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Biomedical subjects

D J Freeman

Publications and source records attributed to D J Freeman.

At least 37 records · Page 2Linked to original sources
PubMed1996

Comparative perilymph permeability of cephalosporins and its significance in the treatment and prevention of suppurative labyrinthitis.

Cephalosporins are nonototoxic antibiotics that provide excellent coverage for almost all bacteria that can cause suppurative labyrinthitis. In this study we performed comparative perilymph permeability determinations of the three cephalosporins that we deemed to have the most clinical potential in these varied situations. Perilymph pharmacokinetic profiles were established for ceftazidime, cefuroxime, and cefotaxime and its metabolite desacetylcefotaxime in 36 guinea pigs by using the technique of high-performance liquid chromatography. At 1, 2, 3, 4, and 6 hours after intravenous administration of the three cephalosporins at a dose of 100 mg/kg of body weight, ceftazidime consistently exhibited the highest perilymph concentration. Desacetylcefotaxime showed the next highest capacity for penetration into perilymph. Keeping in mind that the choice of drug for the treatment of suppurative labyrinthitis should be based foremost on culture and sensitivity studies, we consider ceftazidime to be the first-line agent for treatment and prevention of both meningogenic labyrinthitis and labyrinthitis complicating acute or chronic otitis media.

Animals↗
PubMed1995

Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia: the involvement of insulin, insulin precursor species and insulin resistance.

We have studied low density lipoprotein (LDL) subclass distribution in a group of male patients with non-insulin-dependent diabetes mellitus (NIDDM) and investigated its relationships to fasting and postprandial triglyceride (TG)-rich lipoproteins, insulin resistance, lipoprotein lipase (EC 3.1.1.3; LPL), hepatic lipase (EC 3.1.1.34; HL), lecithin:cholesterol acyl transferase (EC 2.3.1.43; LCAT) and cholesteryl ester transfer protein (CETP) activities. LDL was subfractionated by density gradient ultracentrifugation. Postprandial lipoproteins were measured after an oral fat load using retinyl palmitate as a marker for intestinal TG-rich lipoproteins. Hypertriglyceridaemic NIDDMs (HTG) had a preponderance of small dense LDL particles present in the plasma and reduced amounts of large buoyant species when compared to normotriglyceridaemic patients (NTG) and controls. Both groups of diabetics were more insulin resistant than the controls (P < 0.05) and had raised concentrations of proinsulin (P < 0.05), although insulin content did not differ significantly. 32-33 split proinsulin (SPI) was the major insulin-like molecule present in HTG and was present in significantly higher amounts in these patients (P < 0.05) than either NTG or control subjects and correlated significantly with the presence of small dense LDL particles. After a test meal, the postprandial chylomicron response was greater in HTG than either NTG diabetics or controls (P < 0.05). Chylomicron remnants were present to a greater extent in HTG than in NTG and controls (P < 0.05), although in this case NTG also contained more chylomicron remnants than control subjects (P < 0.05). There was no difference in the LPL activity, CETP and LCAT between diabetics and controls, whereas an increase in hepatic lipase activity was seen in the HTG diabetics (P < 0.05). Both CETP and LCAT activities increased postprandially. Multivariate analysis showed that TG, HDL content and HL activity were the most important determinants of small dense LDL concentration in the fasting state (R2 = 67%). Postprandially, chylomicron remnant clearance, HL and insulin resistance were the major determinants (R2 = 61%) of LDL-III.

Case-Control Studies↗
PubMed1995

Can low-dose clozapine pharmacokinetics predict steady-state plasma concentration?

