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Loading Dose (loading + dose)
Selected AbstractsMeasurement of Antiplatelet Inhibition during Neurointerventional Procedures: The Effect of Antithrombotic Duration and Loading DoseJOURNAL OF NEUROIMAGING, Issue 1 2010DJ Pandya MD ABSTRACT BACKGROUND/OBJECTIVE Symptomatic thromboembolic events are the most common complications associated with aneurysm coiling, and carotid and intracranial stenting. Our objective is to assess the effect of aspirin (ASA) and clopidogrel dose and duration on platelet inhibition using a point of care assay in neurointerventional (NI) suite. METHOD The dose, duration, and point of care platelet function assay data for clopidogrel and aspirin therapy were prospectively collected between February 2006 and November 2007. Inadequate platelet inhibition for ASA was defined as ,550 ASA reaction units (ARU), and for clopidogrel was defined as ,50% inhibition of the P2Y12/ADP receptor RESULTS We collected data from 216 consecutive patients. Inadequate platelet inhibition was noted in 13% of patients on aspirin and 66% of patients on clopidogrel (P -value < .0001). Patients taking clopidogrel 75 mg for ,7 days, 300 mg for 24 hours, and 600 mg same day load had a mean P2Y12/ADP inhibition of 45%, 35% (P- value = .09), and 16%, respectively (P -value = .005). CONCLUSION Premedication with clopidogrel, in contrast to aspirin, does not achieve adequate platelet inhibition in about two-third of the patients. Same day antiplatelet loading may be insufficient to achieve adequate platelet inhibition and should be avoided if clinically feasible. J Neuroimaging 2010;20:64-69. [source] Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder,DEPRESSION AND ANXIETY, Issue 5 2010Vladimir Coric M.D. Abstract Background: Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). Method: This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100,mg/day (after a 1 week loading dose of 300,mg/day), placebo or escitalopram 20,mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. Results: Pexacerfont 100,mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20,mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2-2016) with the HAM-A psychic subscale score for the entire cohort at baseline (FDR-adjusted P=.015). Conclusions: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment. Depression and Anxiety, 2010. © 2010 Wiley-Liss, Inc. [source] Single layer centrifugation of stallion spermatozoa consistently selects the most robust spermatozoa from the rest of the ejaculate in a large sample sizeEQUINE VETERINARY JOURNAL, Issue 7 2010J. M. MORRELL Summary Reasons for performing study: An improvement in sperm quality after single layer centrifugation (SLC) has been seen in previous studies using small sample sizes (for example, n = 10 stallions). There is a need to investigate whether this improvement is repeatable over several breeding seasons with a larger number of stallions (n , 30 stallions). Objective: To make a retrospective analysis of the results of SLC performed on more than 250 sperm samples (176 ejaculates) from 31 stallions in 3 consecutive breeding seasons. Methods: Sperm quality (motility, proportion of morphologically normal spermatozoa and the proportion of spermatozoa with undamaged chromatin) was assessed before and after SLC. Results: All parameters of sperm quality examined were significantly better in sperm samples after SLC than in their unselected counterparts (P<0.001 for each parameter). The yield of spermatozoa obtained after SLC was influenced by the type of extender used and also by the concentration of spermatozoa in the original ejaculate, with fewer spermatozoa being recovered when the loading dose contained a high concentration of spermatozoa. The optimal concentration was approximately 100 × 106/ml. Sperm concentration in the samples loaded on to the colloid influenced the sperm yield while the type of semen extender affected sperm quality and survival. Furthermore, the scaled-up SLC method was found to be suitable for use with a range of ejaculates, with similar sperm kinematics being observed for standard and scaled-up preparations. Conclusions: SLC consistently improved the quality of stallion sperm samples from a large number of ejaculates. The method could be scaled-up, allowing larger volumes of ejaculate to be processed easily from a wide range of stallions. [source] Effects of an adapted intravenous amiodarone treatment protocol in horses with atrial fibrillationEQUINE VETERINARY JOURNAL, Issue 4 2007D. de CLERCQ Summary Reason for performing study: Good results have been obtained with a human amiodarone (AD) i.v. protocol in horses with chronic atrial fibrillation (AF) and a pharmacokinetic study is required for a specific i.v. amiodarone treatment protocol for horses. Objectives: To study the efficacy of this pharmacokinetic based i.v. AD protocol in horses with chronic AF. Methods: Six horses with chronic AF were treated with an adapted AD infusion protocol. The protocol consisted of 2 phases with a loading dose followed by a maintenance infusion. In the first phase, horses received an infusion of 6.52 mg AD/kg bwt/h for 1 h followed by 1.1 mg/kg bwt/h for 47 h. In the second phase, horses received a second loading dose of 3.74 mg AD/kg bwt/h for 1 h followed by 1.31 mg/kg bwt/h for 47 h. Clinical signs were monitored, a surface ECG and an intra-atrial electrogram were recorded. AD treatment was discontinued when conversion or any side effects were observed. Results: Three of the 6 horses cardioverted successfully without side effects. The other 3 horses did not convert and showed adverse effects, including diarrhoea. In the latter, there were no important circulatory problems, but the diarrhoea continued for 10,14 days. The third horse had to be subjected to euthanasia because a concomitant Salmonella infection worsened the clinical signs. Conclusion: The applied treatment protocol based upon pharmacokinetic data achieved clinically relevant concentrations of AD and desethylamiodarone. Potential relevance: Intravenous AD has the potential to be an alternative pharmacological treatment for AF in horses, although AD may lead to adverse drug effects, particularly with cumulative dosing. [source] Effects of intravenous lidocaine overdose on cardiac electrical activity and blood pressure in the horseEQUINE VETERINARY JOURNAL, Issue 5 2001G. A. MEYER Summary This study aimed to identify blood serum lidocaine concentrations in the horse which resulted in clinical signs of intoxication, and to document the effects of toxic levels on the cardiovascular and cardiopulmonary systems. Nineteen clinically normal mature horses of mixed breed, age and sex were observed. Lidocaine administration was initiated in each subject with an i.v. loading dose of 1.5 mg/kg bwt and followed by continuous infusion of 0.3 mg/kg bwt/min until clinical signs of intoxication were observed. Intoxication was defined as the development of skeletal muscle tremors. Prior to administration of lidocaine, blood samples for lidocaine analysis, heart rate, mean arterial blood pressure, systolic blood pressure, diastolic blood pressure, respiratory rate and electrocardiographic (ECG) data were collected. After recording baseline data, repeat data were collected at 5 min intervals until signs of intoxication were observed. The range of serum lidocaine concentrations at which the clinical signs of intoxication were observed was 1.85,4.53 ,g/ml (mean ± s.d. 3.24 ± 0.74 ,g/ml). Statistically significant changes in P wave duration, P-R interval, R-R interval and Q-T interval were observed in comparison to control values, as