Comparison of vancomycin- and teicoplanin-induced histamine release and "red man syndrome".

Twelve healthy adult males participated in a double-blind, randomized, two-way crossover study to determine histamine release and the frequency and severity of "red man syndrome" (RMS) following intravenous administration of vancomycin (15 mg/kg of body weight over 60 min) and teicoplanin (15 mg/kg over 30 min). Concentrations of vancomycin and teicoplanin in serum and concentrations of histamine in plasma were measured at baseline and during and after each infusion. Erythema and pruritus were classified a priori as mild, moderate, or severe. The extent of erythema was determined by the use of a burn chart, and pruritus was assessed by the subject with a rank scale. Global severity of RMS was determined by summation of the individual scores for pruritus and erythema. Baseline areas under the concentration-time curve for histamine were not significantly different for the vancomycin and teicoplanin treatments. Vancomycin caused RMS in 11 of 12 subjects (9 severe and 2 moderate cases) and was associated with a significant increase in plasma histamine (46.7 +/- 31.3 ng.min/ml, P less than 0.05). In contrast, teicoplanin did not cause RMS or elicit significant histamine release (8.7 +/- 13.2 ng.min/ml). Peak concentrations of vancomycin and teicoplanin in serum were 58.8 +/- 8.4 and 148.0 +/- 31.8 micrograms/ml, respectively (P less than 0.05). Assuming equal efficacy, these data suggest that teicoplanin may be a safe alternative agent in subjects experiencing severe RMS due to vancomycin; however, further studies in the clinical setting are needed.     

Antihistamine prophylaxis permits rapid vancomycin infusion.

OBJECTIVE: To determine whether pretreatment with intravenous antihistamines attenuates the symptoms of red-man syndrome associated with rapid vancomycin administration. DESIGN: Prospective, randomized, double-blinded, placebo-controlled study of patients undergoing elective arthroplasty. SETTING: Preoperative unit in a tertiary care center. PATIENTS: Forty preoperative patients (American Society of Anesthesiologists status I-III, receiving vancomycin prophylaxis for elective prosthetic joint replacement or revision. INTERVENTIONS: Elective orthopedic patients were randomly allocated to receive intravenous antihistamines (diphenhydramine, 1 mg/kg, and cimetidine, 4 mg/kg) or placebo before rapid vancomycin infusion (1 g over 10 mins). Hemodynamic measurements, symptoms of histamine release, and plasma histamine levels were obtained in each patient during vancomycin administration. Rapid vancomycin infusion was discontinued in cases of decreases in mean blood pressure of > or =20% or intolerable itching. MEASUREMENTS AND MAIN RESULTS: Clinical symptomatology of red-man syndrome and histamine levels were assessed using Fisher's exact test or Student's t-test. Comparison of baseline and peak histamine levels for both the treated (mean +/- SD, 0.2 +/- 0.2 vs. 4.7 +/- 2.4 ng/mL; p < .0001) and placebo patients (mean +/-SD, 0.2 +/- 0.1 vs. 3.5 +/- 3.4 ng/mL; p = .0002) was statistically significant. Although there was a significant increase in plasma histamine levels during vancomycin infusion, it did not differ between the treatment groups. Only two (11%) of the treated patients developed hypotension, vs. 12 (63%) of the placebo patients (p = .002). Rash was partially attenuated. Twelve (63%) of the treated patients developed rash, compared with 19 (100%) of the placebo patients (p = .008). The rapid infusion was discontinued in two (11%) of the treated patients, compared with 11 (58%) of the placebo patients (p = .005). Four treated patients had no symptoms of histamine release. CONCLUSIONS: Pretreatment with intravenous H1 and H2 antihistamines permitted rapid vancomycin administration in 89% of treated patients. Although protection was incomplete, rash did not predict a need to stop the rapid infusion of vancomycin in our patients.     

Comparison of vancomycin disposition in rats with normal and abnormal renal functions.