Plasma concentrations of clozapine at a given dose vary considerably between patients, but drug levels are not routinely monitored during the normal 4- to 8-week dose escalation period at the beginning of therapy. We hypothesized that the dose required to give a putative threshold therapeutic concentration of 350 micrograms/L could be individualized using pharmacokinetic predictions made at the beginning of normal dose escalation. Low-dose clozapine (25-75 mg every 12 h) was administered to 21 treatment-resistant patients with schizophrenia who had been split into three groups. In group A (six patients), individual target doses were predicted from area under the concentration-time curve data after a single 50-mg dose. In group B (five patients), predictions were made as in group A but at steady state. In group C (10 patients), predictions were based on trough clozapine levels obtained at steady state immediately before dose increase. Dosage was increased, if tolerated, by 25 mg twice daily three times a week for 4-8 weeks according to established clinical practice. Clozapine concentrations were measured weekly, and actual target doses were determined for each patient from dose-concentration plots. In groups A and B, the correlation between actual and predicted target dose was not significant (r = 0.18, p = 0.59). In group C, however, it was significant (r = 0.86, p = 0.0016). These results suggest that individualized doses of clozapine for treatment-resistant patients with schizophrenia can be conveniently predicted from trough drug levels at the start of therapy. Such information would facilitate a more rapid, individualized, and consistent attainment of therapeutic doses than is now the case in clinical practice.

Adult↗
PubMed1995

Stability of FK 506 in whole blood samples.

The effect of storage time and temperature on the stability of FK 506 in patient blood samples and quality control samples was assessed with the Abbott IMx microparticle enzyme immunoassay. Blood FK 506 concentrations measured at days 0, 2, 3, 4, 7, and 14 were stable at room (22 degrees C), refrigerator (4 degrees C), and freezer (-70 degrees C) temperatures for the 2-week study period. Patient samples stored at -70 degrees C for almost 1 year and then reanalyzed for FK 506 were also found to be stable.

Blood Specimen Collection↗
PubMed1995

Cefuroxime: pharmacokinetics in cochlear perilymph, cerebrospinal fluid, and plasma.

Very little is known about the permeability of contemporary antibiotics through the blood:perilymph barrier. In this study, we measure the concentration of cefuroxime in perilymph, cerebrospinal fluid (CSF), and plasma in the guinea pig following intravenous administration by using the technique of high-performance liquid chromatography. The results of our study demonstrate a higher permeability of cefuroxime in perilymph than in CSF with a similar concentration profile over time in both fluids. This suggests that each of the two fluid compartments has its own drug barrier, with little or no free passage from CSF to perilymph. On the basis of these experimental findings, we feel that cefuroxime has considerable potential as an antibacterial agent for the treatment or prevention of bacterial labyrinthitis.

Animals↗
PubMed1994

Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk.

The concentration of plasma LDL subfractions is described in four groups of normocholesterolaemic (total plasma cholesterol < 6.5 mmol/l) male subjects consisting of men with and without coronary artery disease (CAD+/-), as determined by angiography, post-myocardial infarct survivors (PMI) and normal, healthy controls. The CAD(+) and PMI groups were distinguished from the CAD(-) and controls by raised concentrations of plasma triglyceride, very low density lipoprotein (VLDL) cholesterol, small, dense LDL (LDL-III density (d) 1.044-1.060 g/ml) and lower concentrations of high density lipoprotein (HDL) cholesterol and large, buoyant LDL (LDL-I d 1.025-1.034 g/ml). In all groups, a subfraction of intermediate density, LDL-II (d 1.034-1.044 g/ml), was the predominant LDL species but was not related to coronary heart disease risk. Plasma triglyceride showed a positive association with LDL-II (r = 0.51, P < 0.001) below a triglyceride level of 1.5 mmol/l. Above this threshold of 1.5 mmol/l, LDL-II and LDL-I showed significant negative associations with triglyceride (LDL-II r = -0.5, P < 0.001; LDL-I r = -0.45, P < 0.001). Small, dense LDL-III showed a weak positive association with triglyceride that became highly significant above the 1.5 mmol/l threshold (r = 0.54, P < 0.001). While age was positively related to LDL-II within the control subjects (r = 0.3, P < 0.05), there was no difference in the percentage abundance or concentration of LDL-III within control and CAD(-) subjects above and below the age of 40 years. Smoking was associated with a relative deficiency of the LDL-I subfraction (LDL-I to LDL-III ratio in smokers = 0.77, in ex-smokers = 0.95, in non-smokers = 1.89; P < 0.01), as was beta-blocker medication (% LDL-I, users vs. non-users, P < 0.05). Both of these effects could be explained by their primary influence on plasma triglyceride. Analysis of the frequency distributions for the three LDL subfractions revealed the concentration of small, dense LDL-III to be bimodal around a concentration of 100 mg (lipoprotein mass)/100 ml plasma. The calculation of odds ratios based on this figure indicated relative risk estimates of 4.5 (chi 2: P < 0.01) for the presence of coronary artery disease and 6.9 (chi 2: P < 0.001) for myocardial infarction.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Regulation of plasma HDL cholesterol and subfraction distribution by genetic and environmental factors. Associations between the TaqI B RFLP in the CETP gene and smoking and obesity.