a result of lidocaine administration. These changes in ECG values did not fall outside published normal values and were not clinically significant. Heart rate, blood pressures and respiratory rates were unchanged from control values. This study establishes toxic serum lidocaine levels in the horse, and demonstrates that there were no clinically significant cardiovascular effects with serum lidocaine concentrations less than those required to produce signs of toxicity. [source] Intravenous Valproate Sodium in the Treatment of Daily HeadacheHEADACHE, Issue 6 2002Tamara H. Schwartz MD Background.,Treatment of chronic daily headache/transformed migraine is challenging, especially when it is complicated by overuse of analgesics, triptans, or both. One common approach involves the use of repetitive intravenous dihydroergotamine. We investigated the use of intravenous valproate sodium in the treatment of chronic daily headache/transformed migraine in patients who had contraindications to the use of or had failed treatment with dihydroergotamine. Methods.,We administered intravenous valproate sodium (Depacon) to patients with chronic daily headache/transformed migraine (loading dose 15 mg/kg, followed by 5 mg/kg every 8 hours). All analgesics and triptans were discontinued prior to treatment with divalproex sodium, and preventative medications for migraine were begun or continued. All patients received instruction in behavioral modification and the proper use of analgesics and triptans. Results.,Improvement in headache was reported by 80% of the patients treated, and valproate sodium was tolerated well by most. Conclusion.,Intravenous valproate sodium may be of assistance in the initial management of patients with chronic daily headache/transformed migraine and analgesic/triptan overuse, especially when dihydroergotamine is ineffective or contraindicated. [source] Acyclovir-induced neuropsychosis successfully recovered after immediate hemodialysis in an end-stage renal disease patientINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 8 2007Hung-Hsu Yang MD A 70-year-old man developed herpes zoster over the right L5,S2 region for 3 days and was admitted for acyclovir therapy. He had a medical history of rectal cancer status post-colostomy and end-stage renal disease undergoing thrice weekly hemodialysis. Without a prior loading dose, acyclovir 500 mg (7.7 mg/kg) daily was given intravenously in two divided doses. On the third dosage, the patient became confused and agitated and developed insomnia. Within the following 24 h, delirium, visual and auditory hallucinations, disorientation to place and time, as well as impaired recent memory occurred. At the same time, a transient low grade fever (38 °C) was noted but resolved spontaneously after ice pillow (Fig. 1). Figure 1. The clinical and treatment course of the patient The etiology was vigorously explored. He had no history of any neurological or psychiatric disorders. Drug history was reviewed, but no other medications besides acyclovir were currently being used. Physical examination revealed neither meningeal signs nor focal neurological deficits. Serum blood urea nitrogen, glucose, and electrolytes were within normal limits except for an elevated creatinine level at 6.2 and 5.7 mg/dl (before and after neuropsychotic symptoms, respectively). Complete blood count with differentiation was also unremarkable. Cerebrospinal fluid examination was not possible as the patient's family refused the lumbar puncture. Moreover, an electroencephalograph study and head computed tomography scan disclosed no abnormalities. Acyclovir-induced neurotoxicity was suspected. Therefore, acyclovir was discontinued. Subsequently, serum acyclovir and CMMG were checked by enzyme-linked immunosorbent assay. Serum acyclovir level was 1.6 mg/l (normal therapeutic level, 0.12,10.8 mg/l) and CMMG level was 5 mg/l. Emergent hemodialysis (4-h/session) was given; the neuropsychotic symptoms, including agitation, delirium, and visual and auditory hallucinations, greatly abated after the second session. The patient fully recovered after three consecutive days of hemodialysis; the serum was rechecked and revealed that the acyclovir level was below 0.5 mg/l and the CMMG level was undetectable. At the same time, his herpetic skin lesions resolved well. [source] A case of fatal caffeine poisoningACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2010T. RUDOLPH Caffeine is a natural alkaloid methylxanthine that is found in various plants such as coffee or tea. Symptoms of a severe overdose may present with hypokalemia, hyponatremia, ventricular arrhythmias, hypertension followed by hypotension, respiratory failure, seizures, rhabdomyolysis, ventricular fibrillation and finally circulatory collapse. A 21-year-old woman called for the ambulance herself soon after the ingestion of about 10,000 mg of caffeine. At the arrival of the ambulance, the patient went into cardiac arrest almost immediately. After a total resuscitation period of 34 min including seven counter-shocks and 2 mg epinephrine, the patient was stable enough to be transferred to the hospital. The patient soon went into VF again and received two more counter-shocks and 1 mg epinephrine and finally an intravenous bolus dose of 300 mg amiodarone. The initial arterial blood gas showed pH at 6.47, lactate at 33 mmol/l and potassium level at 2.3 mmol/l. Unfortunately, no blood samples for caffeine analysis were taken. Three days after hospital admission, the patient developed myoclonus, which did not respond to medical treatment. Excessive intake of caffeine may produce arrhythmias and pronounced hypokalemia and ensuing ventricular fibrillation. In case of counter-shock-resistant VF, it can be necessary to give an early loading dose of amiodarone. Furthermore, it may be beneficial to replace the potassium as early as possible. Epinephrine and buffer solutions used during resuscitation may further decrease blood potassium levels and should be administrated cautiously. Epinephrine can be replaced by other vasopressor drugs, such as vasopressin without effects on ,-receptors. [source] Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver diseaseJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2009D. S. Small PhD Summary Background and Objective:, Prasugrel is a thienopyridine antiplatelet agent under investigation for the prevention of atherothrombotic events in patients with acute coronary syndrome who undergo percutaneous coronary intervention. Patients with chronic liver disease are among those in the target population for prasugrel. As hepatic enzymes play a key role in formation of prasugrel's active metabolite, hepatic impairment could affect the safety and/or efficacy of prasugrel in such patients. Methods:, This was a parallel-design, open-label, multiple dose study of 30 subjects, 10 with moderate hepatic impairment (Child-Pugh Class B) and 20 with normal hepatic function. Prasugrel was administered orally as a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MDs) for 5 days. Pharmacokinetic parameters (AUC0,t, Cmax and tmax) and maximal platelet aggregation (MPA) by light transmission aggregometry were assessed after the LD and final MD. Results and Discussion:, Exposure to prasugrel's active metabolite was comparable between healthy subjects and those with moderate hepatic impairment. Point estimates for the ratios of geometric least square means for AUC0,t and Cmax after the LD and last MD ranged from 0·91 to 1·14. MPA to 20 ,m ADP was similar between subjects with moderate hepatic impairment and healthy subjects for both the LD and MD. Prasugrel was well tolerated by all subjects, and