Vancomycin levels in the tissues and urine of rats with renal damage were compared with those of control rats. Renal damage was induced by a single intravenous injection of uranyl nitrate. After 5 days, when the plasma urea nitrogen levels had increased 7- to 22-fold, a single intraperitoneal vancomycin injection of 10 mg/kg yielded significantly higher plasma and tissue levels in these rats than in the control rats that did not receive uranyl nitrate. At 73 h after the vancomycin injection, the plasma vancomycin concentration in the rats with renal damage was 1.8 +/- 1.1 microgram/ml (mean +/- standard deviation), whereas in control rats the level had fallen to 0.004 +/- 0.002 microgram/ml. Control rats excreted 50.5% of a single dose in the urine within the 3 days, whereas rats with renal damage excreted only 35.6%. These results indicate that vancomycin pharmacokinetics is affected by renal function in rats. Therefore, the drug should be used very cautiously in patients with impaired renal function. The serum levels must be monitored, and the frequency and size of doses may have to be reduced.     

Pharmacokinetic-pharmacodynamic relationships of morphine in neonates.

Morphine pharmacokinetics and pharmacodynamics (analgesia and sedation) were evaluated after continuous intravenous infusion of morphine in 19 neonates, both preterm and term, whose lungs were ventilated to relieve respiratory distress. Elimination half-life, total plasma clearance, and volume of distribution (mean +/- SD) were 9.6 +/- 3.0 hours, 2.55 +/- 1.65 ml/min/kg (area analysis) or 2.09 +/- 1.19 ml/min/kg (steady-state data), and 2.05 +/- 1.05 L/kg, respectively, and were not significantly different in preterm and term neonates. In neonates with adverse effects of morphine, the plasma clearance was decreased twofold. Mean morphine concentration required to produce adequate sedation in 50% of patients was found to be 125 ng/ml, but concentrations above 300 ng/ml may be associated with adverse effects of morphine. Morphine-6-glucuronide was not detected in the plasma of any neonate, which may explain why neonates require high plasma concentrations of unchanged morphine for sedation.     

Histamine release, complement consumption, and microvascular changes after radiographic contrast media infusion in rabbits.

The intravenous injection of RCM into rabbits produced dose-dependent changes in SAP, MVP, and RBCV, as well as plasma histamine and complement concentrations. After infusion of 8 ml/kg Hypaque-50, SAP dropped from 86 +/- 3 mm Hg to 50 +/- 3, MVP from 42 +/- 2 cm H2O to 26 +/- 3, and RBCV from 0.98 +/- 0.11 mm/sec to 0.37 +/- 0.13. The microvascular changes appeared 10 sec after injection and persisted for 10 to 40 min. During the course of the reaction it was observed that leukocytes adhered to the endothelial walls and red blood cells shrank and finally aggregated in the microvessels. The microvascular changes were accompanied by an increase in plasma histamine concentration, with an average of 44 ng/ml after 2 min, and a drop in total plasma CH50 by an average of 46%. Infusion of 8 ml/kg hyperosmolar saline solution (4.1 gm/dl or 1324 mOsm/L) produced initial changes in microvascular parameters which returned to normal within a few seconds. At the same time plasma histamine concentration increases slightly without changes in complement. It is concluded that the hyperosmolar properties of RCM may contribute to the initial hemodynamic changes observed after RCM infusion. However, the prolonged microcirculatory disturbances produced by RCM in rabbits appear to be a direct effect of the chemotoxicity of these compounds. Part of this chemotoxicity might result form initial release of vasoactive mediators such as histamine and activation of the complement system.     

Vancomycin-induced histamine release and "red man syndrome": comparison of 1- and 2-hour infusions.

