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First Dose (first + dose)
Selected AbstractsAntifracture Efficacy and Reduction of Mortality in Relation to Timing of the First Dose of Zoledronic Acid After Hip Fracture,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2009Erik Fink Eriksen Abstract Annual infusions of zoledronic acid (5 mg) significantly reduced the risk of vertebral, hip, and nonvertebral fractures in a study of postmenopausal women with osteoporosis and significantly reduced clinical fractures and all-cause mortality in another study of women and men who had recently undergone surgical repair of hip fracture. In this analysis, we examined whether timing of the first infusion of zoledronic acid study drug after hip fracture repair influenced the antifracture efficacy and mortality benefit observed in the study. A total of 2127 patients (1065 on active treatment and 1062 on placebo; mean age, 75 yr; 76% women and 24% men) were administered zoledronic acid or placebo within 90 days after surgical repair of an osteoporotic hip fracture and annually thereafter, with a median follow-up time of 1.9 yr. Median time to first dose after the incident hip fracture surgery was ,6 wk. Posthoc analyses were performed by dividing the study population into 2-wk intervals (calculated from time of first infusion in relation to surgical repair) to examine effects on BMD, fracture, and mortality. Analysis by 2-wk intervals showed a significant total hip BMD response and a consistent reduction of overall clinical fractures and mortality in patients receiving the first dose 2-wk or later after surgical repair. Clinical fracture subgroups (vertebral, nonvertebral, and hip) were also reduced, albeit with more variation and 95% CIs crossing 1 at most time points. We concluded that administration of zoledronic acid to patients suffering a low-trauma hip fracture 2 wk or later after surgical repair increases hip BMD, induces significant reductions in the risk of subsequent clinical vertebral, nonvertebral, and hip fractures, and reduces mortality. [source] Qualitative and quantitative evaluation of equine respiratory mechanics by impulse oscillometryEQUINE VETERINARY JOURNAL, Issue 1 2006E. VAN ERCK Summary Reasons for performing study: The long- established conventional reference technique (CRT) for measuring respiratory mechanics in horses lacks sensitivity and there is a need for further refinement in new technology, such as the impulse oscillometry system (IOS). Objectives: To evaluate the potential use of the IOS as a clinical respiratory function test and compare it to the current CRT in horses suffering from common upper and lower airway dysfunctions. Methods: Six healthy horses were tested before and after induction of a unilateral nasal obstruction (UNO) or transient left laryngeal hemiplegia (LLH). Six heaves-affected horses were tested in clinical remission and during a heaves crisis, before and after nebulisation of cumulative doses of a bronchodilator therapy (ipratropium bromide; IPB). Results: As opposed to the CRT, the IOS was able to detect partial upper airway obstruction (UAO) caused by UNO or LLH in resting horses, without differentiating both conditions. Upper airway obstruction caused an upward shift of resistance (Rrs) from 5 to 35 Hz without altering reactance (Xrs). As for the CRT, IOS respiratory parameters measured in heaves-affected horses in crisis differed significantly from values measured during remission. The difference in frequency-dependent behaviour of Rrs and Xrs allowed discrimination between upper and lower airway obstructions. Bronchodilator treatment induced significant dose-dependent changes in Xrs at 5 and 10 Hz, from the first dose. Total pulmonary resistance (RL) and Rrs at 5 Hz were affected from the second dose and displayed similar sensitivity. Although post treatment RL values were comparable to remission, Rrs and Xrs remained significantly different, characterising persistent peripheral obstruction. Conclusions: The IOS was more sensitive than the CRT in detecting partial UAO in resting horses and persistent post treatment peripheral dysfunction in heaves-affected horses. The IOS is a sensitive test that provides graded quantitative and qualitative information on disease-induced respiratory dysfunctions as well as on treatment efficiency in horses. Potential relevance: The IOS could represent a practical and sensitive alternative respiratory function test for routine clinical investigations of common airway obstructive diseases and therapy in horses. [source] Absence of veno-occlussive disease in a cohort of multiple myeloma patients undergoing autologous stem cell transplantation with targeted busulfan dosageEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2006A. Clopés Abstract:,Background:,Plasma concentrations of oral busulfan (BU) were measured in multiple myeloma (MM) patients undergoing autologous peripheral blood stem cell transplantation (ASCT) with a double alkylating conditioning protocol in order to individualise doses of BU based on individual pharmacokinetic parameters and to reduce toxicities related to BU exposure. Patients and methods:,Forty-four consecutive patients with MM participating in the co-operative Spanish protocol were prospectively evaluated. Conditioning regimen prior to autologous infusion consisted of BU followed by melphalan. BU pharmacokinetic parameters were estimated for each patient after the first dose based on measured concentrations and subsequent doses were modified as necessary to achieve target exposure. Results:,Mean BU exposure (AUCss) (±DS) before dosage modification range from 3192 to 12 180 ng h/mL. Twenty-six out of 44 (59%) patients required dose adjustment. None of the patients developed hepatic veno-occlusive disease (VOD). Grade , II oropharyngeal mucositis was observed in the majority of patients (95%) and the severity of mucositis increased with increasing average steady-state BU plasma concentration. There were four treatment-related deaths: two patients died from multiorgan failure and two of respiratory infections. Of the remaining 40 patients, 15 were in complete remission with negative immunofixation, 21 in partial remission and four in stable disease 3 months after ASCT. Conclusions:,The results of the present study show the variability in BU pharmacokinetic parameters and suggest the possible relationship between toxicities and BU exposure. Individualising BU dosage in MM patients undergoing ASCT we observed the absence of VOD. [source] Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2002Annick Rousseau Abstract Over the last 10 years, proofs of the clinical interest of therapeutic drug monitoring (TDM) of certain anticancer