adverse events were mild in severity. Conclusion:, Moderate hepatic impairment appears to have no effect on exposure to prasugrel's active metabolite. Furthermore, MPA results suggest that moderate hepatic impairment has little or no effect on platelet aggregation relative to healthy controls. Overall, these results suggest that a dose adjustment would not be required in moderately hepatically impaired patients taking prasugrel. [source] Development and Validation of a Risk Scoring Model to Predict Net Adverse Cardiovascular Outcomes after Primary Percutaneous Coronary Intervention in Patients Pretreated with 600 mg Clopidogrel: Rationale and Design of the RISK-PCI StudyJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 4 2009IGOR MRDOVIC M.D., Ph.D Background: No comprehensive primary PCI (pPCI) risk model to predict net adverse cardiovascular events (NACE) has been reported with the use of clopidogrel 600 mg, which is now considered the standard loading dose. The primary hypothesis of the RISK-PCI trial is that an accurate risk prediction may be achieved by using clinical, angiographic, and procedural variables available at the time of intervention. Methods: The present single-center, longitudinal, cohort study will include 1,750 consecutive patients with ST-elevation myocardial infarction (STEMI), undergoing pPCI after pretreatment with 300 mg aspirin and 600 mg clopidogrel. The primary end-points of the trial (NACE) include major adverse cardiovascular events (MACE) and major bleeding. A logistic regression model will be developed to predict 30-day and 1-year NACE after pPCI. A risk score derived from study set data will be validated using validation set data. Results: Until June 1, 2008, 1,166 patients have been enrolled. Thirty-day follow-up is available in 1,007 patients. Conclusions: The RISK-PCI study is designed to develop an accurate risk scoring system, using variables available at the time of intervention, to predict long-term adverse outcomes after pPCI. Trial Registration: Current Controlled Trials Register,ISRCTN83474650,http://www.controlled-trials.com/ISRCTN83474650). [source] Impact of Thienopyridine Administration Prior to Primary Stenting in Acute Myocardial InfarctionJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 4 2009LEROY E. RABBANI M.D. The impact of thienopyridine administration prior to primary stenting in acute myocardial infarction (AMI) has not been well studied. We therefore examined the database from the prospective, multicenter, controlled CADILLAC trial in which 1,036 patients were randomized to bare metal stenting with or without abciximab to determine whether patients who received a thienopyridine prior to bare metal stenting in AMI had superior clinical outcomes. Per operator discretion, 659 patients (63.6%; Th+) received either a 500 mg ticlopidine loading dose (n = 623) or a 300 mg clopidogrel loading dose (n = 40), while 377 patients (36.4%; Th-) received no thienopyridine prior to stent implantation. Baseline and procedural characteristics of the two groups, including abciximab use (52.5% vs 52.8%, P = 0.93) were well matched. Th+ compared to Th- patients had lower rates of core lab assessed TIMI 0/1 flow postprocedure (0.8% vs 2.7%, P = 0.01). Th+ compared to Th- patients also had significantly reduced in-hospital and 30-day rates of ischemic target vessel revascularization (TVR) (1.1% vs 3.2%, P = 0.01 and 1.5% vs 3.8%, P = 0.02, respectively) and major adverse cardiovascular events (MACE) (2.7% vs 5.8%, P = 0.01 and 4.0% vs 6.9%, P = 0.03, respectively), results that remained significant after covariate adjustment. In conclusion, in this large prospective, controlled trial, patients receiving a thienopyridine prior to primary stenting in AMI were less likely to have TIMI 0/1 flow postprocedure and experienced reduced in-hospital and 30-day rates of ischemic TVR and MACE compared to those not administered a thienopyridine prior to stent implantation. [source] Crushed Clopidogrel Administered via Nasogastric Tube Has Faster and Greater Absorption than Oral Whole TabletsJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 4 2009M. UROOJ ZAFAR M.B.B.S. Objectives: To compare the absorption of 300 mg clopidogrel administered crushed via nasogastric (NG) tube versus whole tablets taken orally in healthy volunteers. Background: Earlier antiplatelet therapy has proven benefits in treatment of myocardial infarction and in patients undergoing PCI. Aspirin can be delivered early in crushed form via NG tube after CABG surgery to prevent graft occlusion. If clopidogrel given crushed via NG tube provides faster absorption, it could allow earlier clopidogrel loading. Methods: Nine healthy human subjects (34.7 ± 11.1 years, 5 males) were given 300 mg clopidogrel in crushed form via NG tube with 30 mL water after 8 hours of fasting. Plasma levels of the primary circulating inactive clopidogrel metabolite SR26334 were measured after 20 minutes, 40 minutes, 1, 2, 4, 8, 12, and 24 hours of dosing. Following ,2 week washout, same subjects swallowed 300 mg clopidogrel (four 75 mg tablets) after an 8-hour fasting and SR26334 levels were measured at the same time points. Results: Plasma SR26334 concentrations peaked earlier after crushed delivery than after oral intake (44 vs. 70 minutes, P = 0.023) and the median peak was 80% higher (13,083 vs. 7,255 ng/mL, respectively, P = 0.021). At 40 minutes, area under the curve was almost twofold greater with NG administration than oral administration (geometric means ratio = 0.5299, 95% CI = 0.28,0.99, P = 0.048), but was similar over the 24-hour period with both administration methods (geometric means ratio = 1.05, 95% CI = 0.84,1.32, P = 0.646). Conclusions: A 300 mg loading dose of crushed clopidogrel administered via NG tube provides faster and greater bioavailability than an equal dose taken orally as whole tablets. The clinical benefits of this strategy need to be investigated. [source] Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in rats after inhibition of P-glycoproteinJOURNAL OF NEUROCHEMISTRY, Issue 2 2002Jörn Lötsch Abstract Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward transporter at the blood,brain barrier. Inhibition of P-gp may therefore be expected to cause increased CNS uptake of M6G. We directly assessed the spinal concentrations of M6G and its antinociceptive effects in rats following pharmacological inhibition of P-gp. Spinal cord tissue concentrations of M6G were assessed by microdialysis with probes transversally implanted through the dorsal horns of the spinal cord at level L4. Ten rats received M6G intravenously (0.018 mg/kg loading dose plus 0.00115 mg/kg/min for an 8-h infusion), five of them together with PSC833 to inhibit P-gp (32-h infusion, starting 24 h before the addition of M6G). Antinociceptive effects were explored by means of formalin tests. After having obtained evidence for enhanced CNS uptake and antinociception of M6G in the presence of PSC833, additional behavioural experiments were performed in another 32 rats to assess the dose dependency of the antinociceptive effects of M6G either with or without PSC833 in comparison with both PSC833 alone and placebo. Inhibition of P-gp increased the M6G concentrations in the spinal cord approximately three-fold whereas the plasma concentrations were increased only by a factor of 1.4, which resulted in a more than doubled spinal cord/plasma concentration ratio (from 0.08 ± 0.03 for M6G alone to 0.17 ± 0.08 for M6G plus PSC833). Antinociceptive effects of M6G were significantly enhanced by inhibition of P-gp. Inhibition of P-gp alters the transport of M6G across the blood,brain barrier, resulting