Plasma uridine as well as uric acid is elevated following fructose loading.
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Administration, Oral↗
Biomedical subjects
T G Mant
Publications and source records attributed to T G Mant.
Haemodynamic effects of inhibition of nitric oxide synthase and of L-arginine at rest and during exercise.
OBJECTIVE: To compare effects of N(G)-monomethyl-L-arginine (L-NMMA; a NO synthase inhibitor) and L-arginine (a NO synthase substrate) on haemodynamics in healthy men at rest and during exercise. METHODS: We infused L-NMMA and saline placebo intravenously in two groups of eight healthy men. Each group underwent a two-phase, randomized, single-blind crossover study. Men in one group received 3 mg/kg L-NMMA and men in the other group received 6 mg/kg L-NMMA. Haemodynamic measurements were performed before, during and after a 12 min stepped exercise protocol starting 6 min after the intravenous infusion. A further six men received, according to the same study design, 30 g L-arginine over 30 min and saline placebo before exercise. Blood pressure was measured by sphygmomanometry and cardiac output by bioimpedance, allowing computation of total systemic vascular resistance index (SVRI). RESULTS: Infusion of 6 mg/kg L-NMMA into men at rest produced modest increases (compared with effect of saline placebo) in systolic and diastolic blood pressures of 4.1 +/- 1.1 and 12.6 +/- 3.5%, respectively (means +/- SEM, P < 0.01 for both comparisons) and a marked increase in SVRI of 39.2 +/- 5.2% (P < 0.01). Cardiac index and heart rate were 22.0 +/- 3.3 and 17.0 +/- 4.4% lower after administration of L-NMMA (P < 0.01 for each comparison) than after infusion of saline placebo. During exercise there was no significant difference between total SVRI after infusions of L-NMMA and saline (difference not significant, diminished with increasing exercise). Six minutes into recovery the difference between total SVRI after infusions of L-NMMA and saline reappeared with SVRI 25 +/- 6.9% higher after infusion of L-NMMA than after infusion of saline (P < 0.01). Administration of L-arginine had no significant effect on haemodynamics in men at rest, during exercise and during recovery. CONCLUSIONS: Effects of L-NMMA on total systemic vascular resistance during exercise are less marked than are those on subjects at rest, probably because vasodilatation of resistance vessels of skeletal muscle during exercise is mediated mainly by factors other than NO. Our results also suggest that NO synthesis in healthy men is not substrate limited either at rest or during exercise.
Adult↗
Effect of a 15-minute infusion of DDAVP on the pharmacokinetics and pharmacodynamics of REVASC during a four-hour intravenous infusion in healthy male volunteers.
Plasma pharmacokinetics, effect on coagulation parameters, and safety and tolerability of an intravenous infusion of REVASC before, during and after a DDAVP infusion were investigated. Twelve healthy volunteers were given an intravenous bolus dose followed by a constant rate four-hour infusion of REVASC. Fifteen-minute infusions of 0.9% saline and DDAVP were started two and three hours respectively after the start of the REVASC infusion. Plasma REVASC concentrations were not affected by either the saline or DDAVP infusion. REVASC infusion produced an increase in APTT which plateaued between 0.5 and 3 hours. After the DDAVP infusion there was a tendency towards a new lower plateau whilst the REVASC infusion continued. There were no serious adverse events or bleeding episodes throughout the study. In conclusion, the co-administration of intravenous DDAVP has no effect on the plasma pharmacokinetics of REVASC and partially reverses the REVASC-induced increase in APTT. This may represent a role for DDAVP in the partial reversal of anticoagulation induced by REVASC.
Adult↗
Phase I safety and pharmacokinetic profile of an intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302).
