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Biomedical subjects

L E Mather

Publications and source records attributed to L E Mather.

At least 145 records · Page 8Linked to original sources
PubMed1981

An integrated study of pharmacokinetics and pharmacodynamics of chlormethiazole in healthy young volunteers.

Chlormethiazole ethanedisulphonate (0.8%) (Hemineurin, Astra) was administered to 10 healthy unpremedicated volunteers at a constant-rate infusion of 2.5 ml/min for 60 min (Phase 1, n = 5) and 113 min (Phase 2, n = 5). With one exception, chlormethiazole blood concentration-time data were described by a two-compartment open model. Total body clearance was the same in both phases (1.151 . min-1, SD 0.49; and 1.051 . min-1, SD 0.49; and 1.051 . min-1, SD 0.36 respectively) and was similar to the clearance of indocyanine green. No correlation was found between clearance, initial dilution volume (1371, SD 62; and 1251, SD 33 in 1 and 2 phases respectively) or volume of distribution at steady-state equilibrium (3081, SD 91; and 2241, SD 59) with either body weight or estimated lean tissue mass. Slow half-life was 289 min (SD 169) in Phase 1 and 253 min (SD 172) in Phase 2. Moderately heavy sedation associated with amnesia while retaining the ability to readily obey verbal commands was achieved in one subject of Phase 1 and 4 subjects of Phase 2 and occurred at a mean chlormethiazole ethanedisulphonate blood concentration of 9.2 mg . 1(-1) (SD 2.9). Transient nasal irritation was experienced by all subjects during the initial stages of infusion. A rise in pulse rate (33%, SD 8) was a prominent feature but blood pressure and respiratory rates were very stable.

Adolescent↗
PubMed1981

Two-stage infusion of chlormethiazole for basal sedation.

The effectiveness of chlormethiazole in providing basal sedation was studied using a two-stage infusion regimen consisting of an initial loading dose of 60 mg min-1 for 25 min (in the lateral position) followed by a maintenance constant-rate infusion of 10 mg min-1 for 60 min (in the supine position). The regimen was evaluated in five healthy young volunteers who were all moderately sedated throughout most of the infusion, lapsing into sleep when left undisturbed, yet awakened easily to obey commands. Varying periods of amnesia, corresponding with a mean chlormethiazole ethanedisulphonate blood concentration of 10.3 mg litre-1 (SD 3.8) were obtained. Light sedation occurred during the first 10 min and the last 20 min of the total infusion period, corresponding to chlormethiazole blood concentrations of 7.9 mg litre-1 (SD 1.9) and 7.4 mg litre-1 (SD 2.3) respectively. Adverse side-effects were transient nasal irritation, flushing and a coryza-like syndrome. Other side-effects of tachycardia and hypertension may be beneficial in counteracting cardiovascular depression associated with central neural blockade. A high total body clearance of chlormethiazole (mean 1.39 litre min-1, SD 0.58) was found and would contribute to the brief duration of action after termination of the infusion.

Adolescent↗
PubMed1981

Rate of formation of norpethidine from pethidine.

The concentrations of norpethidine in blood were determined in patients recovering from abdominal surgery following both multiple i.m. injections (i.m. group) and the i.v. infusion (i.v. group) of pethidine. The rate of administration of pethidine averaged 25 mg h-1 in both groups. Concentrations of norpethidine were generally small compared with those of pethidine although the ratio of norpethidine to pethidine concentrations increased steadily over the 2 days studied. The rate of increase of blood concentration of norpethidine was 0.013 micrograms ml-1 h-1 in both groups of patients. No significant toxic effects were observed.

Female↗
PubMed1981

Minaxolone, clinical effects and pharmacokinetics. Subanaesthetic infusion regimen.

