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Biomedical subjects

D J Morgan

Publications and source records attributed to D J Morgan.

At least 73 records · Page 4Linked to original sources
PubMed1996

Bacterial vaginosis in pregnancy: distribution of bacterial species in different gram-stain categories of the vaginal flora.

Vaginal swabs for microbiological culture were taken from 174 pregnant women whose vaginal flora had been evaluated by Gram's stain; 50 had grade III flora (bacterial vaginosis, BV), 50 grade II (intermediate), 41 had vaginal flora graded as abnormal which then reverted to grade I (revertants) and 33 had normal flora (controls). The aim was to determine whether bacterial species isolated from women with grade II flora differed from those with grade III flora. Isolation of Lactobacillus spp. decreased from grade I to grade III and that of other aerobic and anaerobic bacterial species increased. There was little difference in the species isolated from women with grade II and grade III flora, but there was a distinct order in which organisms in different species increased in numbers. The vaginal flora of revertants was intermediate between that of healthy controls and those with grade II flora. Coagulase-negative Staphylococcus spp. were isolated from a greater number of revertants than grade I controls but the incidence did not increase in grade II or grade III. Bifidobacterium spp. were isolated from a greater number of revertants than grade I controls and increased further in grade II and grade III. However, Gardnerella vaginalis and Mycoplasma hominis were isolated from a much larger number of women with grade III flora than the other groups. The conclusion is that grade II is a transitional phase between grade I and grade III and that some organisms such as G. vaginalis and M. hominis only reach large numbers in the late stage. The sequence of appearance of the various bacterial species may be a result of the pathophysiological alteration of the vaginal ecosystem associated with BV.

Bacteria↗
PubMed1996

Pharmacokinetics of midazolam in Vietnamese subjects.

In order to examine the investigators' clinical suspicion that Vietnamese patients were more sensitive to the sedative effects of midazolam than were Caucasians, the pharmacokinetics of a single, weight-adjusted intravenous dose of midazolam (0.05 mg/kg) were compared in a group of healthy Caucasian and Vietnamese male volunteers. The Vietnamese group (n = 8) had a significantly lower height, lean body mass and mean weight (59.8 +/- 5.5 vs 72.1 +/- 8.1 kg, respectively) compared with the Caucasian group (n = 8). No significant differences were found between the Vietnamese and Caucasian groups with regard to distribution half-life of midazolam (8.38 +/- 13.1 vs 1.49 +/- 0.63 min, respectively), elimination half-life (2.49 +/- 1.80 vs 1.48 +/- 0.66 h, respectively), clearance (4.93 +/- 1.31 vs 5.90 +/- 2.12 mL/min per kg, respectively), steady state volume of distribution (0.863 +/- 0.497 vs 0.530 +/- 0.132 L/kg, respectively) or percentage of unbound drug in plasma (4.89 +/- 0.74 vs 4.11 +/- 1.08, respectively). This suggests that dosage of midazolam in Vietnamese should be based on total bodyweight. Two Vietnamese subjects who were brothers had marked elevation of distribution half-life and initial volume of distribution and lesser elevations in elimination half-life and volume of distribution at steady state. This suggests that the known subgroup of subjects who demonstrate dyshomogeneity in midazolam volume of distribution may be genetically determined.

Adolescent↗
PubMed1996

Comparison of Gram-stained smears prepared from blind vaginal swabs with those obtained at speculum examination for the assessment of vaginal flora.

