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Biomedical subjects

T Mant

Publications and source records attributed to T Mant.

15 recordsLinked to original sources
PubMed2001

Effect of dexmedetomidine on propofol requirements in healthy subjects.

Dexmedetomidine-propofol pharmacodynamic interaction was evaluated in nine healthy subjects in a crossover design. Dexmedetomidine/placebo was infused using a computer-controlled infusion pump (CCIP) to maintain a pseudo-steady-state plasma concentration of 0.66 +/- 0.080 or 0 ng/mL, respectively. Forty-five minutes after the dexmedetomidine/placebo infusion was started, propofol was infused using a second CCIP to achieve a stepwise logarithmically ascending propofol concentration (1.00 to 13.8 microg/mL) profile. Each propofol step lasted 10 min. Blood was sampled for plasma concentration determination, and pharmacodynamic endpoint assessments were made during the study. Propofol and dexmedetomidine/placebo infusions were terminated when three endpoints (subjects were too sedated to hold a syringe, followed by loss of eyelash reflex, followed by loss of motor response to electrical stimulation) were achieved sequentially. The concentration of propofol associated with 50% probability of achieving a pharmacodynamic endpoint in the absence of dexmedetomidine (EC50; placebo treatment) was 6.63 microg/mL for motor response to electrical stimulation and ranged from 1.14 to 1.98 microg/mL for the ability to hold a syringe, eyelash reflex, and sedation scores. The apparent EC50 values of propofol (EC50APP; concentration of propofol at which the probability of achieving a pharmacodynamic endpoint is 50% in the presence of dexmedetomidine concentrations observed in the current study; dexmedetomidine treatment) were 0.273, 0.544-0.643, and 3.89 microg/mL for the ability to hold a syringe, sedation scores, and motor response, respectively. Dexmedetomidine reduced propofol concentrations required for sedation and suppression of motor response. Therefore, the propofol dose required for sedation and induction of anesthesia may have to be reduced in the presence of dexmedetomidine.

Adolescent↗
PubMed2001

Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma.

BACKGROUND: APC 366, a selective inhibitor of mast cell tryptase, has been shown to inhibit antigen-induced early asthmatic response (EAR), late asthmatic response (LAR), and bronchial hyperresponsiveness (BHR) in a sheep model of allergic asthma. OBJECTIVE: The purpose of this study was to investigate the effects of APC 366 on antigen-induced EAR, LAR, and BHR in mild atopic asthmatics not on any anti-inflammatory therapy. METHODS: Sixteen mild atopic asthmatics, each with a demonstrable antigen-induced EAR, LAR, and BHR to histamine, were recruited into this randomized, double-blinded, crossover study. APC 366 (5 mg)/placebo was administered by aerosol inhalation 3 times per day on treatment days 1 through 4. Allergen challenge was carried out on day 4. Histamine challenge was performed the following morning, 1 hour after final dosing. RESULTS: Subjects were shown to have a significantly smaller overall mean area under the curve for the LAR (P =.012) and mean maximum fall in FEV(1) for the LAR (P =.007) after pretreatment with APC 366 in comparison with placebo. No significant effects on BHR were demonstrable. Although the EAR was reduced by 18% after treatment with APC 366 in comparison with placebo, this was not statistically significant. CONCLUSION: Short-term repeated administration of APC 366 significantly reduced the magnitude of antigen-induced LAR in atopic asthmatics, which supports the role of mast cell tryptase in the pathophysiology of the LAR.

Administration, Inhalation↗
PubMed2000

Pharmacokinetics of recombinant transgenic antithrombin in volunteers.

UNLABELLED: Adequate levels of antithrombin (AT) III are essential for anticoagulation during cardiopulmonary bypass. Levels of AT are often decreased in patients receiving heparin before surgery. In these patients supplementation with exogenous AT can suppress the coagulation pathway and possibly decrease the risk of postoperative coagulopathy. However, the pharmacokinetics of AT have not been extensively analyzed. In this study we investigated the pharmacokinetics of transgenic recombinant AT in healthy volunteers. The concentrations of AT, after initial doses given over 30 min, were best described by a weight-normalized two-compartment model. The fast compartment volume was 41.1 mL/kg and the volume of distribution was 115.4 mL/kg. Intercompartmental clearance was 0. 0763 mL. kg(-1). min(-1) and elimination clearance was 0.0383 mL. kg(-1). min(-1). These variables are equivalent to a distribution half-life of 196 min and an elimination half-life of 2568 min. Approximately 75% of the supplemental dose is removed from plasma by the initial distribution process. A single supplemental dose of transgenic recombinant antithrombin restoring levels to 120%-150% of normal can provide adequate levels for the usual duration of cardiopulmonary bypass. IMPLICATIONS: A single supplemental dose of transgenic recombinant antithrombin restoring levels to 120%-150% of normal can provide adequate levels for the usual duration of cardiopulmonary bypass.

