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Days Treatment (day + treatment)
Selected AbstractsTHIS ARTICLE HAS BEEN RETRACTED STEALTH matters: a novel paradigm of durable primate allograft toleranceIMMUNOLOGICAL REVIEWS, Issue 1 2001J. M. Thomas Summary: We review a novel strategy for tolerance induction developed in rhesus macaques and termed STEALTH. We summarize the evolution of the STEALTH model, the results of successful trials in inducing long-term, stable transplant tolerance in rhesus kidney and diabetic islet recipients and discuss information related to the mechanism by which durable tolerance is induced. STEALTH tolerance is induced by a 3-day treatment course of CD3, immunotoxin (IT) combined with a 14-day treatment with deoxyspergualin (DSG). IT causes profound depletion of sessile lymph node T cells as well as the more accessible circulating T cells. DSG, an inhibitor of HSC 70-mediated NF-,B nuclear translocation, arrests maturation of myeloid dendritic cells, blocks production of proinflammatory cytokines induced by IT administration, and promotes systemic production of Th2 type cytokines that persist indefinitely. Such Th2 cytokine deviation has not been reported in NHP transplant recipients. These studies provide proof of principle in a preclinical model that prevention of both acute and chronic allograft rejection, for at least 2.2,4.9 years of follow-up, can be achieved in NHP in the absence of chronic immunosuppressive drugs or other interventions. This strategy for inducing NHP tolerance is discussed in relation to current tolerance paradigms. [source] A case of mucosal leishmaniasis: beneficial usage of polymerase chain reaction for diagnosisINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 12 2001Hironori Onuma MD A 36-year-old woman, who had emigrated from Japan to Paraguay as a 4-year-old child before returning to Japan in 1991, visited our clinic on November 10, 1997. She had suffered from a persistent ulcer on her forearm as a 6-year-old child and received intravenous injections for a few months, although she did not remember the details of therapy. Since May 1997, she had been aware of redness and swelling on her nose and had been treated with topical corticosteroid, but no improvement had been noted. Physical examination revealed erythematous plaque with crust from the left internal naris to nasolabial region (Fig. 1a). The atrophic plaque that had resulted from prolonged ulceration was found on the right forearm (Fig. 1b). In a biopsy specimen from the erythematous plaque on the nasolabial region, mononuclear dermal infiltrate, consisting of lymphocytes and histiocytes, was seen (Fig. 2a). The histiocytes were filled with Leishman-Donovan (L-D) bodies on a Giemsa staining sample (Fig. 2b). Fiberscopic examination revealed white plaque in the pharynx. The biopsy from the affected mucosa showed the same histopathological finding as with the skin. Figure 1. (a) Erythematous plaque with crust from the left internal naris to nasolabial region. (b) Atrophic plaque on the right forearm Figure 2. (a) In the biopsy specimen from the erythematous plaque on the nasolabial region, a mononuclear dermal infiltrate consisting of lymphocytes and histiocytes was seen. (Hematoxylin-Eosin stain, × 100) (b) The histiocytes were filled with Leishman-Donovan bodies. (Giemsa staining, × 400) Total DNA was purified from the skin biopsy specimen for polymerase chain reaction (PCR) analysis using a specific primer for L (V) braziliensis.1,2 A 70-bp product was amplified (Fig. 3a); furthermore, the specificity of the PCR product was confirmed by Southern hybridization with the probe for L (V) braziliensis (Fig. 3b) and DNA sequence analysis (data not shown). From December 2, 1997, the patient received 20 mg/kg/day sodium stibogluconate (PentostamTM) intravenously for 20 days. After 5 days of treatment, the redness and swelling of the skin lesion was improved, and faint erythema remained at the end of 20 days' treatment. After a 2-week interval, since the erythema remained, another 20-day treatment was performed. All of the skin lesion became scar tissue and L-D bodies could not be found in a skin biopsy specimen. However, L-D bodies were still found in a biopsy from the pharyngeal mucosa that had a normal appearance. Though another additional treatment was planned, the patient refused it. Figure 3. (a) The results of PCR. 70-bps bands appear in lanes 2 and 6. Lane 1, a size marker (pUC19/HapII); lane 2, DNA extracted from the formalin-fixed patient's sample; lane 3, DNA extracted from a formalin-fixed control sample; lane 4, DNA (,); lane 5, DNA extracted from L (V) tropica; lane 6, DNA extracted from L (V) braziliensis. (b) Results of Southern blotting using the PCR products. The PCR products were transferred from agarose gel as shown in Fig. 3 (a). Specific probes were hybridized with 70-bps bands on lanes 2 and 6 [source] Effects of a Brazilian herbal compound as a cosmetic eyecare for periorbital hyperchromia ("dark circles")JOURNAL OF COSMETIC DERMATOLOGY, Issue 2 2009Samara Eberlin PhD Summary Background, Evidence suggests that periorbital hyperchromia (dark circles) occurs mainly as a consequence of postinflammatory hemodynamic congestion producing a typical bruising aspect on the lower eyelids. Aims, To evaluate the clinical effects of Pfaffia paniculata/Ptychopetalum olacoides B./Lilium candidum L.-associated compound (PPLAC) on periorbital hyperchromia and to study in vitro its underlying anti-inflammatory and antioxidant mechanisms. Methods, Twenty-one volunteers presenting with periorbital hyperchromia received a serum sample containing 5.0% PPLAC, which was applied topically in the periorbital area twice a day for 28 days. Skin color was measured using variations in the individual typological angle (,ITA0) and skin luminance (,L*) calculated in the area around the eyes and in the adjacent area. Colorimetric readings were taken at the onset and end of the 28-day treatment. Volunteers were also asked to fill out a questionnaire concerning the improvement in "dark circles." The anti-inflammatory and antioxidant effects of PPLAC were measured by quantification of prostaglandin E2, leukotriene B4, histamine, and superoxide dismutase levels using an in vitro model of human skin culture. Results, Topical application of PPLAC led to a significant improvement in skin luminance and tone in the periorbital area, which was demonstrated by increased values of ITA0 and L* in about 90% of volunteers. In addition, subjects reported reduced intensity and improved appearance of "dark circles." A dose-dependent decreased production of inflammatory mediators, concomitant to increased antioxidant enzyme levels, was observed in our in vitro studies, under basal and lipopolysaccharide-stimulated conditions. Conclusions, Although the precise mechanisms related to PPLAC remain to be clarified, our results indicate that the reduction in the inflammatory process as well as the antioxidant protection