drugs have been established. Numerous studies have shown that TDM is an efficient tool for controlling the toxicity of therapeutic drugs, and a few trials have even demonstrated that it can improve their efficacy. This article critically reviews TDM tools based on pharmacokinetic modelling of anticancer drugs. The administered dose of anticancer drugs is sometimes adjusted individually using either a priori or a posteriori methods. The most frequent clinical application of a priori formulae concerns carboplatin and allows the computation of the first dose based on biometrical and biological data such as weight, age, gender, creatinine clearance and glomerular filtration rate. A posteriori methods use drug plasma concentrations to adjust the subsequent dose(s). Thus, nomograms allowing dose adjustment on the basis of blood concentration are routinely used for 5-fluorouracil given as long continuous infusions. Multilinear regression models have been developed, for example for etoposide, doxorubicin, carboplatin, cyclophosphamide and irinotecan, to predict a single exposure variable [such as area under concentration,time curve (AUC)] from a small number of plasma concentrations obtained at predetermined times after a standard dose. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided, is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Unlike the other a posteriori methods, Bayesian estimation is based on population pharmacokinetic studies and can take into account the effects of different individual factors on the pharmacokinetics of the drug. Bayesian estimators have been used to determine maximum tolerated systemic exposure thresholds (e.g. for topotecan or teniposide) as well as for the routine monitoring of drugs characterized by a very high interindividual pharmacokinetic variability such as methotrexate or carboplatin. The development of these methods has contributed to improving cancer chemotherapy in terms of patient outcome and survival and should be pursued. [source] Effect kinetics of desmopressin-induced platelet retention in healthy volunteers treated with aspirin or placeboHAEMOPHILIA, Issue 1 2000Lethagen Desmopressin is often used for haemostatic treatment in platelet dysfunction, but the effect kinetics of platelet responses and the mechanism of action are poorly known. This study aimed to determine the kinetics of platelet function responses induced by desmopressin in healthy volunteers treated with aspirin or placebo. Another aim was to correlate platelet responses to changes of von Willebrand factor (vWF) in plasma. We measured platelet function with a glass bead retention test, Ivy bleeding time, vWF:Ag and multimeric structure in plasma. Median baseline platelet retention was 12% (normal reference range 16,27%) during aspirin treatment and 18% during placebo. Median peak platelet retention after desmopressin was 33% during aspirin treatment and 34% during placebo. After about 3 h platelet function had returned to baseline. A second desmopressin dose after 3 h stimulated platelet retention to a similar extent as the first dose. There was no correlation between platelet responses and quantitative or qualitative changes of vWF in plasma. Platelet count did not change significantly. Thus, desmopressin's effect on platelet function lasts for about 3 h, but may be prolonged by a second dose immediately thereafter. These findings may have important clinical implications for patients with aspirin-induced platelet dysfunction undergoing surgery. [source] Cardiac Risk Factors and the Use of Triptans: A Survey StudyHEADACHE, Issue 7 2000William B. Young MD Objective.,To describe current practice in triptan use. Background.,Triptans are effective migraine treatments that cause chest symptoms in some patients. True cardiac ischemia is rare. Design.,Headache specialists and family practitioners completed questionnaires regarding the times when triptans are contraindicated, obtaining electrocardiograms (ECGs), and giving the first dose in the office. Results.,Sixty-five headache specialists and 67 family practitioners responded. Headache specialists saw an average of 36.3 patients with headache per week. Family practitioners saw an average of 7.2. Family practitioners and headache specialists had similar opinions regarding the age at which triptans were contraindicated with various numbers of risk factors. Sixty-one percent of headache specialists and 50% of family practitioners would not use a triptan at any age for patients with more than three risk factors (P = NS). Ten percent of headache specialists obtained an ECG for all patients being prescribed triptans, while no family practitioners did (P = .008). Ten percent of both family practitioners and headache specialists never obtained an ECG, even with multiple cardiac risk factors. Headache specialists obtained ECGs more often than family practitioners (P < .002 for one to three risk factors). Family practitioners were more likely to give the first dose of the triptan in the office regardless of cardiovascular risk (58% versus 20%, P < .001). Forty-five percent of headache specialists and 2% of family practitioners never gave the first dose in the office (P < .001). Family practitioners gave the first dose in the office more readily than headache specialists in patients with no risk factors (P = .001), but not for one or more risk factors. Conclusions.,No consensus exists among family practitioners or headache specialists about when to avoid using a triptan due to excessive cardiac risk factors, when to obtain an ECG prior to using a triptan, and when to give the first dose of a triptan in the office. Headache specialists are more likely to obtain ECGs, whereas family practitioners are more likely to give the first dose of a triptan in the office. [source] Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled studyINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 1 2001Johannes Ring MD Background Chronic idiopathic urticaria (CIU) is the most common type of chronic urticaria, and pruritus is the most prominent symptom. Antihistamines are the first-line treatment for CIU. Sedation and anticholinergic adverse effects are often experienced with the first-generation antihistamines and there is a risk of cardiovascular adverse effects and drug interactions with some second-generation agents. Hence, new treatment options are needed. Desloratadine is a new, potent, nonsedating antihistamine that has an excellent cardiovascular safety profile. Methods This was a multicenter, randomized, double-blind, placebo-controlled study designed to determine the efficacy and safety of desloratadine in the treatment of moderate-to-severe CIU. A total of 190 patients, aged 12,79 years, with