Total intravenous anaesthesia with sufentanil-midazolam for major abdominal surgery

Haemodynamic and endocrine stress responses were compared during total intravenous anaesthesia with sufentanil and midazolam or fentanyl and midazolam in patients undergoing elective major abdominal surgery. Twenty-two ASA I and II patients were allocated randomly to receive sufentanil (induction 1.5 micrograms kg-1 plus infusion 1.5 micrograms kg-1 h-1) or fentanyl (induction 10 micrograms kg-1 plus infusion 10 micrograms kg-1 h-1) supplemented with 0.15 microgram kg-1 sufentanil or 1 microgram kg-1 fentanyl as necessary. Midazolam was infused to obtain plasma concentrations of 500-600 ng ml-1. Ventilation was with oxygen-enriched air. The opioid infusion was reduced post-operatively by half and benzodiazepine effects were reversed by titration with flumazenil. Mean arterial pressure, heart rate and cardiac index decreased in both groups after induction (cardiac index: sufentanil 4.94 +/- 0.45 to 2.99 +/- 0.18 litre min-1; fentanyl 4.97 +/- 0.45 to 3.71 +/- 0.36 litre min-1), but all returned to baseline during surgery. With sufentanil; mean arterial pressure was lower throughout the study period, and heart rate was lower intra-operatively. Oxygen uptake decreased in both groups after induction (sufentanil 289 +/- 29 to 184 +/- 21 ml min-1; fentanyl 318 +/- 32 to 216 +/- 32 ml min-1) and remained low with sufentanil until flumazenil was given. Adrenaline concentrations increased in both groups but there was no intergroup difference. The median noradrenaline concentration was lower intra-operatively with sufentanil (0.47 nmol litre-1 (range 0.06-6.77)) than with fentanyl (0.73 nmol litre-1 (0.07-4.58)). Cortisol, glucose and lactate concentrations increased in both groups. Bradycardia occurred in four patients with sufentanil and in three with fentanyl. There were two cases of marked thoracic rigidity with sufentanil and one with fentanyl.     

Snake F(ab')2 antivenom from hyperimmunized horse: pharmacokinetics following intravenous and intramuscular administrations in rabbits

PURPOSE: The pharmacokinetics of a currently available horse F(ab')2 antivenoms to Vipera aspis, V. ammodytes, and V. berus (Ipser Europe) and a new more purified and pasteurized preparation (SAV) was investigated in the rabbit. METHODS: An immunoradiometric assay using an affinity-purified goat IgG horse F(ab')2 specific and the same IgG labelled with iodine 125 as a tracer was developed. The limit of quantification in plasma was 0.032 microgram/ml. Specificity study showed that mouse F(ab')2 and Fab did not cross-react. RESULTS: Pharmacokinetic analysis showed that the plasma F(ab')2 concentration followed a biexponential decline after intravenous bolus administration with distribution and elimination half-lives of 2.66 +/- 0.18 hrs and 49.69 +/- 4.13 hrs, respectively. The total volume of distribution (Vdss or Vd beta) was between 209 and 265 ml.kg-1 and was similar to the volume of the extracellular fluid in the rabbit (300 ml.kg-1). Total body clearance ranged from 3.33 to 3.96 ml.h-1.kg-1. After intramuscular administration which was only investigated with SAV, Tmax was 48 hrs and the absolute bioavailability was 42%. CONCLUSIONS: No difference in pharmacokinetics was observed between the two antivenom preparations following the intravenous administration. In contrast, a reduced rate and extent of absorption was shown following intramuscular administration.     

