Serum amino acid patterns and toxicity symptoms following the absorption of irrigant containing glycine in transurethral prostatic surgery

The relationships between the serum concentrations of amino acids, the volume of irrigating fluid absorbed and symptoms of glycine toxicity were analysed in 18 patients who had undergone transurethral resection of the prostate and in whom intravascular absorption of irrigating fluid containing 2.2% glycine had been recorded. A mean of 7% of the transferred glycine could be detected in the serum within 10 min of irrigant absorption. The half-life of glycine in serum was twice as long when the volume of irrigant absorbed exceeded 1500 ml (100 min; n = 6), and the serum levels of alanine, aminobutyrate, proline and serine were significantly more elevated, than when the volume of irrigant absorbed was between 900 and 1300 ml (n = 6). Where the amount of glycine transferred exceeded 0.5 g.kg-1, symptoms of glycine toxicity developed, their onset coinciding with a rapid increase in the serum levels of non-essential amino acids other than glycine.     

Amino acid concentrations in serum and urine after intravenous infusion of 1.5% glycine in prostatectomy patients.

Glycine 1.5% was given by intravenous infusion at a rate of 50 mg/min over 20 min to 10 patients (aged 57-79 years) scheduled for transurethral prostatectomy. The concentrations of amino acids in serum and urine were measured at 0, 10, 20, 50, 80, and 140 min in the experiments in order to study how elderly men handle a glycine load. The results show an increase in the serum concentrations of alanine, proline, glutamine, glycine, serine, and threonine. The apparent distribution volume for the excess glycine was 33 +/- 9 L, the half-life was 41 +/- 7 min, and the total body clearance was 0.56 +/- 0.08 L/min, while the renal clearance for glycine was 36 +/- 14 ml/min (mean +/- SD). There was an increase in the excretion of all amino acids that could be detected in the urine. The renal clearances of urea and creatinine was reduced in some of the patients. The absence of toxic symptoms is consistent with unchanged serum concentrations of ammonia and glutamate.     

Eye symptoms, visual evoked potentials and EEG during intravenous infusion of glycine

Disturbance of vision is a complication that may occur from absorption of the glycine solution used to irrigate the bladder during transurethral operations. We examined for a possible dose-response relationship between glycine dose, eye symptoms and neurophysiological changes after repeated intermittent intravenous infusions of 4.4 g of glycine for up to 22 g over 1 h in 10 male volunteers. The serum glycine concentration increased from 230±75 to 5,232±1,088 μmol/1 (mean±s.d.) during the infusions. We found an increase in diastolic arterial pressure but no significant changes in systolic pressure, heart rate or mental status. Five of the volunteers developed blurring of vision which lasted for 10 30 min. The visual evoked potentials (VEP) of these subjects showed an increase of the P100 and N70 latencies which started after no more than 4.4 g of glycine had been administered. The amplitude of the VEP was preserved and the main frequency of the EEG did not change, indicating that VEP changes were not due to cortical dysfunction. There was no dose-response relationship between glycine infusion and eye symptoms but a sub-group of volunteers responded with both visual disturbances and VEP changes.     

The Pharmacokinetics of Methicillin and Dicloxacillin in Wound Fluid Following Internal Fixation of Trochanteric Fractures

Prior to the operation, patients undergoing internal fixation of pertrochanteric fractures were given a single intravenous dose of either 2 g methicillin (5 patients) or 1 g dicloxacillin (5 patients). During the postoperative period the concentrations of the two antibiotics were examined in the serum and wound fluid. Based on the concentrations obtained per gram of antibiotics administered there was no difference between the two antibiotics. For both antibiotics the wound fluid concentration was higher than the serum concentration. The elimination from the wound fluid was significantly slower than from the serum. Thus the half-life in wound fluid was found to be approximately 1½ times that of the half-life in serum.     

