Biomedical subjects

M Rowland

Publications and source records attributed to M Rowland.

At least 127 records · Page 7Linked to original sources

PubMed1992

Application of the axial dispersion model of hepatic drug elimination to the kinetics of diazepam in the isolated perfused rat liver.

The application of the axial dispersion model to diazepam hepatic elimination was evaluated using data obtained for several conditions using the single-pass isolated perfused rat liver preparation. The influence of alterations in the fraction unbound in perfusate (fu) and perfusate flow (Q) on the availability (F) of diazepam was studied under steady conditions (n = 4 in each case). Changes in fu were produced by altering the concentration of human serum albumin (HSA) in the perfusion medium while maintaining diazepam concentration at 1 mg L-1. In the absence of protein (fu = 1), diazepam availability was 0.011 +/- 0.005 (mean +/- SD). As fu decreased, availability progressively increased and at a HSA concentration of 2% (g/100 ml), when fu was 0.023, diazepam availability was 0.851 +/- 0.011. Application of the axial dispersion model to the relationship between fu and F provided estimates for the dispersion number (DN) of 0.337 +/- 0.197, and intrinsic clearance (CL(int)) of 132 +/- 34 ml min-1. The availability of diazepam during perfusion with protein-free media was also studied at three different flow rates (15, 22.5, and 30 ml min-1). Diazepam availability always progressively increased as perfusate flow increased, with the axial dispersion model yielding estimates for DN of 0.393 +/- 0.128 and CL(int) of 144 +/- 38 ml min-1. The transient form of the two-compartment dispersion model was also applied to the output concentration versus time profile of diazepam after bolus input of a radiolabeled tracer into the hepatic portal vein (n = 4), providing DN and CL(int) estimates of 0.251 +/- 0.093 and 135 +/- 59 ml min-1, respectively. Hence, all methods provided similar estimates for DN and CL(int). Furthermore, the magnitude of DN is similar to that determined for noneliminated substances such as erythrocytes, albumin, sucrose, and water. These findings suggest that the dispersion of diazepam in the perfused rat liver is determined primarily by the architecture of the hepatic microvasculature.

Animals↗

PubMed1992

Absorption of polar drugs following caecal instillation in healthy volunteers.

We have investigated colonic drug absorption in man by the caecal instillation of a multi-component solution of atenolol, cimetidine, frusemide, hydrochlorothiazide and salicylic acid. We found that salicylic acid absorption from this solution was delayed but complete whereas the absorption of atenolol, cimetidine, frusemide and hydrochlorothiazide was four- to five-fold lower than expected from oral bioavailability studies.

Adult↗

PubMed1992

The influence of gastrointestinal transit on drug absorption in healthy volunteers.

1. The effect of variability of gastric emptying and oro-caecal transit on the absorption of a multicomponent solution of frusemide, atenolol, hydrochlorthiazide and salicylic acid has been studied in six healthy subjects. Each subject was studied on five separate occasions: three times under basal conditions, once following metoclopramide and once following codeine pretreatment in an attempt to speed and slow transit respectively. 2. Inter-subject variability of gastric emptying, oro-caecal transit and the rate and extent of drug absorption was considerable. 3. The absorption of salicylic acid appeared rate-limited by gastric emptying but the rate and extent of frusemide, atenolol and hydrochlorthiazide absorption were unrelated to measures of gastric emptying or oro-caecal transit. 4. Codeine phosphate caused a two-fold delay in oro-caecal transit but did not influence gastric emptying while metoclopramide had no significant effect on either function. 5. Metoclopramide and codeine had no significant effect on the rate or extent of absorption of any of the study drugs. 6. Within the limits of this experiment, oro-caecal transit time did not appear to be an important determinant of frusemide, atenolol, hydrochlorothiazide or salicylic acid absorption. Other factors must account for the observed variability in drug absorption.

Administration, Oral↗

PubMed1992

Effects of a non-absorbable osmotic load on drug absorption in healthy volunteers.