OBJECTIVE: To determine whether Gram-stained smears obtained from blind vaginal swabs could be used reliably for the assessment of the vaginal flora. DESIGN: A prospective, blind comparative study. SETTING: The antenatal clinic of a district general hospital. PARTICIPANTS: Eighty-eight women examined and screened for the presence of bacterial vaginosis during their first antenatal clinic visit. Two smears were obtained for each woman, the first prepared from a vaginal swab taken blindly and the second at speculum examination. The smears were Gram-stained and classified according to the Nugent score: Grade 1 (normal), Grade 2 (intermediate), Grade 3 (bacterial vaginosis). RESULTS: Eight of the 88 pregnant women were identified as having bacterial vaginosis on the basis of the smear taken at speculum examination, and these were correctly identified as having bacterial vaginosis by smears prepared from the blindly taken swab. This gives the blind vaginal swab technique for detecting bacterial vaginosis a sensitivity and specificity of 100% when compared with swabbing at speculum examination. The flora of two women were graded as intermediate, and of 75 as normal by both techniques. Only in three cases was there a disparity between the two techniques, a difference that was not statistically significant (kappa = 0.8546, 95% CI 0.6945 to 1.0). CONCLUSIONS: Vaginal smears prepared from correctly taken blind vaginal swabs can be used to assess the vaginal flora and screen for bacterial vaginosis. This method could be used in epidemiological studies of bacterial vaginosis in the general population and for screening antenatal populations for abnormal vaginal flora.

Double-Blind Method↗
PubMed1996

(S)-4'-hydroxypropranolol causes product inhibition and dose-dependent bioavailability of propranolol enantiomers in the isolated perfused rat liver and in rat liver microsomes.

1. Previous evidence suggests that the dose-dependent bioavailability of racemic propranolol may be partly due to product inhibition. We have examined this further by studying the individual enantiomers of propranolol in the perfused rat liver (IPRL) and in rat liver microsomes. 2. In recirculating IPRL experiments, (R)-propranolol (n = 7) or (S)-propranolol (n = 4) were infused at rates of 75, 150 and 231 nmol/min for three sequential 36-min phases. In single-pass experiments, (R)-propranolol (n = 4) or (S)-propranolol (n = 4) were administered at rates of 80, 136 and 239 nmol/min for three sequential 30-min phases. Steady-state bioavailability increased 10-20-fold over this dose range with both enantiomers in both recirculating and single-pass experiments. At the higher administration rates of (S)-propranolol, bioavailability in recirculating experiments was significantly greater than that in single-pass experiments, whereas there was no significant difference for (R)-propranolol. This suggests product inhibition of (S)- but not (R)-propranolol metabolism. 3. Of the metabolites examined, racemic 4'-hydroxypropranolol (4-OHP) inhibited the formation of 4-OHP, 5'-hydroxypropranolol (5-OHP) and desisopropylpropranolol (DIP) from (S)-propranolol and (R)-propranolol in microsomal studies (IC50 20 microM). Tissue levels of (S)-4-OHP in recirculating experiments (28.0 microM) at the highest dose (239 nmol/ min) of (S)-propranolol were greater than its IC50 of 20 microM, suggesting that 4-OHP is the inhibiting metabolite in the intact liver. The absence of evidence for product inhibition with (R)-propranolol in perfused livers suggests that (S)-4-OHP inhibits 4-hydroxylation of each isomer but (R)-4-OHP does not. 4. We conclude that in the recirculating IPRL, product inhibition of propranolol metabolism is evident with the (S)-isomer, but not he (R)-isomer, and that the inhibiting metabolite is (S)-4-OHP.

Animals↗
PubMed1996

Conjugation of para-nitrophenol by isolated perfused fetal sheep liver.

Using our recently described, isolated perfused fetal sheep liver model, we have studied the metabolism and disposition of para-nitrophenol (PNP) in intact fetal liver. Fetal sheep (mean gestational age, 137 +/- 7 days; range, 127-145 days; n = 8) were delivered under anesthesia near term, and the livers were isolated and perfused in situ, via the umbilical vein, in an oxygenated 1-liter recirculating system, at pH 7.40 at 37 degrees C. The perfusate delivery rate was 4.39 +/- 1.46 ml/g liver/min. Either a 14-micromol (n = 4), 72-micromol (n = 3), or 144-micromol (n = 5) bolus dose of PNP was added to the reservoir. Samples were taken from the reservoir every 5-10 min, and all bile was collected at 15-30-min intervals. Elimination of PNP from perfusate demonstrated Michaelis-Menten kinetics, and the calculated pharmacokinetic parameters for PNP elimination were KM = 13.0 +/- 9.66 microM, Vmax = 32.1 +/- 22.4 nmol/min/g liver, and intrinsic clearance = 3.39 +/- 2.54 ml/min/g liver. At the end of the 120-min perfusion period, PNP could be accounted for entirely as PNP-sulfate (PNP-S) and PNP-glucuronide (PNP-G). The perfusate ratio of PNP-S to PNP-G at 120 min was 2.21 +/- 0.88 at the 14-micromol dose, 0.86 +/- 0.56 at the 72-micromol dose, and 0.31 +/- 0.17 at the 144-micromol dose, because of saturation of sulfate production with increasing dose. PNP-S and PNP-G were eliminated into bile in small amounts (<3% of dose), and the PNP-S/PNP-G ratio in bile was 1. We conclude that near-term fetal sheep liver can metabolize PNP to PNP-G and PNP-S with efficiencies that may be comparable to those of adults, that, as in adults, sulfation is of low capacity, relative to glucuronidation, and that, unlike adults, fetuses have little capacity to transport the PNP-G formed in the hepatocytes into bile.