Pharmacokinetics of fosfomycin in hemodialyzed patients

The pharmacokinetics of fosfomycin, an original antimicrobial agent, were investigated in 11 voluntary hemodialyzed patients. Fosfomycin, 2 g, was administered intravenously, 15 minutes before hemodialysis began in group 1 (6 patients), and just after hemodialysis in group 2 (6 patients). Blood samples were collected during 8 hours (group 1) and during 44 hours (group 2). Antibiotic concentrations were determined microbiologically. In group 1, half-life was 4.2 +/- 0.27 hours, total clearance 65.1 +/- 7.1 ml/mn and clearance by hemodialyzer 103 +/- 10 ml/mn. In group 2 plasma levels were 60 mg/l at the 44th hour and half-life was 48.8 +/- 17.5 hours. These results suggest that fosfomycin is actively eliminated by the hemodialyzer in group 1, and largely retained between two dialysis sessions in group 2. As for therapy, intravenous administration of 2 g after dialysis and further administration after each succeeding session are proposed.     

Blood levels and half-life of methylmethacrylate after tourniquet release during knee arthroplasty

Summary The blood levels and the half-life of monomeric methylmethacrylate after tourniquet release were studied in nine patients with osteoarthrosis or rheumatoid arthritis of the knee joint, treated with the Townley prosthesis under spinal anesthesia. Several ventricular extrasystoles were monitored in one patient with high blood levels of monomeric methylmethacrylate (119.80 g/ml). The blood levels of monomeric methylmethacrylate ranged between 0.10 and 1.44 g/ml in the rest of the patients. The half-life of monomeric methylmethacrylate in vivo was 47–55 min.     

Blood ammonia levels after intravenous infusion of glycine solution with and without ethanol.

OBJECTIVE: Absorption of glycine 1.5% during transurethral resection of the prostate may increase blood ammonia levels, but hyperammonaemia has not been described when the fluid also contained ethanol 1%. The aim of this experimental study was to evaluate whether ethanol 1% reduces glycine-induced hyperammonaemia. MATERIAL AND METHODS: Two intravenous infusions of glycine solution with and without ethanol 1% added were given on different occasions to 20 male volunteers (mean age 30 years). Half of them received 22 g of glycine over 50 min and the others approximately 18 g over 30 min. Blood ammonia was measured before and 30 min after the infusion. The serum levels of free amino acids were measured on 7 occasions during 10 of the experiments. RESULTS: The glycine infusions increased blood ammonia levels from 37 micromol/l (median, 10th and 90th percentile limits 34-53) to 57 micromol/l (27-110; p < 0.001). The change was greater after the larger glycine dose, regardless of whether the fluid contained ethanol (p < 0.05). The only amino acid concentration correlating with blood ammonia was glycine, which showed higher levels in those who had a rise in blood ammonia of 50% or more. CONCLUSIONS: Ethanol 1% did not reduce the increase in blood ammonia concentration after the administration of glycine solution.     

The kinetics of aminosidine in renal patients with different degrees of renal failure.

The plasma concentration and urinary excretion after a single 500 mg dose of Aminosidine have been studied in 12 patients with different degrees of renal failure and 4 normal subjects. In normal subjects the plasma half-life is 2.47 hr; in patients with creatinine clearance (Ccr) of 30-60 ml/min, its 6.7 hrs.; in patients with Ccr of 10-30 ml/min, it is 16.7hrs.; in patients with Ccr less than 10 ml/min, it is 36.6 hrs. A dose of 0.5 g of Aminosidine should be given to normal subjects every 12 hr. When renal function is reduced, the interval (in hr) between doses should be the following: Ccr 60-40 ml/min: 19-28;Ccr 40-30 ml/min; 28-35; Ccr 30-20 ml/min: 35-47; Ccr 20-10 ml/min: 47; Ccr less than 10 ml/min: 76.     

