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Selected AbstractsCardiopulmonary, blood and peritoneal fluid alterations associated with abdominal insufflation of carbon dioxide in standing horsesEQUINE VETERINARY JOURNAL, Issue 3 2003F. G. LATIMER Summary Reasons for performing study: Abdominal insufflation is performed routinely during laparoscopy in horses to improve visualisation and facilitate instrument and visceral manipulations during surgery. It has been shown that high-pressure pneumoperitoneum with carbon dioxide (CO2) has deleterious cardiopulmonary effects in dorsally recumbent, mechanically ventilated, halothane-anaesthetised horses. There is no information on the effects of CO2 pneumoperitoneum on cardiopulmonary function and haematology, plasma chemistry and peritoneal fluid (PF) variables in standing sedated horses during laparoscopic surgery. Objectives: To determine the effects of high pressure CO2 pneumoperitoneum in standing sedated horses on cardiopulmonary function, blood gas, haematology, plasma chemistry and PF variables. Methods: Six healthy, mature horses were sedated with an i.v. bolus of detomidine (0.02 mg/kg bwt) and butorphanol (0.02 mg/kg bwt) and instrumented to determine the changes in cardiopulmonary function, haematology, serum chemistry and PF values during and after pneumoperitoneum with CO2 to 15 mmHg pressure for standing laparoscopy. Each horse was assigned at random to either a standing left flank exploratory laparoscopy (LFL) with CO2 pneumoperitoneum or sham procedure (SLFL) without insufflation, and instrumented for measurement of cardiopulmonary variables. Each horse underwent a second procedure in crossover fashion one month later so that all 6 horses had both an LFL and SLFL performed. Cardiopulmonary variables and blood gas analyses were obtained 5 mins after sedation and every 15 mins during 60 mins baseline (BL), insufflation (15 mmHg) and desufflation. Haematology, serum chemistry analysis and PF analysis were performed at BL, insufflation and desufflation, and 24 h after the conclusion of each procedure. Results: Significant decreases in heart rate, cardiac output and cardiac index and significant increases in mean right atrial pressure, systemic vascular resistance and pulmonary vascular resistance were recorded immediately after and during sedation in both groups of horses. Pneumoperitoneum with CO2 at 15 mmHg had no significant effect on cardiopulmonary function during surgery. There were no significant differences in blood gas, haematology or plasma chemistry values within or between groups at any time interval during the study. There was a significant increase in the PF total nucleated cell count 24 h following LFL compared to baseline values for LFL or SLFL at 24 h. There were no differences in PF protein concentrations within or between groups at any time interval. Conclusions: Pneumoperitoneum with CO2 during standing laparoscopy in healthy horses does not cause adverse alterations in cardiopulmonary, haematology or plasma chemistry variables, but does induce a mild inflammatory response within the peritoneal cavity. Potential relevance: High pressure (15 mmHg) pneumoperitoneum in standing sedated mature horses for laparoscopic surgery can be performed safely without any short-term or cumulative adverse effects on haemodynamic or cardiopulmonary function. [source] Review of studies and guidelines on fasting and procedural sedation at the emergency departmentINTERNATIONAL JOURNAL OF EVIDENCE BASED HEALTHCARE, Issue 2 2010Joseph Antonio D Molina MD MSc(Public Health) Abstract Aim, Procedural sedation and analgesia allows urgent procedures to be performed safely by preserving patients' airway reflexes. Fasting, which is required before deeper levels of sedation, and where the airway reflexes are not preserved, is difficult to impose in emergencies. This paper aims to synthesise evidence on the need for pre-procedure fasting to minimise aspiration among adults undergoing procedural sedation and analgesia for emergency procedures. Methods, Overviews, guidelines with graded recommendations and primary studies on aspiration and pre-procedure fasting in procedural sedation and analgesia were retrieved from Medline, Cochrane, and Center for Reviews and Dissemination Databases. Terms searched were procedural sedation, fasting, emergency and sedation. Results, One primary study and one guideline were included. The American College of Emergency Physicians Clinical Policies Subcommittee on Procedural Sedation and Analgesia issued a recommendation based on ,preliminary, inconclusive or conflicting evidence, or on panel consensus'. The recommendation states: ,recent food intake is not a contraindication for administering procedural sedation and analgesia . . .'