Adult↗
PubMed1998

Maximum tolerated dose and pharmacodynamics of eptastigmine in elderly healthy volunteers.

Eptastigmine is a new acetylcholinesterase (AChE) inhibitor currently under development for the symptomatic treatment of Alzheimer disease. This study was conducted to establish the maximum tolerated dose and the pharmacodynamics of eptastigmine in nine healthy elderly volunteers. Subjects received single oral doses of 8 mg, 20 mg, 32 mg, and 40 mg eptastigmine and placebo according to a double-blind, randomized, rising-dose, five-way crossover design. Adverse events, blood pressure, heart rate, body temperature, forced expiratory volume, salivary flow, and pupilar activity were closely monitored during treatment. Pharmacodynamic activity of eptastigmine was evaluated with an assay of AChE activity in red blood cells. Eptastigmine doses of 8 mg, 20 mg, and 32 mg were well tolerated. Two of four subjects receiving the 40-mg dose developed profound AChE inhibition (58-59%) and reported severe adverse events (nausea, vomiting, syncope, and bradycardia), precluding further administration in the remaining subjects. Eptastigmine administration produced a weak effect on supine heart rate, body temperature, and pupil diameter. There were no effects on blood pressure, forced expiratory volume, salivary flow, and near point of focus. Acetylcholinesterase activity was inhibited in a dose-related fashion according to a sigmoidal (logistic) function. The mean (+/- SEM) maximum inhibition of AChE activity (Imax) was 14.5+/-3.3%, 20.4+/-2.3%, 28.7+/-2.9%, 45.2+/-1.3% and 53.6+/-2.9% after placebo, 8 mg, 20 mg, 32 mg, and 40 mg of eptastigmine, respectively. The theoretical maximum response (Emax) was 72.9%, and the dose that produced half of the maximum response (ED50) was 29.5 mg. At 24 hours, residual AChE inhibition ranged from 9% to 15%, with a half-life of recovery of the enzyme of approximately 10 hours. The maximum tolerated dose of eptastigmine after single-dose oral administration in healthy elderly subjects is 32 mg. Single oral doses of eptastigmine produce sustained, dose-related inhibition of AChE activity. Adverse events are related to the degree of AChE inhibition.

Aged↗
PubMed1997

Initial human experience with MK-462 (rizatriptan): a novel 5-HT1D agonist.

AIMS: We evaluated the pharmacokinetics and pharmacodynamics of oral MK-462 in comparison with oral sumatriptan in healthy male volunteers. METHODS: Sixteen healthy male volunteers were studied in a rising, single dose, alternating panel design with eight subjects per panel. Matching placebo was administered to two of eight study subjects at each dose level of MK-462 in a randomized, double-blind fashion. RESULTS: MK-462 was rapidly absorbed with a median tmax of 1.3 h (range 1-3 h) vs a tmax for sumatriptan of 2.5 h (range 1-4 h, P < 0.001). Administration of either MK-462 or sumatriptan produced maximal mean elevations of 5-10 mmHg in systolic and diastolic blood pressures without effect on heart rate; the changes occurred sooner following MK-462, consistent with more rapid absorption. Both MK-462 and sumatriptan provoked mild increases in serum growth hormone without any effect on serum prolactin concentrations. The most commonly reported symptom following MK-462 was drowsiness. CONCLUSIONS: These results indicate that the novel 5-HT1D agonist, MK-462, is rapidly absorbed following oral administration and warrants further investigation of its utility in the treatment of acute migraine.

Administration, Oral↗
PubMed1997

Lack of sedative and cognitive effects of diphenhydramine and cyclobenzaprine in elderly volunteers.

A double-blind, in-clinic, placebo-controlled, randomized, three-period crossover study was undertaken to investigate the potential sedative and cognitive effects of diphenhydramine 50 mg, p.o. and cyclobenzaprine 5 mg, p.o. in elderly volunteers. Subjects were given 10 doses of each treatment over a 4-day period according to a t.i.d. schedule. A battery of cognitive tests was administered 2 h after the first and last dose of each treatment period and subjects also completed visual analogue scale subjective ratings at regular intervals. There was no evidence that either drug caused drowsiness or affected cognitive test performance. These findings contrast with previous data using similar assessments in young volunteers, which indicated clear diphenhydramine-induced impairments. Contrary to commonly held belief, the elderly appear to be less sensitive than the young to the central nervous system effects of oral diphenhydramine.

Aged↗
PubMed1995

Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/Org31540) with high affinity to antithrombin III in man.