Vancomycin-induced "red man syndrome" (RMS) is mediated in part by histamine release, and its severity is correlated with the area under the plasma histamine concentration-time curve. Ten adult male volunteers participated in a randomized, double-blind, two-way crossover trial (1-week washout interval between regimens) to determine the effect of 1- and 2-h infusions of vancomycin (1.0 g) on histamine release and on the frequency and severity of RMS. The severity of RMS was classified a priori as mild, moderate, or severe from a combined score of pruritus and extent of erythema. Serial concentrations of histamine in plasma and concentrations of vancomycin in serum were measured at baseline and during and after each infusion. Of 10 subjects, 8 had evidence of RMS during the 1-h infusion (3 mild, 3 moderate, and 2 severe), whereas only 3 of the 10 subjects (all mild) had RMS during the 2-h infusion (P less than 0.05). The 1-h infusion was associated with a significantly greater peak concentration of histamine in plasma (1.8 +/- 0.7 versus 1.0 +/- 0.3 ng/ml, P = 0.004) and a greater total release of histamine (74.3 +/- 54.1 versus 36.4 +/- 22.6 ng.min/ml, P = 0.017) than was the 2-h infusion. These data suggest that administration of vancomycin over 2 h reduces the frequency and severity of RMS and the amount of histamine released compared with those after a 1-h infusion in healthy volunteers.     

Sympathetic modulation of biochemical and physiological response to immune degranulation in canine bronchial airways in vivo.

The effect of sympathetic stimulation on bronchial smooth muscle contractile response after mast cell degranulation with Ascaris suum antigen was studied in 36 natively allergic dogs in situ. Bronchial smooth muscle response was measured isometrically in a single right middle lobe bronchus. A dose of antigen causing maximal release of mediator was administered to the bronchus through the bronchial arterial circulation. Serial plasma histamine concentrations were determined at 15-s intervals after intra-arterial (i.a.) administration of antigen. Samples of blood were obtained simultaneously from right heart and femoral artery, and arteriovenous difference (AVd) in histamine concentration across the bronchus was determined during mast cell degranulation. In nine dogs showing bronchial mast cell degranulation to antigen challenge, bronchial smooth muscle contraction was 22.3 +/- 2.95 g and the mean AVd in histamine concentration across the bronchus was 188 +/- 41.5 ng/ml. Six other dogs having muscarinic blockade with 0.75-1.0 mg/kg intravenous atropine were given i.a. antigen after 1 min of steady-state sympathetic stimulation with intravenous 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). Sympathetic stimulation during Ascaris suum antigen challenge caused complete inhibition of bronchial smooth muscle contractile response to i.a. antigen (P less than 0.001), and a significant AVd in histamine concentration across the bronchus (9.8 +/- 16.0 ng/ml; P less than 0.01 vs. control) was not detected. Peak plasma histamine concentration in control dogs was 1,138 +/- 237 ng/ml vs. 310 +/- 135 ng/ml in animals receiving sympathetic stimulation (P less than 0.01). In four dogs undergoing systemic anaphylaxis to i.v. antigen, subsequent sympathetic stimulation with i.v. DMPP reduced bronchomotor tone to approximately 70% of base-line control. Exogenously induced sympathetic stimulation can substantially inhibit systemic mast cell degranulation to Ascaris suum antigen in allergic dogs. Maximal stimulation of the sympathetic nervous system causes substantial inhibition of respiratory mast cell secretion of histamine and bronchial smooth muscle contraction to circulating mediator.     

Nifedipine: kinetics and dynamics in healthy subjects

Kinetics and pharmacologic effects of three formulations of nifedipine were examined in six healthy young men in a crossover design. Each subject received intravenous nifedipine, 0.015 mg/kg body weight, 20 mg in a capsule, and 20 mg in a slow-release tablet. Changes in heart rate (HR), blood pressure, heart dimensions, and plasma norepinephrine levels (PNE) were examined serially. Plasma concentrations of nifedipine (Cp) and urinary metabolite concentrations were measured by liquid chromatography. After intravenous injection the elimination t1/2 was 1.7 +/- 0.4 hr, systemic clearance was 26.7 +/- 5.4 l/hr, and volume of distribution was 0.8 +/- 0.2 l/kg. After the capsule, Cp rose rapidly, to a maximum concentration (Cmax) of 117 +/- 15 ng/ml at a maximum time (tmax) of 1.4 +/- 0.5 hr. After the sustained release tablet tmax was 4.2 +/- 0.7 hr and Cmax was 26 +/- 10 ng/ml. Nifedipine bioavailability was 56% +/- 25% for the capsule and 52% +/- 13% for the tablet, but there were large interindividual differences. Urinary excretion was 58% +/- 13% 24 hr after intravenous injection, and after 32 hr was 55% +/- 13% after capsules and 32% +/- 8% after tablets. HR increased briefly after intravenous injection and after capsules (15 to 20 bpm), but not significantly after tablets. Diastolic blood pressure (DBP) fell briefly after capsules (8 to 10 mm Hg), but there was a sustained effect after tablets. Cardiac dimensions were unchanged. PNE levels paralleled plasma drug levels in the three experiments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of subcutaneous naltrexone pellets in the rat