Stability, tissue metabolism, tissue distribution and blood partition of azosemide

Stability of azosemide after incubation in various pH solutions, human plasma, human gastric juice, and rat liver homogenates, metabolism of azosemide after incubation in 9000 g supernatant fraction of various rat tissue homogenates in the presence of NADPH, tissue distribution of azosemide and M1 after intravenous (i.v.) administration of azosemide, 20 mg kg-1, to rats, and blood partition of azosemide between plasma and blood cells from rabbit blood were studied. Azosemide seemed to be stable for up to 48 h incubation in various pH solutions ranging from two to 13 at an azosemide concentration of 10 micrograms mL-1; more than 93.4% of azosemide was recovered, and a metabolite of azosemide, M1, was not detected. However, the drug was unstable in pH1 solution: 75.8% of azosemide was recovered and 2.16 micrograms mL-1 of M1 (expressed in terms of azosemide) was formed after 48 h incubation in pH 1 solution at an azosemide concentration of 10 micrograms mL-1. Azosemide was stable in both human plasma and rat liver homogenates for up to 24 h incubation at an azosemide concentration of 1 microgram mL-1, and in human gastric juice for up to 4 h incubation at an azosemide concentration of 10 micrograms mL-1. However, all rat tissues studied had metabolic activity for azosemide in the presence of NADPH, with heart having a considerable metabolic activity: approximately 22% of azosemide disappeared and 9.32 micrograms of M1 was formed per gram of heart (expressed in terms of azosemide) after 30 min incubation of 50 micrograms of azosemide in 9000 g supernatant fraction of heart homogenates. The tissue to plasma ratios of azosemide (T/P) were greater than unity only in the liver (1.26) and kidney (1.74); however, M1 showed high affinity for all tissues studied except the brain and spleen when each tissue was collected at 30 min after i.v. administration of azosemide to rats. The equilibrium plasma to blood cell concentration ratios of azosemide were independent of azosemide blood concentrations: the values were 2.78-4.25 at azosemide blood concentrations of 1, 10, and 20 micrograms mL-1 in three rabbits. There was negligible 'blood storage effect' of azosemide, especially at low blood concentrations of azosemide, such as 1 and 10 micrograms mL-1.     

Percutaneous absorption and disposition studies of methotrexate in rabbits and rats

The absorption and disposition of methotrexate (MTX) in the plasma, synovial fluid (SF), skin, and muscle tissue were studied following administration of a topical MTX gel in rabbits and rats. In rabbits, MTX concentrations in the plasma increased steadily toward the peak (5.9 +/- 2.8 ng mL-1) which appeared at approximately 2 h postdose and declined with the elimination half-life of 4.48 +/- 1.74 h. At 1 h after the topical dose, the MTX concentrations in the skin (49.0 +/- 19.8 micrograms g-1), muscle (12.7 +/- 3.3 ng g-1), and SF (19.2 +/- 10.1 ng g-1) underneath the dosed stifle joint were significantly higher (p < 0.05) than those of the untreated stifle joint, indicating the potential therapeutic value of topical delivery of MTX for rheumatoid arthritis. A large fraction (approximately 59%) of MTX which was found in the skin at 1 h postdose was present in the stratum corneum, indicating its extensive binding capacity for MTX. The MTX concentrations in the muscle and SF of the dosed stifle joint at 1 h postdose were 1.8 and 2.6 times higher than those in the dosed elbow joint, respectively, reflecting the effect of dose site on the permeation of MTX. Using a new filter paper method, the amounts of SF obtained from the elbow and stifle joints of four rabbits were 26.3 +/- 8.3 and 48.8 +/- 5.2 mg, respectively. A significant enhancer effect of N,N-diethyl-n-toluamide (DEET) on the disposition of MTX in the stratum corneum of rabbit ear was observed (p < 0.05) by the tape-stripping method. In rats, the gel containing 4% DEET resulted in a twofold increase in the permeation of MTX into the muscle over the 4 h period postdose. A modified HPLC method with a linear calibration curve (r > 0.999) over the range of 2-50 ng mL-1. quantitation limit of 0.5 ng mL-1, and mean recovery of approximately 87% was used for the quantitation of MTX in the tissue and fluid samples.     