Healthy male volunteers received single or multiple intravenous infusions of an intercellular adhesion molecule-1 antisense phosphorothioate oligodeoxynucleotide, ISIS 2302, in a rising-dose (0.06-2.00 mg/kg infused over 2 hr), double-blind, placebo-controlled trial. Brief, dose-related increases in activated partial thromboplastin time were seen at the time of peak plasma concentration (C(max)). Clinically insignificant increases in C3a were seen after higher, repeated doses, but C5a, blood pressure and pulse were unaffected. No adverse events or other laboratory abnormalities were related to treatment with the drug. ISIS 2302 C(max) was linearly related to dose and occurred at the end of infusion. Plasma half-life for intact drug (53-54 min) and total oligonucleotide (67-74 min) were similar at the two doses (0.5 and 2.0 mg/kg) at which extensive pharmacokinetic data were collected. Nonlinear changes in area under the plasma concentration/time curve and steady-state volume of distribution with increasing dose suggested a saturable component to disposition. Metabolites co-migrating with n-1, n-2 and n-3 chain-shortened versions of ISIS 2302 appeared very rapidly in plasma, and disposition and metabolism appeared unaltered by repeated dosing. ISIS 2302 was well tolerated and behaved reproducibly with respect to plasma pharmacokinetics and expected side effects.
Adult↗
The tolerance and pharmacokinetics of clinafloxacin (CI-960) in healthy subjects.
The single-dose tolerance and pharmacokinetics of clinafloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy volunteers. Single oral doses of 25, 50, 100, and 200 mg were well tolerated. Adverse events after placebo and clinafloxacin were similar, with mild drowsiness, dizziness, headache, and rash being reported most frequently. The frequency and intensity of side-effects did not increase with dose. Clinafloxacin was rapidly absorbed, with Cmax occurring at approximately 40 min postdose. Plasma concentrations increased proportionately and, following 100 or 200 mg doses, remained above MIC90s required for most nosocomial pathogens for at least 12 h. Clinafloxacin elimination half-life averaged 5.2 h and renal clearance was approximately 200 mL/min. About 50% of the administered dose was excreted unchanged in the urine.
Adult↗
A retrospective analysis of the prevalence of HIV seropositivity and its demographics in the normal healthy volunteer population of a phase-I clinical drug study unit.
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Adult↗
The effect of HN-65021 on responses to angiotensin II in human forearm vasculature.
We studied the effect of (2-butyl-4-chloro-1[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]methyl]-1H-imadazole-5-carboxylic acid,-1-(ethoxycarbonyloxy) ethyl-ester (HN-65021), on angiotensin II induced vasoconstriction in forearm vasculature of eight healthy men. Placebo and HN-65021 (5, 10 and 100 mg) were administered orally. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of angiotensin II (0.3-1000 pmol min-1) 2 h after dosing. HN-65021 inhibited angiotensin II, causing a shift to the right of the dose-response curve. Angiotensin II (100 pmol min-1) decreased mean blood flow in the infused arm by 63.1 +/- 3.2% when infused following placebo and by 49.9 +/- 4.3%, 50.7 +/- 3.5% and 36.4 +/- 2.8% following HN-65021 doses of 5.10 and 100 mg respectively. These results demonstrate that HN-65021 antagonises angiotensin II receptor mediated vasoconstriction in human forearm resistance vessels.
Adult↗
Safety and potency of ANQ 9040 in male volunteers.
BACKGROUND: ANQ 9040 is an experimental nondepolarizing neuromuscular relaxant. Initial investigations in animals had indicated a rapid onset of action comparable to that of succinylcholine. The purpose of this study was to assess the safety and potency of ANQ 9040 in humans. METHODS: ANQ 9040 was assessed in 41 male volunteers. Anesthesia was induced with propofol and maintained with a propofol infusion and 60% N2O/40% O2. Neuromuscular function was measured by mechanomyography using train-of-four stimulation of the ulnar nerve every 12 s. After an initial pilot study, 23 volunteers received a single dose of ANQ 9040 of between 0.5 and 1.1 mg/kg to determine the dose-response relationship. The final 10 volunteers were given twice the estimated ED95 of ANQ 9040 as a single bolus dose. RESULTS: The estimated ED50 and ED95 of ANQ 9040 were 0.6 and 1.3 mg/kg, respectively. Apart from an increase in heart rate, no important adverse effects were noted after ANQ 9040 administration in the dose range 0.5-1.1 mg/kg. In the volunteers who received 2.6 mg/kg ANQ 9040, a substantial increase in plasma histamine was observed. This was associated with a 12% decrease in mean arterial pressure and a 49% increase in heart rate. In this group, the mean onset time to neuromuscular block was 51.3 s. CONCLUSIONS: ANQ 9040 is a rapid-onset neuromuscular blocking agent. However, twice the ED95 dose is associated with significant histamine release and tachycardia. This finding suggests that this drug will not be useful in clinical practice.