Subcutaneous implantation of naltrexone pellets is a standard method of producing chronic blockade of opioid receptors. In the present experiments, rats were treated with two, 30-mg naltrexone pellets and the pharmacokinetics and pharmacodynamics examined. This dosing method produced high plasma naltrexone levels (350 ng/ml) by 1 hr which declined over an implant period of 192 hr (24 ng/ml). Approximately 40% of the systemically available naltrexone (15.6 mg) was released in the first 24 hr. A total of 39.8 mg was released over the 192-hr implantation period. At 192 hr after implantation, naltrexone produced a greater than 50-fold shift to the right in the dose-response curve for morphine analgesia relative to placebo-implanted controls. When naltrexone pellets were removed at 192 hr after implantation, morphine analgesia (10 mg/kg) returned with a time course that was inversely related to the elimination of naltrexone. Pharmacokinetic analysis indicated that naltrexone has a terminal elimination half-life of 4.6 hr. Probit analysis revealed a linear plasma level-response relationship for naltrexone antagonism of morphine analgesia with a plasma ED50 of 2.1 ng/ml when plasma morphine levels average 1126 ng/ml. In the rat, s.c. naltrexone pellets are a dosage form that provides a rapid release of systemic drug. The systemic availability of naltrexone continues for at least 192 hr after implantation. The high potency of naltrexone permits continued antagonism of morphine even when the systemic availability of naltrexone from the pellets has greatly diminished.     

Effects of cytochrome P-450 inhibitors on the in vivo metabolism of all-trans-retinoic acid in rats

This study examines the effects of ketoconazole, R 75 251 and some other cytochrome P-450 inhibitors on the in vivo metabolism of all-trans-retinoic acid (RA) in normal rats. Oral treatment with ketoconazole or R 75 251 (40 mg/kg, -1 hr) reduced the elimination rate of i.v. injected RA from plasma: the half-life of RA increased from 27 min in control-treated animals to 43 min and 76 min after dosing with ketoconazole and R 75 251, respectively. However, neither drug had an effect on the distribution volume of the retinoid. Two hours after i.v. injection of RA, residual plasma levels of the retinoid were 11.2 ng/ml in ketoconazole and 22.7 ng/ml in R 75 251-treated rats. The other P-450 inhibitors, aminoglutethimide, cimetidine, itraconazole, metyrapone and saperconazole, showed no sparing effect on RA elimination: plasma levels of the acid were below 1 ng/ml, as in control-treated animals. Administration of ketoconazole or R 75 251 (40 mg/kg, -2 hr) to rats also enhanced endogenous plasma concentrations of RA. Levels of the retinoid were raised from mostly undetectable values (less than 0.5 ng/ml) to 1.3 +/- 0.1 and 2.5 0.1 ng/ml after treatment with ketoconazole and R 75 251, respectively. These data are indicative of the important contribution of the cytochrome P-450 enzyme system to the in vivo metabolic process of RA. In vivo inhibition of the P-450 pathway not only increased the biological half-life of exogenously administered RA, but also enhanced the endogenous plasma level of this vitamin A derivative.     

