefore, mass spectral analyses of selected urine samples, including the transient peak on day 10, were repeated using MBA derivatization, and comparable results were obtained. The results show that clenbuterol was undetectable in horse urine by day 5 after administration. However, an unexpected secondary peak of clenbuterol was observed at day 10 after administration that averaged ,1 ng/mL. Because of this secondary peak, the detection time for clenbuterol (0.8 g/kg, b.i.d. × 10 days) is at least 11 days if the threshold for detection is set at 1 ng/mL. [source] Effects of Sairei-to on the pharmacokinetics of nifedipine in ratsPHYTOTHERAPY RESEARCH, Issue 1 2008Mika Ikehata Abstract Sairei-to is a traditional herbal medicine used to complement, and as an alternative to, Western drugs. The aim of this study was to evaluate the pharmacokinetic interactions between Sairei-to and nifedipine (NFP), a substrate for CYP3A, in rats. NFP-oxidizing activity and the pharmacokinetics of NFP were examined after a single or 1-week of administration of Sairei-to (EK-114). NFP-oxidizing activity was enhanced transiently around 24 h after a single administration of EK-114 (1400 mg/kg). In vivo, the first-pass metabolism of NFP increased in the small intestine at 24 h after the administration of EK-114, and this effect disappeared at 72 h. Co-administration of EK-114 tended to inhibit the metabolism of NFP. On the other hand, when EK-114 was given at a high dose (1400 mg/kg) for 1 week, the oxidation of NFP in the small intestine was inhibited, and Cmax and AUC after the oral administration of NFP increased. In addition, a clinical dose of EK-114 (140 mg/kg) did not alter the pharmacokinetics of NFP, regardless of the administration schedule. EK-114 was suggested to affect the metabolism of NFP. However, the CYP3A-mediated pharmacokinetic interaction on the concomitant use of EK-114 may not be clinically significant. Copyright © 2007 John Wiley & Sons, Ltd. [source] In vitro drug interaction between diflunisal and indomethacin via glucuronidation in humansBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2006Yuji Mano Abstract It was reported that the plasma concentration of indomethacin was increased with concomitant oral dosages of diflunisal in humans. Both indomethacin and diflunisal are glucuronidated in humans. The effects of diflunisal on the indomethacin glucuronidation were thus investigated in vitro using human liver microsomes (HLM) and human intestine microsomes (HIM) in order to assess the drug,drug interaction. The glucuronidation of indomethacin in HLM showed atypical kinetics with Km and Ksi values of 210 and 89.5 µM, respectively, while HIM exhibited Michaelis,Menten kinetics with a Km value of 17.4 µM. Diflunisal inhibited the indomethacin glucuronidation in HLM with IC50 values ranging from 100 to 231 µM. In HIM, inhibition of the indomethacin glucuronidation by diflunisal was more potent with IC50 values of 15.2,48.7 µM. When the clinical dose of diflunisal (250 mg b.i.d.) is taken into consideration, it is expected that the diflunisal concentration in the intestine would be higher than the IC50 values for indomethacin glucuronidation in the intestine. These findings suggest that the clinical drug,drug interaction between diflunisal and indomethacin may be at least partly attributable to the inhibition of indomethacin glucuronidation by diflunisal in the intestine. Copyright © 2006 John Wiley & Sons, Ltd. [source] Comparative Cognitive Effects of Carbamazepine and Gabapentin in Healthy Senior AdultsEPILEPSIA, Issue 6 2001Roy Martin Summary: ,Purpose: This study compared the cognitive effects of carbamazepine (CBZ) and gabapentin (GBP) in healthy senior adults by using a randomized, double-blind crossover design. Methods: Thirty-four senior adults were randomized to receive one of the two drugs followed by a 5-week treatment period. A 4-week washout phase preceded initiation of the second drug. Antiepileptic drugs (AEDs) were titrated to target doses of either CBZ (800 mg/day) or GBP (2,400 mg/day). Primary outcome measures were standardized neuropsychological tests of attention/vigilance, psychomotor speed, motor speed, verbal and visual memory, and the Profile of Mood State (POMS), yielding a total of 17 variables. Each subject received cognitive testing at predrug baseline, end of first drug phase, end of second drug phase, and 4 weeks after completion of the second drug phase. Results: Fifteen senior adults (mean age, 66.5 years; range, 59,76 years) completed the study. Seniors completing the study did not differ significantly from noncompleting seniors in terms of demographic features or baseline cognitive performances. Fifteen of the 19 seniors not completing the study dropped out while receiving CBZ. Adverse events were frequently reported for both AEDs, although they were more common for CBZ. Mean serum levels for the completers were within midrange clinical doses (CBZ, 6.8 ,g/ml; GBP, 7.1 ,g/ml). Significant differences between CBZ and GBP were found for only one of 11 cognitive variables, with better attention/vigilance for GBP, although the effect was modest. Performances on the nondrug average were significantly better