in enhanced spinal cord uptake and enhanced antinociception. [source] Drug treatment of neonatal seizures by neonatologists and paediatric neurologistsJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 7 2005Kathryn Browning Carmo Objective:, To survey anti-epileptic drug (AED) treatment of early-onset neonatal seizures by neonatologists and paediatric neurologists. Methods:, A self-administered questionnaire was posted to Australian and New Zealand neonatologists and paediatric neurologists. Participants were given the hypothetical case of a full-term infant with early-onset seizures following perinatal asphyxia and asked to nominate their preferred AED for treatment of three seizure episodes during the first 24 h. Results:, One hundred and seven (57%) of 187 individuals answered the questionnaire: neonatologists responded more often than neurologists (,2 (1,187) = 7.18, P = 0.007). Phenobarbitone was used by 95% of the respondents to treat the first episode of seizures and 75% of them used an appropriate loading dose (20 mg/kg). Phenobarbitone was used by 84 and 40% of the respondents to treat the second- and third-seizure episodes, respectively. Neonatologists used phenobarbitone, phenytoin and a benzodiazepine with equal frequency to treat a third episode of seizures, whereas neurologists rarely used a benzodiazepine. Neonatologists used significantly larger total doses of phenobarbitone than neurologists. Very few respondents used pyridoxine to treat recurrent seizures that were historically linked to perinatal asphyxia and hypoxic,ischaemic encephalopathy. Neonatologists were more likely than neurologists to discontinue AED within a few days of seizure cessation (,2 (1,106) = 11.60, P = 0.0006). Conclusions:, Australian and New Zealand neonatologists and paediatric neurologists generally use phenobarbitone to treat neonatal seizures presumed to be owing to hypoxic,ischaemic encephalopathy, though they do not always use appropriate doses. Neonatologists use phenobarbitone, phenytoin or a benzodiazepine for second and third episodes of seizures, whereas neurologists tend not to use benzodiazepines. Neonatologists use larger total doses of phenobarbitone than neurologists in pursuit of seizure control. Neonatologists discontinue AED earlier than neurologists. [source] Lack of Clinical Efficacy of a Phosphodiesterase-4 Inhibitor for Treatment of Heaves in HorsesJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2006Jean-Pierre Lavoie Phosphodiesterase-4 (PDE 4) enzyme inhibitors have been shown to have anti-inflammatory properties in various animal disease processes and therefore could be effective drugs for the treatment of equine airway diseases. The purpose of this study was to evaluate the efficacy and adverse effects of the PDE 4 inhibitor L-826,141 in horses with heaves. In a blinded parallel design, horses with heaves exposed daily to moldy hay were given a placebo for 14 days and then administered either L-826,141 (n = 6; loading dose of 1 mg/kg IV followed by 0.5 mg/kg IV q48h) or dexamethasone (n = 6; 0.04 mg/kg IV q24h) from days 15 to 29 (study 1). Pulmonary function and bronchoalveolar (BAL) cytology were evaluated weekly from baseline (day 0) to 29 days. In study 2, horses were treated with L-826,141 (1.0 mg/kg IV q24h) for 8 days. Although ex vivo lipopolysaccharide-induced tumor necrosis factor (TNF)-, and LTB4 production by fresh blood were inhibited up to 90% after repeated administrations of L-826,141, this treatment failed to improve lung function. In contrast, dexamethasone (positive control) treatment resulted in significant improvement in lung mechanics and airway function in all horses. Neither drug had a significant effect on BAL total cell counts and differential cytology. Administration of the PDE 4 inhibitor L-826,141 for up to 14 days to horses with heaves was not associated with an improvement in airway function or inflammation. These findings suggest that the PDE 4 enzyme is not a key mediator of lung inflammation in heaves. [source] Correlation between serum concentrations following continuous intravenous infusion of dexmedetomidine or medetomidine in cats and their sedative and analgesic effectsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2000Ansah Dexmedetomidine (DEX) may have some therapeutic advantages over the racemate medetomidine (MED). Here we have examined how serum concentrations of DEX correlate with some of its anaesthetic effects. Cats (n = 6) were administered with a continuous stepwise intravenous (i.v.) infusion of DEX or MED on different occasions in a cross-over design. Maintenance infusion rates (mg/kg/min) used were: DEX = 0.25 (MED = 0.50); DEX = 1 (MED = 2) and DEX = 4 (MED = 8) for infusion steps 1, 2 and 3, respectively. Each maintenance infusion lasted at least 50 min and was preceded with a loading dose. There was no significant difference between serum DEX and 0.5 serum MED concentrations at any dose level nor was there a significant difference between serum DEX and the (entire) serum MED concentrations. There was no significant difference between DEX and MED for sedation, analgesia, muscular relaxation and heart and respiratory rates. For both DEX and MED, serum drug concentration and analgesia were dose-dependent and sedation increased until the end of infusion step 2 (dose level 2) and decreased at the end of step 3 (dose level 3). Muscular relaxation was not dose-dependent. We conclude that increasing the blood concentration of DEX or MED beyond a certain level decreases the level of sedation instead of increasing it even though analgesia increases. The rate at which DEX and MED are metabolized in cats may not be the same. [source] The prophylactic use of tranexamic acid and aprotinin in orthotopic liver transplantation: A comparative study ,LIVER TRANSPLANTATION, Issue 2 2004Antonia Dalmau The efficacy of tranexamic acid (TA) and aprotinin (AP) in reducing blood product requirements in orthotopic liver transplantation (OLT) was compared in a prospective, randomized and double-blind study. One hundred and twenty seven consecutive patients undergoing OLT were enrolled; TA was administered to 64 OLT patients at a dose of 10mg /kg/h and aprotinin was administered to 63 OLT patients at a loading dose of 2x106 KIU followed by an infusion of 500,000 KIU/h. The portocaval shunt could not be performed in 14 OLT patients in the TA group and in 13 OLT patients in the AP group. However, all OLT patients that received either drug were included in the analysis. Perioperative management was standardized. Hemogram, coagulation tests, and blood product requirements were recorded during OLT and during the first 24 hours. No differences in diagnosis, Child score, preoperative coagulation tests, and intraoperative data were found between groups. No significant differences were observed in hemogram and intraoperative coagulation tests with the exception of activated partial thromboplastin time (aPTT). Similarly, there were no intergroup differences in transfusion requirements. Thromboembolic events, reoperations and mortality were similar in both groups. In conclusion, administration of regular doses of TA and AP during OLT did not result in large differences between the two groups. (Liver Transpl 2004;10:279,284.) [source] Dexmedetomidine and arousal affect subthalamic neurons,MOVEMENT DISORDERS, Issue 9 2008William Jeffrey Elias MD Abstract Stereotactic neurosurgeons hesitate to employ sedation in cases requiring microelectrode recording (MER). We report our experience with dexmedetomidine during MER of subthalamic nucleus (STN). Eleven Parkinsonian patients received dexmedetomidine during deep brain