Nitric oxide synthase inhibition restores vasopressor effects of norepinephrine in ovine hyperdynamic sepsis

To investigate the hypothesis that nitric oxide synthase (NOS) inhibition restores the vasopressor response to norepinephrine (NE) in ovine hyperdynamic sepsis, eight sheep were chronically instrumented. In the non-septic portion of the study, NE was titrated to achieve an increase in mean arterial pressure (MAP) by 15 mm Hg ("small dose"). Small-dose NE was repeated 1 h after administration of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; bolus 5 mg/kg, followed by 1 mg.kg-1.h-1). After 3 days of recovery, sepsis was induced by a continuous endotoxin infusion (Salmonella typhosa, 10 ng.kg-1.h-1). Three animals died during this period (data excluded). After 24 h, small-dose NE was given. If MAP increased less than 15 mm Hg, the NE dose was increased to achieve the targeted MAP change ("large dose"). Finally, both doses of NE were given after L-NAME administration. To increase MAP by 15 mm Hg in nonseptic animals, the rate of NE infusion was 0.18 +/- 0.03 microgram.kg-1.min-1 (small dose). During L-NAME infusion, this NE dose increased MAP by 32 +/- 8 mm Hg. In septic animals, small-dose NE increased MAP by only 9 +/- 2 mm Hg (P < 0.05 versus nonseptic state). To increase MAP by 15 mm Hg, the NE dose had to be increased to 0.34 +/- 0.06 microgram.kg-1.min-1 (large dose). During L-NAME infusion, NE administration increased MAP by 16 +/- 2 mm Hg and 28 +/- 4 mm Hg (small and large dose, respectively). Thus, L-NAME restored the vasopressor response to NE in sepsis, and increased the vasopressor response to NE in a similar fashion in healthy and septic sheep.     

Influence of apolipoprotein E polymorphism on the tracking of childhood levels of serum lipids and apolipoproteins over a 6-year period. The Bogalusa Heart Study

This study was designed to test the hypothesis that in the in vivo dog heart, increases in cyclic (c) GMP and also decreases in cAMP induced by intracoronary administration of acetylcholine are associated with depressed myocardial function. In 10 open-chest anesthetized dogs, 0.5 microgram.kg-1.min-1 of acetylcholine was infused into the left anterior descending coronary artery. The intracoronary infusion of acetylcholine was continued simultaneously with 0.1 microgram.kg-1.min-1 of isoproterenol. Regional segment work was calculated as the integrated product of force (auxotonic force transducer) and segment shortening (sonomicrometry). Regional myocardial O2 consumption was calculated from blood flow measurements and regional O2 saturations. Competitive radioligand binding assays were used to determine the intracellular level of cAMP and cGMP in the myocardium. Local intracoronary infusion of acetylcholine significantly reduced regional segment work (from 36.7 +/- 6.5 to 19.1 +/- 3.7 x 10(-3) J/min) and O2 consumption (from 6.4 +/- 0.8 to 3.8 +/- 0.7 mL O2.min-1.100 g-1). This was related to a decrease in cAMP levels (from 364 +/- 25 to 262 +/- 17 pmol/100 g) and an increase in cGMP levels (from 1.34 +/- 0.06 to 1.78 +/- 0.15 pmol/100 g). When isoproterenol (0.1 microgram.kg-1.min-1) was added to the acetylcholine infusion line, cAMP levels tripled to 769 +/- 84 pmol/100 g, while O2 consumption rose to 6.6 +/- 1.4 mL O2.min-1.100 g-1. However, regional work was only partially restored (25.7 +/- 4.8 x 10(-3) J/min). Thus, both cAMP decrements and cGMP elevation occurred together with the negative inotropic effect of acetylcholine, and increased cAMP alone (produced by isoproterenol) did not fully overcome the acetylcholine effect. This was associated with elevated intracellular levels of cGMP.     

Detection of an anatoxin-a(s)-like anticholinesterase in natural blooms and cultures of cyanobacteria/blue-green algae from Danish lakes and in the stomach contents of poisoned birds

