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.

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.

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.

Clinical safety of SonoVue, a new contrast agent for ultrasound imaging, in healthy volunteers and in patients with chronic obstructive pulmonary disease.

RATIONALE AND OBJECTIVES: To evaluate the safety profile of SonoVue, a new echo-contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles, in healthy volunteers and in patients with chronic obstructive pulmonary disease (COPD). METHODS: Safety and tolerability of SonoVue were evaluated in 66 healthy volunteers during two placebo-controlled phase I studies (a single intravenous ascending-dose study in 36 volunteers given SonoVue doses of 0.003 to 0.12 mL/kg and a multiple-dose study in 30 subjects given cumulative doses of 0.15 to 0.6 mL/kg) and in 12 patients with COPD of various degrees of clinical severity, who were given SonoVue at a dosage of 4 mL (corresponding to 0.057 mL/kg in a 70-kg patient). Adverse events were monitored up to 48 to 72 hours after administration. All volunteers underwent extensive safety assessments (monitoring of vital signs, electrocardiogram, blood oxygen saturation, laboratory assessments, and Mini-Mental test) up to 24 to 72 hours after administration. In addition, patients with COPD underwent specific lung function tests, such as forced expiratory volume, forced vital capacity, and forced midexpiratory flow. RESULTS: No serious adverse events occurred throughout the study. All nonserious adverse events were minor, mild, and rapidly self-resolving. No difference in the incidence of adverse events was observed among the various dosages of SonoVue and between SonoVue and placebo. There were no clinically significant changes in any of the safety assessments. No statistically significant differences between SonoVue and placebo were observed in mean forced expiratory volume, forced vital capacity, or forced midexpiratory flow levels. No substantial changes from baseline in blood oxygen saturation were observed for either study agent at any postinjection time point. CONCLUSIONS: SonoVue showed a good safety profile both in healthy subjects and in patients with COPD.

Clinical pharmacology of moclobemide, a new reversible monoamine oxidase inhibitor.

The clinical pharmacology of the new reversible monoamine oxidase (MAO) inhibitor, moclobemide, was examined in three separate studies in healthy male volunteers. In a single oral dose study, moclobemide (25-150 mg) was rapidly absorbed from the gastrointestinal tract and had a relatively short plasma half-life (mean 1.3 h after 150 mg). A decrease in the plasma concentrations of the noradrenaline metabolite 4- hydroxy-3-methoxyphenylglycol (HMPG), however, indicated a longer time to peak pharmacodynamic effect and longer duration of activity. Assay of platelet MAO activity did not reveal any evidence of irreversible inhibition of the B form of the isoenzyme. Single oral doses of moclobemide (150 and 300 mg) significantly lowered the threshold to the cardiovascular effects ('cheese reaction') of intravenous tyramine. However, after repeated administration of 100 mg three times daily for over 2 weeks, moclobemide caused significantly less potentiation than did phenelzine (15 mg three times per day) on the cardiovascular effects of oral tyramine, a clinically more relevant model. The MAO-B inhibitor, selegiline (5 mg once daily), also lowered the oral tyramine threshold significantly. Moclobemide was generally well tolerated by these healthy volunteers.

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.

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.

Investigation of a case of prednisolone malabsorption.

Malabsorption of prednisolone administered as enteric coated tablets was suspected following therapeutic failure in an asthmatic. This was investigated by cortisol estimation and a Synacthen test and substantiated by the demonstration of abnormally low absorption of prednisolone from these tablets which nevertheless were normally absorbed by a volunteer. The absorption of prednisolone from conventional tablets in this patient was normal.

Coma and metabolic acidosis early in severe acute paracetamol poisoning.

Coma and profound metabolic acidosis early in acute paracetamol poisoning have been described in three patients. Of five further patients (four female, one male, aged 17-80 years) with severe poisoning (plasma paracetamol concentration greater than 800 mg/l, 4-12 h postingestion), four were deeply unconscious on admission and two had a severe metabolic acidosis. Signs of hepatorenal damage were minimal and no additional poisons were detected except salicylates (plasma concentration 290 mg/l) in one instance. Plasma paracetamol half-lives were prolonged (median 9.4 h, range 4.8-39 h) and one patient sustained massive hepatic damage and a further patient died despite treatment with intravenous acetylcysteine. Paracetamol poisoning, when associated with exceptionally high plasma concentrations, can give rise to coma and metabolic acidosis in the absence of hepatic failure or other drugs. Although unusual, other such presentations may not have been recognized because a toxicology screen was not performed.

Acute carbon tetrachloride poisoning in 19 patients: implications for diagnosis and treatment.

Acute carbon tetrachloride poisoning in 19 patients was confirmed by means of laboratory analysis of blood specimens. The whole-blood carbon tetrachloride concentrations ranged from 0.1-31.5 mg/l. Vomiting (11 patients), abdominal pain (5), diarrhoea (4), and coma/drowsiness (6) were the commonest symptoms and signs. Out of 13 patients treated with intravenous acetylcysteine 7 showed mild hepatic damage, 1 had moderate hepatic damage, and 1 with a history of alcoholism sustained massive hepatorenal damage and needed haemodialysis. Of the 6 patients (1 lost to follow-up) who were not given acetylcysteine 3 had hepatorenal failure and needed dialysis, and 1 died. The possibility of carbon tetrachloride poisoning after ingestion of, or exposure to, chlorinated hydrocarbons and in patients presenting with hepatic or renal impairment without obvious cause should not be ignored. Prompt treatment with acetylcysteine may minimise subsequent hepatorenal damage.