against deleterious elements may be considered as an integral approach to preserve the integrity of vascular endothelium, preventing the hemodynamic congestion that culminates in the formation of "dark circles" around the eyes. [source] Editorial: Does multi-family day treatment hit the spot that other treatments cannot reach?JOURNAL OF FAMILY THERAPY, Issue 2 2005Ulrike Schmidt No abstract is available for this article. [source] Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l -DOPA-induced dyskinesiaJOURNAL OF NEUROCHEMISTRY, Issue 6 2003M. Lundblad Abstract We have examined the ability of KW-6002, an adenosine A2a antagonist, to modulate the dyskinetic effects of l -DOPA in 6-hydroxydopamine-lesioned rats. In animals rendered dyskinetic by a previous course of l -DOPA treatment, KW-6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with l -DOPA. A second experiment was undertaken in order to study the effects of KW-6002 in l -DOPA-naive rats. Thirty-five animals were allotted to four groups to receive a 21-day treatment with: (i) KW-6002 (10 mg/kg/day); (ii) l -DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus l -DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only produced a significant relief of motor disability in the rotarod test in the absence of any abnormal involuntary movements. Combined treatment with l -DOPA and KW-6002 improved rotarod performance to a significantly higher degree than did each of the two drugs alone. However, this combined treatment induced dyskinesia to about the same degree as did l -DOPA alone. In situ hybridization histochemistry showed that KW-6002 treatment alone caused an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and l -DOPA nor l -DOPA alone significantly altered the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with l -DOPA, KW-6002 did not have any modulatory effect on prodynorphin mRNA expression or FosB/,FosB-like immunoreactivity in the dopamine-denervated striatum. These results show that monotreatment with an adenosine A2a receptor antagonist can relieve motor disability without inducing behavioural and cellular signs of dyskinesia in rats with 6-hydroxydopamine lesions. Cotreatment with KW-6002 and l -DOPA potentiates the therapeutic effect but not the dyskinesiogenic potential of the latter drug. [source] Treatment of perennial allergic rhinitis with lactic acid bacteriaPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 2 2004Ming Fuu Wang Probiotics are perceived to exert beneficial effects in the prevention and treatment of allergic diseases via modifying the gut ecosystem. The aim of this study was to assess whether ingestion of fermented milk containing Lactobacillus paracasei-33 (LP-33), a strain newly isolated from the human intestinal tract, can improve the quality of life of patients with perennial allergic rhinitis. In a randomized, double-blind, placebo-controlled trial, we gave patients fermented milk with (n = 60) or without (n = 20) the addition of LP-33 (2 × 109 colony-forming units per bottle) for 30 days. A modified questionnaire concerning pediatric rhinoconjunctivitis quality of life was administered to all subjects or their parents at each clinical visit. Scores for the overall quality of life significantly decreased in the LP-33 group as compared with the placebo group, in both frequency (,16.02 ± 2.14 vs. ,7.27 ± 3.55, respectively; p = 0.037) and level of bother (,16.35 ± 2.33 vs. ,6.20 ± 3.13, respectively; p = 0.022) after the 30-day treatment. Subjects reported no severe adverse effects such as fever, abdominal pain, or diarrhea. The results suggest that ingestion of LP-33-fortified fermented milk for 30 days can effectively and safely improve the quality of life of patients with allergic rhinitis, and may serve as an alternative treatment for allergic rhinitis. [source] Panax notoginseng (Burk.) effects on fibrinogen and lipid plasma level in rats fed on a high-fat dietPHYTOTHERAPY RESEARCH, Issue 2 2003A. F. G. Cicero Abstract Several studies have shown that notoginsenoides improve diastolic function in hypertensive subjects, induce the fibrinolytic system in in vitro models and act as antiproliferative agents on vessel leiomyocytes. Our aim was to evaluate their effect on fibrinogen and lipid plasma levels compared with a well-known HMGCoA reductase inhibitor. Seventy Wistar male adult rats on a fat-enriched diet were treated orally with P. notoginseng pulverized root (43,mg/kg/day or 86,mg/kg/day; 20 animals per group), fluvastatin (3,mg/kg/day; 20 animals) or physiological saline (5,mL/kg/day; 10 animals). The ten rats on a normocaloric diet were also treated with 5,mL/kg/day of physiological saline. After a 28-day treatment, the rats were killed and their blood analysed with standard procedures. Treatment with 43,mg/kg/day of P. notoginseng or 3,mg/kg/day of fluvastatin showed similar activity in decreasing total cholesterol (,23.70%, ,19.29%, respectively) and triglycerides (,21.59%, ,18.55%). The most evident effect of P. notoginseng was the reduction of fibrinogenaemia in treated rats compared with the control values (,38.10%; p,<,0.001), no dose-relationship being shown in this effect. Moreover, no significant variation in HDL cholesterol and glucose levels was observed nor did relevant behavioural changes occur in association with the root intake. Besides a moderate, non dose-related decrease in the plasma lipid levels, P. notoginseng appeared to induce a significant reduction in the rat fibrinogenaemia. Copyright © 2003 John Wiley & Sons, Ltd. [source] Phase 1 trial of temozolomide plus irinotecan plus O6 -benzylguanine in adults with recurrent malignant gliomaCANCER, Issue 13 2009Jennifer A. Quinn MD Abstract BACKGROUND: The current study was a phase 1 clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG). The trial was designed to determine the maximum tolerated dose (MTD) and toxicity of irinotecan (CPT-11) when administered with temozolomide (TMZ) and O6 -benzylguanine (O6 -BG). METHODS: All 3 drugs, CPT-11, TMZ, and O6 -BG, were administered on Day 1 of a 21-day treatment. First, patients were treated with a 1-hour bolus infusion of O6 -BG at a dose of 120 mg/m2 followed immediately by a 48-hour continuous infusion of O6 -BG at a dose of 30 mg/m2/d. Second, within 60 minutes of the end of the 1-hour bolus infusion of O6 -BG, TMZ was administered orally at a dose of 355 mg/m2. Third, 1 hour after administration of TMZ, CPT-11 was infused over 90 minutes. Patients were accrued to 1 of 2 strata based on CYP3A1- and CYP3A4-inducing antiepileptic drug (EIAED) use; dose escalation was conducted independently within these strata. RESULTS: Fifty-five patients were enrolled. In both strata, the dose-limiting toxicities were hematologic and included grade 4 neutropenia, febrile neutropenia, leukopenia, and/or thrombocytopenia. For Stratum 1 (EIAEDs), when TMZ was administered at a dose of 355 mg/m2, the MTD of CPT-11 was determined to be 120 mg/m2. In contrast, for Stratum 2 (no