Glycine attenuates endotoxin-induced liver injury by downregulating TLR4 signaling in Kupffer cells

BACKGROUND: Several experimental studies have observed better outcomes after glycine treatment in patients with endotoxin-induced liver injuries, but its molecular mechanism is not yet fully understood. The purpose of this study was to evaluate the hypothesis that glycine attenuates endotoxin-induced liver injury by affecting endotoxin signal transduction in liver macrophages. METHODS: An animal model of endotoxin-induced liver injury was established by intraperitoneally injecting mice with 10 mg/kg body weight endotoxin fed a pretreatment diet with or without 5% (w/w) glycine. Blood and liver samples were obtained for analysis of liver morphology and to determine concentrations of alanine aminotransferase, endotoxin receptor Toll-like receptor 4 (TLR4), tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-10 at various time points after injection. To investigate the effect of glycine on liver macrophages, Kupffer cells (KCs) were isolated and challenged by LPS (100 ng/mL), with or without glycine (4 mmol/l) pretreatment, and the expressions of TLR4, IL-10, and TNF-alpha were assayed at mRNA and protein levels. DNA-binding activity of nuclear factor-kappa B (NF-kappaB) was also analyzed using enzyme-linked immunosorbent assay. RESULTS: Dietary glycine significantly improved the survival rate of endotoxemic mice (P < .05), whereas serum alanine aminotransferase and TNF-alpha levels were significantly decreased at different time points (P < .05); IL-10 levels were increased (P < .05). Concurrently, LPS-induced hepatic tissue injury was attenuated as indicated by morphologic analysis; secretion of IL-10 in liver tissue (P < .05) was enhanced; and expression of TLR4 and TNF-alpha in liver tissue was downregulated (P < .05). Consistent with these in vivo experiments, enhanced secretion of IL-10 and inhibited expression of TLR4 and TNF-alpha caused by glycine pretreatment were also observed in LPS-stimulated KCs. NF-kappaB DNA-binding activity was also significantly inhibited by glycine (P < .05, respectively). CONCLUSIONS: Dietary glycine improved survival rates and liver function in endotoxemic mice by regulating the production of proinflammatory or anti-inflammatory cytokines in liver. It attenuated liver injury by deactivating KCs through inhibiting TNF-alpha secretion and increasing IL-10 production. The downregulative effect of glycine on the endotoxin signaling pathway and TLR4/NF-kappaB/TNF-alpha may be a novel potential mechanism by which glycine inhibits KC activity.     

Effect of glycine on isolated,perfused rabbit livers following 48-hour preservation in University of Wisconsin solution without glutathione

Glycine has been shown to decrease membrane injury in isolated cells due to hypoxia or cold ischemia. The mechanisms of action of glycine are not known, but glycine may be useful in organ preservation solutions or in treating recipients of liver transplantation. In this study the isolated, perfused rabbit liver was used to measure how glycine affected liver performance after 48-h preservation in University of Wisconsin (UW) solution without added glutathione. UW solution is less effective for 48-h liver preservation when glutathione is omitted. Rabbit livers stored for 48 h without glutathione show a large increase in enzyme release (LDH and AST) from the liver and a reduction in bile production. The addition of 15 mM glycine to UW solution, in place of glutathione, did not improve bile production or reduce enzyme release. However, infusion of 10 mM glycine into the reperfused liver lowered LDH release significantly (from 2383±562 units/100 g to 1426±286 units/100 g) during the initial reperfusion of the 48-h preserved liver. Hepatamine, a parenteral nutrition solution containing glycine, as well as other amino acids, was also effective in lowering LDH release from the preserved liver. Although glycine reduced LDH release, it did not decrease the amount of AST released from the liver, nor did it improve bile production. Thus, we conclude that glycine, either in UW solution or given to the liver upon reperfusion, has no significantly beneficial effect as tested in this model. Further testing of glycine, however, should be conducted in an orthotopic transplant model in the rat or dog.     