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.

Pharmacokinetics of intravenous and oral sodium 2-mercaptoethane sulphonate (mesna) in normal subjects.

The pharmacokinetics of mesna (sodium 2-mercaptoethane sulphonate) and its inactive disulphide, dimesna, were investigated using high performance liquid chromatography in six normal subjects following intravenous and oral administration of 800 mg mesna. The mean maximum mesna concentration after i.v. administration was 111 (s.d. +/- 28.3) nmol ml-1 and the mean maximum dimesna concentration was 183 (s.d. +/- 41.6) nmol ml-1. Following oral mesna dosing the mean peak mesna concentration was 19.6 (s.d. +/- 10.2) nmol ml-1 but mesna was only found in the plasma of five of the six subjects. The mean peak dimesna concentration was 22.5 (s.d. +/- 12.4) nmol ml-1. Following i.v. mesna administration, the mean half-life of mesna was 21.8 (s.d. +/- 3.1) min and total body clearance 1.23 (s.d. +/- 0.31) l kg-1 h-1. The mean half-life of dimesna was 1.17 (s.d. +/- 0.32) h. It was not possible to determine their half-lives after oral mesna administration. The mean mesna concentration in the 0-4 h urine collection was 9.6 (s.d. +/- 10.7; range 1.4-28.7) nmol ml-1 following i.v. mesna injection. After oral mesna the highest mesna concentration occurred in either the 0-4 or 4-8 h urine collections. The mean peak mesna concentration was 2.5 (s.d. +/- 1.7) mumol ml-1 (c.f. estimated uroprotective concentration of 1.7 mumol ml-1). The mean 4 h urinary clearance of the uroprotective species mesna was 0.413 (s.d. +/- 0.136) l kg-1 h-1. After both i.v. and oral mesna the urinary excretion of mesna is predominantly during the first 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol poisoning.

A 3-year-old boy with severe ethanol poisoning metabolised ethanol more rapidly than expected (0.33 g/l/hour or 7.16 mmol/l/hour) and recovered fully with conservative management. It is concluded that active elimination techniques are unnecessary for most children with acute ethanol poisoning.

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.

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.

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.

Adverse reactions to acetylcysteine and effects of overdose.

Since the introduction in 1979 of intravenous acetylcysteine (Parvolex) as an antidote for overdosage of paracetamol the National Poisons Information Service and the manufacturer have been notified of 38 adverse reactions that were anaphylactoid in nature and 19 accidental overdoses. The most common feature of the anaphylactoid reaction to normal dosage was rash; other features reported included angioedema, hypotension, and bronchospasm; all the patients recovered. The features associated with an overdose of acetylcysteine were similar but more severe; two patients died, but the extent to which the overdose of acetylcysteine may have been implicated was not clear in either case.

Recovery after severe oxprenolol overdose complicated by rhabdomyolysis.

The first recorded case of beta-blocker overdose complicated by rhabdomyolysis is described.

The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension.

AIMS: Brachial artery administration of nebivolol increases forearm blood flow in normotensive subjects through activation of the L-arginine/NO pathway. The aim of the present study was to investigate the effect of brachial artery administration of nebivolol in subjects with essential hypertension. METHODS: We studied eight patients with uncomplicated essential hypertension and serum cholesterol less than 6.9 mmol l-1. Antihypertensive medication was discontinued 2 weeks before the study in previously treated patients. Following cannulation of the left brachial artery, saline was infused to establish baseline blood flow, followed by increasing doses of nebivolol (88.5, 177 and 354 microg min-1, each dose for 6 min), followed by saline for 12 min, followed by a 30 min infusion of L-NMMA (2 mg min-1 ). During the final 18 min of the L-NMMA infusion, nebivolol was coinfused using the same doses as before. Forearm blood flow was measured in both arms using venous occlusion plethysmography. RESULTS: Blood flow in the noninfused arm did not change significantly throughout the study. In the infused arm blood flow increased significantly in a dose-related manner during the first series of nebivolol infusions from 2.76+/-0.39 ml min-1-1 100 ml forearm-1 during the baseline period to 4.40+/-0.60 ml min-1-1 100 ml forearm-1 (mean+/-s.e. mean, n=8, P=0.0003 by anova ). L-NMMA antagonized the vasodilator effect of nebivolol: baseline blood flow in the infused arm was 2.41+/-0.53 ml min-1 100 ml forearm-1 and 2.94+/-0.42 ml min-1 100 ml forearm-1 during coinfusion of the top dose of nebivolol with L-NMMA (P=0.0006 for an effect of L-NMMA on nebivolol response). There were no serious adverse events. CONCLUSIONS: Nebivolol causes vasodilation in the forearm vascular bed in subjects with essential hypertension. Since this response is antagonized by L-NMMA, the vasodilatation is probably caused by activation of the L-arg/NO pathway.