Ten natural bloom samples of cyanobacteria from the Danish lakes Knud s? (5), Ravn s? (4), and Salten Langs? (1) collected during 1993-1995 were assayed for toxicity by mouse bioassay, for acetylcholinesterase inhibiting activity by a colorimetric method, and for microcystins by enzyme-linked immunosorbent assay. In the mouse bioassay, seven samples were neurotoxic, two were non-toxic and one gave a protracted toxic response. One of the non-toxic and the single protracted toxic sample both contained anticholinesterase activity equivalent to 4 micrograms anatoxin-a(s) g-1. The neurotoxic samples contained equivalents to 20-3300 micrograms anatoxin-a(s) g-1. The highest anticholinesterase activities (equivalent to 2300 and 3300 micrograms anatoxin-a(s) g-1, respectively) were found in samples collected from Lake Knud s? in connection with bird-kills in 1993 and 1994. Small amounts of microcystins (0.1-0.9 microgram g-1) were detected in all samples but one. All Lake Knud s? and Lake Ravn s? samples were dominated by Anabaena lemmermannii, and the Lake Salten Langs? sample by several species of Anabaena. Gel filtration profiles indicated similarity between the toxic component from the Lake Knud s? 1994 bloom with registered bird-kills and anatoxin-a(s) isolated from Anabaena flos-aquae NRC-525-17. Anticholinesterase-producing cultures of A. lemmermannii were isolated from the Lake Knud s? 1993 bloom. These laboratory cultures produced anatoxin-a(s) equivalents of 29-743 micrograms g-1. Other cultures of A. lemmermannii isolated from Lake Knud s? and Lake Ravn s? were hepatotoxic or non-toxic. Dead birds collected from Lake Knud s? during the neurotoxic 1993 Anabaena bloom possibly died from cyanobacterial toxicosis. The stomach contents contained colonies and single trichomes of Anabaena, and anticholinesterase activities equivalent to 2.1-89.7 micrograms anatoxin-a(s) kg-1 body weight and microcystins (53-95 ng kg-1) were also detected.     

Plasma, urinary and biliary residues in cattle following intramuscular injection of nortestosterone laurate

The synthetic androgen 19-nortestosterone (beta-NT) has been used illegally as a growth promoter in cattle production in the European Union. Elimination of beta-NT and its metabolites in plasma, urine and bile was studied in three cattle with cannulated gallbladders following intramuscular injection at a single site of 500 mg of the laurate ester (NTL) containing 300.5 mg beta-NT. Using enzyme immunoassay quantification, plasma Cmax of free beta-NT was 0.5 +/- 0.15 microgram/L (mean +/- SEM). Concentrations of free beta-NT in plasma were consistently greater than the assay limit of quantification (0.12 microgram/L) for 32.7 +/- 13.42 days. Mean residence time for the beta-NT in plasma was 68.5 +/- 20.75 days. Following sample preparation by immunoaffinity chromatography, high-resolution GC-MS was used to quantify beta-NT and alpha-NT in urine and bile. beta-NT was detected irregularly in urine from two of the three animals post injection. The principal metabolite present in the urine, alpha-NT, was detected for 160.3 +/- 22.67 days post injection. Cmax for alpha-NT in urine was 13.7 +/- 5.14 micrograms/L. Mean urinary AUC0-183 days for alpha-NT was 845.7 +/- 400.90 (microgram h)/L. In bile, alpha-NT was the only metabolite detected for 174.3 +/- 8.67 days post treatment. Cmax for alpha-NT in bile was 40.8 +/- 12.70 micrograms/L and mean biliary AUC0-183 days for alpha-NT was 1982.6 +/- 373.81 (microgram h)/L. Concentrations of alpha-NT in bile samples were greater than those in urine samples taken at the same time. The mean ratio of biliary:urinary AUC0-183 days was 3.0 +/- 0.72. It is concluded that bile is a superior fluid for detection of alpha-NT following injection of NTL, owing to the longer period during which residues may be detected after administration.     