肝硬化患者复合瑞芬太尼时异丙酚的药代动力学

目的 研究肝硬化患者复合瑞芬太尼时异丙酚的药代动力学.方法拟在内镜下行食道静脉曲张套扎术的肝硬化患者10例(试验组);拟行胃镜检查术患者10例(对照组),肝功能未见异常,男女各半,年龄18～55岁,体重40～75 kg.静脉注射异丙酚1.5 mg/kg和瑞芬太尼0.5 μg/kg,5 min后再次静脉注射异丙酚0.5 mg/kg和瑞芬太尼0.2 μg/kg.分别于给药前、给药后2、5、10、15、20、30、45、60、80、120 min时采集桡动脉血样,采用气相色谱质谱联用法测定血浆异丙酚浓度,采用DAS 2.0软件计算药代动力学有关指标.结果 异丙酚的血药浓度.时间曲线符合开放性三室模型;与对照组比较,试验组分布半衰期、消除半衰期、终末半衰期、血药浓度-时间曲线下面积和转运速率常数差异无统计学意义(P＞0.05),表观分布容积和清除率升高(P＜0.01).结论 肝硬化患者复合瑞芬太尼麻醉时,异丙酚的表观分布容积和清除率升高,而其他药代动力学参数无明显变化.

Abstract：

Objective To investigate the pharmacokinetics of propofol when combined with remifentanil in patients with liver cirrhosis.Methods Ten patients (5 males, 5 females) with liver cirrhosis scheduled for endoscopic esophageal varix ligation (test group) and 10 cases (5 males, 5 females) with normal liver function scheduled for gastroscopy (control group), aged 18-55 yr, weighing 40-75 kg, were studied. The patients were unpremedicated. All the patients received iv injection of propofol 1.5 mg/kg and remifentanil 0.5 μg/kg, and 5 min later propofol 0.5 mg/kg and remifentanil 0.2 μg/kg was given again. Blood samples were taken from radial artery before administration and at 2, 5, 10, 15, 20, 30, 45, 60, 80 and 120 min after administration for determination of the plasma propofol concentration using gas chromatography-mass spectrography. The pharmacokinetic parameters were calculated using DAS 2.0 software.Results The pharmacokinetics of propofol was best described by a three-compartment open model. There was no significant difference in the distribution half-life, elimination halflife , terminal half-life, area under the curve and transfer rate constant between the two groups ( P ＞ 0.05) . The apparent volume of distribution of propofol and clearance were significantly increased in test group compared with control group (P ＜0.01) .Conclusion When propofol combined with remifentanil is used in patients with liver cirrhosis, the apparent volume of distribution of propofol and clearance are significantly increased, while no changes in the other pharmacokinetic parameters are found.     

Correction of anaemia with darbepoetin alfa in patients with chronic kidney disease receiving dialysis.

BACKGROUND: Darbepoetin alfa is a new recombinant erythropoietic protein with a 3-fold longer half-life than recombinant human erythropoietin (rHuEpo). The optimal starting dose and frequency of administration of darbepoetin alfa were investigated for treating renal anaemia in dialysis patients. METHODS: Two multicentre, sequential dose-escalation studies examined the i.v. route of administration of darbepoetin alfa in haemodialysis patients (n=75) and the s.c. route in peritoneal dialysis patients (n=47). Patients were randomized to receive darbepoetin alfa at doses ranging from 0.075 to 0.75 microg/kg/week administered as either a once weekly or a three-times weekly injection. Patients achieving the primary endpoint of a > or = 1 g/dl increase in haemoglobin after 4 weeks continued darbepoetin alfa for up to 52 weeks. Safety was assessed by adverse event reports, changes in laboratory values and vital signs, and antibody screening. RESULTS: Darbepoetin alfa produced dose-related increases in haemoglobin over the first 4 weeks of treatment in both studies. Two dose levels (0.45 and 0.75 microg/kg/week) increased the haemoglobin by > or = 1 g/dl in 60-80% of patients, and no difference between once weekly and three-times weekly dosing was apparent. For patients who continued treatment up to 52 weeks, haemoglobin was maintained between 10 and 13 g/dl from mean baseline values of 8.4 and 8.7 g/dl. The adverse event profile was similar to that associated with rHuEpo therapy, and no antibodies to darbepoetin alfa were detected. CONCLUSIONS: Darbepoetin alfa is safe and effective for the treatment of anaemia in dialysis patients. The optimal weekly starting dose is 0.45-0.75 microg/kg and once weekly dosing is possible for both the s.c. and i.v. routes of administration.     