Minaxolone, infused at a constant rate of 0.01 mg/kg/min produced drowsiness followed by a sleep-like state from which subjects could be easily awakened. After the infusion was stopped, initial recovery was rapid, and completed within 45 minutes. The ability to produce this state rapidly and reversibly would have great value in outpatient surgery, short operative procedures and for basal sedation during procedures performed under regional anaesthesia. In common with many intravenous induction agents, involuntary skeletal muscle movement and twitching during the latter part of the infusion regimen was observed in some subjects. The rapid recovery was consistent with the pharmacokinetic characteristics of Minaxolone, i.e. high total body clearance (near or even exceeding that of indocyanine green) and rapid redistribution. However, renal clearance of unchanged Minaxolone was negligible.

Adult↗
PubMed1981

Pethidine clearance during continuous intravenous infusions in postoperative patients.

1 Pethidine pharmacokinetics in ten female patients during continuous i.v. infusion for 32 h post-surgery have been determined. 2 The blood clearance of pethidine (mean +/- 2.d.) measured directly was 599 +/- 135 ml/min and is in marked contrast to some reported values. 3 Other model-dependent pharmacokinetic parameters were consistent with previously reported values. 4 Pethidine and indocyanine green clearance were correlated but the correlation was mediated through body weight. 5 Pethidine clearance and steady state concentration were predictable retrospectively from linear multivariable equations involving simple physical characteristics of the patient.

Female↗
PubMed1981

Absorption and bioavailability of oral erythromycin.

1 Extent and rate of absorption of erythromycin were studied in 24 healthy volunteers whose disposition kinetics after i.v. injections had been previously documented. 2 Two clinically attractive oral dosage regimens were administered: erythromycin stearate tablets 1 h before meals (Regimen A), and erythromycin base capsules 30 min after start of meals (Regimen B), each equivalent to erythromycin 250 mg, 6 h apart for 9 doses. 3 Serum concentrations of erythromycin measured during the 1st and 9th (steady-state) dosing intervals resulted in higher maximum serum concentrations for Regimen A (median 1.1, range 0-3.3 and 2.7, 0.6-7.3 mg/l for Doses 1 and 9, respectively) compared with Regimen B (0.4, 0-2.2 and 1.4, 0.2-4.9 mg/l). 4 Absorption occurred earlier with Regimen A with times to maximum concentrations (median, range) being 128, 60-greater than 360 and 118, 75-210 min for doses 1 and 9 respectively, (lag times 75, 15- greater than 360 and 73, 10-110 min) compared with 303, 130-greater than 360 and 173, 45-greater than 360 min (lag times 183, 70-greater than 360 and 190, 20-330 min) for Regimen B. 5 Where it could be assessed, absolute bioavailability for Regimen A was approximately 30% (Dose 1) and 65% (Dose 9) and 40% for both doses of Regimen B. 6 Whereas individual serum concentration-time curves were accurately predicted by the mean for Regimen A, predictability for Regimen B was impossible due to prolonged and variable lag time. 7 The large intersubject variability in erythromycin serum concentration after oral administration, has been shown conclusively to be related to variability in absorption kinetics and absolute bioavailability rather than to variability in disposition kinetics.

Administration, Oral↗
PubMed1981

Direct measurement of chlormethiazole extraction by liver, lung and kidney in man.

1 Chlormethiazole was used as a basal sedative for patients undergoing angiographic procedures. 2 Blood samples were drawn opportunistically to examine chlormethiazole extraction across liver, lungs and kidney. 3 Extraction across liver was typically 70-80% and apparently unrelated to input concentrations. Evidence for extraction across lung and kidney was inconclusive but these could each be approximately 20%. 4 Pharmacokinetics of chlormethiazole derived from compartment models were in accord with previous reports and were characterised by a high total body clearance (1-1.5 l/min). 5 Postural changes associated with the radiological procedures caused fluctuating blood concentrations which appear as noise in curve fitting procedures. 6 Pharmacokinetic properties derived from compartment theory cannot cope with these perturbations because of the restriction imposed by time averaging (i.e. mean clearances, half-lives and volumes are produced). Systematic studies of pharmacokinetic properties of perfusion-limited drugs such as chlormethiazole must be developed in such a way as to allow for independent variation of flow and extraction.