. The primary study conducted by Bell in an emergency department in Australia compared patients who last ate or drank more than 6 and 2 h from induction, respectively, with those who last ate or drank within 6 and 2 h. There were no cases of aspiration in both groups. Out of 118 patients who fasted, 1 (0.8%) vomited, as did one of 282 patients (0.4%) who did not fast. Conclusions, Aspiration risk is expected to be lower in procedural sedation and analgesia than in general anaesthesia. Current guidelines rely on expert consensus due to the lack of primary studies. Contextualisation of existing guidelines are quick and efficient strategies for developing locally relevant tools. [source] Chrono and clinical pharmacokinetic study of tacrolimus in continuous intravenous administrationINTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2001Shigeru Satoh Abstract Background: The circadian variation of clinical pharmacokinetics of tacrolimus in kidney transplant recipients receiving continuous intravenous administration has not been clarified. The aim of this study was to evaluate the circadian variation of this drug in continuous intravenous administration, with regard to the dosing scheme for conversion from intravenous to oral therapy. Methods: The blood concentration,time curve was studied in 10 living-related kidney transplant recipients, aged 18,51 years (mean, 36.5 years), 1 day before operation for preoperative oral administration, the third postoperative day for continuous intravenous administration and the sixth postoperative day at the conversion from intravenous to oral therapy. Results: Although the total body clearance of daytime was slightly higher than that of night-time, the intravenous tacrolimus infusion maintained an adequate therapeutic blood concentration for 24 h. There were significant differences between the preoperative and the postoperative state in the area under the curve, total body clearance and bioavailability for the oral administration. The mean absolute bioavailability was 17.7% in preoperative and 11.1% in postoperative state, respectively and a large interindividual variation was confirmed in this parameter, which was 7.0,27.2% for preoperative and 6.4,22.0% for postoperative area under the curve, respectively. Conclusion: This study proposes that intravenous administration is a safe and appropriate method to achieve the required blood concentration in patients with various tacrolimus metabolism in the early post-transplant period. As the oral tacrolimus absorption was found to be variable between preoperative and postoperative states in identical patients, the conversion dosage cannot be calculated from preoperative oral or postoperative intravenous pharmacokinetics. Frequent blood concentration monitoring is needed to ensure safe treatment. [source] Resistance, biguanide sorption and biguanide-induced pentose leakage during encystment of Acanthamoeba castellaniiJOURNAL OF APPLIED MICROBIOLOGY, Issue 6 2004N.A. Turner Abstract Aims:, This study investigates the effects of biguanides during encystment of Acanthamoeba castellanii. Methods and Results:, A non-nutrient encystment system was used to investigate the changes in the levels of sorption (uptake) of three non-cysticidal concentrations (10, 20 and 50 ,g ml,1) of chlorhexidine diacetate (CHA) and polyhexamethylene biguanide (PHMB) as well as their effects on viability and leakage of pentose sugars during the first 36 h of encystment. Trophozoites treated with CHA or PHMB were more sensitive and generally sorbed more of each biocide than cysts. During encystment, the largest increases in resistance developed between 18 and 36 h for both biguanides with the resistance emerging to biguanide concentrations of 10 or 20 ,g ml,1 between 18 and 24 h. At 50 ,g ml,1 resistance emerged between 24 and 36 h. There was a general decrease in biocide sorption during encystment between 0,24 and 0,21 h for CHA and PHMB, respectively, at a concentration of 50 ,g ml,1. The greatest decline in biguanide-induced pentose leakage was between 0 and 12 h. Conclusions:, The results suggest that during encystment some of the changes in the susceptibility to CHA or PHMB may be related to decreases in the levels of biocide sorption, which is limited by the developing cyst wall. Significance and Impact of the Study:, During