Blockade of (+/-) 12-chloroscoulerine on feed-back regulation of dopamine D2 autoreceptors

AIM: To verify whether (+/-) 12-chloroscoulerine (CSL) is antagonist or agonist effect to D2 autoreceptors. METHODS: The levodopa content accumulated in the rat striatum was measured by HPLC-ECD, and the DA neuron firing activity in the substantia nigra zona compacta (SNC) was recorded. RESULTS: The accumulated levodopa content induced by CSL 40 mg.kg-1 was much more than that of 1,4-butyro-lactone (BL) group (P < 0.01). After i.p. injection of apomorphine (Apo) 5 mg.kg-1, the levodopa content was decreased below that of BL group (P < 0.05). The Apo inhibition on levodopa content was completely reversed by CSL (40 mg.kg-1, i.p.) and then increased the levodopa content (2.5 +/- 1.1 micrograms.g-1) over that of Apo group (0.7 +/- 0.3 microgram.g-1, P < 0.01). In the electrophysiologic recording, Apo (15 micrograms.kg-1, i.v.) induced the decrease of SNC DA cell firing rate nearly to zero. At the accumulated dose of CSL up to 80 micrograms.kg-1 (i.v.), the inhibition of Apo was attenuated and the firing activity was restored to predrug level. CONCLUSION: CSL showed an antagonistic action, an action to D2 autoreceptors.     

Influence of dopamine receptor and adrenoceptor blockade on the hemoconcentrating and hypotensive actions of atrial natriuretic peptide

Atrial natriuretic peptide (ANP) lowers mean arterial pressure (MAP) and increases hematocrit through reduction in plasma volume caused by a transcapillary shift of plasma fluid and protein toward the interstitium. We examined the consequences of blockade of the dopaminergic and adrenergic systems on the hypotensive and hemoconcentrating responses to ANP. Changes in MAP, hematocrit, and plasma protein concentration (PPC) were measured in anesthetized acutely binephrectomized rats, during infusion of ANP alone (1 microgram.kg-1.min-1 for 45 min) or in the presence of haloperidol (20 micrograms.kg-1.min-1), phentolamine (15 micrograms.kg-1.min-1), or propranolol (10 micrograms.kg-1.min-1). Infusion of ANP reduced MAP by 8.6 +/- 1.3% and increased hematocrit by 9.0 +/- 0.6% (both p < 0.005 vs. vehicle). PPC increased (4.4 +/- 0.6%; p < 0.005 vs. vehicle) significantly less than hematocrit, indicating extravasation of proteins. The ANP-evoked reduction in MAP was not affected in haloperidol- or phentolamine-treated rats (-8.8 +/- 2.3 and -10.5 +/- 2.4%, respectively; both p < 0.005 vs. vehicle) but was abolished in propranolol-treated rats (+3.2 +/- 1.3%; p = ns vs. vehicle). The ANP-induced increase in hematocrit was slightly attenuated in haloperidol-, phentolamine-, and propranolol-treated rats (7.5 +/- 0.7, 7.3 +/- 0.8, and 6.0 +/- 1%, respectively). In addition, the coefficient of reflection, an index of the permeability to proteins, was higher in these three groups (0.41 +/- 0.06, 0.49 +/- 0.08, and 0.57 +/- 0.14, respectively) than in control rats infused with ANP (0.27 +/- 0.03), indicating an attenuation of the ANP-induced extravasation of proteins. Thus, in binephrectomized rats, the hypotensive activity of ANP requires a beta-adrenergic component, whereas its hemoconcentrating action is, at least in part, dependent upon dopaminergic and adrenergic activation.     

Pharmacokinetics of isosorbide dinitrate in healthy volunteers after 24-hour intravenous infusion

No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate (IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2 micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady-state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half-lives of ISDN, IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38 minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min-1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.     

Quantitation of acetazolamide in rat plasma, brain tissue and cerebrospinal fluid by high-performance liquid chromatography

A simple and sensitive high-performance liquid chromatographic method for the analysis of acetazolamide (AZ) in rat blood (plasma/serum, whole blood and serum ultrafiltrate), brain tissue and cerebrospinal fluid (CSF) was described. Quantitative extraction of AZ with ethyl acetate from both buffered plasma and brain tissue homogenate (pH 8.0) was achieved. Each extract was evaporated to dryness and the residue was chromatographed on a reversed-phase column. CSF was directly analysed without extraction step. The limits of detection were 0.05 microgram ml-1 for plasma, 0.02 microgram g-1 for brain tissue and 0.004 microgram ml-1 for CSF. Calibration curves were linear over the working ranges of 0.1-100 micrograms ml-1 for plasma, 0.05-50 micrograms g-1 for brain tissue and 0.025-50 micrograms ml-1 for CSF. The reproducibility of AZ assay in the rat biologic media indicated very low relative standard deviations (RSDs). The recoveries of AZ added to plasma and brain tissue were more than 96% with an RSD of less than 5%. The present method was applied to studies of plasma concentration profiles of the drug after administration and its distribution into central nervous system.     

Evidence for an inhibitory effect of physiological levels of insulin on the growth hormone (GH) response to GH-releasing hormone in healthy subjects

It has been previously reported that in healthy subjects, the acute reduction of free fatty acids (FFA) levels by acipimox enhances the GH response to GHRH. In the present study, the GH response to GHRH was evaluated during acute blockade of lipolysis obtained either by acipimox or by insulin at different infusion rates. Six healthy subjects (four men and two women, 25.8 +/- 1.9 yrs old, mean +/- SE) underwent three GHRH tests (50 micrograms iv, at 1300 h) during: 1) iv 0.9% NaCl infusion (1200-1500 h) after oral acipimox administration (250 mg) at 0700 h and at 1100 h; 2) 0.1 mU.kg-1.min-1 euglycemic insulin clamp (1200-1500 h) after oral acipimox administration (250 mg at 0700 h and at 1100 h); 3) 0.4 mU.kg-1.min-1 euglycemic insulin clamp (1200-1500 h) after oral placebo administration (at 0700 and 1100 h). Serum insulin (immunoreactive insulin) levels were significantly different in the three tests (12 +/- 2, 100 +/- 10, 194 +/- 19 pmol/L, P < 0.06), plasma FFA were low and similar (0.04 +/- 0.003, 0.02 +/- 0.005, 0.02 +/- 0.003, not significant), and the GH response to GHRH was progressively lower (4871 +/- 1286, 2414 +/- 626, 1076 +/- 207 micrograms/L 120 min), although only test 3 was significantly different from test 1 (P < 0.05). Pooling the three tests together, a significant negative regression was observed between mean serum immunoreactive insulin levels and the GH response to GHRH (r = -0.629, P < 0.01). Our results indicate that in healthy subjects, acipimox and hyperinsulinemia produce a similar decrease in FFA levels and that at similar low FFA, the GH response to GHRH is lower during insulin infusion than after acipimox. These data suggest that insulin exerts a negative effect on GH release. Because the insulin levels able to reduce the GH response to GHRH are commonly observed during the day, for instance during the postprandial period, we conclude that the insulin negative effect on GH release may have physiological relevance.     

Moxifloxacin in the therapy of experimental pneumococcal meningitis

The activity of moxifloxacin (BAY 12-8039) against a Streptococcus pneumoniae type 3 strain (MIC and minimum bactericidal concentration [MBC] of moxifloxacin, 0.06 and 0.25 microgram/ml, respectively; MIC and MBC of ceftriaxone, 0.03 and 0.06 microgram/ml, respectively) was determined in vitro and in a rabbit model of meningitis. Despite comparable bactericidal activity, 10 micrograms of moxifloxacin per ml released lipoteichoic and teichoic acids less rapidly than 10 micrograms of ceftriaxone per ml in vitro. Against experimental meningitis, 10 mg of moxifloxacin per kg of body weight per ml reduced the bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as ceftriaxone did (mean +/- standard deviation, -0.32 +/- 0.14 versus -0.39 +/- 0.11 delta log CFU/ml/h). The activity of moxifloxacin could be described by a sigmoid dose-response curve with a maximum effect of -0.33 delta log CFU/ml/h and with a dosage of 1.4 mg/kg/h producing a half-maximal effect. Maximum tumor necrosis factor activity in CSF was observed later with moxifloxacin than with ceftriaxone (5 versus 2 h after the initiation of treatment). At 10 mg/kg/h, the concentrations of moxifloxacin in CSF were 3.8 +/- 1.2 micrograms/ml. Adjunctive treatment with dexamethasone at 1 mg/kg prior to the initiation of antibiotic treatment only marginally reduced the concentrations of moxifloxacin in CSF (3.3 +/- 0.6 micrograms/ml). In conclusion, moxifloxacin may qualify for use in the treatment of S. pneumoniae meningitis.     