Animals↗
PubMed1995

Effects of sensory (teasing) exposure to food on oral propranolol bioavailability.

In order to further examine the mechanism of the increase in the plasma propranolol concentration versus time curve (AUC) caused by ingestion of propranolol with food, we administered R, S-propranolol tablets (0.5 mg kg-1) orally to healthy human volunteers and dogs in the presence and absence of sensory exposure to food without ingestion (teasing). Six healthy human volunteers were fasted on one occasion and on the other they were presented with an appetising meal, without eating it (teasing protocol). There was a strong trend to a greater propranolol AUC in the teasing protocol (139 +/- 54 mg mL-1 h-1 fasting, 178 +/- 105 mg mL-1 h-1 teasing; p = 0.1), and time of peak concentration (tmax) was significantly prolonged (80 +/- 22 min and 120 +/- 32 min, respectively; p < 0.03). Further studies were carried out in dogs who received R-propranolol (2 mg kg-1) as an oral solution by gavage tube on four different occasions: fasting, following intragastric administration of a high-value liquid meal, following teasing with food in the animal house at normal feeding time (high-intensity teasing). There were no significant differences in pharmacokinetic parameters between the fasting and intragastric food protocols. Low-intensity teasing resulted in significantly lower AUC and peak concentrations (Cmax) compared with fasting (p < 0.05), confirming food effect patterns known to occur in dogs. High-intensity teasing resulted in significantly greater AUC and Cmax compared with fasting (p < 0.05), reproducing in dogs the increase in propranolol AUC known to occur with food ingestion in humans. These findings suggest that the mechanism of the 'food effect' may involve physiological responses to the sight and smell of food additional to mechanisms activated by ingestion.

Administration, Oral↗
PubMed1995

Determinants of placental drug transfer: studies in the isolated perfused human placenta.

There is little information on the effects of maternal and fetal placental blood flow rates, which can change independently, on the placental transfer rate of drugs of different placental permeabilities. We examined the effects of varying maternal and fetal perfusion flow rates on the placental transfer of three model compounds; antipyrine (high permeability), diclofenac (intermediate permeability), and cimetidine (low permeability) in the single-pass, dual-perfused lobule of the isolated human placenta. In variable flow ratio experiments (n = 9) fetal perfusate flow rate was held constant while a different maternal flow rate was used in each of five 25-min phases such that the maternal/fetal flow ratio ranged from 0.16 to 3.3. In constant flow ratio experiments (n = 4), the flow ratio was kept at 2.0, while maternal and fetal flow rates were varied from 4-18 and 2-9 mL/min, respectively. In the variable flow ratio experiments, the fetal transfer fraction (fetal venous/maternal arterial drug concentrations) varied approximately fivefold among the five phases for each of the three drugs. Therefore, placental transfer was flow dependent regardless of placental drug permeability. By contrast, in the constant flow ratio experiments, fetal transfer fraction was unchanged throughout the five phases for each of the three drugs. Of the various kinetic models that have been formulated to account for the different possible vessel geometries, the double pool flow model, which is a venous equilibrium model and predicts the least efficient drug transfer rate of those proposed, together with a small maternal arteriovenous shunt, produced the best fit overall.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Oxygen supplementation restores theophylline clearance to normal in cirrhotic rats.