Adolescent↗
Nonlinear multiple-dose pharmacokinetics of the dopamine reuptake inhibitor vanoxerine.
The human pharmacokinetics of vanoxerine (GBR 12909) were studied in 14 normal subjects with a multiple-dose regimen. In a crossover design, each subject received daily oral doses of 25, 75, and 125 mg for 14 days at each dose level with washout periods of 7 days duration. Drug concentrations in serum during and after dosing were estimated by an HPLC method sensitive to 2 nmol/L (corresponding to 1.04 ng/mL). Drug accumulation was observed during dosing at the two highest dose levels, but near steady-state conditions were attained within 9-11 days of dosing. Estimates of steady-state concentrations all showed statistically significant deviations from dose linearity in the form of disproportionately higher concentrations at higher dose levels than expected from drug concentrations in serum at lower doses. The nonlinear pharmacokinetics was most likely due to increasing bioavailability with dose. The mean elimination half-lives were 53.5 and 66.0 h at 75 and 125 mg/day, respectively, in accordance with the observed time to reach near steady-state conditions. These estimates were higher than previous estimates in less extensive studies.
Adult↗
Food intake increases the relative oral bioavailability of vanoxerine.
Each of 12 healthy male subjects received single oral doses of 100 mg vanoxerine (GBR 12909), a dopamine reuptake inhibitor with potential antidepressant activity, on three different occasions (fasting, after a low-fat meal and after a high-fat meal) according to a randomized, cross-over design. The mean tmax value increased from 0.82 h after fasting to 1.44 h after a low-fat meal and to 2.46 h after a high-fat meal. Only modest food effects were seen on mean Cmax values (55 nM, 52 nM and 84 nM, after fasting, after the low-fat meal and after the high-fat meal, respectively) but values of AUC up to the last measurable concentration (AUC(0,t)) increased by 76% (from 110 to 194 nM h) after the low-fat meal and by 255% (from 110 to 391 nM h) after the high-fat meal compared with fasting. All of these effects were statistically significant except for the differences in tmax and Cmax between fasting and the low-fat meal. The mechanism of these changes is unclear, but it seems likely that food may lower the first-pass metabolism of vanoxerine, as has been shown for other lipophilic basic drugs.
Administration, Oral↗
Pharmacokinetics of rufloxacin in patients with impaired renal function.
The pharmacokinetics of rufloxacin were investigated in normal subjects and in patients with various degrees of renal failure after the administration of a single oral 400-mg dose. Twenty-four subjects were classified by glomerular filtration rate (GFR) normalized for body surface area. Group 1 subjects had GFRs of > 80 ml/min, group 2 subjects had GFRs from 30 to 80 ml/min, group 3 subjects had GFRs from 8 to 29 ml/min, and group 4 subjects had GFRs of < 8 ml/min. The patients in group 4 were on continuous peritoneal dialysis or underwent hemodialysis 48 h after dosing. Plasma and urinary rufloxacin concentrations were determined by high-performance liquid chromatography. A two-compartment model was used to calculate rufloxacin pharmacokinetic parameters. Apparent total body clearance of the drug was linearly related to GFR (r = 0.696; P < 0.01). The elimination half-life increased proportionally with the severity of renal impairment, with values of 30 +/- 3, 36 +/- 5, and 44 +/- 3 h in groups 1, 2, and 3, respectively. In patients with moderate renal failure, dosage adjustment of rufloxacin is not needed. The rufloxacin dose interval should be prolonged to 48 h as the GFR falls below 30 ml/min/1.73 m2.
Adult↗
Multiple-dose pharmacokinetics of lomefloxacin: rationale for once-a-day dosing.