EIAEDs), when TMZ was administered at a dose of 200 mg/m2, the MTD of CPT-11 was determined to be 80 mg/m2. CONCLUSIONS: The authors believe that the results of the current study provide the foundation for a phase 2 trial of O6 -BG in combination with CPT-11 and TMZ in patients with MG. Cancer 2009. © 2009 American Cancer Society. [source] Comparison of the efficacy and safety of miconazole 50-mg mucoadhesive buccal tablets with miconazole 500-mg gel in the treatment of oropharyngeal candidiasis,CANCER, Issue 1 2008A prospective, comparative, multicenter, neck cancer, phase III trial in patients treated with radiotherapy for head, randomized, single-blind Abstract BACKGROUND. Topical antifungal treatments are recommended but rarely used as first-line therapy for oropharyngeal candidiasis (OPC) in patients with cancer. Miconazole Lauriad 50-mg mucoadhesive buccal tablet (MBT) Loramyc reportedly delivered rapid and prolonged, effective concentrations of miconazole in the mouth. The objective of the current study was to compare MBT with miconazole 500-mg oral gel (MOG) in patients with head and neck cancer. METHODS. Two hundred eighty-two patients with head and neck cancer received a 14-day treatment of either single-dose MBT or MOG administered in 4 divided doses. The primary endpoint was clinical success at Day 14, and secondary endpoints included clinical success at Day 7, clinical cure, improvement in clinical symptoms, mycologic cure, recurrence rate, and safety. RESULTS. The success rate was statistically not inferior (P < .0001) in the MBT population to the rate observed in the MOG group (56% vs 49%, respectively; P < .0001). After adjustment for the extent of lesions and salivary secretions, a trend toward superiority was observed in favor of MBT (P = .13), particularly among patients with multiple lesions (P = .013). Results for secondary endpoints were comparable to those observed for the primary endpoint. Compliance with MBT was excellent, and >80% of patients completed treatment. Both treatments were safe. CONCLUSIONS. The success rate of MBT Loramyc was significantly not inferior to that of MOG in the treatment of cancer patients with OPC; and, after adjusting for prognostic variables, it was more effective than MOG. MBT was well tolerated and, thus, may be recommended as first-line treatment in cancer patients who have OPC as an alternative to systemic antifungal agents. Cancer 2008. © 2007 American Cancer Society. [source] An Overview of SR121463, a Selective Non-Peptide Vasopressin V2 Receptor AntagonistCARDIOVASCULAR THERAPEUTICS, Issue 3 2001C. Serradeil-Le Gal ABSTRACT SR121463 is a selective, orally active, non-peptide antagonist of vasopressin (AVP) V2 receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free-water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V2 receptors and exhibits a remarkably selective V2 receptor profile. SR121463 and [3H]SR121463 are used, therefore, as selective probes for characterization and labeling of V2 receptors. In various functional studies in vitro, SR121463 behaves as a potent antagonist. It inhibits AVP-stimulated human renal adenylyl cyclase and dDAVP (1-desamino, 8-D arginine-vasopressin)-induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V2 receptor mutant. In vitro, SR1 21463 rescued misfolded V2 AVP receptor mutants by increasing cell surface expression and restoring V2 function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose-dependent aquaresis with no major changes in urinary Na+ and K+ excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10-day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V2 (or V2 -like) receptors involved in vascular relaxation or clotting factor release in vitro and in vivo. In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V2 receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V2 receptors. Pure V2 receptor antagonists are likely to be therapeutically useful in several water-retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V2 receptors (e.g., glaucoma). [source] Emotional processing in children with conduct problems and callous/unemotional traitsCHILD: CARE, HEALTH AND DEVELOPMENT, Issue 2 2008M. Woodworth Abstract Background A considerable body of evidence now suggests that conduct problem (CP) children with callous/unemotional (CU) traits differ in many ways from CP children without these characteristics. Previous research has suggested that there are important differences for youth with CP and CU characteristics in their ability to process emotional information. The current study investigated the ability of children with disruptive behaviour disorders to label emotional faces and stories. Methods Participants (aged 7,12) were involved in a summer day treatment and research programme for children with disruptive behaviour problems. Two tasks were administered that were designed to measure participant's ability to recognize and label facial expressions of emotion, as well as their ability to label emotions in hypothetical situations. Results Results indicated that children with higher levels of CU traits, regardless of whether they had elevated CP scores, were less accurate in identifying sad facial expressions. Interestingly, children with higher CU scores were more accurate in labelling fear than were children with lower CU scores, while children with high CP but low CU traits were less accurate than other children in interpreting fearful facial emotions. Further, children's recognition of various emotional vignettes was not associated with CP, CU traits or their interaction. Conclusions The current study demonstrated that it was the combination of CP and a high number of CU traits that differentiated emotional attributions. Consistent with previous research, youth with CU traits had more difficulty in identifying sad facial expressions. However, contrasting with some previous studies, higher CU traits were associated with more accurate perceptions of fearful expressions. It is possible that there is something specific to fear recognition for individuals with more psychopathic, CU traits that actually make them more successful for observing or recognizing fearful expressions. Additional research is needed to clarify both the recognition and processing of fear expression in CP children with and without CU. [source] Effects of the timing of initial feeding on growth and survival of spotted mandarin fish Siniperca scherzeri larvaeJOURNAL OF FISH BIOLOGY, Issue 6 2009L. Zhang The effects of delayed first feeding on growth and survival of spotted mandarin fish Siniperca scherzeri larvae were examined under controlled conditions. Morphometric characters [yolk-sac volume, oil globule volume, head depth (HD), body depth (BD), eye diameter (ED), musculature height (MH), mouth diameter (MD) and total length (LT)], body mass (M), specific growth rate (SGR) and survival were evaluated under different first-feeding time (2, 3, 4 and 5 days after hatching). Larvae began to feed