1. We have studied the effects of a non-absorbable osmotic load on the absorption of a multicomponent solution of frusemide, atenolol, hydrochlorothiazide and salicylic acid in six healthy volunteers. 2. Each subject was studied on up to four separate occasions. The drugs were administered in one of four solutions: a) a mannitol/electrolyte solution, b) a double-strength mannitol/electrolyte solution, c) a glucose/electrolyte solution and d) water. Lactulose or sulphasalazine were added as oro-caecal transit markers. Lactulose was included in the mannitol- and glucose-based solutions, adding a further non-absorbable osmotic load, and sulphasalazine was added to the water, adding little osmotic load. 3. The absorption of atenolol and hydrochlorothiazide was two- to three-times less from all lactulose-containing solutions than from the sulphasalazine-containing solution. The absorption of frusemide and salicylic acid was similar from all four solutions. 4. The largest non-absorbable osmotic load impaired the absorption of atenolol and hydrochlorothiazide most and the incorporation of glucose only partly restored absorption. 5. These results suggest that transmucosal water movement is an important determinant of atenolol and hydrochlorothiazide absorption but is less relevant for the absorption of frusemide and salicylic acid. Furthermore, these data demonstrate a previously unrecognised interaction between a commonly prescribed laxative--lactulose, and atenolol and hydrochlorothiazide.

Adult↗

PubMed1992

Absorption kinetics of cyclosporin in the rat.

Cyclosporin was administered (6 mg kg-1, i.v.) over 15 min, or (10 mg kg-1) by gavage, to two groups of 5 rats. Following i.v. infusion, cyclosporin exhibited triphasic behaviour with mean +/- s.e.m. disposition half-lives of 9.0 +/- 1.3 min, 4.0 +/- 0.5 h and 16.0 +/- 1.7 h. Following oral administration, peak blood concentration (Cmax) of 1290 +/- 93 ng mL-1 was reached after 5 h, when cyclosporin absorption essentially ceased. The absolute bioavailability (F) of cyclosporin was 24.0%. Standard laboratory rat chow consisting of 2% corn oil did not appear to alter cyclosporin absorption kinetics.

Absorption↗

PubMed1992

Distribution of antipyrine in the rat liver.

The rate and extent of hepatic distribution of antipyrine was examined in the rat isolated perfused liver. Tritiated water and [14C]antipyrine were injected simultaneously into the portal vein as a bolus using either Krebs-Ringer bicarbonate or rat plasma as the perfusate. The effluent profiles of each compound using the two perfusates were superimposable, a finding expected for water and consistent for antipyrine, which was negligibly bound in rat plasma. Although full recovery (97%) of administered material was achieved with both compounds, the fractional output profile for antipyrine peaked at a lower value (0.10 mL-1) and at a later time (24 s) than water (0.14 mL-1, 17.5 s), due to antipyrine having a larger volume of distribution (water 0.61 mL (g liver) -1); antipyrine 0.81 mL (g liver)-1). This observation is explained by antipyrine binding to, or partitioning into cellular components. Nonetheless, like water, distribution of antipyrine into hepatic cells is perfusion rate limited as evidenced by the superimposition of the dimensionless plots of fractional output vs time normalized to mean residence time.

Animals↗

PubMed1992

Circumsporozoite genotyping of global isolates of Plasmodium vivax from dried blood specimens.

The prevalence and global distribution of two circumsporozoite (CS) genotypes of Plasmodium vivax (VK210 and VK247) were determined by genetic analysis of isolates from 234 malaria-infected patients. Whole blood specimens were collected on filter paper from patients infected with malaria in Thailand, Mexico, Papua New Guinea, Peru, Afghanistan (Pakistan), India, and western Africa and from 50 asymptomatic smear-negative controls. Following extraction of DNA from the filter paper samples, the CS gene was amplified by the polymerase chain reaction and genotyped by using oligoprobes specific for the VK210 and VK247 repeat epitopes. The sensitivity of genotyping from a single blood dot was 95.2%. The VK247 CS genotype was identified in the blood of patients from all seven study areas and was the predominant form present in samples from Thailand (83%) and Papua New Guinea (90%). In contrast, VK247 DNA was present in only 9% of isolates from Mexico. Individuals infected with both genotypes simultaneously were identified in all study areas except Mexico and were particularly common in Thailand (58%) and Papua New Guinea (60%). These findings indicate that the VK247 genotype of P. vivax is widely distributed but that its prevalence varies geographically. In addition, we conclude that use of samples of whole blood on filter paper is a practical and sensitive method for determining the genotypes of large numbers of malaria isolates collected in field settings.

Amino Acid Sequence↗

PubMed1991

Physiologic modeling of cyclosporin kinetics in rat and man.