Six dosage regimens of oral lomefloxacin, a new difluorinated quinolone, were given to healthy volunteer subjects for 7 days in a randomized, placebo-controlled trial to evaluate pharmacokinetics and tolerability and to determine the optimum dosage schedule. Single daily doses of lomefloxacin up to 800 mg and multiple doses up to 600 mg twice daily (1,200 mg/day) were well tolerated. At all dose levels and schedules, lomefloxacin was well absorbed and achieved peak plasma concentrations approximately 1 hour after administration. Urine concentrations were approximately 100 times the plasma concentrations. Elimination half-lives of 7-8 hours were found for all dosage regimens. Steady-state was achieved on the second day of dosing. Little accumulation was observed. A 400 mg oral dose provided a mean peak plasma concentration of 3.43 micrograms/mL, and trough concentrations at steady state that were above the minimum inhibitory concentration for 90% (MIC90) of most common Enterobacteriaceae. The 400 mg dose produced a urine concentration of greater than 80 micrograms/mL during the 12- to 24-hour period after the dose, thus exceeding the MIC90 for clinical isolates such as Pseudomonas aeruginosa, Serratia marcescens, and methicillin-susceptible and -resistant Staphylococcus aureus. There was good agreement between the results of this study and previously reported single-dose data. In summary, lomefloxacin's rapid absorption, long half-life, and high sustained plasma and urine concentrations should permit effective once-daily administration in many clinical situations.
Adolescent↗
Clinical impressions and cardiorespiratory effects of a new fluorinated inhalation anaesthetic, desflurane (I-653), in volunteers.
The new volatile anaesthetic, desflurane (I-653), was administered to 10 healthy, unpremedicated young male volunteers in order to determine its cardiorespiratory effects and the characteristics and acceptability of its inhalation. All volunteers breathed either sub-anaesthetic (1.8% inspired) or anaesthetic (5.4% inspired) concentrations of the anaesthetic without coughing, breath-holding, salivation or other untoward respiratory response. Respiratory minute volume and alveolar ventilation decreased and ventilatory rate increased. Systemic arterial pressure decreased (diastolic more than systolic) and heart rate remained unchanged. Cardiac rhythm remained unaltered, except in one volunteer who experienced a single premature atrial contraction. Volunteers stated that the odour of desflurane was not irritating or unpleasant. Exposure to the agent for approximately 90 min resulted in rapid and clear-headed recovery.
Anesthesia Recovery Period↗
The lack of relationship between acetylator phenotype and idiopathic systemic lupus erythematosus in a South-east Asian population: a study of Indians, Malays and Malaysian Chinese.
An association of idiopathic systemic lupus erythematosus (ISLE) with genetically determined N-acetylation polymorphism has been suspected from previous studies, mainly on Caucasian populations in which there is an approximate incidence of 50% of slow and rapid acetylators. The present study is of the incidence of ISLE and acetylator status in a mixed population of Malaysia. The results did not support an association between ISLE and acetylator status: the frequencies of slow acetylators in the ISLE patients who were Malaysian Chinese and Malay were 13 and 38% respectively. This did not differ significantly from the respective healthy groups (20 and 29%). The small number of Indians in the survey did not allow a valid comparison, but the figures did suggest a lack of association between ISLE and acetylator status.
Acetylation↗
Effects of a selective thromboxane receptor antagonist (GR32191B) and of glyceryl trinitrate on bleeding time in man.
1. GR32191B is a potent and selective thromboxane receptor antagonist. Glyceryl trinitrate (GTN) also inhibits platelet function in vitro. Both have been reported to prolong bleeding time. Since they may be used together in patients with coronary artery disease, we have investigated the possibility of an interaction between them. 2. Twenty-four healthy male volunteers were treated with GR32191B using a double-blind placebo-controlled crossover design. Bleeding times were determined before and after GR32191B or placebo and during co-administration of GTN. Plasma GR32191B concentration was measured. Platelet aggregation in response to adenosine diphosphate and to a thromboxane mimetic, U46619, was measured ex vivo. Urinary excretion of thromboxane (TX)B2 and 2,3-dinor-TXB2 was determined in 24 h urine samples. 3. Twelve hours after GR32191B (80 mg; p.o.), the plasma concentration was 36.6 +/- 2.7 nM (mean +/- s.e. mean) and bleeding time was increased by 66%. Ninety minutes after a second dose (40 mg; p.o.) the plasma concentration was 431.9 +/- 23.6 nM but bleeding time was not further prolonged. 4. Responses of platelets to U46619 were selectively antagonised following GR32191B. Urinary excretion rates of TXB2 and 2,3-dinor TXB2 were similar after treatment with GR32191B or placebo. 5. GTN (1 mg sub-lingually) had no significant effect on bleeding time 90-100 min following either placebo or GR32191B. 6. We conclude that GR32191B, in a dose that causes profound yet specific blockade of thromboxane receptors, causes only a modest prolongation of bleeding time that is unaffected by a therapeutic dose of GTN. This may prove advantageous when GR32191B is used in patients with ischaemic heart disease.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Button battery ingestion: a review.