Amelioration of the development of multiple organ dysfunction syndrome by somatostatin via suppression of intestinal mucosal mast cells

Multiple organ dysfunction syndrome (MODS) is the most serious complication of trauma or infection. Our previous study has shown that activated intestinal mucosal mast cells (IMMC) might play an important role in the development of MODS. Somatostatin (SST), one of the peptides derived from gut, is an important regulator in the neuroendocrine-immune network. However, the effects of SST on IMMC, especially in the situation of MODS, remain unclear. The aim of this study was to investigate the effect of SST on the activity of IMMC in MODS. A rat model of MODS was established 24 h after intraperitoneal injection of zymosan at dosage of 75 mg/kg. SST was injected into the tail vein 30 min after intraperitoneal inoculation of zymosan. Animals were sacrificed 25 h after zymosan injection. The concentration of histamine and tumor necrosis factor-alpha (TNF-alpha) in plasma and intestinal tissue was measured. The pathological changes of vital organs, including intestine, liver, kidney, and lung, were studied under light microscopy. The ultramicrostructures of IMMC were observed by transmission electron microscopy. Obvious improvement of pathological changes of vital organs was observed in the rats with MODS treated with SST at 2.3 ng/kg/h. PO2 was increased by 50% (P < 0.05). The histamine level in the intestinal tissue of rats with MODS treated with SST (14.50 +/- 1.08 ng/g protein) was significantly higher than that of the group without treatment (8.60 +/- 0.50 ng/g protein, P < 0.01). Furthermore, degranulation of IMMC in the rats treated with SST was less obvious. The in vitro inhibitive effect of SST on the histamine release rate of IMMC was negatively correlated to its concentration (r = -0.991, P < 0.01). In conclusion, suppression of IMMC activity might be an important mechanism of the protective effects of SST in rats with a high risk of MODS.     

Pharmacokinetics of vancomycin in patients undergoing continuous ambulatory peritoneal dialysis.

The pharmacokinetics of vancomycin were studied in four patients on continuous ambulatory peritoneal dialysis. After a single intravenous infusion of 10 mg/kg of total body weight, multiple blood, urine, and dialysate samples were collected during a 72-h evaluation period. The steady-state volume of distribution was 0.73 +/- 0.07 (mean +/- standard deviation) liters/kg with a beta half-life of 90.2 +/- 24.2 h. The continuous ambulatory peritoneal dialysis clearance of vancomycin was 1.35 +/- 0.35 ml/min, and the serum clearance was 6.4 +/- 1.1 ml/min. Peritoneal dialysate concentrations of vancomycin were rapidly attained after the intravenous infusion and averaged 2.2 +/- 0.7 mg/liter throughout the 72-h observation period. A loading dose of 23 mg/kg followed by a maintenance dose of 17 mg/kg every 7 days should attain and maintain therapeutic serum and dialysate concentrations. More frequent dosing may be necessary for less susceptible organisms.     

Kinetics of fenoximone, a new cardiotonic, in healthy subjects

Fenoximone, a new cardiotonic, was given to six healthy men as a single intravenous dose of 1 mg/kg and a single oral dose of 3 mg/kg as solution in a crossover study. Plasma concentrations were monitored for 8 hr and urine was collected for 24 hr. Peak plasma concentrations (Cmax) were reached 30 min after the oral dose. Decay of plasma concentrations was fitted to a mean (+/- SD) elimination t1/2 (t1/2 beta) of 60 +/- 14 min after intravenous injection and 78 +/- 26 min after oral dosing. Mean total body clearance for intravenous dosing was 2062 +/- 846 ml/min, renal clearance (ClR) was 5.3 +/- 2.4 ml/min, and extrapolated volume of distribution was 0.37 +/- 0.26 l/kg. The sulfoxide derivative was detected as the main metabolite. Cmax of the sulfoxide metabolite occurred 10 min after the end of the intravenous infusion and 20 to 60 min after oral dosing. From the decay of the plasma concentrations of the sulfoxide, the t1/2 beta s were calculated as 132 +/- 15 min after intravenous injection and 140 +/- 27 min after oral dosing of fenoximone. ClR of the sulfoxide was 499 +/- 106 ml/min after intravenous injection; 24-hr urinary recovery of the sulfoxide was 75.7% +/- 5.7% after intravenous injection and 64.3% +/- 10.4% after oral dosing. Mean oral bioavailability of fenoximone was 53% (range 44% to 69%).     

Effects of antihistamines on the lung vascular response to histamine in unanesthetized sheep. Diphenhydramine prevention of pulmonary edema and increased permeability.