at least a 6-week history of CIU and who were currently experiencing a flare of at least moderate severity, were randomly assigned to therapy with desloratadine 5 mg or placebo once daily for 6 weeks. Twice daily, patients rated the severity of CIU symptoms (pruritus, number of hives, and size of largest hive), as well as the impact of CIU symptoms on sleep and daily activity. Patients and investigators jointly evaluated therapeutic response and overall condition. Safety evaluations included the incidence of treatment-emergent adverse events, discontinuations due to adverse events, and changes from baseline in vital signs, laboratory parameters, and ECG intervals. Results Desloratadine was superior to placebo in controlling pruritus and total symptoms after the first dose and maintained this superiority to the end of the study. Measures of sleep, daily activity, therapeutic response, and global CIU status were also significantly better with desloratadine after the first dose; these clinical benefits were also maintained throughout the 6-week study. No significant adverse events occured. Conclusions Desloratadine 5 mg daily is a safe and effective treatment for CIU with significant benefits within 24 h and maintained through the treatment period. [source] The effect of dichloroacetic acid and trichloroacetic acid on DNA methylation and cell proliferation in B6C3F1 miceJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2001Rongrong Ge Abstract The chlorine disinfection by-products, dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are carcinogenic in mouse liver. We have previously reported that DCA and TCA induced DNA hypomethylation in mouse liver. In the present study, we determined the temporal association for DNA hypomethylation and cell proliferation. Female B6C3F1 mice were administered daily doses of 500 mg/kg DCA or TCA by gavage and sacrificed at 24, 36, 48, 72, and 96 hours after the first dose. The proliferating cell nuclear antigen-labeling index in the liver was increased at 72 and 96 hours by both DCA and TCA, that is, at 72 hours the index was 1.00 ± 0.21, 0.51 ± 0.11, and 0.095 ± 0.016 for DCA, TCA, and the vehicle control, respectively. The mitotic index was also significantly increased at 96 hours. The promoter region for the c- myc gene was hypomethylated only at 72 and 96 hours and not at the earlier sacrifices. Similarly, the methylation of the c- myc gene in the kidney and urinary bladder was decreased only at 72 and 96 hours. In summary, enhancement of cell proliferation and decreased methylation of the c- myc gene were first observed simultaneously at 72 hours after the start of exposure. Thus, the results support the hypothesis that DCA and TCA induce DNA hypomethylation by inducing DNA replication and preventing the methylation of the newly synthesized strands of DNA. © 2001 John Wiley & Sons, Inc. J Biochem Mol Toxicol 15:100,106, 2001 [source] Antifracture Efficacy and Reduction of Mortality in Relation to Timing of the First Dose of Zoledronic Acid After Hip Fracture,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2009Erik Fink Eriksen Abstract Annual infusions of zoledronic acid (5 mg) significantly reduced the risk of vertebral, hip, and nonvertebral fractures in a study of postmenopausal women with osteoporosis and significantly reduced clinical fractures and all-cause mortality in another study of women and men who had recently undergone surgical repair of hip fracture. In this analysis, we examined whether timing of the first infusion of zoledronic acid study drug after hip fracture repair influenced the antifracture efficacy and mortality benefit observed in the study. A total of 2127 patients (1065 on active treatment and 1062 on placebo; mean age, 75 yr; 76% women and 24% men) were administered zoledronic acid or placebo within 90 days after surgical repair of an osteoporotic hip fracture and annually thereafter, with a median follow-up time of 1.9 yr. Median time to first dose after the incident hip fracture surgery was ,6 wk. Posthoc analyses were performed by dividing the study population into 2-wk intervals (calculated from time of first infusion in relation to surgical repair) to examine effects on BMD, fracture, and mortality. Analysis by 2-wk intervals showed a significant total hip BMD response and a consistent reduction of overall clinical fractures and mortality in patients receiving the first dose 2-wk or later after surgical repair. Clinical fracture subgroups (vertebral, nonvertebral, and hip) were also reduced, albeit with more variation and 95% CIs crossing 1 at most time points. We concluded that administration of zoledronic acid to patients suffering a low-trauma hip fracture 2 wk or later after surgical repair increases hip BMD, induces significant reductions in the risk of subsequent clinical vertebral, nonvertebral, and hip fractures, and reduces mortality. [source] Potent and Selective Inhibition of Human Cathepsin K Leads to Inhibition of Bone Resorption In Vivo in a Nonhuman PrimateJOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2001George B. Stroup Abstract Cathepsin K is a cysteine protease that plays an essential role in osteoclast-mediated degradation of the organic matrix of bone. Knockout of the enzyme in mice, as well as lack of functional enzyme in the human condition pycnodysostosis, results in osteopetrosis. These results suggests that inhibition of the human enzyme may provide protection from bone loss in states of elevated bone turnover, such as postmenopausal osteoporosis. To test this theory, we have produced a small molecule inhibitor of human cathepsin K, SB-357114, that potently and selectively inhibits this enzyme (Ki = 0.16 nM). This compound potently inhibited cathepsin activity in situ, in human osteoclasts (inhibitor concentration [IC]50 = 70 nM) as well as bone resorption mediated by human osteoclasts in vitro (IC50 = 29 nM). Using SB-357114, we evaluated the effect of inhibition of cathepsin K on bone resorption in vivo using a nonhuman primate model of postmenopausal bone loss in which the active form of cathepsin K is identical to the human orthologue. A gonadotropin-releasing hormone agonist (GnRHa) was used to render cynomolgus monkeys estrogen deficient, which led to an increase in bone turnover. Treatment with SB-357114 (12 mg/kg subcutaneously) resulted in a significant reduction in serum markers of bone resorption relative to untreated controls. The effect was observed 1.5 h after the first dose and was maintained for 24 h. After 5 days of dosing, the reductions in N-terminal telopeptides (NTx) and C-terminal telopeptides (CTx) of type I collagen were 61% and 67%, respectively. A decrease in serum osteocalcin of 22% was also observed. These