Pharmacokinetics of gentamicin following single-dose parenteral administration to goats

The disposition kinetics of parenterally administered gentamicin (5 mg kg-1) has been studied in Gaddi goats. The serum concentration-time profile was described by bi-exponential and mono-exponential equations following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration with elimination half-life values of 0.96 +/- 0.09, 2.37 +/- 0.47 and 3.56 +/- 0.39 h, respectively. The apparent volume of distribution following i.v. administration (Vdarea: 0.26 +/- 0.041 kg-1) reflected limited extracellular distribution of the drug. The bioavailability was higher following i.m. administration (96.3%) compared to s.c. (76.9%). In view of the significantly longer biological half-life and larger area under the curve values, the s.c. route may be preferred. It is concluded that a suitable and practical dosage recommendation for gentamicin in goats would be 3.35 mg kg-1 body weight given s.c. at 12 h intervals.     

Pharmacokinetics of doxycycline in pigs following oral administration in feed

Doxycycline medicated feed was administered to healthy fattening pigs for an 8-day period either for 1 h every 12 h or ad libitum. The average dosage regimen ranged between 11.8 and 13.3 mg/kg/day. Doxycycline concentrations were determined in plasma, lung and nasal mucosa using a high performance liquid chromatography assay (HPLC). The agreement between the doxycycline HPLC assay and a bioassay was also assessed in plasma. Following the multiple medicated feed administration every 12 h, the plasma concentrations were best described by a one-compartmental model with first-order absorption. Steady-state plasma concentrations ranged between 0.7 and 1 microgram/mL. The mean accumulation factor and elimination half-life were, respectively, 1.8 +/- 0.4 and 5.9 +/- 1.0 h. Following ad libitum administration of medicated feed, steady-state plasma concentrations ranged between 0.9 and 1.5 micrograms/mL. At the end of the treatment, the doxycycline lung and nasal mucosa concentrations were 1.7 +/- 0.4 micrograms/g and 2.9 +/- 0.6 micrograms/g, respectively. These data validate the dosage regimen tested in order to control pig respiratory infections, provided that controlled clinical studies are confirmatory.     

Immunologic function of the harderian gland in chickens

1. The pharmacokinetics of methyldopa after oral and intravenous administration was studied in hypertensive and normotensive patients. After intravenous administration methyldopa plasma concentrations decayed according to a two-compartment open model. 2. For intravenous administration the overall elimination constant Ke1 was 0.56 +/- 0.03 h-1, the volume of distribution of the central compartment 0.29 +/- 0.80 1 kg-1 and the plasma clearance rate 11.2 +/- 0.6 1 h-1. 3. Plasma half-times during the beta-phase of the methyldopa plasma decay curve following intravenous and oral administration were 2.8 +/- 1.3 and 2.1 +/- 0.7 h, respectively. 4. Maximal plasma levels in hypertensive out-patients show great variation and range from 0 to 1.9 microgram ml-1. 5. No relationships were found between maximal methyldopa plasma levels in patients under treatment and control of hypertension.     

Effects of loprinone hydrochloride on hemodynamics and respiratory oxygenation in patients after cardiac surgery

Loprinone hydrochloride (Lop), a phosphodiesterase fraction III inhibitor and positive inotrope, was recently released in Japan. We evaluated its dose-related effects on hemodynamics and oxygenation as as well as on plasma levels of Lop in ten patients after cardiac surgery. Immediately after admission to the intensive care unit, baseline hemodynamics and arterial blood gas data were obtained; patients with inotropic support, were given 0.1, 0.2, 0.3 microgram.kg-1.min-1.lop over 1 hour incrementally, and additional data were obtained. CI increased significantly from baseline (2.1 +/- 0.3 l.min-1.m-2) to 3.2 +/- 0.8 at 0.3 microgram.kg-1.min-1. Systemic vascular resistance decreased significantly from baseline (2853 +/- 439 dynes.sec.cm-5.m-2) to 1554 +/- 440 at 0.3 micrograms. kg-1.min-1, and mean arterial pressure also decreased significantly from baseline. There were no significant changes in heart rate (HR), central venous pressure (CVP), pulmonary artery occlusion pressure (PAOP), or PaO2.FIO2(-1) in patients over the period evaluated. Plasma levels of Lop rapidly increased to 27.8 ng.ml-1 (effective level; 20 ng.ml-1) at 0.3 microgram.kg-1.min-1. In this study, Lop was shown to effectively increase CI in patients after cardiac surgery with no significant changes in HR, CVP, PAOP or PaO2/FIO2. Thus, Lop has a beneficial effect in the treatment of patients with low cardiac output immediately after cardiac surgery.     