exogenously at 2 days after hatching (DAH) and the point of no return (PNR) occurred between 5 and 6 DAH at 23° C, range ±1·0° C. The yolk volume of larvae first-fed at 2 days had a significant difference compared with that of larvae first-fed at 3, 4 and 5 days on 3 and 4 DAH. The larvae first-fed at 2 days achieved comparatively better growth performance than that of 3, 4 and 5 days. On 5 DAH, all morphometric characters had significant differences between 2 and 5 days and 2 and 4 days initial feeding, respectively. Total mortality was recorded on 9 DAH for the larvae first-fed at 5 days. On 12 DAH, significant differences were observed between 2 and 4 days and 3 and 4 days initial feeding for all morphometric characters. From 16 DAH to the end of experiment, all growth variables of the larvae first-fed at 2 days were significantly higher than those in other treatments. The SGR (2,9 DAH) first-fed at 2 and 3 days were significantly higher than 4 and 5 day treatments, and the SGR (9,16 DAH) first-fed at 2 days was significantly higher than 3 and 4 day treatments. There was no significant difference, however, of SGR (16,28 DAH) among treatments. Survival rate was significantly higher at 2 days initial feeding (27·42%) when compared with 3 (15·96%) and 4 days (7·92%) initial feeding at the end of experiment. The present study suggests that the first feeding of S. scherzeri larvae should be initiated at 2 days after hatching for achieving good growth and survival. [source] Effect of Cogent db, a herbal drug, on serum and tissue lipid metabolism in experimental hyperglycaemic ratsDIABETES OBESITY & METABOLISM, Issue 3 2003G. Saravanan Aims:, We have previously reported the antidiabetic effect of Cogent db. The present study with alloxan-induced hyperglycaemic rats is focused on the mechanism of action, specifically on the activity of hepatic lipogenic enzymes, serum and tissue lipids. Methods:, Male Wistar rats body weight of 180,200 g (six normal and 18 diabetic rats) were used in this study. The rats were divided into four groups after the induction of alloxan diabetes: normal rats; diabetic control; diabetic rats given Cogent db (0.45 g/kg body weight); diabetic rats given glibenclamide (600 µg/kg body weight). After 40 days treatment, fasting blood glucose, plasma insulin, activities of hepatic lipogenic enzymes, serum and tissue lipids were determined in normal and experimental animals. Results:, Oral administration of Cogent db for 40 days resulted in significant reduction in blood glucose, serum and tissue (liver and kidney) lipids, whereas the level of plasma insulin and the activity of hepatic lipogenic enzymes were significantly increased in alloxan diabetic rats. Similar studies using glibenclamide have been conducted to compare the mode of action of these two drugs. Conclusions:, Thus our study shows that Cogent db exhibits a strong antihyperlipidaemic effect, which could exert a beneficial action against macrovascular complications (cardiovascular disease) associated with diabetes mellitus. [source] Antitumor activity of a novel antisense oligonucleotide against Akt1JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2009Heejeong Yoon Abstract The AKT pathway is an important therapeutic target for cancer drug discovery as it functions as a main point for transducing extracellular and intracellular oncogenic signals. Moreover, alternations of the AKT pathway have been found in a wide range of cancers. In the present study, we found that an Akt1 antisense oligonucleotide (Akt1 AO) significantly downregulated the expression of AKT1 at both the mRNA and protein levels and inhibited cellular growth at nanomolar concentrations in various types of human cancer cells. Combined treatment of Akt1 AO with several cytotoxic drugs resulted in an additive growth inhibition of Caki-1 cells. The in vivo effectiveness of Akt1 AO was determined using two different xenograft nude mouse models. Akt1 AO (30,mg/kg, i.v. every 48,h) significantly inhibited the tumor growth of nude mouse subcutaneously implanted with U251 human glioblastoma cells after 27 days treatment. Akt1 AO (30,mg/kg, i.p continuously via osmotic pump) also significantly inhibited the tumor formation in nude mice implanted with luciferase-expressing MIA human pancreatic cancer cells (MIA-Luc) after 14 days of treatment. The luciferase signals from MIA-Luc cells were reduced or completely abolished after 2 weeks of treatment and the implanted tumors were barely detectable. Our findings suggest that Akt1 AO alone or in combination with other clinically approved anticancer agents should be further explored and progressed into clinical studies as a potential novel therapeutic agent. J. Cell. Biochem. 108: 832,838, 2009. © 2009 Wiley-Liss, Inc. [source] A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgeryJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2007B. I. ERIKSSON Summary.,Background:,YM150, a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism (VTE), a well-known risk after orthopaedic surgery. Objectives:,To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study. Patients/methods:,Patients (174) undergoing hip replacement surgery were randomized per cohort to oral once daily YM150 or subcutaneous enoxaparin (40 mg daily) in a 4:1 ratio for 7,10 days treatment. The YM150 doses were 3, 10, 30 and 60 mg by sequential four-dose escalation cohorts. The primary endpoint was major and/or clinically relevant non-major bleeding. The incidence of VTE was defined as a composite of verified symptomatic events and/or positive findings at bilateral venography on the last treatment day. An independent adjudication committee evaluated blindly the outcomes of the open-label study. Results:,No major and three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI, 0.1,15.1) in the 3 mg and 2 (5.7%; 95% CI, 1.0,18.8) in the 10 mg YM150 dose groups. Of 147 patients (84%) with an evaluable venogram, VTE was observed in 51.9% (95% CI, 31.9,71.4), 38.7% (95% CI, 22.6,57.0), 22.6% (95% CI, 9.7,39.4), and 18.5% (95% CI, 7.5,36.5) in the YM150 dose groups 3, 10, 30 and 60 mg, respectively. A significant YM150 dose-related trend in VTE incidence was found (P=0.006). VTE with enoxaparin was 38.7% (95% CI, 22.6,57.0). Conclusions:,YM150, 10,60 mg daily, starting 6,10 h after primary hip replacement, was shown to be safe, well tolerated and effective. [source] Accuracy of the stool antigen test in the diagnosis of Helicobacter pylori infection before treatment and in patients on omeprazole therapyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2001G. Manes To evaluate the Helicobacter pylori stool antigen (HpSA) test in the assessment of H. pylori infection and the effect of omeprazole treatment on its accuracy. Methods: Study 1: 140 dyspeptic patients were enrolled in the study and defined as H. pylori positive if histology and rapid urease test, or culture alone were positive. HpSA was performed on all patients and 13C-urea breath test (UBT) on 87. Study 