Aged↗
PubMed1981

Transfer of pethidine to CSF following intravenous administration.

To help delineate the contributions to analgesia evoked by central and spinal opiate receptors, pethidine was administered intravenously to dogs by bolus followed by infusion. Plasma and cerebrospinal fluid were sampled and assayed for pethidine. Cerebrospinal fluid concentrations followed a similar time course to plasma but with lower concentrations. The average cerebrospinal fluid:plasma ratio was 0.4 and resembled the fraction of unbound pethidine in plasma. It was concluded that cerebrospinal fluid concentrations after intravenous administration were so low that spinal action would be unlikely.

Animals↗
PubMed1981

Pharmacodynamics of minaxolone, a new steroidal anesthetic.

Studies were designed to examine blood concentration-response relationships for minaxolone administered to sheep by either i.v. infusion or bolus injection in both clinical doses and overdoses. Responses examined included effects on sensory nervous, cardiovascular and respiratory systems. The ratio of fatal blood concentrations to anesthetic blood concentrations (therapeutic ratio) was 3 to 4 without respiratory support other than endotracheal intubation to maintain a patent airway. Minaxolone consistently depressed respiration rate, raised PACO2 and depressed PAO2. Death resulted from respiratory failure. With intermittent positive pressure ventilation, the therapeutic ratio was raised to 30 to 40. Duration of anesthesia after bolus doses was directly related to the logarithm of the dose. Cardiovascular effects were minimal with clinical doses and mild overdoses and included slight tachycardia, slightly elevated blood pressure and increased total peripheral resistance with little or no change in cardiac output. With gross overdoses, stable hypotension and depressed cardiac output resulting from decreased stroke volume occurred. Its excellent anesthetic properties and lack of deleterious effects at normal doses on the cardiovascular system commend minaxolone for further evaluation.

Anesthetics↗
PubMed1981

Peridural meperidine in humans: analgesic response, pharmacokinetics, and transmission into CSF.

Effective analgesia resulted from the injection of peridural meperidine in two groups of cancer patients, eight with postoperative pain and eight with intractable pain. Peridural meperidine HCl, 100 mg (n = 8), in 10 ml saline administered to patients following surgery was followed by a median duration of analgesia of 6 hours (range 4-20 hours) over periods ranging from 1-4 days. Peridural meperidine HCl, 30-100 mg (n = 8), in 10 ml saline administered to patients with intractable pain gave a median duration of analgesia of 8 hours (range 4-20 hours) over periods ranging from 1-9 days. There was no obvious tendency towards tolerance. In all patients, the onset of analgesia was within 5 min and was complete within 30 min. This analgesia paralleled the rise in CSF meperidine concentrations following peridural administration. Systemic absorption of peridurally administered meperidine occurred with a half-life of 15-30 min and produced blood concentrations high enough to contribute to analgesia after approximately 20 min in the majority of patients. There was no objective evidence in any neurological change nor sympathetic blockade after peridural meperidine. From this evidence the dorsal horn of the spinal cord may be the major site of action as distinct from the axonal blockade produced by local anesthetics, indicating 'selective' spinal analgesia.

Adult↗
PubMed1980

Multiple intramuscular injections: a major source of variability in analgesic response to meperidine.