stimulation surgery. Seven received continuous IV infusions during MER in the STN. The bispectral index (BIS) was used to estimate the level of consciousness. The quality of MER was evaluated as a function of BIS, clinical arousal, and dexmedetomidine dose. MER during wakefulness (BIS > 80; 0.1 to 0.4 mcg/kg/hr dexmedetomidine) was similar to the unmedicated state. Subthalamic MER was reduced when the patient was asleep or unarousable (BIS < 80). Anxiolysis persisted for hours. Arousal affects STN neurons. Dexmedetomidine "cooperative sedation," from which the patient is easily aroused, provides interpretable STN MER and prolonged anxiolysis. We suggest dexmedetomidine infusions without a loading dose, a relatively low infusion rate, and discontinuation after completion of the bur holes. © 2008 Movement Disorder Society [source] Intraoperative loading attenuates nausea and vomiting of tramadol patient-controlled analgesia. (Show-Chwan Memorial Hospital, Changhua, Taiwan) Can J Anaesth 2000;47:968,973.PAIN PRACTICE, Issue 2 2001Wei-Wu Pang Sixty adult patients scheduled for elective abdominal surgery were enrolled into this prospective, randomized, double-blinded study. The patients were anesthetized in a similar manner. At the beginning of wound closure, the patients were randomly allocated to receive tramadol (Group 1) or normal saline (Group 2). Pain control and adverse effect assessments were done in the PACU and every 6 h for 48 h post drug by an independent observer. The loading dose was 290 ± 45 mg in Group 1 and 315 ± 148 mg in Group 2. In PACU, more nausea and vomiting both in terms of incidence and severity were observed in patients with postoperative loading than in those with intraoperative loading of tramadol. Conclude that administering the loading dose of tramadol during surgery decreases the nausea and vomiting associated with a high dose of tramadol and improves the quality of tramadol PCA in the relief of postoperative pain. Comment by Lian-Kah Ti, M.D. The clinical application and conclusions of this study have to be questioned. It was not surprising that a loading dose of tramadol could effectively be given intraoperatively. What was surprising was that the authors chose not to give any analgesics either preoperatively or intraoperatively for relatively major surgery in an older population, potentially risking morbidity. Indeed, analgesics were withheld in the control group until the patients were extubated, awake, responsive, and complained of pain. Another source of concern was the large loading dose used. Based on their own experience, the authors gave doses of 300 mg of tramadol, which far exceeded the maximum recommended single dose of 100 mg as stated in the manufacturer's instruction for use. The authors did not report any intraoperative hemodynamic consequences from the loading dose, although they noted that the amount of isoflurane required was decreased. The authors concluded that the decreased nausea and vomiting seen in the patients receiving tramadol intraoperatively resulted from the patients being anesthetized at the point when peak plasma levels were achieved. An alternative explanation could be that the patients in the control group had greater postoperative pain (initial VAS of 5.9), and that pain itself resulted in the increased nausea and vomiting. Therefore, the value of this study is doubtful. [source] Effects of dexmedetomidine on intraoperative motor and somatosensory evoked potential monitoring during spinal surgery in adolescentsPEDIATRIC ANESTHESIA, Issue 11 2008JOSEPH D. TOBIAS MD Summary Background:, Dexmedetomidine may be a useful agent as an adjunct to an opioid,propofol total intravenous anesthesia (TIVA) technique during posterior spinal fusion (PSF) surgery. There are limited data regarding its effects on somatosensory (SSEPs) and motor evoked potentials (MEPs). Methods:, The data presented represent a retrospective review of prospectively collected quality assurance data. When the decision was made to incorporate dexmedetomidine into the anesthetic regimen for intraoperative care of patients undergoing PSF, a prospective evaluation of its effects on SSEPs and MEPs was undertaken. SSEPs and MEPs were measured before and after the administration of dexmedetomidine in a cohort of pediatric patients undergoing PSF. Dexmedetomidine (1 ,g·kg,1 over 20 min followed by an infusion of 0.5 ,g·kg,1·h,1) was administered at the completion of the surgical procedure, but prior to wound closure as an adjunct to TIVA which included propofol and remifentanil, adjusted to maintain a constant depth of anesthesia as measured by a BIS of 45,60. Results:, The cohort for the study included nine patients, ranging in age from 12 to 17 years, anesthetized with remifentanil and propofol. In the first patient, dexmedetomidine was administered in conjunction with propofol at 110 ,g·kg,1·min,1 which resulted in a decrease in the bispectral index from 58 to 31. Although no significant effect was noted on the SSEPs (amplitude or latency) or the MEP duration, there was a decrease in the MEP amplitude. The protocol was modified so that the propofol infusion was incrementally decreased during the dexmedetomidine infusion to achieve the same depth of anesthesia. In the remaining eight patients, the bispectral index was 52 ± 6 at the start of the dexmedetomidine loading dose and 49 ± 4 at its completion (P = NS). There was no statistically significant difference in the MEPs and SSEPs obtained before and at completion of the dexmedetomidine loading dose. Conclusion:, Using the above-mentioned protocol, dexmedetomidine can be used as a component of TIVA during PSF without affecting neurophysiological monitoring. [source] Pharmacokinetics and analgesic effects of intravenous propacetamol vs rectal paracetamol in children after major craniofacial surgeryPEDIATRIC ANESTHESIA, Issue 7 2008SANDRA A. PRINS MD PhD Summary Background:, The pharmacokinetics and analgesic effects of intravenous and rectal paracetamol were compared in nonventilated infants after craniofacial surgery in a double-blind placebo controlled study. Methods:, During surgery all infants (6 months,2 years) received a rectal loading dose of 40 mg·kg,1 paracetamol 2 h before anticipated extubation. On admittance to the pediatric surgical ICU, the children were randomized to receive either a 15 min intravenous infusion of 40 mg·kg,1 propacetamol, a prodrug of paracetamol, or 20 mg·kg,1 paracetamol rectally every 6 h. A population pharmacokinetic analysis of the paracetamol plasma concentration time-profiles was undertaken using nonlinear mixed effects models. The visual analogue scale (VAS) (score 0,10 cm) and COMFORT Behavior scale (score 6,30) were used to monitor analgesia in the 24-h period following surgery. Results:, Twelve infants received intravenous propacetamol and 14 paracetamol suppositories. Paracetamol pharmacokinetics were described according to a two-compartmental model with linear disposition. Pharmacokinetic parameters were standardized to a 70 kg person using allometric ,1/4 power' models. Parameter estimates were: absorption half-life from the rectum 4.6 h, propacetamol hydrolysis half-life 0.028 h, clearance 12 l·h,1·70 kg,1, intercompartmental clearance 116 l·h,1·70 kg,1, central and peripheral volume of distribution 7.9 and 44 l·70 kg,1, respectively. During the 24-h study period 22 infants exhibited VAS scores <4 cm, which was considered a cutoff point. On single occasions four patients, two in each group, exhibited a VAS score ,4 cm. Nine patients in the rectal treatment group and three patients in the intravenous treatment group received midazolam for COMFORT-B scores