BACKGROUND/AIMS: Capillarization associated with hepatic fibrosis may present a functional barrier to oxygen diffusion into the hepatocyte, and restriction on cellular oxygen supply may represent the rate-limiting constraint on hepatic oxidative drug metabolism. The aim of this study was to test this hypothesis by examining the effect of oxygen supplementation on plasma theophylline clearance in 10 control and 10 cirrhotic rats. METHODS: Theophylline (3 mg/kg) was administered intravenously on two separate occasions, 24 hours apart, during which time the rats breathed either room air or oxygen (95%) from 1 hour before dosing until the end of plasma sampling with a randomized order of gas exposure. RESULTS: Theophylline clearance was significantly reduced by a mean of 37% (n = 10; P = 0.003) in cirrhotic rats compared with controls. Oxygen supplementation significantly improved plasma theophylline clearance in cirrhotic rats by a mean of 40% (n = 10; P = 0.007), whereas clearance remained unchanged in healthy rats. Clearance in oxygen-supplemented cirrhotic rats was not significantly different from that in controls (P > 0.05). CONCLUSIONS: These novel findings indicate an important role for hepatic oxygenation in improving drug disposition in cirrhosis, which may have potentially important clinical implications for the management of this disease.

Administration, Inhalation↗
PubMed1995

Serum lipid and glucose concentrations with a propofol infusion for cardiac surgery.

OBJECTIVE: To document changes in serum lipids and glucose with a propofol infusion technique for cardiac surgery. DESIGN: Prospective cohort. SETTING: University teaching hospital. PARTICIPANTS: 22 elective cardiac surgical patients. INTERVENTIONS: Frequent venous blood sampling. MEASUREMENTS AND MAIN RESULTS: Serum lipids and glucose were measured at 10 time periods perioperatively, from preinduction until 4 hours post-cardiopulmonary bypass. Plasma propofol concentrations were also measured in 10 of these patients. There was a significant increase in glucose (P < 0.0005) and decreases in cholesterol (P < 0.0005), high-density lipoprotein (P = 0.004), and low-density lipoprotein (P < 0.0005); there was no significant change in triglycerides (P = 0.39). The propofol infusion resulted in acceptable plasma levels throughout the procedure and allowed early extubation in the intensive care unit, after a mean (SD) of 7.14 (5.9) hours. There was a strong correlation between triglyceride and propofol levels at most time periods (r = 0.38 to 0.98). CONCLUSIONS: This study demonstrates that a propofol infusion technique does not result in elevation of serum lipids and supports its increased popularity in maintenance of anesthesia for cardiac surgery.

Adult↗
PubMed1995

Quality of pharmacokinetic research in oncology.

The usefulness of pharmacokinetically guided individualisation of drug therapy will depend, among other things, on the quality of the analytical and pharmacokinetic methods used. We surveyed the quality of analytical and pharmacokinetics methodology and reporting in a literature search of the oncology literature from 1987 to 1992, using the Medline database. Thirty articles that examined relationships between normal tissue toxicity and area under the plasma concentration-time curve (AUC) formed the study sample. Analytical procedures were adequately described in 77% of the articles, but details of validation of the assay were seriously deficient in the great majority of articles. Methods for calculation of AUC were also deficient in over half of the articles. The findings suggest that greater attention needs to be paid to the quality of pharmacokinetic investigation in oncology, otherwise progress in the use of pharmacokinetically guided individualisation of dosage may be hindered.

Antineoplastic Agents↗
PubMed1995

Adults with spina bifida and/or hydrocephalus.

Recent advances in medical technology enable many children with complex disabilities to survive into adulthood and to have certain expectations of life. One of these expectations is the continuity of specialist health care in an adult setting. This paper describes a new out-patient service which aims to provide optimum care, continuity and consistency of service for adults with spina bifida and/or hydrocephalus. The need for specialist health input into this service, in order to monitor the neurological, urological and psychosocial complications often associated with spina bifida and/or hydrocephalus is recognised. In one year (1992), 86 young adults with spina bifida and/or hydrocephalus attended for annual or more frequent assessment, either independently or with their families or carers. A variety of health and social problems were treated. In response to demand, a multi-disciplinary assessment unit, which includes the services of both medical and nursing specialists, occupational and physiotherapists, psychologists and access to specialist surgical opinions has recently opened at the Chelsea and Westminster Hospital. This new service attempts to meet some of the needs described in the outpatient audit. Adults with other disabilities are requesting to use this service. A longitudinal study to monitor quality, and outcome is indicated from this initial survey.