To see whether antihistamines could prevent and reverse histamine-induced pulmonary edema and increased lung vascular permeability, we compared the effects of a 4-h intravenous infusion of 4 mug/kg per min histamine phosphate on pulmonary hemodynamics, lung lymph flow, lymph and plasma protein content, arterial blood gases, hematocrit, and lung water with the effects of an identical histamine infusion given during an infusion of diphenhydramine or metiamide on the same variables in unanesthetized sheep. Histamine caused lymph flow to increase from 6.0+/-0.5 to 27.0+/-5.5 (SEM) ml/h (P less than 0.05), lymph; plasma globulin concentration ratio to increase from 0.62+/-0.01 to 0.67+/-0.02 (P less than 0.05), left atrial pressure to fall from 1+/-1 to -3+/-1 cm H2O (P less than 0.05), and lung lymph clearance of eight protein fractions ranging from 36 to 96 A molecular radius to increase significantly. Histamine also caused increases in lung water, pulmonary vascular resistance, arterial PCO2, pH, and hematocrit, and decreases in cardiac output and arterial PO2. Diphenhydramine (3 mg/kg before histamine followed by 1.5 mg/kg per h intravenous infusion) completely prevented the histamine effect on hematocrit, lung lymph flow, lymph protein clearance, and lung water content, and reduced histamine effects on arterial blood gases and pH. 6 mg/kg diphenhydramine given at the peak histamine response caused lymph flow and lymph: plasma protein concentration ratios to fall. Metiamide (10 mg/kg per h) did not affect the histamine lymph response. We conclude that diphenhydramine can prevent histamine-induced pulmonary edema and can prevent and reverse increased lung vascular permeability caused by histamine, and that histamine effects on lung vascular permeability are H1 actions.     

Morphine-induced skin wheals: a possible model for the study of histamine release

We evaluated the ability of morphine to release histamine when injected intradermally in man. Mathematic analysis of the dose-response (wheal) relationship suggested that two different effects were involved. The effect of low doses of morphine (0.05 to 1 microgram) was clearly antagonized by naloxone (0.4 or 1.2 mg im 30 minutes before), whereas the effect of higher doses (5 to 50 micrograms) was not modified. The median effective doses of morphine (ED50) for the low dose range effect were 0.07 +/- 0.01 and 0.08 +/- 0.01 microgram before naloxone and 0.14 +/- 0.02 and 0.15 +/- 0.03 microgram after 0.4 and 1.2 mg doses, respectively. Astemizole (45 mg po 30 minutes before) and oxatomide (60 mg po 120 minutes before) produced similar inhibition of histamine-induced wheals, but there were clear differences in their effects on wheals elicited by morphine. Morphine ED50 values for the low dose range effect rose from 0.09 +/- 0.01 to 0.20 +/- 0.01 microgram after astemizole and from 0.08 +/- 0.01 to 0.46 +/- 0.04 microgram after oxatomide. Opiate receptors may be involved in some of the effects produced by morphine injection in the human skin, but morphine-induced wheals seem to offer a suitable model for the evaluation of agents capable of inhibiting histamine release in man.     