exceeding 17 (P < 0.05). Conclusions:, Intravenous propacetamol proved to be more effective than rectal paracetamol in infants after craniofacial surgery. Midazolam was more frequently administered to patients receiving paracetamol suppositories, indicating that these children experienced more distress, possibly caused by pain. [source] Comparison of patient-controlled analgesia with and without a background infusion after appendicectomy in childrenPEDIATRIC ANESTHESIA, Issue 5 2003Karamehmet Yildiz MD Summary Background: There have been many studies using patient-controlled analgesia (PCA) and opioids for postoperative analgesia in children. In this study, we investigated the efficacy, usefulness and analgesic consumption of two different PCA programmes [bolus dose alone (BD) or bolus dose with background infusion (BD + BI)] to evaluate postoperative analgesia for children after emergency appendicectomy. Methods: Forty children, aged between 6 and 15 years and ASA class I or II, undergoing emergency appendicectomy were randomly allocated into two groups. The children were given a loading dose of pethidine 0.3 mg·kg,1 and 150 ,g·kg,1 bolus intravenously in group BD (n = 20) and pethidine 0.3 mg·kg,1 loading dose, 75 ,g·kg,1 bolus and 15 ,g·kg,1·h,1 background infusion in group BD + BI (n = 20). The lockout interval was 20 min in both groups. Results: There were no significant differences in pain, sedation and nausea scores during the 24-h postoperative period between the groups (P > 0.05). Pethidine consumption was significantly lower in group BD + BI than that in group BD for the first 24-h period (P < 0.05). Conclusions: We demonstrated that both these PCA programmes were effective and reliable for postoperative pain relief in children. We believe that giving information about PCA to the children and their parents is useful during the preoperative period. However, the background infusion with lower bolus dose in PCA did not increase pethidine consumption. [source] Latest news and product developmentsPRESCRIBER, Issue 22 2007Article first published online: 28 DEC 200 Glitazones: benefits outweigh the risks Following a review of the safety of rosiglitazone and pioglitazone, the European Medicines Agency (EMEA) has concluded that their benefits outweigh their risks in the approved indications. The review was prompted by reports of an increased risk of fractures in women and, in patients taking rosiglitazone, ischaemic heart disease. The EMEA concluded that prescribing information for rosiglitazone should now include a warning that, in patients with ischaemic heart disease, it should only be used after careful evaluation of each patient's individual risk, and the combination of rosiglitazone and insulin should only be used in exceptional cases and under close supervision. No change was considered necessary to the prescribing information for pioglitazone. Modern dressings no better? A systematic review has found only weak evidence that modern dressings are better than saline gauze or paraffin gauze for healing acute and chronic wounds (Arch Dermatol 2007;143: 1297-304). The analysis, which included 99 studies, found that only hydrocolloids were demonstrably better than older dressings for healing chronic wounds, and alginates were superior to other modern dressings for debriding necrotic wounds. There was no evidence that modern dressings offered superior overall performance to the older alternatives. Hospital inflation twice primary care level The cost of drugs prescribed in secondary care but dispensed in the community increased by 6.4 per cent in 2006 - twice the rate of inflation in primary care - according to the latest statistics on hospital prescribing in England. The increase follows a reduction in costs in 2005 after the introduction of the new PPRS scheme. Data from The Information Centre (www.ic.nhs.uk) show that hospital medicines make up about 24 per cent of the NHS drugs budget. Secondary care has a consistently better record than primary care in prescribing lower-cost alternatives within therapeutic categories, eg simvastatin and pravastatin among the statins, omeprazole and lansoprazole among PPIs, and ACE inhibitors among drugs acting on the renin angiotensin system. The most expensive drug prescribed by hospital specialists and dispensed in the community is interferon beta. MHRA limits the use of fibrates The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that fibrates should now be reserved for the treatment of isolated severe hypertriglyceridaemia. They should be considered for hypercholesterolaemia only when a statin or other treatment is contraindicated or not tolerated. In the latest Drug Safety Update, the MHRA says there is insufficient evidence of long-term benefits from fibrates, and first-line use is no longer justified because the evidence for the benefits of statins is robust. The MHRA also warns that some breastfeeding infants have increased susceptibility to the adverse effects of codeine taken by their mother, and that St John's wort may affect the hepatic metabolism of any anticonvulsant. Annual zoledronic acid infusion cuts mortality after hip fracture Once-yearly infusion of zoledronic acid (Aclasta) after hip fracture reduces deaths over a two-year period by 28 per cent compared with placebo, US investigators say (N Engl J Med 2007;357:1799-809). The HORIZON Recurrent Fracture Trial randomised 2127 men and women (mean age 75) within 90 days of surgery for hip fracture to zoledronic acid 5mg yearly or placebo. Mortality over 1.9 years of follow-up was 9.6 per cent with zoledronic acid and 13.3 per cent with placebo. Zoledronic acid also significantly reduced the rate of any new clinical fractures (by 35 per cent) and new clinical vertebral fractures(by 45 per cent),but the lower rate of hip fracture (2.0 vs 3.5 per cent with placebo) was not statistically significant. Rivastigmine patch for mild to moderate AD Rivastigmine (Exelon) is now available as a transdermal patch for the treatment of mild to moderate Alzheimer's disease. Applied once daily, the patch delivers 9.5mg per 24 hours and, says manufacturer Novartis, is associated with a lower incidence of nausea and vomiting than a comparable oral dose. The patch is available in two strengths: 4.6mg per 24hr is equivalent to oral doses of 3 or 6mg per day, and the 9.5mg per 24hr patch is equivalent to 9 or 12mg per day orally. The recommended dose of the patch is 9.5mg per day; both strengths cost £83.84 for 30 patches. Women more aspirin resistant than men? The cardioprotective effect of low-dose aspirin may be lower in women than men, say Canadian investigators (BMC Medicine 2007;5:29 doi: 10.1186/1741-70155-29). Their meta-analysis of 23 randomised trials involving a total of 113 494 participants found that aspirin significantly reduced the risk of nonfatal but not fatal myocardial infarction (MI). About one-quarter of the variation in its effects on nonfatal MI was accounted for by the sex mix of the trial population. Separating the results by sex showed the reduction in risk with aspirin use was statistically significant in men (relative risk, RR, 0.62) but not in women (RR 0.87). Look after physical health of mentally ill GPs and other primary care workers should take more responsibility for the physical health of their mentally ill patients, say advocacy groups. Mind and Body: Preventing and Improving Physical Health Problems in Patients With Schizophrenia points out that the mental health needs of patients with schizophrenia are met in secondary care, but their physical health needs should be met in primary care. In particular, the metabolic effects of antipsychotics may