Adult↗
PubMed1995

Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update.

The effects of liver disease on pharmacokinetics and pharmacodynamics are highly variable, and difficult to predict as the mechanisms of these effects are not well understood. Since the majority of the published literature is concerned with cirrhotic liver disease, this review also focuses mainly on this area. Four different theories have been proposed to account for the effects of chronic liver disease with cirrhosis on hepatic drug elimination: the sick cell theory; the intact hepatocyte theory; the impaired drug uptake theory; and the oxygen limitation theory. While some data in support of each of the first 2 theories have been published recently, a large amount of clinical data would appear to refute both of these theories. These clinical data are substantially consistent with the latter 2 theories, which regard the decreased permeability of the capillarised sinusoid as the critical feature in cirrhosis. Further work is required to determine the applicability of each of these theories. In cirrhosis, drug glucuronidation is spared relative to oxidative drug metabolism; however, in advanced cirrhosis this pathway may also be impaired substantially. There is evidence that in cirrhosis other conjugation pathways may also be impaired to variable degrees. Growing evidence suggests that biliary drug excretion is impaired in cirrhosis. Recent studies with several racemic drugs indicate that the disease can have different effects on the hepatic elimination of individual enantiomers, which may lead to a change in the concentration-response relationships of racemic drugs in cirrhosis. A major finding which has emerged in recent years is that, even with moderate degrees of hepatic impairment, there is a decrease in clearance of drugs or active metabolites normally cleared by the kidney. The effect on renal clearance of unbound drug may be masked if there is a concomitant decrease in plasma protein binding of the drug. Neither serum creatinine levels nor creatinine clearance are useful markers of the renal dysfunction associated with cirrhosis. Both may greatly overestimate renal function in patients with cirrhosis due to increased fractional renal tubular secretion of creatinine. Altered receptor sensitivity has been observed with some drugs in cirrhosis, while for other drugs there is no change in pharmacodynamics. Precise determination of drug dosage in cirrhosis requires information on changes in pharmacodynamics and plasma protein binding in addition to changes in drug elimination. Pharmacokinetic investigations in a variety of chronic liver diseases without cirrhosis (e.g. carcinoma, schistosomiasis and viral hepatitis) suggest that in the absence of cirrhosis, impairment of drug elimination is not sufficient to warrant reduction of drug dosage. However, if cirrhosis is present, 'safe' drug use requires an awareness of the possibility of multiple interactions between changes in hepatic and renal disposition and pharmacodynamics. In chronic liver disease with cirrhosis, dosage reduction is the general rule regardless of the route of elimination of drug or metabolite.

Animals↗
PubMed1995

Effects of chronic left ventricular failure on hepatic oxygenation and theophylline elimination in the rat.

The effect of heart failure on the hepatic elimination of low-clearance drugs has not been clearly defined. We investigated the effect of left ventricular failure on theophylline clearance in rats. Cardiovascular function and theophylline pharmacokinetics were studied in conscious rats 6-8 weeks after left anterior descending coronary artery ligation. Rats with infarcts involving > 35% of the left ventricle (N = 9) had severe left ventricular failure, and, compared with control rats (N = 9), had reduced cardiac output (97.3 +/- 18.2 vs. 132 +/- 26 ml/min; p < 0.05), reduced mean arterial blood pressure (86 +/- 20 vs. 109 +/- 16 mm Hg; p < 0.05), markedly elevated left ventricular end-diastolic pressure (25.9 +/- 13.6 vs. 10.6 +/- 3.9 mm Hg; p < 0.01), and increased lung weight. There was also an increase in central venous pressure (6.44 +/- 2.60 vs. 3.67 +/- 2.60 mm Hg; p < 0.05), but no evidence of hepatic congestion, as judged by liver weights (14.7 +/- 1.5 vs. 15.3 +/- 1.3 g) and liver histology. However, total hepatic blood flow, total hepatic oxygen delivery, and theophylline clearance were found to be similar in both groups (1.66 +/- 0.30 vs. 1.75 +/- 0.38 ml/min/g liver weight; 12.4 +/- 1.8 vs. 13.3 +/- 3.7 mumol/min/g liver weight and 0.451 +/- 0.097 vs. 0.438 +/- 0.079 ml/min/100 g body weight), respectively. Taking the infarct group as a whole, total hepatic oxygen delivery was linearly correlated to theophylline clearance (r = 0.66, p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Fetal hepatic propranolol metabolism. Studies in the isolated perfused fetal sheep liver.