data show that inhibition of cathepsin K results in a significant reduction of bone resorption in vivo and provide further evidence that this may be a viable approach to the treatment of postmenopausal osteoporosis. [source] Rituximab as an adjunct to plasma exchange in TTP: A report of 12 cases and review of literature,JOURNAL OF CLINICAL APHERESIS, Issue 5 2008Sushama Jasti Abstract Idiopathic thrombotic thrombocytopenic purpura (TTP) is caused by the production of autoantibodies against the Von Willebrand factor cleaving enzyme. This provides a rationale for the use of rituximab in this disease. We report a retrospective review of 12 patients treated with rituximab for TTP refractory to plasma exchange. Eleven patients were treated during initial presentation, and one patient was treated for recurrent relapse. Ten patients responded to treatment. Median time to response after first dose of rituximab was 10 days (5,32). Of the 11 patients treated during initial presentation, nine remain free of relapse after a median follow-up of 57+ months (1+,79+). Two patients died during initial treatment. One patient was lost to follow-up 1 month after achieving complete response. The patient treated for recurrent disease during second relapse remained disease free for 2years, relapsed and was treated again with rituximab, and was in remission for 22 months. She relapsed again, was retreated, and has now been in remission for 21+ months. We conclude that rituximab is an useful addition to plasma exchange treatment in TTP, but its exact role and dosing need to be verified in prospective studies. J. Clin. Apheresis, 2008. © 2008 Wiley-Liss, Inc. [source] Prevalence of high antibody titers of pertussis in Turkey: reflection of circulating microorganism and a threat to infantsJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 3 2007Berrin Esen Abstract Acute pertussis infection among adults can cause its transmission to the larger population, especially to infants and young children, who can develop severe disease. In order to determine an age-dependent pertussis immune response, anti-pertussis toxin (PT) antibody was detected by the indirect enzyme-linked immunosorbent assay (ELISA) method in serum samples from 2,085 healthy subjects ranging in age from 6 months to ,60 years. Also included in the evaluation were responses to a questionnaire including sociodemographic characteristics, vaccination, and infection history. Titers of 50,99 ELISA units (EU)/mL and of ,100,EU/mL were accepted as indicative for recent exposure or infection. In addition, 30,EU/mL was estimated to be a sufficient titer in women of childbearing age to protect their newborns until administration of their first dose of pertussis vaccine. After the age of 4,5 years, presence of high-titered antibodies that increase with age might be a reflection of circulating infection and indicate the magnitude of the threat to infants. According to the questionnaires, in the groups younger than 15 years old, three to four doses of diphtheria toxoid-whole cell pertussis-tetanus toxoid (DwPT) were administered in 47.2 to 77.4%, 91.2 to 100.0%, and 83.5 to 100.0% of participants in Diyarbakir, Samsun, and Antalya, respectively. In addition, up to half of the expectant mothers we studied lacked a sufficient level of estimated antibody titers. To protect infants from life-threatening pertussis infection, improving vaccination coverage to ensure herd immunity and uniformly establishing coverage throughout the country are essential. Furthermore, revaccination with acellular vaccine for schoolchildren as well as for the households of pregnant women is recommended. J. Clin. Lab. Anal. 21:154,161, 2007. © 2007 Wiley-Liss, Inc. [source] Factors predicting successful outcome following neostigmine therapy in acute colonic pseudo-obstruction: A prospective studyJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2 2006RAJIV MEHTA Abstract Aim:, To evaluate predictors of neostigmine response in patients with acute colonic pseudo-obstruction. Methods:, Twenty-seven patients with acute colonic pseudo-obstruction were enrolled in the study. All patients had received initial conservative management such as nil orally, nasogastric suction, rectal tube placement and correction of electrolyte imbalance for the first 24 h. Those who did not resolve with conservative management received 2 mg neostigmine intravenously. The same dose was repeated after 24 h in patients who did not response to the first dose (initial non-responders), or in those patients who relapsed after an initial response (initial responders). All non-responders to neostigmine underwent colonoscopic decompression followed by 2 mg neostigmine infusion for 30 min. A sustained response was defined as the resolution of symptoms and colonic dilatation on a plain radiograph. Results:, The study enrolled 27 patients; 18 were male (67%), and the median age was 60 years (range 18,78 years). Eight (30%) patients had spontaneous resolution. Initial response with neostigmine was observed in 16 (84%) patients, of which 10 (63%) had a sustained response. Nine patients (three initial non-responders and six initial responders) had received a second dose of neostigmine. A sustained response was seen only in five initial responders. Four patients who did not respond to neostigmine underwent colonoscopic decompression followed by neostigmine infusion and had a sustained response. Neostigmine responders were more likely to be postoperative patients (11 of 15 (73%) vs one of four (25%), P = 0.07), less likely to have electrolyte imbalance and to be on antimotility agents (three of 15 (20%) vs four of four (100%), P = 0.009 and two of 15 (13%) vs four of four (100%), P = 0.003). Conclusions:, Electrolyte imbalance and usage of anti-motility agents are factors associated with a poor response, while postoperative patients showing good response to neostigmine therapy. [source] Intrathecal neostigmine with bupivacaine for infants undergoing lower abdominal and urogenital procedures: dose responseACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2009Y. K. BATRA Background: Intrathecal (IT) neostigmine produces dose-dependent analgesia in adults. However, the dose of spinal neostigmine has not been investigated in infants. The purpose of this study was to assess spinal anesthesia (SA) duration provided by four doses of spinal neostigmine added to bupivacaine for lower abdominal and urogenital procedures in infants. Methods: Seventy-five infants were randomized into five groups. The control group B received IT plain 0.5% hyperbaric bupivacaine. Groups BN.25, BN.50, BN.75, and BN1.0 received bupivacaine with 0.25, 0.5, 0.75, and 1 ,g/kg of neostigmine, respectively. The