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Oral Dose (oral + dose)

Distribution by Scientific Domains
Medical Sciences79%
Chemistry14%
Life Sciences6%
Distribution within Medical Sciences
Pharmacology & Pharmaceutical Medicine34%
General & Introductory Veterinary Medicine8%
Neurology5%
General & Internal Medicine2%
20 Other Subdomains51%

Kinds of Oral Dose

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    • Selected Abstracts

    Evaluations of toxicity of Turraeanthus africanus (Méliaceae) in mice

    ANDROLOGIA, Issue 6 2009
    D. Massoma Lembè
    Summary Turraeanthus africanus (Meliacaeae) is known to possess a broad spectrum of pharmacological, medicinal and therapeutic properties. However, no extensive safety studies have been conducted on these extracts to date. The aim of this study was to evaluate toxicity of the aqueous extract of Turraeanthus africanus (Meliacaeae) after oral and intraperitoneal administration in mice. The acute toxicity was evaluated after single daily administration of the aqueous extract orally at doses of 0, 5, 10, 15, 20, 30 g kg,1 or by the intraperitoneal route at doses of 0, 3, 6, 9, 12 g kg,1 of raw material. The subacute toxicity was evaluated only by the intraperitoneal route for 6 weeks at doses of 1.5, 3, 6 g kg,1 of raw material. Oral doses up to 30 g kg,1 of the aqueous extract of Turraeanthus africanus (TA) did not produce mortality or significant changes in the general behaviour and gross appearance of internal organs of rats. However, the intraperitoneal administration of the aqueous extract of Turraeanthus africanus caused dose-dependent lethal effects. The acute intraperitoneal toxicity (LD50) of TA extract in mice was 7.2 g kg,1. In subacute toxicity in mice, after the intraperitoneal administration of TA extract for 6 consecutive weeks, the feed consumption was significantly affected at the dose 3 g kg,1 with P < 0.05 and at the dose 6 g kg,1 with P < 0.001 and consequently had significant effect with P < 0.05 in body weight of animals. Level of triglyceride of treated animals lowered at dose 1.5 g kg,1 with P < 0.001 and at dose 3 g kg,1 and 6 g kg,1 with P < 0.05. Total cholesterol level of treated animals lowered at dose 1.5 g kg,1 with P < 0.005 and at dose 3 and 6 g kg,1 with P < 0.001. HDL cholesterol level of treated animals lowered up to dose 6 g kg,1 with P < 0.05 while levels of LDL cholesterol, serum and tissue creatinine of treated animals lowered at dose 3 g kg,1 and dose 6 g kg,1 with P < 0.05. Serum protein level of treated animal enhanced at dose 1.5 g kg,1 and at dose 6 g kg,1 with P < 0.05 while tissue creatinine level of treated animal enhanced with P < 0.001. The histology of liver, kidney and lung of the treated mice indicated morphological change of these organs (data not shown). No significant difference was observed during treatment concerning the haematological parameters. The results suggest that the plant is not toxic through the oral route in mice and that parenteral administration should be avoided. [source]

    Repaglinide treatment amplifies first-phase insulin secretion and high-frequency pulsatile insulin release in Type 2 diabetes

    DIABETIC MEDICINE, Issue 10 2005
    M. Hollingdal
    Abstract Aims/hypothesis First-phase insulin release and coordinated insulin pulsatility are disturbed in Type 2 diabetes. The present study was undertaken to explore a possible influence of the oral prandial glucose regulator, repaglinide, on first-phase insulin secretion and high-frequency insulin pulsatility in Type 2 diabetes. Methods We examined 10 patients with Type 2 diabetes in a double-blind placebo-controlled, cross-over design. The participants were treated for 6 weeks with either repaglinide [2,9 mg/day (average 5.9 mg)] or placebo in random order. At the end of each treatment period, first-phase insulin secretion was measured. Entrainment of insulin secretion was assessed utilizing 1-min glucose bolus exposure (6 mg/kg body weight every 10 min) for 60 min during (A) baseline conditions, i.e. 12 h after the last repaglinide/placebo administration, and (B) 30 min after an oral dose of 0.5 mg repaglinide/placebo with subsequent application of time-series analyses. Results Postprandial (2-h) blood glucose was significantly reduced by repaglinide after 5 weeks of treatment (P < 0.001). The fall in HbA1c did not reach statistical significance (P = 0.07). AUCins,0,12 min during the first-phase insulin secretion test was enhanced (P < 0.05). In addition, glucose entrained insulin secretory burst mass and amplitude increased markedly (burst mass: repaglinide, 44.4 ± 6.0 pmol/l/pulse vs. placebo, 31.4 ± 3.3 pmol/l/pulse, P < 0.05; burst amplitude: repaglinide, 17.7 ± 2.4 pmol/l/min vs. placebo, 12.6 ± 1.3 pmol/l/min, P < 0.05) while basal insulin (non-pulsatile) secretion was unaltered. After acute repaglinide exposure (0.5 mg) basal insulin secretion increased significantly (P < 0.05). Neither acute nor chronic repaglinide administration influenced frequency or regularity of insulin pulses during entrainment. Conclusion/interpretation Repaglinide augments first-phase insulin secretion as well as high-frequency insulin secretory burst mass and amplitude during glucose entrainment in patients with Type 2 diabetes, while regularity of the insulin release process was unaltered. Diabet. Med. (2005) [source]

    27 years of croup: An update highlighting the effectiveness of 0.15 mg/kg of dexamethasone

    EMERGENCY MEDICINE AUSTRALASIA, Issue 4 2009
    Milana Dobrovoljac
    Abstract Objective: To update an earlier observational study (1980,1995) documenting dramatic improvements in the management of croup with the mandatory use of a single oral dose of dexamethasone and to ascertain whether a reduction from a dose of 0.6 to 0.15 mg/kg in 1995 maintained these improved outcomes over the next 11 years. Methods: We evaluated retrospectively the experience of children with croup in Princess Margaret Hospital for Children, the only tertiary paediatric hospital in Western Australia, over the subsequent 11 year period from 1996 to 2006 inclusive. Data were updated from ED, general hospital and the intensive care unit records to show the numbers of children presenting to the hospital, admitted, transferred to intensive care and intubated. We also recorded the length of hospital stay and representation rate of all cases within 7 days. Results: The dramatic improvements in outcomes for croup, including reduced admission rates, length of stay, transfers to the intensive care unit, intensive care unit days and number of intubations as reported in our earlier paper, were maintained using 0.15 mg/kg dexamethasone. Admission rates for croup have fallen from 30% in the early 1990s to less than 15% in recent years, whereas the representation rate has risen slightly. Conclusion: The improved outcomes for children with croup presenting to our paediatric ED have been maintained with a reduced, single oral dose of 0.15 mg/kg of dexamethasone. [source]