2: 75 patients testing positive using both UBT and HpSA, were given omeprazole 20 mg for 2 weeks (Group A) or omeprazole 40 mg for 2 weeks (Group B), or OAC for 1 week (group C). A Helicobacter pylori stool antigen test was performed on all patients on days 3, 5, 7 and 14 during treatment, and also on days 7 and 14 post-treatment in groups A and B. UBT was performed in groups A and B on days 7 and 14 during treatment, and days 7 and 14 post-treatment. Results: 80/140 patients were H. pylori positive. The sensitivity and specificity of HpSA were 93.8 and 90%, similar to UBT (93.9 and 92.1%). Omeprazole significantly reduced both HpSA and UBT values, resulting in a decreased accuracy. Of 25 patients receiving 20 mg omeprazole, HpSA gave 5 and 6 false negatives after 7 and 14 days treatment respectively, while UBT gave 4 and 7 false negatives after 7 and 14 days treatment. Of 25 patients receiving 40 mg omeprazole, HpSA gave 7 and 9 false negatives after 7 and 14 days of treatment, while UBT gave 8 and 9 false negatives after 7 and 14 days of treatment. Two weeks after stopping omeprazole treatment, the HpSA and UBT were positive in all cases. Conclusions: The Helicobacter pylori stool antigen test is valuable in the assessment of H. pylori infection. Short-term omeprazole treatment decreases the accuracy of both HpSA and UBT in a similar manner. [source] Endogenous and exogenous ghrelin enhance the colonic and gastric manifestations of dextran sodium sulphate-induced colitis in miceNEUROGASTROENTEROLOGY & MOTILITY, Issue 1 2009B. De Smet Abstract, Ghrelin is an important orexigenic peptide that not only exerts gastroprokinetic but also immunoregulatory effects. This study aimed to assess the role of endogenous and exogenous ghrelin in the pathogenesis of colitis and in the disturbances of gastric emptying and colonic contractility during this process. Dextran sodium sulphate colitis was induced for 5 days in (i) ghrelin+/+ and ghrelin,/, mice and clinical and histological parameters were monitored at days 5, 10 and 26 and (ii) in Naval Medical Research Institute non-inbred Swiss (NMRI) mice treated with ghrelin (100 nmol kg,1) twice daily for 5 or 10 days. Neural contractility changes were measured in colonic smooth muscle strips, whereas gastric emptying was measured with the 14C octanoic acid breath test. Inflammation increased ghrelin plasma levels. Body weight loss, histological damage, myeloperoxidase activity and IL-1, levels were attenuated in ghrelin,/, mice. Whereas absence of ghrelin did not affect changes in colonic contractility, gastric emptying in the acute phase was accelerated in ghrelin+/+ but not in ghrelin,/, mice. In agreement with the studies in ghrelin knockout mice, 10 days treatment of NMRI mice with exogenous ghrelin enhanced the clinical disease activity and promoted infiltration of neutrophils and colonic IL-1, levels. Unexpectedly, ghrelin treatment decreased excitatory and inhibitory neural responses in the colon of healthy but not of inflamed NMRI mice. Endogenous ghrelin enhances the course of the inflammatory process and is involved in the disturbances of gastric emptying associated with colitis. Treatment with exogenous ghrelin aggravates colitis, thereby limiting the potential therapeutic properties of ghrelin during intestinal inflammation. [source] Effects of inhaled fluticasone propionate on CTLA-4-positive CD4+CD25+ cells in induced sputum in mild asthmaticsRESPIROLOGY, Issue 7 2008Tomotaka KAWAYAMA Background and objective: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) signalling of regulatory T cells regulates mucosal lymphocyte tolerance and differentiation, and may therefore have a beneficial effect in allergic diseases such as asthma. The aim of this study was to evaluate the effects of fluticasone propionate (FP) on CD4+CD25+ T cell co-expression of CTLA-4 in the sputum of mild asthmatic subjects. Methods: Eleven mild, stable asthmatic subjects completed a double-blind, randomized, cross-over, placebo-controlled study to compare the effects of 14 days 200 µg twice daily FP and placebo. Before and after treatment, airway hyperresponsiveness was measured, and sputum was induced for measurements of CTLA-4+CD4+CD25+ cells, eosinophils and levels of IL-10, IL-13 and transforming growth factor (TGF)-, Results: FP treatment increased co-expression of CTLA-4 on sputum CD4+CD25+ cells from a mean (SEM) of 7.9% (1.8) to 12.7% (3.3) after 14 days treatment (P < 0.05) compared with placebo. FP treatment also significantly increased IL-10 levels, reduced per cent sputum eosinophils, and reduced airway hyperresponsiveness (P < 0.05). There was a significant negative correlation between the change in airway hyperresponsiveness and per cent sputum eosinophils (P < 0.01), but no correlation with changes in CTLA-4+CD4+CD25+ cells (P > 0.05). There was no change in the levels of sputum IL-13 or TGF-, Conclusions: The percentage of airway CTLA-4+CD4+CD25+ cells increased after FP treatment, coincident with improvements in airway inflammation and hyperresponsiveness. Whether improved asthma assessments are related to the increase in CTLA-4+CD4+CD25+ cells and thus improved regulation of T-cell tolerance and differentiation will require a larger sample size to determine. The normalization of CTLA-4+CD4+CD25+ cells in asthma may contribute to the management of this disease. [source] Effect of Black maca (Lepidium meyenii) on one spermatogenic cycle in ratsANDROLOGIA, Issue 5 2006G. F. Gonzales Summary Lepidium meyenii (Maca) grows exclusively between 4000 and 4500 m above sea level in the Peruvian central Andes. The hypocotyls of this plant are traditionally used in the Andean region for their supposed fertility-enhancing properties. The hypocotyls have different colours. Of these, Black maca has better effects on spermatogenesis. The present study aimed to test the hypothesis that Black maca has early effects during a spermatogenic cycle (12 days) of male rats. For this, testicular spermatid, epididymal sperm and vas deferens sperm counts were measured after 1, 3, 5, 7 and 12 days of treatment with Black maca. Aqueous extract of Black maca was given orally by daily gavage at a dose of 2 g kg,1. In a spermatogenic cycle, compared with day 1, daily sperm production (DSP) was lower at day 7 (control), whereas with Black maca, the difference was observed at day 12. Epididymal sperm count was higher in rats treated with Black maca at days 1, 3 and 7, but similar to controls at days 5 and 12; similarly sperm counts in vas deferens was higher in rats treated with Black maca in days 3, 5 and 7, but similar to controls at days 1 and 12. From this, it is suggested that first action of Black maca was at epididymal level increasing sperm count after 1 day of treatment, whereas an increase in sperm count was observed in vas deferens at day 3 of treatment. Finally, an increase in DSP was observed after 7 days of treatment with Black maca. Testicular testosterone was not affected after 