primary variable was the duration of anesthesia assessed by recovery of hip flexion. Postoperative pain with facial expression, leg activity, arm activity, crying and consolability scale score,and rescue analgesic requirements were the secondary variables measured, and the side effects were noted. Results: Seventy-three infants completed the study. There was a significant linear increase in SA duration with IT neostigmine to 65.2 (4.3) min with 0.5 ,g/kg (P<0.01), 88.2 (5.1) with 0.75 ,g/kg (P<0.001) and 92 (4.3) with 1 ,g/kg (P<0.001) from 52.4 (4.3) min with bupivacaine alone. SA duration showed no significant difference between plain bupivacaine and BN.25 (P=0.100) or between groups BN.75 and BN1.0 (P=0.451). Groups BN.75 and BN1.0 had significantly reduced pain scores, and the median duration before the first dose rescue analgesic was requested prolonged significantly (P<0.001) compared with the other three groups. Conclusions: IT neostigmine at a dose of 0.75 ,g/kg added to bupivacaine significantly prolonged SA duration with reduced postoperative pain scores and rescue analgesic requirements in infants undergoing lower abdominal and urogenital procedures. No additional benefits were provided on increasing it to 1 ,g/kg. [source] Regulation of Soluble Guanylyl Cyclase Activity by Oestradiol and Progesterone in the Hypothalamus But Not Hippocampus of Female RatsJOURNAL OF NEUROENDOCRINOLOGY, Issue 6 2007A. Reyna-Neyra Oestradiol and progesterone act in the hypothalamus to coordinate the timing of lordosis and ovulation in female rats in part through regulation of nitric oxide (NO) and cyclic guanosine monophosphate (cyclic GMP) signalling pathways. Soluble guanylyl cyclase is an enzyme that produces cyclic GMP when stimulated by NO and plays a crucial role in the display of lordosis behaviour. We examined the effects of oestradiol and progesterone on the stimulation of cyclic GMP synthesis by NO-dependent and independent activators of soluble guanylyl cyclase in preoptic-hypothalamic and hippocampal slices. Ovariectomised Sprague-Dawley rats were injected with oestradiol (2 µg oestradiol benzoate, s.c.) or vehicle for 2 days. Progesterone (500 µg, s.c.) or vehicle was injected 44 h after the first dose of oestradiol. Rats were killed 48 h after the first oestradiol or vehicle injection, and hypothalamus and hippocampus were obtained. NO-dependent activation of soluble guanylyl cyclase was induced by NO donors, sodium nitroprusside or diethylamine NONOate; NO-independent activation of soluble guanylyl cyclase was induced with 3-(5,-hydroxymethyl-2,-furyl)-1-benzyl indazole and 5,-cyclopropyl-2-[1,2fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyridine-4-ylamine. The NO-dependent activators of soluble guanylyl cyclase produced a concentration-dependent increase in cyclic GMP accumulation and induced significantly greater cyclic GMP accumulation in preoptic-hypothalamic slices from animals treated with oestradiol and progesterone than in slices from rats injected with vehicle, oestradiol or progesterone alone. Hormones did not modify soluble guanylyl cyclase activation by NO-independent stimulators or influence NO content in preoptic-hypothalamic slices. Oestradiol and progesterone did not affect activation of soluble guanylyl cyclase in hippocampal slices by any pharmacological agent, indicating a strong regional selectivity for the hormone effect. Thus, oestradiol and progesterone, administered in vivo, enhance the ability of NO to activate soluble guanylyl cyclase in brain areas modulating female reproductive function without an effect on production of NO itself. [source] Hepatitis B vaccination is effective for babies weighing less than 1800 gJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 5 2006Wee-Bin Lian Aim: This trial studied the effectiveness of early hepatitis B (HepB) immunisation in babies weighing less than 1800 grams, born of HepB surface-antigen-negative mothers. Methods: The first vaccine dose was given once clinical stability was achieved, with second and third doses given 1 and 6 months later, respectively. HepB serology, done using Abbott ElA (phase 1) and Abbott Axsym (phase 2) before and after June 2001, respectively, was checked at birth (Sero1), prior to (Sero2) and 6 months after (Sero3) the third dose. A booster dose was recommended when Sero3 showed a non-immune status (<10 mIU/mL). Results: Median birth weight and gestational age (n = 118) were 1295 [range 475, 1780] g and 31 [range 24, 37] completed weeks, respectively. Sero1 (median age of 4 [range 1, 34] days) showed 64% (n = 113) to be non-immune. The first dose of vaccine was administered at a median weight of 1268 [range 530, 1790] g, median age of 6 [range 1,63] days and median post-menstrual age of 32 [range 24,37] completed weeks. Sero2 (median age of 179 [range 112,260] days), for 110 babies (93.2%) showed immunity in 48.2% (median titres , Phase 1: 26 [range 10, 150] mIU/mL; Phase 2: 34 [range 10, 1000] mIU/mL). Sero3 revealed seroprotection in 77.8% (median titres , Phase 1: 102 [range 12, 150] mIU/mL; Phase 2: 162 [range 16, 1000] mIU/mL). The more mature the bady at time of first dose, the more likely he is to achieve seroprotection (85% amongst those administered at and beyond 33 weeks; 91% among those administered at and beyond Day 10 at Sero3). Conclusions: Early HepB immunisation in infants <1800 g can be safely recommended, with booster doses necessary at 1 year for some infants. [source] SAFETY OF DEXTROAMPHETAMINE AND COCAINE COMBINATIONS IN COCAINE USERSALCOHOLISM, Issue 2008William Murff Two studies evaluated the safety and abuse liability of d-amphetamine in combination with cocaine in twenty cocaine-using research volunteers maintained in a controlled research laboratory. The first study tested low doses of d-amphetamine (15 mg) administered orally as a 1.5-hr pretreatment before low intranasal doses (48 mg) of cocaine. The study was double-blind, double-dummy, and placebo-controlled. A dose run-up procedure was employed to maximize safety. All drug effects were modest and the main finding of the study was diminished subjective effects of cocaine on a replicate determination of the original cocaine dose. The second study examined higher doses of d-amphetamine (30 mg, p.o.) and cocaine (96 mg, i.n.), alone and in combination, without a gradual dose run-up. Cocaine alone increased subjective mood, cocaine craving, and ratings indicating cocaine abuse potential. Again, replicate administration of cocaine produced lesser subjective effects than the first dose. D-amphetamine alone increased systolic and mean arterial pressures, but produced minimal effects on subjective mood. The combination of d-amphetamine and cocaine never