Fenoldopam improves renal hemodynamics impaired by positive end-expiratory pressure

BACKGROUND: Mechanical ventilation with positive end-expiratory pressure (PEEP) can impair renal hemodynamics. Fenoldopam, a dopamine receptor agonist, has been shown, in animal experiments, to improve renal perfusion. The purpose of the current study was to examine the effects of this agent on altered renal hemodynamics secondary to positive pressure ventilation. METHODS: Twelve patients requiring mechanical ventilation of their lungs and PEEP for the treatment of hypoxemia after multiple trauma or visceral surgery were studied. Hemodynamic variables, renal vascular resistance, urine flow, creatinine, inulin and PAH clearance, and excretion of sodium and potassium (NaE and KE) were measured before and after introduction of a level of PEEP high enough to decrease urine flow rate by 25% or more, and after administration of intravenous fenoldopam. RESULTS: No hemodynamic effect resulted from 0.1 microgram.kg-1.min-1, but 0.2 micrograms.kg-1.min-1 fenoldopam decreased both diastolic and mean arterial blood pressure from 66 +/- 37 (mean +/- SEM) to 57 +/- 21 mmHg, and from 83 +/- 3 to 74 +/- 4 mmHg, respectively. Renal vascular resistance was reduced from 54 +/- 12 to 19 +/- 5 dynes.s.cm-5 at 0.2 micrograms.kg-1.min-1. Fenoldopam produced a dose-related increase in renal blood flow and PAH clearance. With 0.2 micrograms.kg-1.min-1 fenoldopam, urine flow increased from 81 +/- 25 to 116 +/- 29 ml/h, NaE from 28 +/- 7 to 85 +/- 70 microM/min, and KE from 65 +/- 12 to 109 +/- 16 microM/min. CONCLUSIONS: The results of the current study indicate that intravenous fenoldopam at a dose of 0.2 micrograms.kg-1.min-1 improves renal hemodynamics and increases Na and K excretion in patients requiring mechanical ventilation of their lungs and PEEP. These effects are probably caused by an increased kidney perfusion secondary to renal artery vasodilation.     

Pharmacokinetic analysis of low-dose intra-peritoneal cis-platinum administration

Pharmacokinetic parameters after intra-peritoneal administration of low-dose cis-platinum (CDDP) were analysed in order to evaluate the possibility of applying low-dose 5-FU/CDDP therapy (1-FP) for outpatients. Four patients with advanced gastric cancer were the subjects of this study. CDDP at a dose of 20 mg/body was administered intra-peritoneally, and peripheral venous blood was collected at 30 min, 4, 8, 24, 48, 72, 96 and 120 hr after drug administration. The plasma platinum (Pt) concentration was determined by atomic absorption spectrometry. Pharmacokinetic parameters were calculated using a two-compartment open model. C max, AUC, t1/2 alpha and t1/2 beta of total-Pt were 1. 27 +/- 0.21 micrograms/ml, 95.28 +/- 16.93 micrograms.hr/ml, 1.91 +/- 0.76 hr and 190.2 +/- 125.6 hr, respectively. Total-Pt concentration at 120 hr, after administration was 0.54 +/- 0.14 microgram/ml. This result suggests that intraperitoneal low-dose CDDP administration is a promising method for 1-FP therapy for outpatients, because the plasma total-Pt level is maintained at a sufficiently high level for a long period.