7 days treatment with Black maca. In conclusion, Black maca affects sperm count as early as 1 day after beginning of treatment. [source] Pharmacokinetic interaction between fluoxetine and metoclopramide in healthy volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2006Laurian Vlase Abstract The pharmacokinetic interaction of fluoxetine with metoclopramide in healthy volunteers was evaluated. A dose of 20 mg metoclopramide in combination with 60 mg fluoxetine was administered to 24 healthy male volunteers in a two treatment study design, separated by 8 days in which the fluoxetine alone was administered as a single p.o. dose daily. Plasma concentrations of metoclopramide were determined during a 24 h period following drug administration. Metoclopramide plasma concentrations were determined by a validated HPLC method. Pharmacokinetic parameters of metoclopramide were calculated using non-compartmental analysis. In the two periods of treatment, the mean peak plasma concentrations (Cmax) were 44.02 ng/ml (metoclopramide alone) and 62.72 ng/ml (metoclopramide after pre-treatment with fluoxetine). The times taken to reach Cmax and tmax, were 1.15 h and 1.06 h, respectively. The total areas under the curve (AUC0,,) were 312.61 ng.h/ml and 590.62 ng.h/ml, respectively. The half-life values (t1/2) were 5.52 h and 8.47 h. Statistically significant differences were observed for both AUC0,, and t1/2 of metoclopramide when administered alone or after 8 days treatment with fluoxetine. The experimental data demonstrate the pharmacokinetic interaction between fluoxetine and metoclopramide and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed. Copyright © 2006 John Wiley & Sons, Ltd. [source] Lithium isotopes: differential effects on renal function and histologyBIPOLAR DISORDERS, Issue 4 2001Peter M Stoll Objectives: Reduction in renal concentrating ability has been reported in patients undergoing chronic lithium treatment. Prior work has demonstrated differences in physiological effects of the stable lithium isotopes, 6Li and 7Li. Here, we measured the degree of polyuria, polydipsia and kidney histological changes induced in rats by equimolar amounts of 6LiCl, 7LiCl and the commercially available mixture of both isotopes. Methods: Rats were given 1.0 mEq/kg of either 6LiCl, 7LiCl or ,nLiCl' (isotope mixture, 93% 7LiCl) by subcutaneous injection twice daily for up to 49 days. Twenty-four-hour urine volume and water intake were measured daily. Kidneys from rats treated for 7 days with 1.5 mEq/kg 6LiCl, 7LiCl and vehicle were examined under light microscopy and histopathologic changes graded on a 4-point scale of severity. Results: All rats showed loss in renal concentrating ability manifested by increasing urine volume and water intake. Peak effects occurred after 9,13 days treatment, then declined to stable levels at two to three times pre-treatment level. Mean peak effect was significantly greater for 6LiCl than for 7LiCl. Chronic effects of 6LiCl (weeks 3,7 of treatment) on polyuria and polydipsia were persistently higher than that of 7LiCl. nLiCl effect was intermediate. Kidneys from rats treated for 7 days with 6LiCl showed more frequently severe lesions in renal tubules than did 7LiCl-treated rats. Conclusions: Our current data and prior studies suggest that elimination or reduction of 6Li from pharmaceutical preparations may merit further evaluation as a possibly less potentially nephrotoxic form of lithium treatment. [source] Gefitinib,phenytoin interaction is not correlated with the 14C-erythromycin breath test in healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2009Stephanie Chhun WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The response to gefitinib is variable and could be explained partly by the interindividual variability in gefitinib exposure. , Gefitinib is mainly metabolized by CYP3A4 and CYP2D6, and is to a lesser extent a P-glycoprotein (P-gp) substrate. , Patients with cancer are at high risk of drug,drug interactions, such as with phenytoin, a potent CYP3A4 inducer. WHAT THIS STUDY ADDS , The reduced systemic exposure of gefitinib with multiple-dose phenytoin treatment. , An effect attributed to the possible induction of intestinal CYP3A4 because of the lack of correlation between changes in gefitinib disposition and the erythromycin breath test and the lack of association between allelic variant in the ABCB1 gene and baseline and induced oral gefitinib clearance. , The CYP2D6 extensive metabolizer seems to be less sensitive to the interaction with phenytoin, as the magnitude of induction of gefitinib clearance was greater in CYP2D6 poor metabolizers than in CYP2D6 extensive metabolizers. AIMS We aimed to describe the pharmacokinetic interaction between phenytoin, a potent CYP3A4 and P-glycoprotein (P-gp) (ABCB1) inducer, and gefitinib, a CYP3A4, CYP2D6 and P-gp substrate. METHODS An open-label, randomized, two-phase crossover study was conducted. Eighteen healthy male volunteers (nine homozygous CC and nine homozygous TT as determined by their ABCB1 C3435T polymorphism in exon 26) received a single oral dose of 250 mg gefitinib alone or after 5 days treatment with phenytoin (5 mg kg,1 daily). Gefitinib plasma concentrations were determined by high-performance liquid chromatography. Hepatic CYP3A4 activity was evaluated by the 14C-erythromycin breath test (ERMBT) and the ABCB1 and CYP2D6 genetic polymorphisms were determined by the TaqMan allelic discrimination assay and long polymerase chain reaction, respectively. RESULTS Following treatment with phenytoin, mean gefitinib Cmax and AUC0,, decreased by 26 ± 44% [95% confidence interval (CI) for the difference 5,48%, P= 0.005] and 47 ± 26% (95% CI for the difference 34,60%, P= 0.001), respectively, and apparent oral clearance increased by 126 ± 93% (95% CI for the difference 80,172%, P= 0.004). Concomitantly, phenytoin increased the mean ERMBT by 91 ± 44% (95% CI 75,105%, P < 0.001) from baseline, but the extent of liver CYP3A4 induction was not correlated to the extent of interaction. Furthermore, this interaction was independent of ABCB1 genetic polymorphism. The CYP2D6 genotype was slightly but significantly related to gefitinib clearance (P= 0.04) during the control phase. CONCLUSIONS The significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent of ABCB1 polymorphism, but may involve presystemic CYP3A-mediated intestinal first-pass. [source] Reduced signal transduction by 5-HT4 receptors after long-term venlafaxine treatment in ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2010R Vidal BACKGROUND AND PURPOSE The 5-HT4 receptor may be a target for antidepressant drugs. Here we have examined the effects of the dual antidepressant, venlafaxine, on 5-HT4 receptor-mediated signalling events. EXPERIMENTAL APPROACH The effects of 21 days treatment (p.o.) with high (40 mg·kg,1) and low (10 mg·kg,1) doses of venlafaxine, were evaluated at different levels of 5-HT4 receptor-mediated neurotransmission by using in situ hybridization, receptor autoradiography, adenylate cyclase assays and electrophysiological recordings in rat brain. The selective noradrenaline reuptake inhibitor, reboxetine (10 mg·kg,1, 21 days) was also evaluated on 5-HT4 receptor density. KEY RESULTS Treatment with a high dose (40 mg·kg,1) of venlafaxine did not alter 5-HT4 mRNA expression, but decreased the density of 5-HT4 receptors in caudate-putamen (% reduction = 26 ± 6), hippocampus (% reduction = 39 ± 7 and 39 ± 8 for CA1 and CA3 respectively) and substantia nigra (% reduction = 49 ± 5). Zacopride-stimulated adenylate cyclase activation was unaltered following low-dose treatment (10 mg·kg,1) while it was attenuated in rats treated with 40 mg·kg,1 of venlafaxine (% reduction = 51 ± 2). Furthermore, the amplitude of population spike in pyramidal cells of CA1 of hippocampus induced by zacopride was significantly attenuated in rats receiving either dose of venlafaxine. Chronic reboxetine did not modify 5-HT4 receptor density. CONCLUSIONS AND IMPLICATIONS Our data indicate a functional desensitization of 5-HT4 receptors after chronic venlafaxine, similar to that observed after treatment with the classical selective inhibitors of 5-HT reuptake. [source] (Pro3)GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapyBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2008P L McClean Background and purpose: Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline-3 gastric inhibitory polypeptide ((Pro3)GIP) can reverse or prevent many of the metabolic abnormalities associated with diet-induced obesity-diabetes (diabesity). This study has examined the ability of a novel and longer-acting form of (Pro3)GIP, (Pro3)GIP mini-polyethylene glycol ((Pro3)GIP[mPEG]), to counter diet-induced diabesity in mice, using a daily and intermittent dosing regime. Experimental approach: We studied the actions of (Pro3)GIP[mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity. Key results: (Pro3)GIP[mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro3)GIP[mPEG] inhibited GIP-induced cAMP and insulin production in vitro. A greater and prolonged antagonism of GIP-induced glucose-lowering action was followed (Pro3)GIP[mPEG] administration, compared with (Pro3)GIP. In contrast with (Pro3)GIP, mice injected once every 3 days for 48 days with (Pro3)GIP[mPEG] displayed reduced body weight gain and hyperinsulinemia with improved glucose tolerance and insulin secretory responses, compared with high-fat-fed controls. Daily i.p. injection of (Pro3)GIP, (Pro3)GIP[mPEG] or (Pro3)GIP b.i.d. for 21 days also decreased body weight, circulating plasma insulin levels and improved glucose tolerance, compared with high-fat controls. Plasma triglycerides were decreased by (Pro3)GIP[mPEG] and (Pro3)GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro3)GIP[mPEG] was also effective over 16 days treatment of genetically obese-diabetic ob/ob mice. Conclusions and implications: These data demonstrate the utility of GIP receptor antagonism for the treatment of diabesity and the potential offered by (Pro3)GIP[mPEG] as a long-acting stable GIP receptor antagonist. British Journal of Pharmacology (2008) 155, 690,701; doi:10.1038/bjp.2008.317; published online 11 August 2008 [source] A case of mucosal leishmaniasis: beneficial usage of polymerase chain reaction for diagnosisINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 12 2001Hironori Onuma MD A 36-year-old woman, who had emigrated from Japan to Paraguay as a 4-year-old child before returning to Japan in 1991, visited our clinic on November 10, 1997. She had suffered from a persistent ulcer on her forearm as a 6-year-old child and received intravenous injections for a few months, although she did not remember the details of therapy. Since May 1997, she had been aware of redness and swelling on her nose and had been treated with topical corticosteroid, but no improvement had been noted. Physical examination revealed erythematous plaque with crust from the left internal naris to nasolabial region (Fig. 1a). The atrophic plaque that had resulted from prolonged ulceration was found on the right forearm (Fig. 1b). In a biopsy specimen from the erythematous plaque on the nasolabial region, mononuclear dermal infiltrate, consisting of lymphocytes and histiocytes, was seen (Fig. 2a). The histiocytes were filled with Leishman-Donovan (L-D) bodies on a Giemsa staining sample (Fig. 2b). Fiberscopic examination revealed white plaque in the pharynx. The biopsy from the affected mucosa showed the same histopathological finding as with the skin. Figure 1. (a) Erythematous plaque with crust from the left internal naris to nasolabial region. (b) Atrophic plaque on the right forearm Figure 2. (a) In the biopsy specimen from the erythematous plaque on the nasolabial region, a mononuclear dermal infiltrate consisting of lymphocytes and histiocytes was seen. (Hematoxylin-Eosin stain, × 100) (b) The histiocytes were filled with Leishman-Donovan bodies. (Giemsa staining, × 400) Total DNA was purified from the skin biopsy specimen for polymerase chain reaction (PCR) analysis using a specific primer for L (V) braziliensis.1,2 A 70-bp product was amplified (Fig. 3a); furthermore, the specificity of the PCR product was confirmed by Southern hybridization with the probe for L (V) braziliensis (Fig. 3b) and DNA sequence analysis (data not shown). From December 2, 1997, the patient received 20 mg/kg/day sodium stibogluconate (PentostamTM) intravenously for 20 days. After 5 days of treatment, the redness and swelling of the skin lesion was improved, and faint erythema remained at the end of 20 days' treatment. After a 2-week interval, since the erythema remained, another 20-day treatment was performed. All of the skin lesion became scar tissue and L-D bodies could not be found in a skin biopsy specimen. However, L-D bodies were still found in a biopsy from the pharyngeal mucosa that had a normal appearance. Though another additional treatment was planned, the patient refused it. Figure 3. (a) The results of PCR. 70-bps bands appear in lanes 2 and 6. Lane 1, a size marker (pUC19/HapII); lane 2, DNA extracted from the formalin-fixed patient's sample; lane 3, DNA extracted from a formalin-fixed control sample; lane 4, DNA (,); lane 5, DNA extracted from L (V) tropica; lane 6, DNA extracted from L (V) braziliensis. (b) Results of Southern blotting using the PCR products. The PCR products were transferred from agarose gel as shown in Fig. 3 (a). Specific probes were hybridized with 70-bps bands on lanes 2 and 6 [source] Gastroprotective properties of Myristica malabarica against indometacin-induced stomach ulceration: a mechanistic explorationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2007Debashish Banerjee The healing activity of the methanol extract of the spice rampatri, Myristica malabarica, (RM) and omeprazole against indometacin-induced stomach ulceration has been studied in a mouse model. Treatment with RM (40 mg kg,1 per day) and omeprazole (3 mg