Efficacy of daptomycin in experimental endocarditis due to methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus is becoming increasingly prevalent as both a nosocomial and a community-acquired pathogen. Daptomycin, a lipopeptide antibiotic now in phase III clinical trials, is rapidly bactericidal in vitro against a range of gram-positive organisms, including methicillin-resistant S. aureus (MRSA). In this study, we compared the efficacy of daptomycin with that of vancomycin, each with or without rifampin, in a model of experimental aortic valve endocarditis due to MRSA. The infecting strain (MRSA strain 32) was susceptible to daptomycin (MIC = 1 micro g/ml), vancomycin (MIC = 0.5 micro g/ml), and rifampin (MIC = 0.5 micro g/ml). Daptomycin was administered at 25 or 40 mg/kg q24h (q24h) by subcutaneous injection in an attempt to simulate human doses of 4 and 6 mg/kg q24h, respectively. Vancomycin was given at 150 mg/kg q24h by continuous intravenous infusion. Rifampin was given at 25 mg/kg by intramuscular injection q24h. Treatment was started 6 h postinoculation and continued for 4.5 days. Outcome was assessed by counting the residual viable bacteria in vegetations. The mean peak daptomycin levels in serum at 2 h after subcutaneous administration of 25 and 40 mg/kg were 64 and 91 micro g/ml, respectively. Daptomycin was undetectable in serum at 24 h. The total exposure was comparable to that achieved clinically in humans receiving the drug. Bacterial counts (mean log(10) number of CFU per gram +/- the standard deviation) in untreated controls reached 10.6 +/- 0.8. In treated rats, bacterial counts were as follows: vancomycin, 7.1 +/- 2.5; daptomycin at 25 mg/kg, 5.5 +/- 1.7; daptomycin at 40 mg/kg, 4.2 +/- 1.5. The difference between daptomycin at 40 mg/kg and vancomycin at 150 mg/kg was statistically significant (P = 0.004). In the study of combination therapy, vegetation bacterial counts were as follows: daptomycin at 40 mg/kg, 4.6 +/- 1.6; rifampin, 3.6 +/- 1.3; vancomycin plus rifampin, 3.3 +/- 1.1; daptomycin plus rifampin, 2.9 +/- 0.8. The difference between daptomycin and daptomycin plus rifampin was statistically significant (P = 0.006). These results support the continued evaluation of daptomycin for serious MRSA infections, including infective endocarditis.     

Kinetics of intravenous and intramuscular morphine

The disposition of parenteral morphine was assessed in two pharmacokinetic studies. In Study 1, 10 mg of morphine sulfate was administered by intravenous (IV) infusion, intramuscular (IM) injection, or both, to 8 healthy young adult male volunteers. Plasma morphine concentrations were determined by radioimmunoassay in multiple blood samples drawn after each dose. Mean (+/-SE) kinetic parameters following IV morphine were: volume of distribution (Vd), 3.2 (+/- 0.3) L/kg; elimination half-life (t1/2beta), 2.9 (+/- 0.5) hr; clearance, 14.7 (+/- 0.9) ml/min/kg; extraction ratio, 0.70 (+/- 0.04). After IM morphine, peak plasma levels ranged from 51 to 62 ng/ml and were reached within 20 min of injection. The absorption half-life averaged 7.7 (+/- 1.6) min. Systemic availability was 100% complete. In study 2, 4 elderly male patients (61 to 80 yr of age) received 45 to 80 mg of morphine sulfate IV prior to operative repair of an abdominal aortic aneurysm. Morphine pharmacokinetics were determined as described above. Kinetic variables were Vd, 4.7 (+/- 0.2) L/kg; t1/2beta, 4.5 (+/- 0.3) hr; clearance, 12.4 (+/- 1.2) ml/min/kg; extraction ratio, 0.59 (+/- 0.05). Both studies demonstrate that morphine distribution is rapid and extensive and its t1/2beta relatively short. IM morphine is rapidly and completely absorbed.     

Behavioural evidence that systemic morphine may modulate a phasic pain-related behaviour in a rat model of peripheral mononeuropathy.

In a model of peripheral mononeuropathy produced by 4 ligatures around the sciatic nerve, we investigated the effects of various i.v. doses of morphine on the vocalization thresholds elicited by paw pressure and compared the effects obtained with the same doses in normal rats. In neuropathic rats, morphine (0.1 and 0.3 mg/kg) produced a significant analgesic effect on the lesioned hind paw, maximum at 15 min post injection with a recovery at 20-25 min. For doses of 0.6 and 1 mg/kg, a modification of the kinetics was observed, with maximum effect at 20-30 min post injection and a recovery at 50-80 min. An analgesic effect was also observed on the unlesioned side, significantly less potent than that observed on the lesioned paw. The effect of 1 mg/kg morphine was almost totally reversed by a 0.1 mg/kg dose of systemic naloxone. The effects induced by the successive doses of morphine on the lesioned paw appeared higher than in normal rats (maximum vocalization thresholds (% of control) following 1 mg/kg morphine (N = 12) were 193.92 +/- 6.57% versus 154 +/- 3.5% in normal rats N = 3), whereas they were comparable to those obtained from the sham-operated paw. The present data clearly show that morphine induces potent antinociceptive effects in a rat model of neuropathy, which seems to contradict the classical view that neuropathic pain is opioid resistant. Some possible pathophysiological mechanisms are discussed.     