A physiologic pharmacokinetic model of cyclosporin has been developed in the rat aimed at predicting the time course of drug concentrations in blood, organs, and tissues. The model assumes that tissue distribution is perfusion-rate limited and that each tissue acts as a well-stirred compartment. The unbound equilibrium distribution ratios as well as the values of the fraction unbound and the distribution isotherm of cyclosporin between erythrocytes and plasma are included in the rate equations describing the time course of the drug concentration in each tissue. Parameter values for the rat were obtained experimentally from a continuous infusion study, in which 2.7 and 13.9 mg/kg per day doses of cyclosporin were administered subcutaneously to each of two groups of rats by osmotic pumps for 6 days. Steady-state cyclosporin concentrations in blood, CSF, and 18 different organs and tissues, were determined by a monoclonal antibody RIA. Differences in values of the unbound equilibrium distribution ratios in some tissues and unbound clearance indicated that both the processes of distribution and elimination may have elements of nonlinearity over the range of dosing rates tested. The model was evaluated in the rat with a kinetic experiment in which a 6-mg/kg dose of cyclosporin was infused intravenously over 15 min, with measurements of blood concentrations until 56 hr. Good agreement was obtained for the volume of distribution at steady state (blood), Vss, between the perfusion model and that calculated from the kinetic experiment. Also, the model prediction of the blood concentration temporal profile agreed closely with that observed except in the early moments, when distribution out of blood occurred considerably slower than predicted. On scaling the model up to humans, good agreement was found between the predicted plasma concentration-time profile and Vss and experimental data from the literature. Both rat and human data suggest that partition into adipose tissue plays an important role in the pharmacokinetics of cyclosporin.

Animals↗

PubMed1991

Further insight into the stereoselective interaction between warfarin and cimetidine in man.

The urinary profile of R- and S-warfarin, following administration of a single (25 mg) oral dose of racemic warfarin, alone or on day 4 of a 9-day chronic administration of cimetidine (800 mg once daily), was investigated in eight healthy male volunteers. Based on estimated apparent formation clearance values, cimetidine inhibited significantly only the formation of R-6-hydroxywarfarin and R-7-hydroxywarfarin.

Cimetidine↗

PubMed1991

Behaviour and fitness of gamma HCH/dieldrin resistant and susceptible female Anopheles gambiae and An.stephensi mosquitoes in the absence of insecticide.

The effects of gamma HCH/dieldrin resistance genes on various fitness components of mosquito larvae and adult females in the absence of insecticide were investigated in backcrossed strains of Anopheles gambiae Giles and An.stephensi Liston. Among larvae, heterozygotes (RS) developed slightly but significantly faster than homozygotes for resistance (RR) or susceptibility (SS). The lifetime fecundity of RR females in population cages was only half to two-thirds that of SS and RS females despite similar longevities; several reasons were identified: RR gravid females were less responsive to oviposition-site stimuli, their spontaneous activity--as measured in an acoustic actograph--was only half that of SS or RS females, and RR females produced fewer eggs per unit bloodmeal. When inseminated females were recorded in LD 12:12, RR were again less active than SS or RS. When the lighting was switched to a regime simulating full-moonlight, the activity pattern of SS and RS changed and they flew for longer periods. In contrast, the activity of RR females was the same in LD 12:12 as in 'moonlight'. In a test simulation of potential predation, RR mosquitoes took to flight least readily. All component tests on adult females therefore point to RR as being the least fit of the three genotypes. The behavioural tests suggest that resistance has raised the response threshold of RR females to diverse stimuli. A possible physiological mechanism underlying RR behaviour is that a change in the cyclodiene receptor on the chloride channels has increased their permeability to chloride ions, causing hyper-inhibition of the nervous system.

Animals↗

PubMed1991

Activity and mating competitiveness of gamma HCH/dieldrin resistant and susceptible male and virgin female Anopheles gambiae and An.stephensi mosquitoes, with assessment of an insecticide-rotation strategy.