produced effects greater than cocaine alone except for one subject who had an asymptomatic hypertensive episode. The data are interpreted in light of the possible use of stimulants for the treatment of cocaine dependence. [source] Characterization of the Acute Cardiac Electrophysiologic Effects of Ethanol in DogsALCOHOLISM, Issue 9 2007Guilherme Fenelon Background: Alcohol has been related to atrial fibrillation (holiday heart syndrome), but its electrophysiologic actions remain unclear. Methods: We evaluated the effects of alcohol in 23 anesthetized dogs at baseline and after 2 cumulative intravenous doses of ethanol: first dose 1.5 ml/kg (plasma level 200 mg/dl); second dose 1.0 ml/kg (279 mg/dl). In 13 closed-chest dogs (5 with intact autonomic nervous system, 5 under combined autonomic blockade and 3 sham controls), electrophysiologic evaluation and monophasic action potential (MAP) recordings were undertaken in the right atrium and ventricle. In 5 additional dogs, open-chest biatrial epicardial mapping with 8 bipoles on Bachmann's bundle was undertaken. In the remaining 5 dogs, 2D echocardiograms and ultrastructural analysis were performed. Results: In closed-chest dogs with intact autonomic nervous system, ethanol had no effects on surface electrocardiogram and intracardiac variables. At a cycle length of 300 milliseconds, no effects were noted on atrial and ventricular refractoriness and on the right atrial MAP. These results were not altered by autonomic blockade. No changes occurred in sham controls. In open-chest dogs, ethanol did not affect inter-atrial conduction time, conduction velocity, and wavelength. Atrial arrhythmias were not induced in any dog, either at baseline or after ethanol. Histological and ultrastructural findings were normal but left ventricular (LV) ejection fraction decreased in treated dogs (77 vs. 73 vs. 66%; p = 0.04). Conclusion: Ethanol at medium and high doses depresses LV systolic function but has no effects on atrial electrophysiological parameters. These findings suggest that acute alcoholic intoxication does not directly promote atrial arrhythmias. [source] Effect of Repeated Doses of Ethanol on Hepatic Mg2+ Homeostasis and MobilizationALCOHOLISM, Issue 7 2007Andrew Young The acute administration of a first dose of ethanol (EtOH) to rat liver cells reduces the amount of Mg2+ extruded by a second dose of EtOH or the subsequent addition of adrenergic agonists. In contrast, the Mg2+ extrusion normally elicited by the ,1 -adrenergic or , -adrenergic agonist does not impair the Mg2+ mobilization induced by the subsequent addition of EtOH. Inhibition of EtOH metabolism by 4-methylpyrazole abolishes almost completely the Mg2+ extrusion induced by the first dose of EtOH, and partially enlarges that elicited by the second dose of alcohol or the subsequent adrenergic stimulation. Ethanol-treated liver cells stimulated by the adrenergic agonist show a reduced level of membrane-bound G,s as well as a reduced cellular cAMP content. Analysis of cellular Mg2+ distribution indicates that EtOH administration decreases the Mg2+ content of the cytoplasm, mitochondria, and endoplasmic reticulum to a comparable extent. These data indicate that acute EtOH administration directly impairs cellular Mg2+ homeostasis and also prevents a further Mg2+ mobilization by additional doses of alcohol or ,1 -adrenoceptor and , -adrenoceptor agonist by decreasing cytosolic and intraorganelle Mg2+ content and by affecting G-protein membrane distribution/signaling. [source] The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trialsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2009C. VEYRAT-FOLLET Summary.,Background: Idraparinux, a long-acting synthetic pentasaccharide, is a specific antithrombin-dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events. Objectives: To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials. Patients and methods: Idraparinux was administered once-weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance <30 mL min,1). A population pharmacokinetic model was developed using data from 704 patients with acute deep-vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations. Results: A three-compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady-state were 0.0255 L h,1, 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half-life was 66.3 days and time to steady-state was 35 weeks. At steady-state, exposures were similar for patients without and with severe renal impairment receiving adjusted-dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux , rapid onset of action and long-acting anticoagulant effect , offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux. [source] Anaphylactic reaction after the first dose of sublingual immunotherapy with grass pollen tabletALLERGY, Issue 6 2009Hans De Groot No abstract is available for this article. [source] Tenoxicam controls pain without altering orthodontic movement of maxillary caninesORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 1 2009GM Arantes Structured Abstract Authors,,, Arantes GM, Arantes VMN, Ashmawi HA, Posso IP Objectives,,, To study the efficacy of tenoxicam for pain control, its potential for preemptive analgesia, and its influence on the orthodontic movement of upper canine teeth. Design,,, This was a randomized controlled double-blind cross-over study. The patients were divided into three groups. Two groups received tenoxicam in daily doses of 20 mg orally for 3 days. Group A received the first dose of the drug before orthodontic activation and group B, just afterwards. Group C (control) received a placebo for 3 days. All groups had access to 750 mg of paracetamol up to four times a day. Three orthodontic activations were performed at 30-day intervals. Each patient belonged to two different groups. Pain intensity was assessed using a descriptive Pain Scale and a Visual Analog Scale. Setting and Sample Population,,, Private clinic; 36 patients undergoing bilateral canine tooth retraction. Results,,, The statistical analysis did not show any difference in movement between the active groups and the control at any time. There was no statistical difference between the groups that received tenoxicam. Pain intensity in these groups was lower than in the placebo group. The difference in pain intensity between the active groups and the control was greatest at the assessment made 12 h after activation and it tended to zero, 72 h after activation. Conclusions,,, Tenoxicam did not influence orthodontic movement of the upper canines. It was effective for pain control and did not present any preemptive analgesic effect. [source] Recovery characteristics of sevoflurane or halothane for day-case anaesthesia in children aged 