    Modulation of plasma lipid levels affects benzo[a]pyrene-induced DNA damage in tissues of two hyperlipidemic mouse models

    ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 4 2003
    Daniëlle M.J. Curfs
    Abstract The role of plasma lipids in the uptake, transportation, and distribution of lipophilic carcinogens like benzo[a]pyrene (B[a]P) remains unclear. Therefore, we studied the effects of dietary-modulated plasma lipids on B[a]P-induced DNA damage in several organs of two hyperlipidemic mouse models. Male apolipoprotein E (ApoE)*3-Leiden (n = 22) and ApoE knockout (ApoE-KO) mice (n = 20) were fed a high-fat cholesterol (HFC) diet or low-fat cholesterol (LFC; standard mouse chow) diet for 3 weeks, after which the animals were exposed to a single oral dose of 5 mg/kg bw B[a]P or vehicle and killed 4 days later. Plasma lipids were determined and DNA adducts were measured in aorta, heart, lung, liver, brain, and stomach. Total cholesterol and low-density lipoprotein (LDL) cholesterol were increased in all animals on a HFC diet, whereas a decrease of triglycerides was seen only in the ApoE-KO mice. In ApoE-KO mice on a normal diet, DNA-adduct levels were highest in aorta (10.8 ± 1.4 adducts/108 nucleotides), followed by brain (7.8 ± 1.3), lung (3.3 ± 0.7), heart (3.1 ± 0.6), liver (1.5 ± 0.2) and stomach (1.2 ± 0.2). In the ApoE*3-Leiden mice, adduct levels were equally high in aorta, heart, and lung (4.6 ± 0.7, 5.0 ± 0.5 and 4.6 ± 0.4, respectively), followed by stomach (2.7 ± 0.4), brain (2.3 ± 0.2), and liver (1.7 ± 0.2). In the ApoE-KO mice, the HFC diet intervention resulted in lower adduct levels in lung (2.1 ± 0.2), heart (1.9 ± 0.2), and brain (2.9 ± 0.5), as compared with the LFC group. In contrast, a nonsignificant increase of adducts was found in aorta (13.1 ± 1.5). A similar but nonsignificant trend was observed in the ApoE*3-Leiden mice. Multiple regression analysis showed that in aorta, DNA adducts were inversely related to plasma triglycerides (P = 0.004) and were also modulated by the ApoE genotype (P < 0.001). The results of the present study support further investigation into the role of dietary modulation of plasma lipids, ApoE, and polycyclic aromatic hydrocarbon exposure on the formation of DNA adducts in chronic degenerative diseases. Environ. Mol. Mutagen. 42:243,249, 2003. © 2003 Wiley-Liss, Inc. [source]

    Effect of di(n -butyl) phthalate on testicular oxidative damage and antioxidant enzymes in hyperthyroid rats

    ENVIRONMENTAL TOXICOLOGY, Issue 3 2007
    Ena Lee
    Abstract This study compared the effects of di(n-butyl) phthalate (DBP) on the oxidative damage and antioxidant enzymes activity in testes of hyperthyroid rats. Hyperthyroidism was induced in pubertal male rats by intraperitoneal injection of triiodothyronine (T3, 10 ,g/kg body weight) for 30 days. An oral dose of DBP (750 mg/kg) was administered simultaneously to normal or hyperthyroid (T3) rats over a 30-day period. No changes in body weight were observed in the hyperthyroid groups (T3, T3 + DBP) compared with controls. There were significantly higher serum T3 levels observed in the hyperthyroid rats than in the control, but the serum thyroid stimulating hormone levels were markedly lower in the hyperthyroid rats. DBP significantly decreased the weight of the testes in the normal (DBP) and hyperthyroid (T3 + DBP) groups. The serum testosterone concentrations were significantly lower in only DBP group. DBP significantly increased the 8-hydroxy-2-deoxyguanosine (8-OHdG) level in the testes, whereas the DBP-induced 8-OHdG levels were slightly higher in T3 + DBP group. Superoxide dismutase and glutathione peroxidase activities were significantly higher in the testes of the DBP or T3 + DBP groups. Catalase (CAT) activity was significantly higher in the DBP treatment group, but the T3 + DBP group showed slightly lower DBP-induced CAT activity. The testicular expression of thyroid hormone receptor ,-1 (TR,-1) was significantly higher in the DBP groups, and androgen receptor (AR) expression was not detected in the DBP treatment group. In addition, DBP significantly increased the peroxisome proliferator-activated receptor-r (PPAR-r) levels in the testis. These results suggest that hyperthyroidism can cause a change in the expression level of PPAR-r in testes, and may increase the levels of oxidative damage induced by the metabolic activation of DBP. © 2007 Wiley Periodicals, Inc. Environ Toxicol 22: 245,255, 2007. [source]

    Effects of dietary N -acetylcysteine on the oxidative stress induced in tilapia (Oreochromis Niloticus) exposed to a microcystin-producing cyanobacterial water bloom,

    ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 8 2009
    María Puerto
    Abstract Fish can be exposed to toxic cyanobacterial cells in natural waters and fish farms and suffer from oxidative damage. The present study investigates the effects of N-acetylcysteine (NAC), a glutathione (GSH) precursor, on the oxidative stress induced by Microcystis cyanobacterial cells containing microcystins (MCs) in tilapia fish (Oreochromis niloticus). Variation in lipid peroxidation (LPO) levels, carbonyl group content, reduced glutathione to oxidized glutathione ratio (GSH: GSSG), and catalase (Enzyme Commission [EC] 1.11.1.6), superoxide dismutase (SOD; EC 1.15.1.1), glutathione reductase (GR; EC 1.8.1.7), glutathione peroxidase (GPx; EC 1.11.1.9), and glutathione S-transferase (EC 2.5.1.18) activities in liver and kidney of tilapia exposed to a single oral dose of 120 ,g MC-LR (with leucine [L] and arginine [R])/fish and killed in 24 h were investigated in the absence and presence of 20.0, 44.0, and 96.8 mg NAC/fish/d. Results showed a protective role of NAC, depending on the dose and the biomarker considered. The increase in LPO (1.9-and 1.4-fold in liver and kidney, respectively) and the decreased protein content and GSH:GSSG in the liver induced by MCs were recovered mainly by the lower doses of NAC employed. Antioxidant enzyme activities increased (range, 1.4-to 1.7-fold) by MCs also were ameliorated by NAC, although the highest level used induced significant alteration of some enzymatic activities, such as SOD, GPx, and GR. Thus, NAC can be considered to be a useful chemoprotectant that reduces hepatic and renal oxidative stress in the prophylaxis and treatment of MC-related intoxications in fish when careful attention is given to its application dose because of its own pro-oxidant activity, as shown in the present study at 96.8 mg NAC/ fish/d. [source]

    Pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western subjects

    EPILEPSIA, Issue 8 2009
    Peter Zannikos
    Summary Purpose:, To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations. Methods:, An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5,8; subsequently, 500 mg on days 9,12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid-chromatography-mass-spectrometry. Results:, Following a single dose, carisbamate Cmax and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80,125% limits, which are considered not to be of clinical significance. With dose,body weight normalization, Cmax and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80,125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half-life were similar in both groups, ranging from 35.1,41.4 ml/h/kg and 11.5,12.8 h. Discussion:, Carisbamate plasma exposure (AUC) and Cmax in Japanese subjects is ,20,25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality. [source]

    A Comparative Pharmacokinetic Study in Healthy Volunteers of the Effect of Carbamazepine and Oxcarbazepine on Cyp3a4

    EPILEPSIA, Issue 3 2007
    Astrid-Helene Andreasen
    Summary:,Purpose: Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction. Methods: Ten healthy, male volunteers participated in an open, randomized crossover study consisting of two periods separated by a 4-week wash-out period. The subjects received 1200 mg oral OXCZ daily for 17 days and 800 mg oral CBZ for 17 days. A single 200 mg oral dose of quinidine was administered at baseline and following administration of CBZ and OXCZ. Outcome parameters were the formation clearance of 3-hydroxyquinidine dose and the ratio of the AUCs of 3-hydroxyquinidine to quinidine. Results: Formation clearance of 3-hydroxyquinidine was increased by means of 89% (CI: 36,164; p = 0.0022) and 181% (CI: 120,260, p < 0.0001) after treatment with OXCZ and CBZ, respectively, compared to baseline. The relative inductive effect of CBZ was 46% higher than for OXCZ. AUC ratio increased by means of 161% (CI: 139,187, p < 0.0001) (OXCZ) and 222% (CI: 192,257, p < 0.0001) (CBZ). Quinidine Cmax decreased by means of 29% (CI: 16,40, p = 0.0018) (OXCZ) and 33% (CI: 18,45, p = 0.0020) (CBZ). T½ decreased by means of 12% (CI: 6,17, p < 0.0014) (OXCZ) and 32% (CI: 25,38, p < 0.0001) (CBZ). tmax was not changed in either period. Conclusion: We confirm a clinically significant inductive effect of both OXCZ and CBZ. The inductive effect of CBZ was about 46% higher than that of OXCZ, a difference that may be of clinical relevance. [source]

    Endothelin receptors blockade blunts hypoxia-induced increase in PAP in humans

    EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2010
    I. Pham
    Eur J Clin Invest 2010; 40 (3): 195,202 Abstract Background, Activation of the endothelin-1 (ET-1) pathway may be involved in hypoxia-induced pulmonary vasoconstriction, increase in pulmonary pressure and high altitude pulmonary oedema. Thus, we investigated the effect of the ETA/ETB receptor antagonist, bosentan, on pulmonary artery systolic pressure (PASP) in healthy subjects (n = 10). Design, We used a double-blind, placebo-controlled, randomized, cross-over design to study the effects of a single oral dose of bosentan (250 mg) on PASP after 90-min-exposure to normobaric hypoxia (FiO2 = 0·12). We measured PASP and cardiac output by echocardiography, systolic arterial blood pressure, arterial O2 saturation (SaO2), and blood gases at rest and during a sub-maximal exercise. Results, PASP in normoxia at rest was 23·5 ± 2·7 and during exercise 39·8 ± 11·6 mmHg (P < 0·0001). During the placebo period, hypoxia induced a significant decrease in SaO2, PaO2 and PCO2 and increase in pH. PASP at rest increased significantly: 32·1 ± 3·5 mmHg (P < 0·001 vs. normoxia). Bosentan significantly blunted the hypoxia-induced increase in PASP: bosentan: 27·0 ± 3·3 mmHg, P = 0·002 vs. placebo at rest, but not during exercise: bosentan 39·8 ± 11·6 vs. placebo 43·0 ± 8·5 mmHg, ns. Bosentan had no effect on the hypoxia-induced changes in blood gases, or on cardiac output and systolic arterial blood pressure, which were not modified by hypoxia. Conclusion, A single oral dose of bosentan blunted an acute hypoxia-induced increase in PASP in healthy subjects, without altering cardiac output or systemic blood pressure. [source]

    CLINICAL STUDY: FULL ARTICLE: Immunomodulating properties of gamma-hydroxybutyrate (GHB), flunitrazepam and ethanol in ,club drugs' users