Ethanol monitoring of transurethral prostatic resection during inhaled anesthesia.

The purpose of this study was to examine the precision of a method of breath-alcohol analysis used to monitor absorption of irrigating fluid during transurethral resection of the prostate performed under inhaled anesthesia. A breath-alcohol analyzer (Alcolmeter SD-2) was placed between the endotracheal tube and the Bains' circuit. The concentration of ethanol in the breath, serum sodium concentration, and volumetric fluid balance were measured at 10-min intervals during 38 operations when the irrigating fluid contained 1.5% glycine and 1% ethanol. Ethanol monitoring detected absorption rates that exceeded 14 +/- 8 mL/min (mean +/- SD). In 17 patients in whom hyponatremia developed immediately in connection with absorption, the volume of irrigating fluid absorbed (up to 1950 mL) could be predicted from a single expired-breath test with a standard error of 325 mL. When the alcohol measurements were corrected for absorption time, the standard error was 215 mL. Seven other patients received 2.2% wt/vol glycine as irrigating fluid, and ethanol (0.35 g/kg) was administered by intravenous infusion. The direct and indirect measurements of the blood-alcohol concentration agreed well. These results confirm that ethanol monitoring is a viable technique during inhaled anesthesia for transurethral resection of the prostate.     

VISUAL EVOKED POTENTIALS AND CHANGES IN SERUM GLYCINE CONCENTRATION DURING TRANSURETHRAL RESECTION OF THE PROSTATE

Visual evoked potentials were recorded in 10 patients undergoingtransurethral prostatectomy under subarachnoid anaesthesia.They were compared with those obtained in a control group (n=5) having other operative procedures also under spinal anaesthesia.Serum concentrations of glycine, ammonia, glucose and sodium,and osmolality, were determined during the perioperative period.The prostatectomy group demonstrated a significant prolongationof visual evoked potential P₂ latency in the postoperative periodwhen compared with preoperative values (P<0.01). No significantchanges in latency occurred in the control group when measuredat similar times. The prostatectomy group demonstrated a significantincrease in serum glycine concentration (P<0.01); changesin serum ammonia and sodium concentrations and osmolality werenot significant. There was no correlation between visual evokedpotential latency and changes in serum glycine concentration.Changes in visual evoked potential during transurethral prostatectomymay be the result of an accumulation of a metabolite of glycine.     

Pharmacokinetics of sufentanil in general surgical patients under different conditions of anaesthesia

The pharmacokinetics of sufentanil were studied in 56 surgical patients after an intravenous bolus of 2 μg kg^-1, in association with neurolept analgesia or volatile anaesthetics (halothane, enflurane and isoflurane). Plasma concentrations of sufentanil were measured by radioimmunoassay. The kinetics of sufentanil were comparable under neurolept analgesia and under anaesthesia with halothane, enflurane or isoflurane. The overall mean elimination half-life was 182 min, Vd⁸⁵ 169 1 and the plasma clearance 910 ml min^-1. Except for the isoflurane subgroup, there was no significant correlation between half-life, the volume of distribution or clearance with age (24–77 years) or body weight (45–95 kg).     