This study investigated in a healthy population (n = 220) the association of the TaqI B restriction fragment length polymorphism (RFLP) in the cholesteryl ester transfer protein (CETP) gene with plasma high-density lipoprotein (HDL) cholesterol concentration and subfraction distribution. A raised HDL cholesterol level was found in B2B2 homozygotes (B2 cutting site absent) and was associated specifically with a 45% increase in HDL2 compared with B1B1 homozygotes (B1B1, 77 +/- 39 mg/100 mL, mean +/- SD; B2B2, 112 +/- 59 mg/100 mL; P < 0.01). Total plasma, very-low-density lipoprotein, and HDL triglyceride levels did not differ among the genotype groups, nor did plasma apolipoprotein AI levels (B1B1, 1.45 +/- 0.35 mg/mL, mean +/- SD; B2B2, 1.56 +/- 0.33 mg/mL). Thus, the genetic variation appeared to be independent of metabolic factors that are known to regulate HDL levels. Plasma CETP exchange activity was unlikely to be the cause of the association, since it did not differ between genotype groups and was not correlated with HDL2 concentration. Multivariate analysis demonstrated that the TaqI B polymorphism had an effect on HDL cholesterol and HDL2 that was independent of age, sex, body mass index, oral contraceptive use, exercise, alcohol consumption, and plasma triglycerides. In smokers, the presence of the B2B2 genotype did not result in increased HDL cholesterol or HDL2, whereas in obese subjects, the difference between B1B1 and B2B2 individuals was diminished. We conclude that the TaqI B RFLP is associated with a quantitatively significant effect on plasma HDL2 levels that is independent of plasma triglycerides and interacts with lifestyle factors.

Adult↗
PubMed1994

Determinants of LDL subfraction distribution and concentrations in young normolipidemic subjects.

Human low-density lipoproteins (LDLs) comprise a spectrum of particles that vary in size, density, chemical composition, metabolic behavior, and atherogenicity. To identify determinants of this heterogeneity, we measured the percent distribution and plasma concentration of the three major LDL subfractions in 34 young healthy subjects. These parameters were correlated in univariate and multivariate analyses with various body and lifestyle factors; plasma lipids and lipoprotein; and the activities of cholesteryl ester transfer protein, lipoprotein lipase, and hepatic lipase (HL). Women (n = 15) had significantly more large, buoyant LDL (LDL-I; density, 1.025 to 1.034 g/mL) and high-density lipoprotein2 (HDL2) than men (n = 19). Both the percentage and concentration of LDL-I were correlated negatively with very-low-density lipoprotein triglycerides (VLDL-TG) and HL; they were correlated positively with HDL-cholesterol (HDL-C) and HDL2. In addition, percent LDL-I was negatively correlated with plasma triglycerides, VLDL-C, LDL-C, and apo-lipoprotein (apo) B concentrations. The concentrations of intermediate and small, dense LDL (LDL-II and LDL-III; density, 1.034 to 1.044 and 1.044 to 1.060 g/L, respectively) were positively correlated with LDL-C. LDL-III concentrations were also related to plasma cholesterol and apoB concentrations and HL activity. On multivariate analyses, approximately one third of the variability in LDL-I was explained by HL and plasma triglycerides. More than 80% of the variation in LDL-II was accounted for by a model that combined LDL-C and plasma apoB with body mass index and VLDL-TG.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The ins/del polymorphism in the signal sequence of apolipoprotein B has no effect on lipid parameters.