    ADDICTION BIOLOGY, Issue 3 2010
    Simona Pichini
    ABSTRACT Despite the increasing concern about gamma-hydroxybutyrate (GHB) toxicity in users, no studies have addressed GHB and other club drugs effects on the immune system under controlled administration. Lymphocyte subsets and functional responsiveness of lymphocytes to mitogenic stimulation were measured in 10 healthy male recreational users of GHB who participated in five experimental sessions within the framework of a clinical trial. The study was randomized, double blind, double dummy and cross-over. Drug conditions were: a single oral dose of GHB (40 mg/kg or 60 mg/kg), ethanol (0.7 g/kg), flunitrazepam (1.25 mg) and placebo. Acute GHB produced a time-dependent immune impairment in the first 4 hours after drug administration associated with an increase in cortisol secretion. Although total leukocyte count remained unchanged, there was a significant decrease in the CD4 T/CD8 T-cell ratio, as well as in the percentage of mature T lymphocytes, probably because of a decrease in both the percentage and absolute number of T helper cells. A significant decrease was also observed in natural killer cells and in functional responsiveness of lymphocytes to mitogenic stimulation. Flunitrazepam administration did not produce any change in the immune system, while ethanol intake produced a decrease in B lymphocytes and in lymphocyte proliferative response to mitogens. These results provide the first evidence that GHB intake under a controlled environmental setting impairs the immunological status and confirms the alterations in the immune function caused by ethanol. [source]

    Hepatoprotective activity of picroliv, curcumin and ellagic acid compared to silymarin on paracetamol induced liver toxicity in mice

    FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2009
    C. Girish
    Abstract Oxidative stress is implicated as a common pathologic mechanism contributing to the initiation and progression of hepatic damage in a variety of liver disorders. Present study attempts to evaluate the hepatoprotective activity of picroliv, curcumin and ellagic acid in comparison to silymarin using paracetamol (PCM) induced acute liver damage. Hepatotoxicity was induced by administering a single oral dose of PCM (500 mg/kg) and was assessed by quantifying the serum enzyme activities, phenobarbitone induced sleeping time and histopathological analysis of liver tissues. The antioxidant parameters, malondialdehyde (MDA), reduced glutathione (GSH) and catalase of the liver tissue were also assessed. The herbal drugs were administered for 7 days by oral route at 50 and 100 mg/kg. PCM induced hepatic damage was manifested by a significant increase in the activities of marker enzymes (alanine transaminase, aspartate transaminase and alkaline phosphatase) in serum and MDA level in liver. There was also a significant decrease in activity of GSH and catalase levels. The histopathological examination on toxic models revealed centrizonal necrosis and fatty changes. Pretreatment of mice with picroliv, curcumin and ellagic acid reversed these altered parameters towards normal values, which were compared with silymarin. The normalization of phenobarbitone induced sleeping time suggests the restoration of liver cytochrome P450 enzymes. This study supports the use of these active phytochemicals against toxic liver injury, which may act by preventing the lipid peroxidation and augmenting the antioxidant defense system or regeneration of hepatocytes. These active phytochemicals may be developed as drugs for the treatment of liver diseases. [source]

    The ameliorative effect of cysteine prodrug l -2-oxothiazolidine-4-carboxylic acid on cisplatin-induced nephrotoxicity in rats

    FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2007
    B.H. Ali
    Abstract Pathogenesis of nephrotoxicity of the synthetic anticancer drug cisplatin (CP) involves generation of reactive oxygen species and free radicals in the kidney cortex, and cysteine prodrug l -2-oxothiazolidine-4-carboxylic acid (OTC) has been confirmed to have a strong antioxidant action. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of OTC on CP nephrotoxicity in rats. OTC was given at an oral dose of 150 mg/kg/day for 7 days. On day 7, some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg. Rats were killed, blood and urine samples were collected, and the kidneys were removed 6 days after CP treatment. Nephrotoxicity was evaluated histopathologically by light microscopy, and biochemically by measuring the concentrations of creatinine and urea in serum, reduced glutathione (GSH) concentration and superoxide dismutase (SOD) activity in renal cortex, and by urinalyses. CP significantly increased the concentrations of urea and creatinine (P < 0.05) by about 128% and 170% respectively. CP treatment reduced cortical GSH concentration by about 34% (P < 0.05), and the activity of SOD by about 28% (P < 0.05). CP treatment significantly increased urine volume and N -acetyl- , - d -glucosaminidase (NAG) activity, and significantly decreased osmolality and protein concentrations. OTC significantly mitigated all these effects. Sections from saline- and OTC-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This appeared to be lessened when CP was given simultaneously with OTC. The concentration of CP in the cortical tissues was not significantly altered by OTC treatment. The results suggested that OTC had ameliorated the histopathological and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, OTC may potentially be useful as a nephroprotective agent. [source]

    Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans

    FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2004
    M. Molimard
    Abstract Absorption, distribution, metabolism and excretion of desloratadine, fexofenadine, levocetirizine, and mizolastine in humans have been compared. The time required to reach peak plasma levels (tmax) is shortest for levocetirizine (0.9 h) and longest for desloratadine (,3 h). Steady-state plasma levels are attained after about 6 days for desloratadine, 3 days for fexofenadine, 2,3 days for mizolastine and by the second day for levocetirizine. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg) and mizolastine (1,1.2 L/kg), larger for fexofenadine (5.4,5.8 L/kg) and particularly large for desloratadine (, 49 l/kg). Fexofenadine and levocetirizine appear to be very poorly metabolized (, 5 and 14% of the total oral dose, respectively). Desloratadine and mizolastine are extensively metabolized. After administration of 14C-levocetirizine to healthy volunteers, 85 and 13% of the radioactivity are recovered in urine and faeces, respectively. In contrast, faeces are the preferential route of excretion for 14C-fexofenadine (80% vs. 11% of the radioactive dose in urine). The corresponding values are 41% (urine) and 47% (faeces) for 14C-desloratadine, 84,95% (faeces) and 8,15% (urine) for 14C-mizolastine. The absolute bioavailability is 50,65% for mizolastine; it is high for levocetirizine as the percentage of the drug eliminated unchanged in the 48 h urine is 77% of the oral dose; the estimation for fexofenadine is at least 33%; no estimation was found for desloratadine. Fexofenadine is a P-glycoprotein (P-gp) substrate and P-gp is certainly involved both in the poor brain penetration by the compound and, at least partially, in a number of observed drug interactions. An interaction of desloratadine with P-gp has been suggested in mice, whereas the information on mizolastine is very poor. The fact that levocetirizine is a substrate of P-gp, although weak in an in vitro model, could contribute to prevent drug penetration into the brain, whereas it is unlikely to be of any clinical relevance for P-gp-mediated drug interactions. [source]

    Plasma antioxidative activity during atorvastatin and fluvastatin therapy used in coronary heart disease primary prevention

    FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2004
    Jan Kowalski
    Abstract We estimated the effect of atorvastatin and fluvastatin on plasma antioxidative activity used in coronary heart disease (CHD) primary prevention. Anti-oxidative activity of blood plasma was determined by Bartosz et al. method [Curr. Top. Biophys. (1998)22:11,13], based on reduction of preformed cation radical of 2,2,azinobis(3-ethylbenzothiazoline-6-sulphonic acid) by blood plasma. The study comprised 35 patients with CHD risk who were randomly divided into two groups. The atorvastatin group comprised 17 patients who were administered the drug orally in a daily dose of 10 mg and the fluvastatin group consisted of 18 patients on an oral dose of 40 mg once daily. The control group comprised 12 healthy subjects with no drug administration. Blood samples were collected from cubital vein before and after 6-week therapy. Significantly (P < 0.05) increased , in comparison with the initial values , antioxidative activity of blood plasma was found in atorvastatin and fluvastatin groups after 6-week therapy. Moreover, the increase in antioxidative plasma activity in atorvastatin group was significantly higher in comparison with the fluvastatin group. The results of our study have demonstrated that atorvastatin and fluvastatin have an additional mechanism independent of the effect on cholesterol concentration. Thus, we presume that administration of these statins in CHD risk patients may have a beneficial effect. [source]

    Determination of enalapril and enalaprilat by enzyme linked immunosorbent assays: application to pharmacokinetic and pharmacodynamic analysis

    FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2002
    Khalid Matalka
    We have developed two enzyme linked immunosorbent assay (ELISA) methods for determining enalapril and enalaprilat in plasma. In this study, 48 healthy subjects received an oral dose of either 10 or 20 mg of enalapril and plasma concentrations of enalapril and enalaprilat were determined by their specific ELISA methods. These plasma concentrations and blood pressure measurements were applied to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of both enalapril and enalaprilat. The enalapril values for the area under the curve (AUC0,,) were 480 ± 216 and 832 ± 325 ngh/mL, maximum plasma concentrations (Cmax) were 310 ± 187 and 481 ± 185 ng/mL, and times required to reach the maximum concentration (tmax) were 1.13 ± 0.22 and 1.09 ± 0.33 h for 10 and 20 mg doses, respectively. The enalaprilat values for AUC0,, were 256 ± 122 and 383 ± 158 ngh/mL, Cmax values were 57 ± 29 and 72.9 ± 33.6 ng/mL and tmax values were 4.28 ± 1.45 and 4.05 ± 01.22 h for 10 and 20 mg doses, respectively. The Cmax values of enalapril were ,10 times higher than those in the literature, which were determined by angiotensin converting enzyme (ACE) inhibition assays following alkaline hydrolysis, but similar to those of enalaprilat. The PD profiles revealed a significant correlation between enalaprilat concentrations in plasma and the decrease in systolic and diastolic blood pressures (r=,0.95 with P < 0.001 and r=,0.95 with P < 0.001), respectively, following a single oral dose of enalapril. These ELISA methods have the advantage of being simple, accurate, sensitive, and do not depend on enalaprilat binding to ACE. Such methods can be used for analysis and kinetic testing of enalapril and enalaprilat in biological fluids. [source]

    Almotriptan Reduces the Incidence of Migraine-Associated Symptoms: A Pooled Analysis

    HEADACHE, Issue 2002
    Roger Cady MD
    Objectives.,Evaluate the reduction in migraine-associated symptoms after administration of a single oral dose of almotriptan. Methods.,This pooled analysis (N=1773) used data from three randomized, placebo-controlled, phase III trials (studies A, B, and C) to determine the incidence of migraine-associated symptoms (defined as nausea, vomiting, photophobia, and phonophobia) 2 hours after a single oral dose of study medication (almotriptan, sumatriptan, or placebo). Outcome data was extracted from studies A and B for placebo and the almotriptan 6.25-mg and 12.5-mg groups, and from study C for placebo, almotriptan 12.5-mg, and sumatriptan 100-mg groups. Results.,The incidence of nausea, photophobia, and phonophobia at 2 hours after dosing with study medication was significantly reduced (all P < .05) with almotriptan 6.25 mg or 12.5 mg compared with placebo. The percentage of patients with vomiting was lower with both doses of almotriptan in studies A and B compared with placebo, although differences were significant only for the 6.25-mg dose in study A (P < .001). For study C, the incidence of nausea, vomiting, photophobia, and phonophobia was similar for almotriptan and sumatriptan and lower than with placebo at 2 hours after dosing. Significant reductions (all P < .05) versus placebo were observed in the incidence of vomiting and phonophobia with almotriptan 12.5 mg, and photophobia and phonophobia with sumatriptan 100 mg. Conclusion.,Almotriptan provides relief from migraine-associated symptoms of nausea, vomiting, photophobia, and phonophobia, and thus represents an attractive treatment option for a wide spectrum of migraine symptomatology. [source]

    Almotriptan Increases Pain-Free Status in Patients With Acute Migraine Treated in Placebo-Controlled Clinical Trials

    HEADACHE, Issue 2002
    FRCP(C), Ninan T. Mathew MD
    Objectives.,Evaluate the efficacy of a single oral dose of almotriptan in achieving pain-free status during treatment of acute migraine attacks. Methods.,This pooled analysis (N=1321) used data from two randomized, placebo-controlled, phase III trials (studies A and B) to determine the proportion of patients with migraine achieving pain-free status 2 hours after a single oral dose of study medication (almotriptan or placebo). Pain was assessed using a 4-point integer scale (0=no headache, 3=severe headache), and recorded in a patient self-assessment booklet. Results.,The proportion of patients pain-free at 2 hours after study medication was significantly greater with almotriptan 6.25 mg (both studies P,.002) and almotriptan 12.5 mg (both studies P,.001) than with placebo. In study A, 11.6% of patients taking almotriptan 12.5 mg versus 2.5% of patients receiving placebo were pain-free at 1 hour (P=.016). At 1.5 hours, 26.8% of patients taking almotriptan 12.5 mg versus 8.8% receiving placebo (P=.001) were pain-free, and at 2 hours, 38.4% on almotriptan versus 11.3% on placebo were pain-free (P<.001). In study B, 23.8% of patients taking almotriptan 12.5 mg were free from pain at 1.5 hours versus 10.2% receiving placebo (P<.001). At 2 hours, 39.2% taking almotriptan 12.5 mg versus 15.3% receiving placebo were pain-free (P<.001). Increases in pain-free status with almotriptan generally occurred in a dose-dependent manner. Conclusion.,Compared with placebo, almotriptan 12.5 mg significantly increases the proportion of patients who are pain-free by as early as 1 hour, and consistently by 1.5 hours, after a single dose. [source]

    Augmentation of atypical antipsychotics with valproic acid.

    HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 8 2009
    An open-label study for most difficult patients with schizophrenia
    Abstract Objective Most difficult inpatients with schizophrenia are in serious needs but obviously underrepresented in clinical trials. Methods Very challenging patients received open-label treatment with atypical antipsychotics concurrently augmented with valproic acid. The primary outcome was the newly developed Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz). Patients improving more than 20 points were classified as responders. Results Mean age and illness duration of 28 participants (22male) were 42 y.o. and 20 years, respectively. They had spent a half of their life admitted after the onset. The average Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) were very severe at 79 and 6.1, respectively, with the baseline Global Assessment of Functioning (GAF) of as low as 21. As a result of augmentation, there were nine responders, 12 partial responders, and seven non-responders including only two patients who got worse. The main antipsychotics were mostly either risperidone or olanzapine. Mean maximum oral dose and blood level of valproic acid were 1907,mg and 91.7,µg/ml, respectively. Overall significant improvements whilst to an inadequate degree were noted in clinical parameters. Valproate augmentation was generally well tolerated but serious adverse effects included thrombocytopenia, anaemia and sedation/falls. Conclusions While these preliminary results need to be tested against tenacious monotherapy or polypharmacy involving clozapine, augmenting atypical antipsychotics with valproic acid can be useful for very severe schizophrenia. Copyright © 2009 John Wiley & Sons, Ltd. [source]

    A novel model of sensitization and oral tolerance to peanut protein

    IMMUNOLOGY, Issue 3 2004
    Jessica Strid
    Summary The prevalence of food allergic diseases is rising and poses an increasing clinical problem. Peanut allergy affects around 1% of the population and is a common food allergy associated with severe clinical manifestations. The exact route of primary sensitization is unknown although the gastrointestinal immune system is likely to play an important role. Exposure of the gastrointestinal tract to soluble antigens normally leads to a state of antigen-specific systemic hyporesponsiveness (oral tolerance). A deviation from this process is thought to be responsible for food-allergic diseases. In this study, we have developed a murine model to investigate immunoregulatory processes after ingestion of peanut protein and compared this to a model of oral tolerance to chicken egg ovalbumin (OVA). We demonstrate that oral tolerance induction is highly dose dependent and differs for the allergenic proteins peanut and OVA. Tolerance to peanut requires a significantly higher oral dose than tolerance to OVA. Low doses of peanut are more likely to induce oral sensitization and increased production of interleukin-4 and specific immunoglobulin E upon challenge. When tolerance is induced both T helper 1 and 2 responses are suppressed. These results show that oral tolerance to peanut can be induced experimentally but that peanut proteins have a potent sensitizing effect. This model can now be used to define regulatory mechanisms following oral exposure to allergenic proteins on local, mucosal and systemic immunity and to investigate the immunomodulating effects of non-oral routes of allergen exposure on the development of allergic sensitization to peanut and other food allergens. [source]

    Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice

    INFLAMMATORY BOWEL DISEASES, Issue 11 2008
    Hitoshi Ichikawa MD
    Abstract Background: Tetomilast (OPC-6535) was originally developed as a compound inhibiting superoxide production in neutrophils. Although its mechanism of action is not completely understood, phosphodiesterase type 4 inhibitory function has been postulated. The therapeutic effect of PDE4 inhibitors has been reported for chronic inflammatory disorders such as chronic obstructive pulmonary diseases. In this study we aimed to examine whether tetomilast could be a novel drug for inflammatory bowel diseases by further clarifying its antiinflammatory effects. Methods: Cytokines from human peripheral blood mononuclear cells were measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Beads Array. The transcripts were quantified by reverse-transcriptase polymerase chain reaction (RT-PCR). Phosphorylation of transcription factors was examined by phosflow. To examine its in vivo effect, a once-daily oral dose of tetomilast was tested in murine IL-10,/, chronic colitis. Results: Tetomilast suppressed TNF-, and IL-12 but not IL-10 production from lipopolysaccharide (LPS)-stimulated human monocytes. It suppressed TNF-,, IFN-,, and IL-10 from CD4 lymphocytes. Tetomilast suppressed cytokine production at the transcriptional level but did not alter phosphorylation of p65, ERK, p38, and STAT3. HT-89, a protein kinase A inhibitor, did not abolish the effect of tetomilast, suggesting that it was independent from the classical cAMP/PKA pathway. IL-10 was not essential to the inhibitory effect of tetomilast on TNF-, and IL-12. Tetomilast ameliorated IL-10,/, chronic colitis with reduced clinical symptoms, serum amyloid A, and histological scores with decreased TNF-, mRNA expression. Conclusions: Tetomilast exerts its antiinflammatory effects on human monocytes and CD4 cells. Combined with in vivo data these findings support the feasibility of tetomilast as a novel drug for inflammatory bowel diseases. (Inflamm Bowel Dis 2008) [source]

    Pharmacokinetics of mesalazine pellets in children with inflammatory bowel disease

    INFLAMMATORY BOWEL DISEASES, Issue 5 2004
    Heleen Wiersma MD
    Abstract Mesalazine is a first-line drug in pediatric inflammatory bowel disease (IBD), and is customarily used to induce and maintain remission in mild to moderate disease. In children, pharmacokinetic data are scarce, and dosage recommendations are largely extrapolated from studies in adults. Aim of the study was to obtain the pharmacokinetic profile of a new mesalazine pellet formulation in children with ulcerative colitis and Crohn's colitis. A single oral dose of 20 mg/kg mesalazine was administered to 13 patients (age 6,16 years). Serial blood and urine sampling for determination of mesalazine and acetylmesalazine was performed before and during 24 hours following ingestion. Maximum plasma concentration of mesalazine (Cmax) was 1332 ng/mL (geometric mean, geometric coefficient of variation [CV]: 0.57), obtained 3.7 hours (tmax; CV: 0.31) after drug administration. Systemic exposure as determined by area under the plasma concentration-time curve (AUC0,, ) was 8712 ng/ml*h (CV: 0.44). Terminal half-life of elimination of mesalazine was 3.5 hours (t1/2; CV: 1.43). This study presents extensive pharmacokinetic data on mesalazine in children with mild-moderately active ulcerative colitis and Crohn's colitis. In comparison with previous experience in adults, pharmacokinetics of mesalazine administered as pellets appear to be similar in both populations. [source]