encystation, changes occur in biguanide sensitivity. The physical barrier of the cyst wall may be an important factor in limiting biocide sorption. [source] A novel approach to assessing percutaneous VX poisoning in the conscious guinea-pig,JOURNAL OF APPLIED TOXICOLOGY, Issue 5 2008Helen Mumford Abstract Nerve agents like VX (S-2-diisopropylaminoethyl-O-ethyl-methylphosphonothiolate) are potent irreversible acetylcholinesterase (AChE) inhibitors. Following percutaneous nerve agent exposure there is a slower rate of absorption, later onset and longer duration of signs of poisoning. Relatively little is known about the physiological effects of percutaneously applied nerve agent in unanaesthetised laboratory animals. Heart rate (ECG), brain electrical activity (EEG), body temperature, locomotor activity and clinical signs were monitored following percutaneous application of VX to conscious guinea-pigs. A fall in heart rate (bradycardia) preceded incapacitation following the highest VX dose, and occurred in the absence of incapacitation at the lower doses. Following the highest dose of VX (0.592 mg kg,1) three out of four animals died within 24 h. The lower two doses of VX (0.296 and 0.148 mg kg,1), produced extended periods of bradycardia in the absence of observable signs of poisoning. Bradycardia preceded, or occurred in the absence of, a temperature decrease; seizure-like EEG changes were not observed at any of the VX doses tested. Acetylcholinesterase activity was significantly inhibited in the blood and most brain areas at 48 h. There were significant dose-related decreases in body weight at 24 and 48 h following VX. This preliminary study suggests that decreased heart rate may be an early sign of the toxic effects of VX, whereas temperature and observable clinical signs are not good early indicators of percutaneous VX poisoning in this animal model. Future studies will use this model to assess the benefit of administering medical countermeasures in response to a defined decrease in heart rate. © Crown Copyright 2007. Reproduced with the permission of the Controller of HMSO. Published by John Wiley & Sons, Ltd. This article was published online on 5 December 2007. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected [30 May 2008]. [source] Pharmacokinetics of fentanyl delivered transdermally in healthy adult horses , variability among horses and its clinical implicationsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2006J. A. ORSINI The safety and pharmacokinetics of fentanyl, delivered transdermally at a dosage of 60,67 ,g/kg, were investigated in six healthy adult horses. Three transdermal fentanyl patches (Duragesic®), each containing 10 mg of fentanyl citrate, were applied to the mid-dorsal thorax of each horse and left in place for 72 h. Plasma fentanyl concentrations were periodically measured throughout this period and for 12 h after patch removal. After an initial delay of approximately 2 h, the plasma fentanyl concentration rose rapidly in a fairly linear fashion, reaching a peak at around 12 h; thereafter, it gradually declined in a roughly linear manner over the next 72 h. There was much individual variation, however. The initial delay ranged from 0 to 5.1 h (mean, 1.91 ± 2.0 h), Tcmax ranged from 8.5 to 14.5 h (mean, 11.4 ± 2.7 h) and Cmax ranged from 0.67 to 5.12 ng/mL (mean, 2.77 ± 1.92 ng/mL). In two horses, the plasma fentanyl concentration failed to reach even 1 ng/mL, whereas in the other four horses it was >1 ng/mL for at least 40 h and for at least 72 h in two of these horses. No adverse effects attributable to fentanyl were observed in any of the horses, indicating that this dosage is safe in systemically healthy adult horses. However, it failed to achieve plasma fentanyl concentrations generally considered to be analgesic (,1 ng/mL) in about one-third of horses. [source] Effects of Gonadotropins on In Vitro Maturation and of Electrical Stimulation on Parthenogenesis of Canine OocytesREPRODUCTION IN DOMESTIC ANIMALS, Issue 1 2010BS Kim Contents The objective of this study was to determine the effects of gonadotropins on in vitro maturation (IVM) and electrical stimulation on the parthenogenesis of canine oocytes. In experiment I, cumulus oocyte complexes were collected from ovaries at a random phase of the oestrus cycle and cultured on maturation medium treated with hCG or eCG for 48 or 72 h. There were no significant differences in the effects on the metaphase II (MII) rate between the hCG and eCG treatment groups over 48 h (5.4% vs 5.5%). The MII rate