1,3 yearsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 1 2000H. Viitanen Background: Our objective was to compare the recovery characteristics of sevoflurane and halothane for short day-case anaesthesia in a specifically limited age group of children 1,3 yr. Methods: Eighty unpremedicated children undergoing day-case adenoidectomy were randomly assigned to receive inhalational induction with either sevoflurane 8% or halothane 5% and nitrous oxide in oxygen (70/30) via a face mask. Tracheal intubation was performed without a muscle relaxant. Anaesthesia was continued with the volatile anaesthetic, adjusted to maintain heart rate and blood pressure within ±20% of initial values. Recovery was evaluated using a modified Aldrete score, a Pain/Discomfort scale and by measuring recovery end-points. A postoperative questionnaire was used to determine the well-being of the child at home until 24 h after discharge. Results: Emergence and interaction occurred significantly earlier after sevoflurane than halothane but discharge times were similar. More children in the sevoflurane group achieved full Aldrete scores within the first 30 min after anaesthesia, although this group suffered more discomfort during the first 10 min. The amount of postoperative analgesic administered was higher and the first dose given earlier in the sevoflurane group. Postoperative vomiting was more common with halothane, but side-effects in the two groups were otherwise similar in the recovery room and at home. Conclusions: In children 1,3 yr, sevoflurane provided more rapid early recovery but not discharge after anaesthesia of <30-min duration. Apart from more vomiting with halothane and more discomfort during the first 10 min after awakening with sevoflurane, the quality of recovery was similar with the two anaesthestics. [source] Co-administration of salbutamol and fluticasone for emergency treatment of children with moderate acute asthma,PEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 7 2005Elizabeth Estrada-Reyes This study aimed to compare the efficacy of nebulized therapy with salbutamol alone or in combination with fluticasone. In a randomized, double-blind clinical trial, 150 children with moderate acute asthma were randomly assigned to receive by nebulizations either (i) three doses of salbutamol 30 ,l/kg per dose, each dose administered every 15 min, (ii) three doses of salbutamol plus two doses of fluticasone 500 ,g/dose at 15 and 30 min after first dose of salbutamol, or (iii) three doses of salbutamol/fluticasone 500 ,g/dose, each combined dose administered every 15 min. Pulse oxymetry (SaO2), peak expiratory flow (PEF) and Wood et al. (Am J Dis Child, 123, 1972, 123) clinical scale were evaluated at baseline, 15, 30, 45, 60, 90 and 120 min after the first nebulization. Patients in the three groups significantly improved since 15 min after the first nebulization. We did not observe differences in the recovery of SaO2 and PEF among the three groups of treatment (p > 0.10). In group 3, children showed better clinical response at 120 min than the other two groups (p < 0.05). No significant adverse effects were observed with any treatment. To summarize, in children with acute moderate asthma, nebulized salbutamol at an accumulated dose of 90 ,l/kg plus fluticasone at an accumulated dose of 1500 ,g produced better clinical relief after 2 h. However, similar PEF and SaO2 responses were observed with salbutamol alone or in combination with different doses of fluticasone. [source] Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib,AMERICAN JOURNAL OF HEMATOLOGY, Issue 10 2009Raman Sood This clinical trial was conducted to determine the safety and efficacy of bortezomib retreatment in patients with multiple myeloma (MM) who had previously responded to bortezomib. Patients with progressive MM who had previously tolerated bortezomib as a single agent or in combination with other drugs, with a minimum of partial response (PR; ,50% M-protein reduction) for ,4 months, who had not received intervening MM therapy, were retreated with bortezomib (days 1, 4, 8, and 11 of a 21-day cycle) with a starting dose being the dose at which the patient ended the initial treatment. Patients were allowed to receive bortezomib on retreatment in combination with dexamethasone, thalidomide, or doxorubicin. Thirty-two patients received bortezomib retreatment (most with added dexamethasone). The median treatment-free interval (last dose of initial bortezomib treatment to first dose of retreatment) was 9.9 (range 2.5,34.0) months. The median duration of retreatment was 2.8 (<1,7.9) months; median total duration of bortezomib treatment was 6.7 (2.5,19.8) months. Based on the investigators' assessment of best response, the overall response rate (complete plus PR) was 50%. The median time from start of retreatment to progressive disease (PD) was 6.6 (95% confidence interval: 5.1,9.6) months. Thirteen patients (41%) experienced PN; bortezomib-related SAEs were reported in four patients. Retreatment with bortezomib alone or in combination is effective and well tolerated in patients with MM who have responded to their initial bortezomib treatment. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source] Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: A children's oncology group study,,PEDIATRIC BLOOD & CANCER, Issue 4 2010MRCP, Rani E. George MD Abstract Background Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors. Procedure Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hr decitabine infusion for 7 days, followed by doxorubicin (45,mg/m2) and cyclophosphamide (1,g/m2) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells. Results The maximum-tolerated dose of decitabine was 5,mg/m2/day for 7 days. Dose-limiting toxicities at 10,mg/m2/day were neutropenia and thrombocytopenia. Decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for ,4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16, respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis. Conclusion Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deactelyase inhibitors should be explored. Pediatr Blood Cancer. 