on 45% of cognitive variables compared with CBZ and 36% compared with GBP. The overall pattern of means favored GBP over CBZ on 15 of 17 (p < 0.001), nondrug over CBZ on 17 of 17 (p < 0.0000), and nondrug over GBP on eight of 17 (NS). Conclusions: Mild cognitive effects were found for both AEDs compared with the nondrug average condition. The magnitude of difference between the two AEDs across the cognitive variables was modest. Self-reported mood was not significantly affected by either AED. However, overall tolerability and side-effect profile of CBZ were poorer than those of GBP in senior adults at doses and titration rates reported in this study. [source] Clenbuterol in the horse: urinary concentrations determined by ELISA and GC/MS after clinical dosesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2001J. D. Harkins Clenbuterol is a ,2 agonist/antagonist bronchodilator marketed as Ventipulmin® and is the only member of this group of drugs approved by the US Food and Drug Administration (FDA) for use in horses. Clenbuterol is a class 3 drug in the Association of Racing Commissioners International (ARCI) classification system; therefore, its identification in postrace samples may lead to sanctions. Recently, the sensitivity of postrace testing for clenbuterol has been substantially increased. The objective of this study was to determine the ,detection times' for clenbuterol after administration of an oral clinical dose (0.8 g/kg, b.i.d.) of Ventipulmin syrup. Five horses received oral clenbuterol (0.8 g/kg, b.i.d.) for 10 days, and urine concentrations of clenbuterol were determined by an enhanced enzyme-linked immunoabsorbent assay (ELISA) test and gas chromatography/mass spectrometric (GC/MS) analysis by two different methods for 30 days after administration. Twenty-four hours after the last administration, urine concentrations of apparent clenbuterol, as measured by ELISA, averaged about 500 ng/mL, dropping to about 1 ng/mL by day 5 posttreatment. However, there was a later transient increase in the mean concentrations of apparent clenbuterol in urine, peaking at 7 ng/mL on day 10 postadministration. The urine samples were also analysed using mass spectral quantification of both the trimethylsilyl (TMS) and methane boronic acid (MBA) derivatives of clenbuterol. Analysis using the TMS method showed that, at 24 h after the last administration, the mean concentration of recovered clenbuterol was about 22 ng/mL. Thereafter, clenbuterol concentrations fell below the limit of detection of the TMS-method by day 5 after administration but became transiently detectable again at day 10, with a mean concentration of about 1 ng/mL. Derivatization with MBA offers significant advantages over TMS for the mass spectral detection of clenbuterol, primarily because MBA derivatization yields a high molecular weight base peak of 243 m/z, which is ideal for quantitative purposes. Therefore, mass spectral analyses of selected urine samples, including the transient peak on day 10, were repeated using MBA derivatization, and comparable results were obtained. The results show that clenbuterol was undetectable in horse urine by day 5 after administration. However, an unexpected secondary peak of clenbuterol was observed at day 10 after administration that averaged ,1 ng/mL. Because of this secondary peak, the detection time for clenbuterol (0.8 g/kg, b.i.d. × 10 days) is at least 11 days if the threshold for detection is set at 1 ng/mL. [source] Teicoplanin-dependent antibodies: detection and characterizationBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2005Stephen F. Garner Summary There are only a few reports of thrombocytopenia associated with clinical doses of teicoplanin, a glycopeptide antibiotic used against Gram-positive bacteria. We investigated 39 patients receiving teicoplanin; 31 were thrombocytopenic with platelet counts between 1,105 × 109/l and 8 were not thrombocytopenic. We identified 14 thrombocytopenic cases (45%) and two (25%) non-thrombocytopenic cases with IgG teicoplanin-dependent platelet-reactive antibodies. Use of glycoprotein (GP) capture enzyme-linked immunosorbent assay with platelets and GPIIb/IIIa transfected Chinese Hamster Ovary cells as well as flow cytometry with GP-deficient platelets indicated that the GPIIb/IIIa complex is a major target antigen of these antibodies. [source] Multiple effects of bevacizumab in angiogenesis: implications for its use in age-related macular degenerationACTA OPHTHALMOLOGICA, Issue 5 2009Angela Carneiro Abstract. Purpose:, This study aimed to elucidate the precise effects of bevacizumab in all steps in the neovascularization process in endothelial cells. Methods:, Human umbilical vein endothelial cells (HUVECs) were incubated with bevacizumab at concentrations within the clinically established range or with identical amounts of excipient. Cell cytotoxicity (evaluated by MTT assay), proliferation (by BrdU incorporation assay), apoptosis (by TUNEL assay), migration (by double-chamber assay) and vessel assembly in matrigel-coated plates were assessed in vitro. Mouse plug matrigel assays were performed to confirm in vitro results. Results:, Incubation of HUVECs with bevacizumab did not