kg,1 per day) for 3 days could effectively heal the stomach ulceration, as revealed from the ulcer indices and histopathological studies. Compared with the ulcerated group, treatment with RM and omeprazole for 3 days reduced the macroscopic damage score by approximately 72% and 76%, respectively (P < 0.001), establishing the efficacy of RM. The extent of ulcer healing offered by 3 days' treatment with RM or omeprazole was better than that observed with natural recovery over 5 and 7 days (P < 0.05). The healing capacities of RM and omeprazole could be attributed to their antioxidant activity as well as the ability to enhance the mucin content of the gastric tissues. Both drugs reduced lipid peroxidation (by 42,44%) and protein carbonyl content (by 34%), and augmented non-protein thiol levels beyond normal values. Furthermore, RM improved the mucin level beyond the normal value, while omeprazole restored it to near normalcy. [source] Residue depletion of thiamphenicol in the sea-bassJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2002L. INTORRE The residue depletion of thiamphenicol (TAP) was investigated in the sea-bass (Dicentrarchus labrax) after 5 days' treatment with medicated food at a dose of 15 or 30 mg/kg bw/day. Fish were sampled for blood and muscle + skin from 3 h until 14 days after treatment. Thiamphenicol concentrations were assayed by high performance liquid chromatography. Thiamphenicol concentrations measured 3 h after stopping treatment were 0.77 ,g/mL and 0.91 (15 mg/kg dose) or 1.32 ,g/mL and 1.47 ,g/g (30 mg/kg dose), in plasma and muscle + skin, respectively. After a withdrawal of 3 days, plasma and tissue concentrations were: 0.08 ,g/mL and 0.03 ,g/g (lower dose) or 0.12 ,g/mL and 0.06 ,g/g (higher dose), respectively. Thiamphenicol was not detectable either in plasma or in tissues on days 7, 10 and 14 following withdrawal of the medicated food. Based on maximum residue levels (MRL) for TAP in fin fish, established at 50 ,g/kg for muscle and skin in natural proportions, a withdrawal period of 5 and 6 days is proposed, after treatment at 15 or 30 mg/kg of TAP with medicated feed pellets, respectively, to avoid the presence of violative residues in the edible tissues of the sea-bass. [source] Antibiotics for uncomplicated urinary tract infection in womenPRESCRIBER, Issue 7 2010MB ChB, Sarah Thompson BSc Most well women with uncomplicated urinary tract infection should respond to three days' treatment with a first-line antibiotic. Our Drug review describes the properties and side-effects of the recommended antibiotics, followed by sources of further information. Copyright © 2010 Wiley Interface Ltd [source] Latest news and product developmentsPRESCRIBER, Issue 12 2008Article first published online: 14 JUL 200 Patients want to stop ,Z' drugs more than benzos A study from Lincolnshire has revealed that patients prescribed a ,Z' drug - zaleplon (Sonata), zolpidem or zopiclone - for insomnia are more likely to want to stop treatment than those prescribed a benzodiazepine (Br J Gen Pract 2008;58:417-22). The cross-sectional survey of 705 patients prescribed a hypnotic for insomnia found that more patients taking a Z drug wanted to stop (23 vs 12 per cent prescribed a benzodiazepine) and tried to stop treatment (52 vs 41 per cent). New NICE guidance NICE has published an updated clinical guideline for the management of type 2 diabetes, covering: the control of blood glucose with lifestyle modification, oral hypoglycaemic drugs and insulin; reducing blood pressure and lipids, antithrombotic therapy and estimating cardiovascular risk; and screening and treatment for long-term complications. There is also a new clinical guideline on cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. New technology appraisals include the use of erythropoietin analogues for cancer-associated anaemia, and adalimumab (Humira) and etanercept (Enbrel) for ankylosing spondylitis; infliximab (Remicade) is not recommended. See New from NICE (pages 13-14) for further details. Prescriber consultant editor wins award Professor Tony Avery, professor of primary care at Nottingham University and consultant editor for Prescriber, has won the John Fry Award for his work in promoting the discipline of general practice through research and publishing as a practising GP. The citation acknowledges Professor Avery as ,quite simply one of the best researchers we have had in general practice,' describing his output of original work and research as impressive. The award commemorates the work of the late Dr John Fry, perhaps the most prominent GP of his generation involved in research. Antihypertensive dose ignores adherence Clinicians take no account of poor adherence when they increase the dose of antihypertensive therapy due to apparent lack of effect, US researchers say (Circulation 2008; published online May 27; doi 10.1161/CIRCULATIONAHA.107.724104). Their retrospective analysis included reimbursement records for 38 327 patients with hypertension who presented with elevated BP (140-200/>90mmHg) in one year (mean 1.8 events per patient). After adjusting for potential confounders, they found that antihypertensive medications were added or the dose of medication increased in about one-third of patients regardless of the degree of nonadherence in the previous year. LABAs improve COPD Inhaled long-acting beta2-agonists (LABAs) improve COPD and do not increase the risk of death, a new safety review has concluded (Chest 2008;133:1079-87). The meta-analysis of 27 RCTs in patients with moderate to severe stable COPD found that LABAs reduced exacerbations by 22 per cent, improved lung function, reduced use of rescue medication and improved quality of life. There was no effect on respiratory deaths, though a combination of a LABA with an inhaled steroid reduced the risk by two-thirds compared with LABA monotherapy. Tiotropium (Spiriva) was associated with a 50 per cent lower risk of exacerbations than LABAs. These findings follow the MHRA's review of LABAs in the treatment of asthma, which found no increase in mortality provided they are used with an inhaled steroid (Drug Safety Update 2008;1:9). Naproxen as effective in acute gouty arthritis Naproxen is as effective as prednisolone in the treatment of acute gouty arthritis, say researchers from The Netherlands (Lancet 2008;371:1854-60). Their study in 118 primary care patients showed that five days' treatment with naproxen 500mg twice daily or prednisolone 35mg daily reduced pain scores to a similar extent with a comparable incidence of adverse effects. Copyright © 2008 Wiley Interface Ltd [source] Combined Therapy with Atorvastatin and Calcineurin Inhibitors: No Interactions with TacrolimusAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2005W. P. D. Lemahieu Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback. Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4 + PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors. [source] | ||||||||||||||||||||||||||||||||||