Effects of glycine on hemodynamic responses and visual evoked potentials in the dog

To study the potential contribution of glycine toxicity in the transurethral resection syndrome, we evaluated hemodynamic and visual evoked potential responses to glycine infusion (1 g/kg) in 22 dogs anesthetized with halothane (1.0-1.2% end tidal. Three dogs received 5% glucose in normal saline without glycine; three received arginine (4 mg/kg) in normal saline without glycine; three received arginine (4 mg/kg) in normal saline without glycine; 10 received glycine (1 g/kg), then arginine (4 mg/kg) 120 min after the completion of glycine infusion; and six received arginine 30 min after the completion of glycine infusion. Arginine was infused to evaluate potential antagonistic effects of glycine toxicity. Blood levels of glycine, ammonia, arginine, urea, and formate were determined after infusions of glycine or arginine. All animals received about 5 ml X kg-1 X hr-1 of normal saline during the 2-4 hr of study. Immediately after glycine infusion, cardiac output increased 57%, whereas systemic vascular resistance and mean arterial pressure decreased 32% and 8%, respectively. Later cardiac output and mean arterial pressure were 41% and 18% less than control levels, whereas systemic vascular resistance returned to control levels. Both amplitude and latency of visual evoked potential waveforms were altered in the animals receiving glycine infusion but not in the control animals. These responses were associated with elevations of blood glycine (149 +/- 5 to 9591 +/- 809 microM/L, mean + SEM) and blood NH3 (10.5 +/- 2.8 to 100.0 +/- 13.6 microM/L), but not with formate levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of multiple-dose cefoperazone in hemodialysis patients

We studied the pharmacokinetics of cefoperazone 2 g i.v. every 12 h for 7 days in 12 patients on hemodialysis with normal hepatic function. The half-life of indocyanine green was determined in each patient via ear oximetry. Serum levels of cefoperazone during dialysis were well described by a two-compartment multidose infusion model. From this model we determined the steady state volume of distribution (Vdss), elimination phase half-life during dialysis T1/2D) and off hemodialysis (T1/2), and the corresponding elimination rate constants (KeD and Ke). Multiple correlations between pharmacokinetic parameters, liver function, and physical characteristics of the patients were evaluated. The T1/2 of cefoperazone was 2.9 h off compared to 2.3 h during hemodialysis. The corresponding elimination rate constants were Ke = 0.45/h versus KeD = 0.80/h. Cefoperazone clearances were 78 ml/min off dialysis compared to 140 ml/min during hemodialysis. Vdss was 0.20 liters/kg. The indocyanine green half-life ranged from 1.8 to 4.6 min with a mean of 2.7 min. The ages of the patients correlated with the beta phase half-life (r = 0.68, p = 0.015). We found no significant correlations among the other parameters including hepatic enzymes and indocyanine green half-life. Thus, hemodialysis approximately doubles the elimination rate constant (clearance), but, assuming drug redistribution kinetics remain unchanged, only shortens half-life by about 20%. Scheduling of a 12-hour dosing regimen to coincide with the end of hemodialysis should obviate any need for alteration of dose. Cefoperazone is thus unique among cephalosporins, since the half-life does not change appreciably with end-stage renal disease or dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Darbepoetin alfa once every 2 weeks for treatment of anemia in dialysis patients: a combined analysis of eight multicenter trials

AIM: Darbepoetin alfa has a longer half-life than epoetin-(EPO) alfa or beta, allowing administration at less frequent intervals for the treatment of renal anemia. The aim of the present analysis was to evaluate the efficacy and tolerability of an every-2-week (Q2W) schedule of darbepoetin alfa in a large cohort of dialysis patients. METHODS: Data were combined from eight similarly designed 24-week phase 3b European studies, in which patients receiving EPO alfa or beta once-weekly were converted to Q2W darbepoetin alfa. Darbepoetin alfa dosage was titrated to maintain hemoglobin (Hb) between 10 and 13 g/dl and efficacy was evaluated during a 4-week evaluation period. RESULTS: In the 1,101 patients assigned to Q2W darbepoetin alfa (i.v., n = 196, s.c., n = 905), mean (SD) Hb levels were 11.53 (0.77) g/dl at baseline and 11.35 (1.04) g/dl at evaluation (mean change in Hb -0.27 g/dl, 95% confidence interval 0.34, -0.20). Hb levels were maintained between 10 and 13 g/dl during evaluation in 85% of patients. Darbepoetin alfa doses were similar at baseline and evaluation, and the i.v. and s.c. routes were associated with similar efficacy and dose requirements. Darbepoetin alfa was well-tolerated. CONCLUSIONS: Q2W darbepoetin alfa is effective in maintaining Hb levels in dialysis patients switched from weekly rHuEPO, regardless of the route of administration and with no notable increase in the weekly equivalent dose.     