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Burns, Electric↗
Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study.
OBJECTIVE: To compare the long term effects of short term intravenous infusions of iloprost with those of oral nifedipine in patients with Raynaud's phenomenon associated with systemic sclerosis. DESIGN: Double blind, placebo controlled, randomised group comparison. SETTING: Dermatology outpatient clinic. PATIENTS: Twenty three patients with Raynaud's phenomenon associated with well documented systemic sclerosis (American Rheumatism Association criteria) and with typical abnormalities in fingernail folds on capillaroscopy. INTERVENTIONS: Twelve patients were randomised to receive intravenous infusions of iloprost starting at 0.5 ng/kg/min and increased by 0.5 ng/kg/min every 15 minutes to a maximum of 2.0 ng/kg/min for eight hours on three consecutive days with a further single infusion at week 8. Placebo capsules were given concurrently. Eleven patients were randomised to receive nifedipine, starting at 30 mg daily and increased to 60 mg daily after four weeks for another 12 weeks. Infusions of placebo were given in the same manner as the infusions of iloprost. One patient from each group withdrew because of social reasons and three patients receiving nifedipine withdrew because of side effects. END POINT: Reduction in number, duration, and severity of attacks of Raynaud's phenomenon, reduction in number of digital lesions, increase in digital blood flow. MEASUREMENTS AND MAIN RESULTS: Measurements were taken at 0, 4, 8, 12, and 16 weeks. Both regimens produced a reduction in the number, duration, and severity of attacks of Raynaud's phenomenon. The mean (SE) number of digital lesions was reduced with iloprost (from 3.5 (1.6) to 0.6 (0.3] and with nifedipine (from 4.3 (0.8) to 1.4 (0.5] after 16 weeks. Hand temperature and digital and microcirculatory blood flow were increased with iloprost but not with nifedipine. CONCLUSION: Both iloprost and nifedipine are beneficial in the treatment of Raynaud's phenomenon. With nifedipine, however, side effects are common. Short term infusions of iloprost provide longlasting relief of symptoms, and side effects occur only during the infusions and are dose dependent.
Administration, Oral↗
Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses.
The pharmacokinetics of five dose levels of lomefloxacin (100, 200, 400, 600, and 800 mg) were examined in a single-dose, double-blind, placebo-controlled study involving 40 subjects. There were eight subjects in each group: five received active drug and three received placebo; each subject was given only one dose. All subjects completed the study, and lomefloxacin was well tolerated at all doses. No drug crystals were noted in the urine at 3 and 6 h after the dose. The mean maximum concentration in serum (Cmax) ranged from 1.11 to 7.46 micrograms/ml for the 100- to 800-mg doses, respectively, and the AUC increased proportionally with the dose. The mean time to Cmax (Tmax) values averaged 64.8 +/- 28.8 min. The elimination half-life and plasma clearance averaged 7.7 +/- 0.52 h and 259 +/- 37 ml/min, respectively. Mean concentrations in urine were highest during the first 4 h after the dose and ranged from 104 to 713 micrograms/ml following the 100- and 800-mg doses, respectively. Concentrations above 20 micrograms/ml in urine were observed in most subjects over 24 h at the three lower doses and averaged over 120 micrograms/ml during the 12- to 24-h interval at the 400-mg dose, thus supporting once-per-day dosing. Excretion rates from urine and the cumulative amount excreted increased in a dose-related fashion. Renal clearance decreased moderately at the higher doses. Thus, lomefloxacin was well tolerated, and dose proportionality was demonstrated by most pharmacokinetic parameters. The 400-mg dose produced concentrations in plasma and urine above the MIC for susceptible pathogens.
4-Quinolones↗