in the co-treatment group of hCG and eCG for 48 h was higher than in each hormone treated group (15.5%, p < 0.05). In experiment 2, the parthenogenetic effect on oocyte development, at various electrical field strengths (1.0, 1.5, 2.0 kV/cm DC) for 60 or 80 ,s with a single DC pulse after IVM on the co-treatment of hCG and eCG, was examined. The rate of pronuclear formation (37.1%) in electrical activation at 1.5 kV/60 ,s without cytochalasin B (CB) was higher than that of oocytes activated in the other groups (p < 0.05). However, we did not observe the cleavage stages. Also, CB did not influence parthenogenesis of canine oocytes. The results showed that the pronucleus formation rate, indicative of the parthenogenesis start point, could be increased by electrical stimulation. Therefore, these results can provide important data for the parthenogenesis of canine oocytes and suggest the probability of parthenogenesis in canines. [source] A Randomized, Double-Blind, Pharmacokinetic Study of Oral Maribavir with Tacrolimus in Stable Renal Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009M. D. Pescovitz Maribavir is being developed as a novel agent for the prevention or treatment of cytomegalovirus infections after stem cell and organ transplantation. This was a randomized, double-blind, placebo-controlled study designed to evaluate the potential pharmacokinetic interaction of concomitant administration of maribavir and tacrolimus. Twenty-five adult renal transplant recipients with stable renal function and stable dosing regimens of tacrolimus were randomized (20 maribavir 400 mg p.o. q12 h: 5 placebo). Tacrolimus whole blood concentration profiles were determined before and after 7 days of co-administration with maribavir. When co-administered with maribavir, tacrolimus mean Cmax increased 38%, tacrolimus trough concentrations (12 h post-dose) increased 57% and tacrolimus AUC(0-,) increased 51%. Apparent oral clearance of tacrolimus decreased 34% and Tmax was delayed by 0.5 h. There were no serious adverse events and no subject prematurely discontinued treatment. Because of the limited 7-day dosing course, the adverse event profile could not be adequately assessed. However, as seen with other maribavir studies, dysgeusia was common (90% of maribavir subjects and 20% of placebo subjects). In conclusion, co-administration of maribavir 400 mg twice daily increases exposure to tacrolimus. Routine therapeutic drug monitoring of tacrolimus blood concentrations should be included both at initiation and completion of maribavir treatment. [source] A study of airway management using the ProSeal LMA® laryngeal mask airway compared with the tracheal tube on postoperative analgesia requirements following gynaecological laparoscopic surgeryANAESTHESIA, Issue 9 2007M. Hohlrieder Summary In a randomised double blind prospective study, we tested the hypothesis that postoperative pain is lower in patients who receive an ProSeal LMAÔ laryngeal mask airway compared with a tracheal tube. One hundred consecutive female patients (ASA I,II, 18,75 years) undergoing laparoscopic gynaecological surgery were divided into two equal-sized groups for airway management with the ProSeal LMA or tracheal tube. Anaesthesia management was identical for both groups and included induction of anaesthesia using propofol/fentanyl, and maintenance with propofol/remifentanil, muscle relaxation with rocuronium, positive pressure ventilation, gastric tube insertion, dexamethasone/tropisetron for anti-emetic prophylaxis, and diclofenac for pain prophylaxis. All types of postoperative pain were treated using intravenous patient-controlled analgesia (PCA) morphine. Patients and postoperative staff were unaware of the airway device used. Data were collected by a single blinded observer. We found that pain scores were lower for the ProSeal LMA at 2 h and 6 h but not at 24 h. Morphine requirements were lower for the ProSeal LMA by 30.4%, 30.6% and 23.3% at 2, 6 and 24 h, respectively. Nausea was less common with the ProSeal LMA than with the tracheal tube at 2 h and 6 h but not at 24 h. There were no differences in the frequency of vomiting, sore throat, dysphonia or dysphagia. We conclude that postoperative pain is lower for the ProSeal LMA than the tracheal tube in females undergoing gynaecological laparoscopic surgery. [source] Degradation patterns of tetracycline antibiotics in reverse micelles and waterBIOMEDICAL CHROMATOGRAPHY, Issue 11 2006Hongkee Sah Abstract The objective of this study was to determine the chemical stability of tetracycline