lead to obesity, diabetes and cardiovascular disease, and weight gain in particular is a frequent reason for nonadherence to treatment. The Mind and Body Manifesto was developed by SANE, The Mental Health Nurses Association, The National Obesity Forum and The Disability Rights Commission and sponsored by Bristol-Myers Squibb Pharmaceuticals Limited and Otsuka Pharmaceuticals (UK) Ltd. Copies are available from elizabeth.green@ ogilvyhealthworld.com. Health eCard costs Some costs quoted in our article on the Health eCard (The Health eCard: the way ahead for medical records?,5 October issue, pages 28-9) have been revised: the card and initial download will cost patients £39.50, and GPs will be entitled to charge patients £10 per annum for subsequent downloads. NICE appraisals of cytokine inhibitors in RA NICE has endorsed the use of the anti-TNF agents adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), normally in conjunction with methotrexate, for the treatment of active RA when methotrexate and another DMARD have failed (also see New from NICE below). NICE has provisionally concluded, subject to consultation, that abatacept (Orencia) should not be recommended for the treatment of RA. Boots and BMJ launch health advice site www.askbootshealth.com is a new website providing information about health and medicines for the public produced by Boots using information provided by the BMJ Publishing Group. The website covers many of the topics already available from NHSDirect, with perhaps more information about available treatments. Diabetes care shows small improvement The third National Diabetes Audit in England and Wales has found that more people with diabetes were achieving the targets set by NICE for cholesterol levels, glycaemic control and blood pressure in 2005/06 - but younger patients were doing less well. Overall, the HbA1C target of ,7.5 per cent was achieved in 60 per cent of people with diabetes compared with 58 per cent in 2004/05. However, HbA1C was >9.5 per cent in 30 per cent of children and young people, of whom 9 per cent experienced at least one episode of ketoacidosis. More topics for NICE New topics referred to NICE include clinical guidelines on ovarian cancer, coeliac disease and stable angina, public health guidance on preventing cardiovascular disease, and technology appraisals on insulin detemir (Levemir) for type 1 diabetes, several treatments for cancer and hepatic and haematological disorders, and biological therapies for juvenile arthritis. New from NICE NICE appraisal on anti-TNFs for RA Since NICE published its first appraisal of agents acting against tumour necrosis factor-alpha (anti-TNFs) for the treatment of RA in 2002, the product licences for etanercept (Enbrel) and infliximab (Remicade) have changed and a new agent, adalimumab (Humira), has been introduced. The anti-TNFs act in different ways. Infliximab is a chimeric monoclonal antibody that binds to TNF-alpha, neutralising its activity. Etanercept, a recombinant human TNF-alpha receptor fusion protein, and adalimumab, a human-sequence antibody, both bind to TNF-alpha and block its interaction with cell surface receptors. Adalimumab also modulates some biological responses induced or regulated by TNF-alpha. These agents are recommended for adults with severe active RA (defined as a disease activity score - DAS28 - greater than 5.1) who have already tried two disease-modifying drugs, including methotrexate (if not contraindicated). Prior treatment should have been of at least six months' duration, including two months at the standard dose (unless limited by toxicity). Anti-TNFs should normally be prescribed with methotrexate; when this is not appropriate, etanercept and adalimumab may be prescribed as monotherapy. Treatment with an anti-TNF should be continued beyond six months only if there is an adequate response (defined as an improvement in DAS28 of at least 1.2). Data from the British Rheumatology Society Biologics register show that, after six months, 67 per cent of patients met NICE criteria for an adequate response; this declined to 55 per cent at 18 months. The basic annual cost of treatment is £9295 for adalimumab 40mg on alternate weeks or etanercept 25mg twice weekly; infliximab costs £3777 for a loading dose, then £7553-£8812 depending on dose. Assuming no progression of disability, the incremental costs per QALY (compared with sequential DMARDs) were £30 200 for adalimumab, £24 600 for etanercept and £39 400 for infliximab. There are no direct comparative trials of the anti-TNFs, and their clinical trial findings are not directly comparable. Unless other factors determine treatment choice, NICE therefore recommends the least expensive. If the first anti-TNF is withdrawn within six months due to an adverse event, a second may be tried. [source] Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: Efficacy and safety results from a Phase II/III randomized controlled studyTHE JOURNAL OF DERMATOLOGY, Issue 4 2010Akihiko ASAHINA Abstract Incidence of psoriasis vulgaris in Asians is estimated at 0.05,0.3%. Studies in North America and Europe demonstrated that adalimumab, a fully human, recombinant, immunoglobulin G1 monoclonal antibody, was efficacious and well-tolerated in patients with chronic plaque psoriasis. This 24-week, placebo-controlled study evaluated the efficacy and safety of three different dosing regimens of adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis (n = 169). Patients were randomized to receive adalimumab 40 mg every other week (eow), adalimumab 80-mg loading dose at week 0 followed by adalimumab 40 mg eow starting at week 2, adalimumab 80 mg eow, or placebo eow given as s.c. injections. The primary efficacy endpoint was the percentage of patients achieving a 75% or greater improvement in Psoriasis Area and Severity Index (PASI 75) score at week 16. At week 16, PASI 75 response rates were significantly greater for all three adalimumab groups (40 mg eow: 57.9%, P < 0.001; 40 mg eow plus loading dose: 62.8%, P < 0.001; 80 mg eow: 81.0%, P < 0.001) versus placebo (4.3%). As early as week 4, the 40-mg eow plus loading dose and 80-mg eow groups achieved significantly greater PASI 75 response rates compared with placebo. Injection-site reactions and hepatic events occurred in greater percentages of adalimumab-treated patients compared with placebo. Adalimumab therapy demonstrated efficacy and safety at all three dosage regimens. Rapid response rate in patients receiving 40 mg eow plus loading dose supports using an 80-mg loading dose in the treatment of psoriasis. [source] Peri-operative use of paracetamolANAESTHESIA, Issue 1 2009C. D. Oscier Summary This article is a review of the peri-operative use of paracetamol. It reviews the pharmacology of paracetamol, highlighting new information about the mechanism of action, and examines its therapeutic use in the peri-operative period, focusing on efficacy, route of administration, and the use of a loading dose to improve early postoperative analgesia. [source] Relationship between Serum Acetaminophen Concentration and N -Acetylcysteine-Induced Adverse Drug ReactionsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2010Sa'ed H. Zyoud However, during the infusion of the loading dose, different types of adverse drug reactions (ADR) may occur. The objective of this study was to investigate the relation between the incidence of different types of ADR and serum acetaminophen concentration in patients presenting to the hospital with acetaminophen overdose. This is a retrospective study of patients admitted to the hospital for acute acetaminophen overdose over a period of 5 years (1 January 2004 to 31 December 