2010;55:629,638. © 2010 Wiley-Liss, Inc. [source] Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantationPEDIATRIC TRANSPLANTATION, Issue 2003Bruce Bostrom Abstract: We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean ± SD, 1.21 ± 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4,12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis. [source] Real-Life Safety and Efficacy of Vardenafil in the Treatment of Erectile Dysfunction,Results from 30,010 U.S. PatientsTHE JOURNAL OF SEXUAL MEDICINE, Issue 2 2007Eric Cheng MD ABSTRACT Introduction., Clinical trials show that vardenafil produces effective and satisfactory first-dose success rates and reliability for erection and intercourse in men with erectile dysfunction (ED). Aim., This study was conducted to evaluate real-life efficacy, safety, and acceptance of vardenafil in men with ED. Methods., This open-label, prospective study, conducted in 6,740 U.S. centers, included an initial visit and one or two follow-up visits within a 2-month period of the first vardenafil dose. Vardenafil was administered in 5,20 mg doses. Main Outcome Measures., Efficacy variables included first-dose success rates for vaginal penetration, maintenance of erection, and satisfaction based on physician and patient assessments. Safety was assessed by adverse events (AEs). Results., A total of 30,010 men were included in the safety/intent-to-treat (S/ITT) analysis, with 26,043 men in the adjusted S/ITT population. Vardenafil improved erectile function in 78% of men, with 75% rating overall efficacy as "satisfying" or "very satisfying." The overall rates of successful penetration and maintenance with vardenafil following the first dose were 78% and 68%, respectively. For men with mild and moderate ED, first-dose success rates for penetration were 89% and 82%, respectively, and for maintenance, 82% and 71%, respectively. First-dose penetration and maintenance of erection rates were 76% and 66%, respectively, for men with self-reported hypertension, and 70% and 60%, respectively, for men with diabetes mellitus. At study end, 67% of patients preferred to continue using vardenafil. The most frequently reported AEs were headache (4%) and flushing (2%). Vardenafil was well tolerated, with a "satisfied/very satisfied" tolerability rating in 75% of cases as assessed by the physician. Conclusions., This observational study demonstrated the tolerability and efficacy of vardenafil in men with ED and comorbidities. Vardenafil provided a high rate of first-dose intercourse success and a favorable safety profile in patients with and without comorbid disease. Cheng E. Real-life safety and efficacy of vardenafil in the treatment of erectile dysfunction,Results from 30,010 U.S. patients. J Sex Med 2007;4:432,439. [source] Efficacy and Safety of Oral Tadalafil in the Treatment of Men in Canada with Erectile Dysfunction: A Randomized, Double-Blind, Parallel, Placebo-Controlled Clinical TrialTHE JOURNAL OF SEXUAL MEDICINE, Issue 5 2005FRCSC, Serge Carrier MD ABSTRACT Introduction., Erectile dysfunction (ED) is a highly prevalent, often undertreated condition. Aim., This 12-week, double-blind, parallel, placebo-controlled study was conducted at 25 sites in Canada to evaluate the efficacy and safety of oral tadalafil, a phosphodiesterase type 5 inhibitor, for the treatment of ED. Methods., Men with ED of organic, psychogenic, or mixed etiology were stratified by baseline ED severity then randomly assigned to placebo (N = 50), tadalafil 10 mg (N = 103), or tadalafil 20 mg (N = 100), taken as needed (maximum, once daily). Main Outcome Measures., Efficacy was assessed by the International Index of Erectile Function (IIEF), a Sexual Encounter Profile diary, and a global assessment question (GAQ). Results., Tadalafil 10 mg and tadalafil 20 mg significantly improved erectile function compared with placebo (P < 0.001, all measures). At end point, the mean IIEF erectile function (EF) domain scores were 14.5, 21.2, and 23.3 of a possible score of 30 for placebo, tadalafil 10 mg, and tadalafil 20 mg, respectively. Patients treated with tadalafil reported greater change from baseline on the IIEF EF domain score compared with placebo, regardless of baseline ED severity. During treatment, the mean per-patient proportion of successful intercourse attempts was higher for tadalafil 10 mg and 20 mg than for placebo (placebo, 31.9%; tadalafil 10 mg, 56.7%; and tadalafil 20 mg, 61.5%), and a greater proportion of patients reported improved erections with tadalafil (GAQ; placebo, 22.0%; tadalafil 10 mg, 67.0%; tadalafil 20 mg, 79.0%). Fifty percent and 62% of patients treated with tadalafil 10 mg and 20 mg, respectively, achieved successful sexual intercourse after their first dose, compared with 31% with placebo. Treatment-emergent adverse events were generally mild or moderate. Conclusion., Tadalafil was an effective, well-tolerated therapy for ED of broad-spectrum etiology and severity. Carrier S, Brock GB, Pommerville PJ, Shin J, Anglin G, Whitaker S, and Beasley CM Jr. Efficacy and safety of oral tadalafil in the treatment of men in Canada with erectile dysfunction: A randomized, double-blind, parallel, placebo-controlled clinical trial. J Sex Med 2005;2:685,698. [source] Effects of infliximab therapy on gene expression levels of tumor necrosis factor ,, tristetraprolin, T cell intracellular antigen 1, and Hu antigen R in patients with rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 7 2007Makoto Sugihara Objective Tristetraprolin (TTP), T cell intracellular antigen 1 (TIA-1), and Hu antigen R (HuR) are adenine/uridine-rich element binding proteins (ABPs) that affect the production of tumor necrosis factor , (TNF,) by binding to TNF messenger RNA (mRNA). TTP promotes deadenylation, TIA-1 inhibits translation, and HuR stabilizes TNF, mRNA. The aims of this study were to understand the posttranscriptional control of TNF, production in patients with rheumatoid arthritis (RA), and to identify parameters that may predict the efficacy of anti-TNF, therapy. Methods Peripheral blood mononuclear cells from 38 patients with RA were obtained before therapy and 2 weeks and 54 weeks after administration of the first dose of infliximab, and from 20 healthy control subjects. TNF,, TTP, TIA-1, and HuR gene expression levels were analyzed by real-time polymerase chain reaction. Results At baseline, TTP and HuR gene expression levels, as well as the TTP:TNF,, TTP:HuR, and TIA-1:TNF, gene expression ratios were lower in patients with RA than in control subjects, while expression of TNF,, TIA-1, and TIA-1:HuR was higher in patients with RA. The TTP:HuR expression ratio decreased significantly after administration of infliximab. Positive correlations were observed between TNF, and TTP, TNF, and TIA-1, TIA-1 and HuR, and TNF, and HuR gene expression in both healthy control subjects and patients with RA. At baseline, the TIA-1:HuR ratio tended to be higher in patients who achieved 50% improvement according to the American College of Rheumatology criteria (ACR50) at week 54 than in those who did not achieve at least an ACR20 response. Conclusion Differences in ABP gene expression may affect TNF, gene expression. A higher TIA-1:HuR expression ratio might correlate with the response to infliximab therapy. [source] | ||||||||||||||||||||||||||||