Meperidine (ethidine) blood concentrations following multiple intramuscular injections (100 mg) over 2 days were determined in 10 female patients undergoing elective abdominal hysterectomies or cholecystectomies. Pain was estimated by subjective bioassay and the relationship between concentration and effect determined. The blood concentration-effect curve was steep with the range from no analgesia to complete analgesia being 0.35--0.45 microgram/ml on day 1 and 0.4--0.5 microgram/ml on day 2. The mean (+/- S.D.) minimum analgesic blood concentration was 0.5 +/- 0.1 microgram/ml (n = 32). Pain control was poor during the first 4-h dosing interval. The first injection post-surgery was also found to be the least representative of all subsequent injections. Blood concentrations fluctuated in phase with dosing interval, but were highly variable. Intra- and inter-patient peak concentrations varied by 2- and 5-fold and times taken to reach the peaks by 3- and 7-fold, respectively. Hence, meperidine blood concentrations were in excess of the minimum analgesic concentration for only about 35% of each of each 4-h dosing interval. Peak concentrations were not consistently correlated with body weight or lean tissue mass. Variable pain control following intermittent intramuscular meperidine injections was shown to be due to inadequate, fluctuating and unpredictable blood concentrations.

Adult↗
PubMed1980

Relationship between blood meperidine concentrations and analgesic response: a preliminary report.

Variability in analgesic responses to intramuscularly administered meperidine has been related to variable and unpredictable blood concentrations after injection. However, the contribution of variability in the relationship between blood concentration and effect has not been examined. The present study was designed to determine the relationship between blood meperidine concentrations and analgesic effects in nine patients during the first two postoperative days. Pain was estimated by subjective bioassay. The blood concentration-effect curves were steep, with a difference of as little as 0.05 microgram/ml between the mean concentrations associated with severe pain and those associated with effective analgesia. Each curve had two inflection points: the maximum concentration still associated with severe pain (MCP) (0.41 microgram/ml, SD = 0.17, n = 76) and the minimum effective analgesic concentration (MEAC) (0.46 microgram/ml, SD = 0.18, n = 19). Interpatient variability of MEAC was appreciable (coefficient of variation = 39 percent) and intrapatient variability was also detected. Variable pain control following intermittent intramuscular injections was shown to be due not only to variation in absorption, as reported previously, but also to variation in the blood meperidine concentration-analgesic response relationships. However, correlations were found between MCP and neuroticism and extroversion scores from a personality inventory and physical variables. Thus, equations that allow prediction of an individual's MCP were derived by multivariable regression. A blood meperidine concentration of 0.7 microgram/ml would be expected to provide freedom from severe pain in approximately 95 per cent of cases. An intravenous infusion regimen for achieving and maintaining this concentration is described.

Adult↗
PubMed1980

Intersubject and dose-related variability after intravenous administration of erythromycin.

1 It is well-known that considerable variability and unpredictability in serum concentrations results from orally administered erythromycin. 2 Disposition kinetics and their variability were studies in 24 healthy subjects after a single dose of erythromycin lactobionate and four doses were studied to evaluate dose-related variability in five other subjects. 3 Erythromycin kinetics were adequately described by a classical two compartment open model with little intersubject variability. 4 Dose-related variability occurred. Clearance was independent of dose but T1/2 beta and Vdss increased with dose. 5 Data are presented to show that non-invasive sampling of urine and saliva are of limited value in studying erythromycin pharmacokinetics.

Adolescent↗
PubMed1980

Low dose chlormethiazole infusion as a supplement to central neural blockade: blood concentrations and clinical effects.

Chlormethiazole ethanedisulphonate (Hemineurin) was administered to provide light sedation in patients undergoing surgery with neural blockade. A two stage intravenous infusion system was used and consisted of a loading dose 1520 mg over 30 minutes followed by a maintenance rate of 10 mg/min for the desired period. Patients were sedated smoothly and reliably but could be roused by verbal contact. Recovery from effects was rapid and this is a result of a high clearance of chlormethiazole from the body (approximately 2 l/min). Blood concentrations of chlormethiazole (base, mean +/- SD) associated with light sedation were 5.5 +/- 3.0 mg/l, while a sleep-like state was achieved with concentrations of 6.7 +/- 3.0 mg/l. Given by controlled intravenous infusion under close supervision, chlormethiazole appears close to being an ideal sedative to supplement neural blockade techniques.

Adolescent↗