2008). Parametric and non-parametric tests were used to test differences between groups depending on the normality of the data. SPSS 15 was used for data analysis. Of 305 patients with acetaminophen overdose, 146 (47.9%) were treated with intravenous N -acetylcysteine and 139 (45.6%) were included in this study. Different types of ADR were observed in 94 (67.6%) patients. Low serum acetaminophen concentrations were significantly associated with cutaneous anaphylactoid reactions but not other types of ADR. Low serum acetaminophen concentration was significantly associated with flushing (p < 0.001), rash (p < 0.001) and pruritus (p < 0.001). However, there were no significant differences in serum acetaminophen concentrations between patients with and without the following ADR: gastrointestinal reactions (p = 0.77), respiratory reactions (p = 0.96), central nervous reactions (p = 0.82) and cardiovascular reactions (p = 0.37). In conclusion, low serum acetaminophen concentrations were associated with higher cutaneous anaphylactoid reactions. Such high serum acetaminophen concentrations may be protective against N -acetylcysteine-induced cutaneous ADR. [source] Nonstationary disposition of valproic acid during prolonged intravenous infusion: contributions of unbound clearance and protein bindingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2001Tori L. Arens Abstract Circadian variations in disposition have been observed for a variety of agents, including anticonvulsants. Valproic acid (VPA), an anticonvulsant used to control generalized and partial seizures, has exhibited diurnal oscillations in steady-state concentrations during long-term administration to humans and non-human primates. The present study was conducted to assess potential diurnal changes in the disposition of VPA during prolonged i.v. infusion in rats. Animals, maintained on a strict 12-h per day light cycle, were equipped with venous cannulae and an arterial microdialysis probe. VPA was administered as a 50-mg/kg loading dose followed by a 42 mg/kg/h infusion for 70 h. Blood and microdialysate samples were obtained at timed intervals after establishment of steady-state throughout two complete light/dark cycles; and total (serum) and unbound (microdialysate) VPA was determined by gas chromatography. Modest oscillations (6,7 h period) in total and unbound VPA were observed; clearance and binding parameters were not different between light and dark periods. However, unbound clearance increased, and unbound fraction decreased, with time over the course of the infusion. These results suggest that time-dependent changes in VPA disposition occur in rats, although oscillations in steady-state concentrations do not appear to be diurnal in nature. Copyright © 2001 John Wiley & Sons, Ltd. [source] Intravenous Levetiracetam as first-line treatment of status epilepticus in the elderlyACTA NEUROLOGICA SCANDINAVICA, Issue 6 2010J. Fattouch Fattouch J, Di Bonaventura C, Casciato S, Bonini F, Petrucci S, Lapenta L, Manfredi M, Prencipe M, Giallonardo AT. Intravenous Levtiracetam as first-line treatment of status epilepticus in the elderly. Acta Neurol Scand: 2010: 121: 418,421. © 2010 John Wiley & Sons A/S. Background,,, Status epilepticus is a condition of prolonged/repetitive seizures that often occurs in the elderly. Treatment in the elderly can be complicated by serious side effects associated with traditional drugs. Objective,,, The aim of this pilot study was to evaluate the short-term efficacy/safety of intravenously administered LEV (IVLEV) as the treatment of choice for SE in the elderly. Methods,,, We enrolled nine elderly patients (five female/four male; median age 78 years) with SE. Two patients had a previous diagnosis of epilepsy; in the remaining seven, SE was symptomatic. SE was convulsive in five and non-convulsive in four. All the patients presented concomitant medical conditions (arrhythmias/respiratory distress/hepatic diseases). As the traditional therapy for SE was considered unsafe, IVLEV was used as first-line therapy (loading dose of 1500 mg/100 ml/15 min, mean maintenance daily dose of 2500 mg/24 h) administered during video-EEG monitoring. Results/conclusions,,, In all the patients but one, IVLEV was effective in the treatment of SE and determined either the disappearance of (7/8), or significant reduction in (1/8), epileptic activity; no patient relapsed in the subsequent 24 h. No adverse events or changes in the ECG/laboratory parameters were observed. These data suggest that IVLEV may be an effective/safe treatment for SE in the elderly. [source] UR-3216: A Manageable Oral GPIIb/IIIa AntagonistCARDIOVASCULAR THERAPEUTICS, Issue 1 2001Kosuke Baba ABSTRACT UR-3216, a prodrug, is a novel, selective, and orally active platelet surface glycoprotein GPIIb/IIIa) receptor antagonist. The most important property of UR-3216 is the very tight binding of its active metabolite to platelets (Ki for resting platelets is <1 nM). UR-2992, the active form of UR-3216, binds to platelets for a long period of time, while the unbound drug is rapidly cleared. Therefore, after an initial loading dose of 0.1 mg/kg, only once daily repeated low maintenance doses of UR-3216 (<0.05 mg/kg p.o.) are required. This regimen maintains a high level of inhibition of platelet aggregation and, due to a small peak-to-trough ratio, severe bleeding is avoided. The therapy with UR-3216 is easy to manage, because it has low peak-to-trough ratio and high efficacy (>80% inhibition of platelet aggregation). In addition, UR-3216 does not produce excessive bleeding or thrombocytopenia and does not interact with abciximab. UR-3216 is excreted mostly in bile, so that it will not accumulate in patients with chronic renal dysfunction. UR-2316 has the following abciximab-like features: (a) its half-lives for residence on platelets, inhibition of platelets aggregation and bleeding time prolongation are 60 to 80 h, 24, and 2 h, respectively; (b) its receptor binding occupancy is similar to that of abciximab (Mab1 is inhibited and Mab2 is unaltered). In conclusion, UR-3216 is a promising, orally active GPIIb/IIIa antagonist for the treatment of cardiovascular diseases. [source] Does caffeine impair cerebral oxygenation and blood flow velocity in preterm infants?ACTA PAEDIATRICA, Issue 9 2010MB Tracy Abstract Aim:, The aim of the study is to assess the effects of an intravenous 10 mg/kg loading dose of caffeine base in cerebral oxygenation, cerebral Doppler blood flow velocity and cardiac output in preterm infants. Methods:, Preterm neonates <34 weeks gestation were investigated at 1 and 4 h following the loading dose of caffeine using Doppler cerebral sonography, cardiac echocardiography and cerebral spatially resolved near-infrared spectroscopy. Results:, Forty infants were studied with a mean gestational age (mean ± standard deviation) of 27.7 (±2.5) weeks, birth weight of 1155 (±431) g and a postnatal age of 2.8 (±2.2) days. Mean Anterior Cerebral Artery peak and time average mean blood flow velocity fell significantly by 14% and 17.7%, respectively at 1 h post-caffeine loading dose, which recovered partially by 4 h. Cerebral Tissue Oxygenation Index fell from pre-dose levels by 9.5% at 1 h with partial recovery to 4.9% reduced at 4 h post-dose. There were no significant changes in left or right ventricular output, transcutaneous oxygen saturation, transcutaneous PCO2 or total vascular resistance. Conclusions:, A loading dose of 10 mg/kg caffeine base resulted in significant reduction at 1 h post-dose in cerebral oxygenation and cerebral blood flow velocity with partial recovery at 4 h. [source] | |||||||||||||||||||||||||||||||||||||