and oxytetracycline hydro-chlorides in reverse micelles. Their reverse micellar solutions were prepared using cetyltrimethylammonium bromide, water and ethyl formate. The aqueous solutions of the tetracycline antibiotics were also prepared for comparison. The reverse micellar and aqueous solutions were stored at 37C. Samples were analyzed by high performance liquid chromatography. When evaluation was performed on an aqueous tetracycline HCl solution, its half-life was estimated to be 329 h. Its chemical stability was not improved after being dissolved in the reverse micelles, and a similar half-life of 330 h was observed. However, there were noticeable differences between the two systems in terms of degradation kinetics and degradation byproducts. On the other hand, oxytetracycline HCl was unstable in water so that its half-life was only 34 h. Very interestingly, pronounced improvement in stability was attained with the reverse micellar system: upon dissolving in the reverse micelles, its half-life was increased to 2402 h. There were also marked differences in degradation patterns and mechanisms of oxytetracycline HCl in water and the reverse micelles. Our study indicates that the reverse micellar system has potential applications in solubilizing and stabilizing oxytetracycline HCl, thereby contributing to the development of its dosage forms. Copyright © 2006 John Wiley & Sons, Ltd. [source] The effect of serotonin and serotonin antagonists on bladder cancer cell proliferationBJU INTERNATIONAL, Issue 3 2006EMAD J. SIDDIQUI OBJECTIVE To investigate the role of serotonin (5-hydroxytryptamine, 5HT) and its antagonists in the proliferation of high-grade bladder cancer cells (HT1376), as high-grade bladder cancer has a rapid rate of progression, invasion and recurrence, and 5HT antagonists inhibit the growth of the prostate cancer cell line (PC3). MATERIALS AND METHODS HT1376 (human grade III transitional cell carcinoma) cells were incubated with either 5HT or 5HT antagonists (5HT1A, 5HT1B, 5HT1D, 5HT2, 5HT3 and 5HT4). After 72 h, cell viability was assessed using the crystal violet assay. The presence of 5HT receptor subtypes on HT1376 cells and sections of human bladder cancer tissue was determined by immunohistochemistry and Western blot analysis. RESULTS 5HT caused a dose-dependent increase in the proliferation of HT1376 cells. The maximum increase in cell proliferation (12%; 12 samples, P < 0.001) was at 10,8m as compared to the control at 72 h. At 10,4m, 5HT1A antagonist (NAN-190 hydrobromide) and 5HT1B antagonist (SB224289 hydrochloride) had a 10% (12 samples, P < 0.001) and 93% (12, P < 0.001) inhibitory effect on HT1376 cell growth, respectively, compared to the control at 72 h. There was immunostaining for 5HT1A and 5HT1B receptors in HT1376 cells and malignant bladder tissue, confirming the presence of these two receptor subtypes. Western blot analysis showed the presence of 5HT1A and 5HT1B receptor proteins with bands of 46 kDa and 43 kDa, respectively. CONCLUSION 5HT1A and to a greater extent 5HT1B antagonists significantly inhibit bladder cancer cell growth. This effect is probably mediated via the 5HT1A and 5HT1B receptors. These results highlight the potential use of 5HT1A and 5HT1B antagonists in the treatment of bladder cancer. [source] 47 Comparison between open and laparoscopic live donor nephrectomyBJU INTERNATIONAL, Issue 2006S. KALOUCAVA Introduction:, Renal replacement therapy is the best management for end stage renal failure. Laparoscopic Donor Nephrectomy (LDN), which is considered safe and effective, began in our unit in July 2003 with an average transplant rate of 12 per year. The aim of this study is to compare the donor morbidity, recovery and costs between Open Donor Nephrectomy (ODN) and LDN. Method:, A retrospective consecutive series of all Donor Nephrectomies since June 2002 were included in this study. Operative details, postoperative donor recovery, donor and recipients renal functions were reviewed. The total costs will also be calculated and compared. Results:, There were 18 LDN and 18 ODN (Total 36 cases) included in this series and equal number of male to female cases. Average operative time for ODN was 2.07 h and LDN was 3.36 h. There was no intra-operative conversion from LDN to ODN and no peri-operative morbidities in either group. The transplanted renal vessel lengths were also compared which showed an average artery length of 40 mm and vein length of 50 mm in the LDN group versus an average of 35 mm artery length and 30 mm vein length in the ODN