present cytotoxicity. Concentrations comparable with those after intravitreal doses of bevacizumab significantly reduced proliferation and migration capacity, and increased apoptotic rates in these cells. In addition, bevacizumab led to a significant decrease in the assembly of capillary-like structures on matrigel assay in comparison with excipient-treated cells. Further substantiating these in vitro findings, bevacizumab also inhibited angiogenesis in a mouse plug matrigel assay, as evaluated by haemoglobin content levels. Conclusions:, These results demonstrate that clinical doses of bevacizumab are able to prevent several steps of the angiogenic process. Bevacizumab is thus currently recommended for treating disorders that present augmented angiogenesis. [source] Suppression of neural activity of bronchial irritant receptors by surface-active phospholipid in comparison with topical drugs commonly prescribed for asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 9 2000Hills Background Much indirect evidence has been put forward previously in support of the concept that surface-active phospholipid (SAPL) normally masks irritant receptors in the lungs and upper respiratory tract; but this physical barrier is deficient in asthmatics, imparting hyperresponsiveness of the bronchoconstrictor reflex. Objective To determine whether exogenous SAPL applied to bronchial mucosa reduces the sensitivity of irritant receptors to a standard challenge used clinically to diagnose asthma and to compare the effects with those of corticosteroids and ,-stimulation. Methods Nerve fibres in the vagi were monitored to record action potentials from irritant receptors identified in the upper airways of rat lungs in response to a methacholine challenge. SAPL in the form of dipalmitoyl phosphatidylcholine (PC) and phosphatidylglycerol (PG) , 7 : 3 PC:PG , was applied as a fine dry powder to enhance surface activity and, hence, chemisorption to epithelium. Comparison was also made with clinical doses of i.v. hydrocortisone and instilled salbutamol together with liquid or solid controls, as appropriate. Results Neural activity of irritant receptors was found to be significantly (P = 0.0018) decreased by topical SAPL by 35.8% in response to a methacholine challenge in contrast to an increase of 11.2% in response to a solid (lactose) control. Instilled salbutamol and i.v. hydrocortisone also decreased responses to the same challenge by 43.4% and 14.7%, respectively, in contrast to a liquid (saline) control which increased by 24.5%. Conclusions Surface-active phospholipid has an appreciable effect upon irritant receptors in rat airways, reducing neural response to a methacholine challenge by an amount comparable to that of Salbutamol. These results support the concept of SAPL masking bronchial irritant receptors and warrant placebo-controlled clinical trials of this dry powder as a means of controlling asthma without the side-effects of current medication. Other possible roles discussed for the SAPL epithelial barrier include the exclusion of viruses and allergens. [source] Heart rate-lowering and -regulating effects of once-daily sustained-release diltiazemCLINICAL CARDIOLOGY, Issue 1 2001William E. Boden M.D. Abstract Background: Epidemiologic evidence suggests that an elevated heart rate (HR) is an adverse and independent prognostic factor in arterial hypertension and other cardiovascular diseases. Although diltiazem is characterized as an HR-lowering calcium antagonist, no studies have quantified the magnitude of HR changes in patients with angina or hypertension. Hypothesis: The study was undertaken to explore the magnitude of proportional HR reduction at varying levels of resting HR with the sustained-release formulation of diltiazem (SR diltiazem) at the usual clinical doses of 200 or 300 mg once daily. Methods: This meta-analysis was conducted on six comparative double-blind studies including 771 patients with angina or hypertension in which SR diltiazem 200,300 mg once daily was compared either with placebo or with other agents known not to influence HR (angiotensin-converting enzyme inhibitors, diuretics). Sustained-release diltiazem decreases elevated baseline HR, with an increasing effect at higher initial rates. Results: Multiple comparisons by baseline HR category showed a significant difference between both groups for baseline HR of 74,84 beats/min and , 85 beats/min (p = 0.001). Sustained-release diltiazem had no significant HR-decreasing effect on baseline HR , 74 beats/min but appears to have a genuine regulating effect on HR: it reduces tachycardia without inducing excessive bradycardia. These findings are in contrast to those with dihydropyridine calcium antagonists, which tend to increase HR and have been associated with an adverse outcome in acute cardiovascular conditions. At the same time, there is evidence to suggest that HR-lowering calcium-channel blockers decrease cardiovascular event rates following myocardial infarction. Conclusion: When calcium antagonists are indicated for use in patients with angina or hypertension, an HR-lowering agent, that is, diltiazem rather than dihydropyridine, should be recommended. [source] | ||||||||||