This paper reports the results of the first administration of the synthetic natural pentasaccharide with high affinity to antithrombin III (NP) in man. This study was mainly focused upon the pharmacokinetic properties and general tolerance of the compound. Subcutaneous injections of doses < 1.43 mg (1000 anti Xa IU) did not generate measurable anti-Xa activities. After subcutaneous injection of increasing doses from 1.43 to 22.9 mg (1000 to 16,000 anti-Xa IU) to young healthy volunteers, it was found that the maximal concentration (Cmax) and the area under curve (AUC) were linearly correlated to the dose, that the total plasma clearances (CI) were constant and almost 3 times lower than those of the current low molecular weight heparins. Cmax were reached between 1 h and 3 h after the injection and the half-lives (t 1/2) were remarkably constant (13.1 h to 13.9 h). During the first 24 h following the injection, around 50% of the total administered dose was recovered in the urine in an active form, indicating that kidney plays a major roles in the elimination of NP. Consistent with these results, when NP was administered to healthy elderly volunteers having a lower creatinine clearance, the half-life of the compound was longer and the clearance lower. At doses exceeding 22.9, Cmax, and AUC were slightly lower than expected, the percentage of the dose recovered in the urine and the total apparent plasma clearance increased, suggesting that the excess of NP unbound to antithrombin III was excreted faster. NP was also administered at various dosages once or twice a day for 7 days to 20 elderly volunteers. Due to the long half-life of the compound the "steady state" was obtained 2 to 3 days after the first injection at which the mean Cmax was increased 1.5 to 2 times. The general tolerance of the compound was excellent. No relevant prolongations of the prothrombin time, of the activated partial thromboplastin time or of the bleeding time were observed. A re-bleeding phenomenon of the bleeding time incision, probably related to friability of the haemostatic plug, occurred in 3 subjects treated with the highest dose regimens: single injection of 26.6 mg (20,000 anti-Xa IU) (young volunteers) and repeated injections of 11.4 mg (8,000 anti-Xa IU) once a day for 7 days (elderly volunteers). At these times, plasma NP concentrations were between 2.9 and 3.6 micrograms.ml-1 (2 and 2.5 anti-Xa IU.ml-1).

Adolescent↗
PubMed1994

A placebo-controlled evaluation of single, escalating doses of CL 284,846, a non-benzodiazepine hypnotic.

This report describes the first evaluation in humans of CL 284,846, a non-benzodiazepine compound with a preclinical profile indicative of sedative/hypnotic properties. Healthy, normal male volunteers were assigned randomly to receive single oral doses of 1, 5, 15, 30, or 60 mg of CL 284,846 or placebo on a double-blind basis. Observations were made over the subsequent 25 hours to determine the safety, pharmacokinetic profile, and psychometric effects of the test compound. CL 284,846 was well tolerated in the normal volunteers, causing no significant changes in vital signs, EEG, ECG, hematologic, or clinical chemistry laboratory parameters. Although few adverse events were noted at doses less than 60 mg, at the highest dose (60 mg), all volunteers reported transient neurologically related adverse events (e.g., impaired concentration, difficulty focusing, and impaired coordination), reflecting the central nervous system action of the compound. Although determination of hypnotic efficacy was not an objective in this Phase I study, daytime treatment with 60 mg of CL 284,846 was associated with greater reports of drowsiness and impaired performance on psychomotor tests. However, memory, as assessed by a word recall test, was not affected at any dose of the compound. Pharmacokinetic analyses revealed CL 284,846 to be absorbed and eliminated rapidly (Tmax = 0.9-1.5 hr, T 1/2 = 0.9-1.1 hr), with a dose-proportional AUC (area under cure). Plasma levels of CL 284,859, the primary desethylated metabolite of CL 284,846, were much lower in humans than in other species, indicating that the metabolism of CL 284,846 in humans may differ from that of rodents and dogs. Overall, CL 284,846 was well tolerated, and the authors recommend repeating dose safety and pharmacokinetic studies in healthy volunteers.

Acetamides↗
PubMed1994

Growth hormone-releasing activity of hexarelin in humans. A dose-response study.

Hexarelin is a new hexapeptide (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2.micrograms.kg-1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng.ml-1 after 0, 0.5, 1 and 2 micrograms.kg-1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0-180) were 0.135, 1.412, 2.918 and 3.695 micrograms.min.ml-1. The theoretical maximum response (Emax) and the dose that produces half of the maximum response (ED50) were estimated using logistic regression. The calculated ED50 values were 0.50 and 0.64 microgram.kg-1 for Cmax and AUC0-180, respectively. The corresponding Emaxs were 55.1 ng.ml-1 and 3936 ng.min.ml-1, thus indicating that the effect after the 2 micrograms.kg-1 dose is very close to the maximal response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans.