    Two-Year Results of Once-Weekly Administration of Alendronate 70 mg for the Treatment of Postmenopausal Osteoporosis

    JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2002
    R Rizzoli
    Abstract The aim of this study was to provide confirmation that once-weekly dosing with 70 mg of alendronate (seven times the daily oral dose) and twice-weekly dosing with 35 mg is equivalent to the 10-mg once-daily regimen and to gain more extensive safety experience with this new dosing regimen. Twelve hundred fifty-eight postmenopausal women (aged 42,95 years) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak young adult mean or prior vertebral or hip fracture) were assigned to receive oral once-weekly alendronate, 70 mg (n = 519); twice-weekly alendronate, 35 mg (n = 369); or daily alendronate 10 mg (n = 370) for a total of 2 years of double-blind experience. Mean BMD increases from baseline (95% CI) at 24 months in the once-weekly, twice-weekly, and daily treatment groups, respectively, were 6.8% (6.4, 7.3), 7.0% (6.6, 7.5), and 7.4% (6.9, 7.8) at the lumbar spine and 4.1% (3.8, 4.5), 4.3% (3.9, 4.7), and 4.3% (3.9, 4.7) at the total hip. These increases in BMD as well as the BMD increases at the femoral neck, trochanter, and total body and the reductions of biochemical markers of bone resorption (urinary cross-linked N-telopeptides of type I collagen [NTx]) and bone formation (serum bone-specific alkaline phosphatase [BSAP]) were similar for the three dosing regimens. All treatment regimens were well tolerated with a similar incidence of upper gastrointestinal (GI) adverse experiences. The incidence rates of clinical fractures, captured as adverse experiences, were similar among the groups. The 2-year results confirm the conclusion reached after 1 year that once-weekly alendronate is therapeutically equivalent to daily dosing, providing patients with a more convenient dosing option that may potentially enhance adherence to therapy. [source]

    Ibandronate: A Comparison of Oral Daily Dosing Versus Intermittent Dosing in Postmenopausal Osteoporosis

    JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2001
    B. J. Riis
    Abstract The objective of this study was to compare efficacy and safety of continuous versus intermittent oral dosing of ibandronate. Two hundred forty women aged 55,75 years with postmenopausal osteoporosis were randomized to active treatment or placebo. Similar total doses of ibandronate were provided by treatment regimens with either continuous 2.5 mg of ibandronate daily (n = 81) or intermittent 20 mg of ibandronate every other day for the first 24 days, followed by 9 weeks without active drug (n = 78). The placebo group (total, n = 81) was crossed over after 12 months to receive either continuous (n = 37) or intermittent ibandronate (n = 35). By 24 months, bone mineral density (BMD) had increased significantly relative to baseline in both active treatment groups. The continuous and intermittent groups showed statistically equivalent increases in lumbar spine BMD of +5.64% (±0.53) and +5.54% (±0.53) and in total hip of +3.35% (±0.40) and +3.41% (±0.40), respectively (per protocol population). Biochemical markers of bone turnover decreased significantly in both treatment groups. The level of marker suppression was similar, although the intermittent group displayed, as expected, more fluctuation over the treatment period. The frequency of adverse events was similar in the treatment groups. In conclusion, the intermittent and continuous regimens showed equivalent changes in BMD and bone turnover. These results confirm previous preclinical findings indicating that the efficacy of ibandronate depends on the total oral dose given rather than on the dosing schedule. This supports development of new flexible dosing regimens targeted to minimize the frequency of dosing, which are expected to improve convenience and lead to enhanced long-term patient compliance. [source]

    Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel

    JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2008
    A.-M. Yousef PhD
    Summary Background and objectives:, Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter-individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel. Methods:, Seventy-six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non-compartmental analysis was used to determine peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), elimination half-life (t1/2e), and area under the curve (AUC0,,). Results:, One-third of volunteers were smokers (n = 27) and one-half had abnormal body weight (n = 39). Smokers had lower AUC0,, (smokers: 6·24 ± 2·32 ,g/h/mL vs. non-smokers: 8·93 ± 3·80 ,g/h/mL, P < 0·001) and shorter half-life (smokers: 5·46 ± 2·99 vs. non-smokers: 8·43 ± 4·26, P = 0·001). Smoking behaviour had no influence on Cmax (P = 0·3) and Tmax (P = 0·7). There was no statistically significant difference in Cmax, AUC0,,, Tmax and t1/2e between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean ± SE; 26·93 ± 0·16 vs. 23·11 ± 0·27). In general, the pharmacokinetic parameters were characterized by considerable inter-individual differences (Cmax = 3·09 ± 0·99 ,g/mL, CV = 32%), (Tmax =0·76 ± 0·24 h, CV = 31·6%), (AUC0,, = 7·98 ± 3·58 ,g/h/mL, CV = 44·8%), and (t1/2e = 7·38 ± 4·10 h, CV = 55·6%). Conclusion:, Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking-cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed. [source]

    Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers

    JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2005
    W. Ridtitid MD FCFPT
    Summary Background:, Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine. Objective:, To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers. Methods:, In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection. Results:, Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC0,t, t1/2, and Cmax when compared with mefloquine alone by 79% (P < 0·001), 39% (P < 0·05) and 64% (P < 0·001) respectively. The AUC0,t,, and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0·05) and 31% (P < 0·05), respectively when compared with mefloquine alone. Conclusions:, Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drug,drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy. [source]