The effects of gamma HCH/dieldrin resistance genes on flight activity and mating competitiveness were investigated in males from backcrossed strains of Anopheles gambiae Giles and An.stephensi Liston. Activity of males and virgin females of both species, as recorded in an acoustic actograph, occurred mainly at dusk (the E peak). The activity pattern of An.gambiae males was not affected by resistance genes; in mating competition and predator avoidance experiments, however, RR males were less successful than RS males which were less successful than SS males. The activity pattern of An.stephensi differed from An.gambiae in that the E peaks of RR males and females in a gradual dusk regime were out of synchrony with those of SS and RS, the E peaks of RR occurring slightly later. Thus, RR males and females tended to mate assortatively in mate competition experiments. When a sudden dusk regime was substituted for the gradual dusk regime, activity of RR An.stephensi became synchronized with SS and RS activity, but in mating competition experiments RR still tended to mate assortatively. Estimates of male competitiveness, together with previously-obtained estimates of female fitness, were included in population genetics models. Computer simulations showed that the frequency of resistance in populations of An.gambiae and An.stephensi should decrease in the absence of insecticide at a rate comparable with known field reversions.

Animals↗

PubMed1991

A two-compartment dispersion model describes the hepatic outflow profile of diclofenac in the presence of its binding protein.

The residence-time distribution (RTD) of diclofenac in the rat single-pass isolated perfused in-situ liver (n = 4) was determined after bolus input into the hepatic portal vein. Addition of human serum albumin (5 g L-1) ensured extensive (greater than 98%) binding of diclofenac within the perfusate. The one-compartment form of the axial dispersion model of hepatic elimination, which assumes instantaneous radial distribution of substrate within the accessible spaces of the liver, failed to describe adequately the RTD of diclofenac. In contrast, the two-compartment form of this model, which assumes that the radial transfer of unbound substrate between the vascular and cellular space is non-instantaneous, provided an excellent description of the diclofenac data. Moreover, the mean (+/- s.d.) value for the hepatic dispersion number (DN) for diclofenac (0.354 +/- 0.076) compared well with that determined for simultaneously injected [125I]human serum albumin (0.456 +/- 0.078) using the one-compartment dispersion model. These estimates of DN, a stochastic parameter which characterizes the axial spreading of individual elements during transit through the liver, were similar in magnitude to those reported for other tracers in the rat perfused liver. The findings suggest that common factors influenced the RTD of diclofenac and its binding protein, and indicate that the two-compartment dispersion model may be a valuable tool for interpreting hepatic impulse-response data for solutes whose hepatic distribution and elimination is influenced by membrane permeability.

Algorithms↗

PubMed1991

Model choice for teicoplanin kinetics in man.

Teicoplanin is a new long half life antibiotic, characterized by a polyexponential profile. A pharmacokinetic study was made in healthy volunteers receiving 15, 20 and 25 mg/Kg iv doses of Teicoplanin. Plasma concentration-time data were fitted by a polyexponential equation, consisting of two, three, four and five terms. The software was PCNONLIN, using the Gauss-Newton method with Harley's and Levenberg's modification and 1/Y2 as a weighting factor, where Y is the predicted concentration. The increase of the number of exponential terms from two to five resulted in a continuous minimization of the sum of the weighted squared residuals. To test whether or not this sum had been sufficiently reduced to justify the fitting with additional exponential terms, Akaike, Gallant and F-ratio test criteria were used. The four exponential equation best fit most of the data sets. However, the estimates of the main parameters (AUC, V, Vss, CL, Css min, Css max, number of doses to reach 95%ss) calculated according to tri and four-exponential models did not significantly differ. In the dose range studied teicoplanin pharmacokinetics are linear. In conclusion, an additional exponential term in the equation can significantly improve the best fit of teicoplanin plasma curves according to the above criteria, but it may not lead to a significant variation of the main pharmacokinetic parameters and derived values. This indicated that for clinical purposes a tri exponential model suffices for describing the kinetics of Teicoplanin in man.

Anti-Bacterial Agents↗

PubMed1990

Pharmacokinetics of individual components of teicoplanin in man.