Hirulog (BG8967) is a direct thrombin inhibitor built by rational design using the protein hirudin as a model (Maraganore et al. [1990]; Biochemistry 29: 7095-101). In order to evaluate the therapeutic potential for hirulog in the management of thrombotic disease, the tolerability and anticoagulant activity of the agent were examined in a study of human volunteers. In a randomized, placebo-controlled study (n = .54), the intravenous infusion of hirulog over 15 min showed a rapid, dose-dependent prolongation of activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). There was a corresponding dose-dependent increase in plasma hirulog levels. The peptide was rapidly cleared with a half-life of 36 min and a total body clearance rate for the peptide of 0.43 l kg-1 h-1. Similar activity was observed following subcutaneous injection but with sustained pharmacodynamic and pharmacokinetic behavior. There was a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous (r = 0.8, p < 0.001) and subcutaneous administration (r = 0.7, p = 0.002). To evaluate the possible interactions of aspirin on the tolerability and anticoagulant activity of intravenous hirulog, a cross-over design was employed in eight subjects. Aspirin administration did not modify the peptide's activity. At the administered dose of 0.6 mg kg-1 h-1 for 2 h, hirulog infusion prolonged APTT from 230 to 260% baseline. The infusion of hirulog in subjects who had received aspirin was not associated with any significant changes in the template bleeding time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Ipecacuanha-induced emesis: a human model for testing antiemetic drug activity.

In a double-blind, randomized, parallel-group study, five groups of 10 healthy men received single 5-minute infusions of 8 mg, 4 mg, 1 mg, 0.25 mg, or 0.1 mg ondansetron (as hydrochloride dihydrate) 30 minutes before oral administration of 30 ml syrup of ipecacuanha. Emetic episodes and nausea (100 mm visual analog scale) were assessed over an 8-hour period. There were no emetic episodes after 8 or 4 mg ondansetron. Seven, nine, and 10 subjects vomited after 1 mg, 0.25 mg and 0.1 mg ondansetron, respectively, with median times to onset of 62, 31, and 37 minutes. Median peak nausea scores were 0 mm for both 8 and 4 mg ondansetron and 30, 53, and 26 mm for 1, 0.25, and 0.1 mg ondansetron. Adverse events were mild. This model showed a close correlation with clinically effective doses of ondansetron. It may be successfully and safely used to assess the antiemetic potential of 5-HT3-receptor antagonists in healthy subjects.

Adolescent↗
PubMed1992

Absence of drug interaction between temafloxacin and low dose heparin.

An open 5-day study was conducted in 12 healthy male volunteers to determine the potential for drug interaction between low dose standard heparin and temafloxacin, a new fluorinated quinolone antibiotic. Heparin 5000IU was administered subcutaneously on the morning of the first and last study days and temafloxacin 600mg was administered twice daily for 4 days. The mean change in activated factor X (antifactor Xa) concentration relative to baseline 2h after coadministration was similar to that after heparin alone. Likewise, changes in activated partial prothrombin time, prothrombin time and thrombin time were similar after either heparin alone or concomitant temafloxacin administration, indicating the absence of interaction between temafloxacin and low dose standard heparin in healthy volunteers.

Administration, Oral↗
PubMed1991

The lack of interaction between temafloxacin and combined oral contraceptive steroids.

In view of the considerable debate concerning the possible failure of contraception in women taking broad spectrum antibiotics, we have examined a group of 12 women aged 22-32 in a controlled study. Each woman had been on long-term therapy with oral contraceptive steroids (OCS) containing ethynylestradiol (EE2) and levonorgestrel (Ng) for at least 6 months and all were in good general health. Blood samples were taken about 11.0 hours after dosing with their OCS on days 5, 6, 7 and 8 of their contraceptive cycle, for measurement of EE2, Ng, FSH and LH by radioimmunoassay. In addition blood samples were taken on days 19, 20 and 21 of the contraceptive cycle for assay of progesterone concentrations in plasma. The study was repeated in the next cycle of use of their OCS during which they took temafloxacin, a broad spectrum quinolone antibiotic in a dose of 600 mg twice daily for 7 days starting on day 1 of the cycle. All women completed the study satisfactorily as judged by diary cards, tablet counts and plasma temafloxacin concentrations. In the early part of the study some nausea and headaches were seen due to taking temafloxacin on an empty stomach but these effects were not seen when the antibiotic was later given with food. There was no evidence of any interaction between temafloxacin and the OCS. The plasma concentration of EE2 was 61.4 +/- 21.1 pg/ml in the control cycle and 68.5 +/- 26.6 pg/ml in the temafloxacin cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Quinolones↗
PubMed1991

Tiagabine.

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Animals↗