    Paeoniae Radix, a traditional Chinese medicine, and CYP2C9 activity

    JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2002
    Han-Jing Xie
    Paeoniae Radix (PR) is a commonly used traditional Chinese medicine. A slight effect of PR on the pharmacokinetics of phenytoin that is mainly metabolised by CYP2C9 has been reported. The aim of this pilot study was to clarify if PR has an effect on losartan oxidation used as a measure of CYP2C9 activity. Three healthy volunteers received a single oral dose of losartan before and after PR treatment. Losartan and E-3174, an active metabolite of losartan, were analysed in 8 hour urine. PR did not seem to have an effect on CYP2C9 activity when the losartan/E-3174 ratios were compared before and after PR treatment (P = 0·56) although a larger study would need to be undertaken to confirm this finding. [source]

    Validation of an LC,MS Method for the Detection and Quantification of BZP and TFMPP and their Hydroxylated Metabolites in Human Plasma and its Application to the Pharmacokinetic Study of TFMPP in Humans,

    JOURNAL OF FORENSIC SCIENCES, Issue 5 2010
    Ushtana Antia M.Sc.
    Abstract:, An LC,MS method was developed for benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP), constituents of "party pills" or "legal herbal highs," and their metabolites in human blood plasma. Compounds were resolved using a mixture of ammonium formate (pH 4.5, 0.01 M) and acetonitrile (flow rate of 1.0 mL/min) with a C18 column. Calibration curves were linear from 1 to 50 ng/mL (R2 > 0.99); the lower limit of quantification (LLOQ) was 5 ng/mL; the accuracy was >90%; the intra- and interday relative standard deviations (R.S.D) were <5% and <10%, respectively. Human plasma concentrations of TFMPP were measured in blood samples taken from healthy adults (n = 6) over 24 h following a 60-mg oral dose of TFMPP: these peaked at 24.10 ng/mL (±1.8 ng/mL) (Cmax) after 90 min (Tmax). Plasma concentrations of 1-(3-trifluoromethyl-4-hydroxyphenyl) piperazine peaked at 20.2 ng/mL (±4.6 ng/mL) after 90 min. TFMPP had two disposition phases (t½ = 2.04 h (±0.19 h) and 5.95 h (±1.63 h). Apparent clearance (Cl/F) was 384 L/h (±45 L/h). [source]

    Trial of fenobam, an mGluR5 antagonist, in adults with Fragile X Syndrome

    JOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008
    R. Hagerman
    Background: Recent advances in the study of the Fragile X knockout mouse model have demonstrated enhanced activity of the metabolic glutamate receptor 5 (mGluR5) pathway. The use of mGluR5 antagonists has rescued behavioural, cognitive and dendritic structural abnormalities in the knockout mouse. An initial phase II trial in adults with FXS was approved by the FDA. Method: We have completed this initial trial of fenobam (50 mg to 150 mg/dose) in twelve adults with FXS (mean age 23.9 (SD 5.4; range 18.7,30.7 years) seen either at UC Davis MIND Institute or at RUSH, University in Chicago, to assess safety, side-effects, and metabolism after a single dose. Results: Outcome measures included prepulse inhibition (PPI) and a continuous performance task (CPT). All patients tolerated this single dose without significant side-effects. The metabolism of fenobam in patients with FXS is similar to controls and peaks at approximately 180 minutes after oral dose. Fifty percent of the patients had a 20% or more improvement in PPI that is significantly different from test-retest changes in PPI previously reported in individuals with FXS (p = 0.03). This effect was more pronounced in males. The majority of patients scored at ceiling on the CPT so it was not a helpful measure to assess medication benefits. Conclusion: This work documents the safety and aspects of the metabolism of fenobam in patients with FXS and will facilitate further expansion of fenobam trials in patients with FXS. Although fenobam is a targeted treatment for FXS, subgroups of autism may also benefit from fenobam treatment. [source]

    Normalization of serum calcium by cinacalcet in a patient with hypercalcaemia due to a de novo inactivating mutation of the calcium-sensing receptor

    JOURNAL OF INTERNAL MEDICINE, Issue 2 2006
    H. J. L. M. TIMMERS
    Abstract. Familial benign hypocalciuric hypercalcaemia (FHH) results from a heterozygous inactivating mutation of the calcium-sensing receptor (CaR) and is characterized by hypercalcaemia, hypocalciuria and inappropriately normal plasma levels of parathyroid hormone. In a minority of patients, a loss of function mutation of the CaR results in severe hypercalcaemia associated with complications for which no effective surgical or medical treatment is available. We investigated the effects of the calcimimetic agent cinacalcet, an allosteric modulator of the CaR, in a 26-year-old man presenting with hypercalcaemia due to a de novo inactivating mutation of the CaR. Complicating features were recurrent psychosis and progressive severe osteoporosis. A single dose of either 30 or 60 mg of cinacalcet resulted in a 63,88% decline in plasma parathyroid hormone levels within 2 h of administration of the agent, reverting to baseline levels after 12 h. Normalization of serum calcium was more gradual but sustained for up to 12 months of treatment with a maintenance twice-daily oral dose of 60 + 30 mg cinacalcet. In addition to its beneficial effects in primary and secondary hyperparathyroidism, cinacalcet may open new therapeutic avenues in the management of a subset of patients with severe hypercalcaemia due to inactivating mutations of the CaR. [source]

    Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: Clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging

    JOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 1 2004
    Martin Rausch PhD
    Abstract Purpose To examine the efficacy of FTY720 as a new agent to reduce inflammatory activity in an animal model of multiple sclerosis (MS) by in vivo macrophage tracking. Material and Methods FTY720 was used for treatment of rats in a model of chronic relapsing experimental autoimmune encephalomyelitis (EAE) at an oral dose of 0.3 mg/kg/day. Magnetic resonance imaging (MRI) based on in vivo tracking of macrophages labeled with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, immunohistological staining (IHC), and neurological readouts was used to study the burden of disease in treated and untreated animals. Results While untreated animals showed severe paralysis of the hind paws, intense accumulation of macrophages in brain tissue, and areas of blood-brain barrier (BBB) disruption, FTY720-treated animals displayed no signs of inflammatory activity or neurological impairment. These observations were made for both acute phase and first relapse. Conclusion Tracking of macrophages by MRI provides direct evidence of the immunomodulatory efficacy of FTY720 in the EAE model and correlates well with neurological symptoms and histology. J. Magn. Reson. Imaging 2004;20:16,24. © 2004 Wiley-Liss, Inc. [source]