We have used an isolated perfused fetal sheep liver preparation to study the fetal hepatic metabolism of propranolol in vitro in the intact organ. Eight livers were perfused in situ via the umbilical vein in an oxygenated recirculating system at 300 ml/min. Radiolabeled 15-microns microspheres were used to quantify the hepatic ductus venosus shunt. Propranolol (4 mg) was dosed into the reservoir as a single bolus and perfusate and bile sampled over 150 min. Propranolol, 4-hydroxy propranolol (4OHP), 5-hydroxy propranolol (5OHP), desisopropylpropranolol (DIP), naphthoxylactic acid (NLA), and alpha-naphthoxyacetic acid (NAA) were assayed by HPLC, before and after deconjugation by enzyme hydrolysis. Mean age was 125 +/- 10 days, and mean liver weight was 66.1 +/- 18.8 g. Oxygen consumption (1.10 +/- 1.03 mumol/g/min), bile flow (0.51 +/- 0.18 microliters/g/min), and perfusion pressure (8.7 +/- 3.3 mm Hg) were stable. Ductus venosus shunt was 41.6 +/- 17.4% of umbilical vein flow. Propranolol clearance was 26.2 +/- 13.4 ml/min, and shunt-corrected extraction of propranolol was 0.26 +/- 0.13. The relative amounts of metabolites in perfusate after 150 min were: 4OHP (25.1%), 5OHP (5.08%) (ring-oxidation products), DIP (6.57%), and NLA (4.33%) (side-chain oxidation products). No alpha NAA (a product of N-dealkylation of NLA) was detected. Except for NLA, metabolites were present predominantly as conjugates. Biliary excretion of unchanged drug and metabolites accounted for a further 1.33% of the propranolol dose. These data indicate that, although the hepatic clearance and extraction of propranolol are low, the fetal sheep liver can metabolize propranolol by both ring- and side-chain oxidation reactions and can conjugate these metabolites.

Animals↗
PubMed1995

Right heart failure impairs hepatic oxygenation and theophylline clearance in rats.

The effect of right heart failure on theophylline clearance was investigated in rats in which right ventricular pressure overload was produced by pulmonary artery constriction (PAC). Fifteen wk after the surgery, compared to sham-operated controls (n = 9), PAC rats (n = 9) showed markedly elevated mean central venous pressure (11 +/- 3 vs 1.44 +/- 0.88 mm Hg, P = .0001), and increased right ventricular weight (0.229 +/- 0.047 vs 0.124 +/- 0.013 g/100 g body weight, P = .0001). Centrilobular hepatic congestion was present in all PAC rats and total hepatic oxygen delivery was reduced significantly compared to controls (146 +/- 58 mumols/min vs. 206 +/- 28 mumol/min; P = .025). In the PAC group, theophylline clearance was reduced (0.82 +/- 0.12 ml/min vs. 0.96 +/- 0.13 ml/min in controls; P = .014), and there was a nonlinear correlation between theophylline clearance and total hepatic oxygen delivery (r = .82). These results suggest that in animals with PAC, metabolism of theophylline was impaired as a result of a reduction in total hepatic oxygen delivery. Therefore, in addition to the known effect of reduced hepatic blood flow on the hepatic clearance of "flow limited" drugs, reduction of hepatic oxygen delivery may be another important mechanism that can lead to reduction in hepatic clearance of capacity-limited drugs in congestive heart failure.

Animals↗