Increased plasma glutamate, glycine, and arginine levels in complex regional pain syndrome type 1

Background: Various inflammatory mediators have been identified as potential contributors to complex regional pain syndrome type 1 (CRPS1), but these mediators do not entirely explain certain manifestations of the syndrome, such as pain. The objective of this study was to investigate the role of amino acids in the pathogenesis of CRPS1.
Methods: We used HPLC to determine plasma concentrations of 16 amino acids, especially those related to the NMDA receptor (e.g., glutamate and glycine) and nitric oxide (NO) synthesis (e.g., arginine and citrulline) in patients with CRPS1 ( n =64) and age- and sex-matched healthy controls ( n =51). Patients rated pain intensity (visual analog scale) and the subjective experience of pain intensity (McGill Pain Questionnaire). Psychological dysfunction was assessed using the SCL-90.
Results: Relative to controls, in CRPS1 patients, plasma levels of glutamate, arginine, taurine, and glycine were increased, and plasma levels of glutamine and the ratio of citrulline to arginine were decreased. Remarkably, in CRPS1 patients there was a highly significant inverse correlation between glutamine and glutamate, although the sum of molar concentrations of glutamate and glutamine remains unchanged. Subjective measures of pain and indicators of psychoneuroticism and emotional instability did not correlate with amino acid levels.
Conclusion: This study shows for the first time a pronounced increase in amino acid levels in this chronic pain syndrome. The marked differences in glutamate, glutamine, glycine, taurine and arginine levels between patients and controls suggest the involvement of both the NDMA receptor and the endothelium-dependent arginine-NO system in CRPS1.     

Cross tolerance to salbutamol occurs independently of beta2 adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol

BACKGROUND: The development of tolerance following the use of long acting beta(2) agonists in asthmatic patients with either the homozygous arginine (Arg-16) or glycine (Gly-16) genotypes is poorly documented, especially in relation to the acute reliever response to salbutamol in constricted airways. A study was undertaken to evaluate the Arg-16 and Gly-16 genotypes for the acute salbutamol response following methacholine bronchial challenge between the first and last doses of formoterol (FM) and salmeterol (SM) combination inhalers. METHODS: Parallel groups of 10 matched homozygous Arg-16 and 10 homozygous Gly-16 patients completed a randomised, double blind, double dummy, crossover study. Following a 1 week washout period, patients received treatment for 2 weeks with either inhaled budesonide (BUD) 200 micro g + FM 6 micro g (two puffs twice daily) or inhaled fluticasone propionate (FP) 250 micro g + SM 50 micro g (one puff twice daily). After washouts and randomised treatments (1 hour after the first and last inhalation) a methacholine challenge was performed followed by salbutamol 200 micro g, with recovery over 30 minutes (the primary outcome). RESULTS: Washout values for forced expiratory volume in 1 second (FEV(1)), methacholine hyperreactivity, and salbutamol recovery were similar for both treatments and genotypes. Pre-challenge FEV(1) values for both genotypes did not differ significantly between the first and last doses of each treatment. Salbutamol recovery as mean (SE) area under the 30 minute time-response curve was significantly delayed (p<0.05) equally in both genotype and treatment groups. There were no differences in salbutamol recovery in either genotype or treatment group. CONCLUSION: Acute salbutamol recovery in methacholine constricted airways was significantly delayed to a similar degree in both genotypes due to cross tolerance induced by FM or SM.