group. The outcome of the recipient's renal function was not affected whether the donor had OPD or LDN. Average length of hospital stay was 6 days in ODN and 4.5 days in LDN. Costs data to follow. Conclusion:, Laparoscopic Donor Nephrectomy (LDN) is safe and effective in a smaller renal transplant unit. [source] Sexual factors and prostate cancerBJU INTERNATIONAL, Issue 3 2003G.G. Giles OBJECTIVE To assess whether prostate cancer might be related to hormone levels and, by inference, to differences in sexual activity. PATIENTS, SUBJECTS AND METHODS In a case-control study of men with prostate cancer aged < 70 years at diagnosis and age-matched control subjects, information was collected on two aspects of sexual activity; the number of sexual partners and the frequency of total ejaculations during the third to fifth decades of life. RESULTS There was no association of prostate cancer with the number of sexual partners or with the maximum number of ejaculations in 24 h. There was a negative trend (P < 0.01) for the association between risk and number of ejaculations in the third decade, independent of those in the fourth or fifth. Men who averaged five or more ejaculations weekly in their 20s had an odds ratio (95% confidence interval) of 0.66 (0.49,0.87) compared with those who ejaculated less often. CONCLUSIONS The null association with the number of sexual partners argues against infection as a cause of prostate cancer in this population. Ejaculatory frequency, especially in early adult life, is negatively associated with the risk of prostate cancer, and thus the molecular biological consequences of suppressed or diminished ejaculation are worthy of further research. [source] Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2001Michael G. Hall Aims NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. Methods A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. Results Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg kg,1 body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (± s.d.) AUC(0,,) (capsule 602 ± 154 vs solution 602 ± 146 µg ml,1 h) or t½ (capsule 55 ± 13 vs solution 54 ± 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,,) and Cmax increased linearly with dose. Following administration of 1 mg NTBC kg,1 in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol ml,1. Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol ml,1 following a dose of 4 mg kg,1 body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione kg,1, but returned to background levels during the following 24 h period. Conclusions NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use. [source] FORMALIN-INDUCED INCREASE IN P2X3 RECEPTOR EXPRESSION IN DORSAL ROOT GANGLIA: IMPLICATIONS FOR NOCICEPTIONCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2009Ai-Hua Pan SUMMARY 1ATP-gated P2X receptors in nociceptive sensory neurons participate in the transmission of pain signals from the periphery to the spinal cord. The effect of formalin on the expression of P2X3 receptors in dorsal root ganglia (DRG) was characterized using molecular and immunological approaches and the patch-clamp technique. 2Adult Sprague-Dawley rats were injected with 100 µL of 5% formalin in the planar surface of the hindpaw and were killed 30 min and 1, 3, 6, 12, 24 and 48 h later for in vitro analyses. The expression and distribution of P2X3 receptors in the lumbar spinal cord and in L5/L6 DRG were examined; 24 and 48 h after formalin injection, currents in neurons were examined using whole-cell patch-clamp recording. 3Western blots showed that anti-P2X3 antibody recognized a major monomer of approximately 64 kDa in DRG. Immunoreactivity for P2X3 receptors was detected predominantly in the cytoplasm and plasma membrane of small (< 25 µm) and middle-sized (25,50 µm) DRG neurons. Expression of the P2X3 transcript in the DRG was unchanged 30 min and 1 h after formalin injection, but increased after 12 h. There was no distinct change in P2X3 immunostaining of the spinal cord lamina at 30 min or 1 h after injection, but after 24 h P2X3 labelling increased. At 24 h after the formalin injection, currents in isolated small and middle-sized DRG neurons were increased by 1 µmol/L ,,,-methylene-ATP. These currents were completely inhibited by 1 µmol/L A-317491, a potent and selective P2X3 receptor antagonist. 4These data suggest that formalin injection leads to early upregulation of P2X3 expression in the spinal cord and DRG and that this may be one of the mechanisms giving rise to nociception. [source] | |||||||||||||||||||||||||