The role of peripheral catecholamines in oxotremorine tremor in the rat and its antagonism by beta adrenoceptor blocking agents.

Oxotremorine, 0.25 mg/kg, produces marked tremor in the rat, which is abolished by scopolamine, 0.5 mg/kg, and is substantially reduced in intensity and duration both by adrenalmedullectomy and by chemical sympathectomy with 6-hydroxydopamine. Oxotremorine increases plasma norepinephrine from 0.62 +/- 0.07 to 3.01 +/- 0.47 ng/ml and plasma epinephrine, from 0.82 +/- 0.14 to 3.42 +/- 0.48 ng/ml, in conscious unrestrained rats. l-Propranolol (0.5-2.5 mg/kg) reduces tremor, and at 2.5 mg/kg is more effective than either chemical sympathectomy or adrenal demedullation. d-Propranolol and sotalol are also active at 4 and 10 times the dose of l-propranolol, respectively. l-Propranolol does not prevent the rise in catecholamines induced by oxotremorine. It is suggested that stimulation of central muscarinic receptors causes tremor by a combination of two effects. There is an increase in cholinergic influence to motor efferents accompanied by an activation of the sympathoadrenal system to release catecholamines which augment tremor by stimulation of beta2 adrenoceptors.     

Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine

INTRODUCTION: There is considerable and unexplained individual variability in the morphine dose-effect relationship. The efflux pump P-glycoprotein regulates brain access and intestinal absorption of numerous drugs. Morphine is a P-glycoprotein substrate in vitro, and P-glycoprotein affects morphine brain access and pharmacodynamics in animals. However, the role of P-glycoprotein in human morphine disposition and clinical effects is unknown. This investigation tested the hypothesis that plasma concentrations and clinical effects of oral and intravenous morphine are greater after inhibition of intestinal and brain P-glycoprotein, with the P-glycoprotein inhibitor quinidine used as an in vivo probe. METHODS: Two randomized, double-blind, placebo-controlled, balanced crossover studies were conducted in normal healthy volunteers after institutional review board-approved informed consent was obtained. In the first protocol, pupil diameter was evaluated after intravenous morphine administration (0.15 mg/kg), 1 hour after oral quinidine or placebo. In the second protocol, plasma morphine and glucuronide metabolite concentrations and pupil diameters were evaluated after oral morphine administration (30 mg), dosed 1 hour after oral quinidine (600 mg) or placebo. RESULTS: Quinidine had no effect on intravenous morphine effects (time to maximum miosis, maximum effect, or area under the curve [AUC] of miosis versus time). Quinidine increased the oral morphine maximum plasma concentration (31.8 +/- 14.9 ng/mL versus 16.9 +/- 7.4 ng/mL, P <.05) and AUC (65.1 +/- 21.5 versus 40.8 ng. h. mL(-1) +/- 14 ng. h. mL(-1), P <.05) but had no effect on elimination rate. Plasma morphine glucuronide concentrations were unchanged; however, the morphine glucuronide/morphine ratios were diminished by quinidine. Differences in oral morphine miosis (AUC, 16.8 +/- 9.3 mm. h versus 10.8 +/- 6.5 mm. h; P <.05) were commensurate with changes in plasma morphine concentration, and concentration-effect relationships were unchanged. Quinidine altered subjective self-assessments of oral but not intravenous morphine effects. DISCUSSION: Quinidine increased the absorption and plasma concentrations of oral morphine, suggesting that intestinal P-glycoprotein affected the absorption, bioavailability, and, hence, clinical effects of oral morphine. However, quinidine had no effect on morphine concentration-effect relationships, suggesting that if quinidine is an effective inhibitor of brain P-glycoprotein then P-glycoprotein did not appear to have a significant effect on brain access of morphine.