Teicoplanin is a new antibiotic consisting of closely related glycopeptides. Following an iv bolus of 400 mg teicoplanin, the pharmacokinetics of the individual components A3-1, A2-1, A2-2, A2-3, A2-4, and A2-5 was studied in five healthy volunteers by HPLC. For each subject, plasma and urine data of the individual components were simultaneously fitted by a triexponential disposition model. No significant differences were observed between the components of the A2 group in the initial volume of distribution, 0.05-0.06 L/kg, and the half-life of the second disposition phase, 2.5-3.0 hr. Significant differences were found in the volume of distribution at steady state (Vss 0.42-0.92 L/kg), the half-lives of the first (0.18-0.26 hr) and the third (48.1-66.8 hr) disposition phases, the total clearance (CL 5.4-19.3 ml/hr per kg), the renal clearance (CLR 2.8-16.1 ml/hr per kg), and the percentage of the administered dose excreted in urine (Ae 53-85%). A highly significant correlation was found between the lipophilicity of the individual components increasing from A2-1 to A2-5, and the values of the kinetic parameters. As the lipophilicity increases the fraction unbound in plasma, Vss, CL, CLR, and Ae decrease, whereas the unbound steady state volume of distribution and the unbound nonrenal clearance increase. A modest degree of accumulation of each teicoplanin component in plasma is predicted to occur at steady state following repeated administration of teicoplanin given daily, with accumulation slightly higher for the more lipophilic components A2-4 and A2-5.

Adult↗

PubMed1990

Pharmacokinetic and pharmacodynamic interaction between the antidepressant tianeptine and oxazepam at steady-state.

To assess if any pharmacokinetic or pharmacodynamic interaction at steady-state occurs between the new antidepressant tianeptine and a benzodiazepine (oxazepam) following multiple oral dosing of both drugs, 12 healthy male volunteers entered a balanced three-way double blind cross-over study. Tianeptine (12.5 mg) and/or oxazepam (10 mg) were given three times daily for 4 days. Pharmacokinetic data within a dosing interval at steady-state showed that there were no statistically significant changes in the pharmacokinetics of either tianeptine (and its two major metabolites) or oxazepam when both drugs were co-administered. Psychometric data showed that there was no synergistic negative interaction between the two drugs and that their combination may result in beneficial effects on "alertness" and "happiness".

Adult↗

PubMed1990

Untreated anorexia nervosa. A case study of the medical consequences.

This case demonstrates the devastating physical sequelae of 30 years of untreated anorexia nervosa. A full array of these consequences occur in this one patient and include the following: malnutrition and hypoproteinemia, electrolyte disturbances, cortical atrophy with hydrocephalus ex vacuo, tricuspid and mitral valvular dysfunction, anemia, impaired lower gastrointestinal motility, delayed gastric emptying, disturbances in the hypothalamic pituitary target organ axes, severe osteoporosis, marked edema, and extreme muscle wasting. Other possible physical sequelae of her anorexia nervosa are discussed. Psychiatrists, as well as other physicians, should be vigilant in diagnosing this illness and treating it as early as possible. This particular patient was in the medical system for numerous admissions and workups over three decades before the correct diagnosis of anorexia nervosa was made.

Aged↗

PubMed1990

An assessment of the effects of impaired renal function and haemodialysis on the pharmacokinetics of fluconazole.

1. The oral pharmacokinetics of fluconazole were studied in three groups of volunteers (n = 5) with various degrees of renal function (GFR greater than 70 ml min-1; 20-70 ml min-1; less than 20 ml min-1) and in a group of patients with chronic end-stage renal failure requiring regular haemodialysis. 2. The pharmacokinetics of fluconazole were markedly affected by impaired renal function with the elimination of half-life in Group III (GFR less than 20 ml min-1) being approximately three times that observed in normal volunteers (Group I). 3. Fluconazole renal clearance was positively correlated with GFR. 4. Non-renal clearance of fluconazole decreased with decreasing renal function. 5. Approximately 38% of the 50 mg dose of fluconazole was removed by haemodialysis extending over a 3 h period.

Adult↗

PubMed1990

Investigations into the potential effects of multiple dose ketorolac on the pharmacokinetics and pharmacodynamics of racemic warfarin.

1. The potential interaction between racemic warfarin given as a 25 mg single oral dose and chronically administered ketorolac was studied in 12 young healthy male volunteers. 2. Ketorolac produced no major change in the pharmacokinetics of (R)- or (S)-warfarin. 3. Ketorolac did not alter the pharmacodynamic profile of racemic warfarin. 4. Ketorolac increased template bleeding time by a factor of 1.35 as compared with placebo. 5. The results suggest that the ketorolac-warfarin interaction is unlikely to be of major clinical significance; however, combined use of ketorolac and warfarin in patients should be undertaken with due caution and appropriate monitoring.

Adult↗