The 'ins/del' polymorphism in the signal sequence of apolipoprotein B alters the hydrophobicity of the signal sequence and therefore would be expected to affect the rate of production of apolipoprotein B (apo B) and the plasma concentrations of lipoproteins containing this apolipoprotein. We sought evidence for an association with plasma lipid levels and this polymorphism in two studies, one using a normal randomly selected population (N = 188) and another using a mildly hypercholesterolaemic group of men aged 45-64 (N = 360). The frequency of the rarer, 'del' allele, was the same in both groups. Likewise no differences in serum cholesterol, serum triglycerides, very low density lipoprotein, low density lipoprotein or high density lipoprotein were seen comparing homozygotes for the signal sequence allele within either group.

Apolipoproteins B↗
PubMed1993

Fluxionate Lewis acidity of the Zn2+ ion in carboxypeptidase A.

Competitive inhibition constants Ki for a series of phenol-ring-substituted derivatives of alpha-(2-hydroxyphenyl)benzenepropanoic acid have been ascertained by observing their influence on the catalytic hydrolysis of a peptide substrate by the zinc enzyme carboxypeptidase A. The pH-dependence of Ki shows that binding is maximal between two pKa values: one is that of the phenol group of the inhibitor, and the other uniformly has a value of 6, the pKa of a Zn(2+)-bound water molecule on the enzyme in the absence of substrate or inhibitor. This is the dependence expected if phenolate binds to the Zn2+ displacing its bound H2O/HO-. A log-log plot of the dissociation constants for the productive forms of inhibitor plus enzyme versus the acid dissociation constants of the phenolic residues in the inhibitors yields a straight line with a slope of +0.76. This number indicates that the active-site metal ion has special capacity for dispersing negative charge, such as builds up on the oxygen atom of a carboxamide group undergoing nucleophilic addition.

Binding Sites↗
PubMed1993

High density lipoprotein metabolism in the horse (Equus caballus).

1. Apolipoprotein A-I dependent lecithin:cholesterol acyl transferase (LCAT) activity was identified in equine lipoprotein deficient plasma (LPDP). 2. LCAT activity showed no breed or sex variation, and was unaltered postprandially. 3. There was no significant cholesteryl ester transfer activity in equine LPDP. 4. Hydrophobic interaction chromatography on phenyl sepharose failed to unmask transfer activity or identify an inhibitor of cholesteryl ester transfer. 5. In 12 Shetland ponies, plasma high density lipoprotein (HDL) concentrations were positively correlated with those of triglyceride, but not with the activities of LCAT, lipoprotein lipase or hepatic lipase.

Animals↗
PubMed1993

Beta-adrenergic responsiveness is regulated selectively in hypertension.

beta-Adrenergic receptor responsiveness is impaired in hypertension. A low-sodium diet both corrects this defect and lowers blood pressure. To determine whether upregulation of beta-adrenergic receptor function in hypertension might be related nonspecifically to lowering of blood pressure, vascular beta-adrenergic response was assessed after pharmacologic antihypertensive treatment by use of dorsal hand vein linear differential transformer techniques in patients with hypertension. Subjects were studied after randomized treatments with placebo and verapamil and after randomized treatments with verapamil and hydrochlorothiazide. After 2 weeks of treatment, verapamil lowered blood pressure in the subjects with hypertension but did not significantly upregulate vascular beta-adrenergic response (58% +/- 8% to 68% +/- 8%; p > 0.2 versus placebo). Further vascular beta-adrenergic responsiveness after treatment with hydrochlorothiazide did not significantly differ from that with verapamil (hydrochlorothiazide, 68% +/- 9%; verapamil, 53% +/- 7%; n = 8, p > 0.3). Thus, reduction of blood pressure with either verapamil or hydrochlorothiazide did not correct the defect in beta-adrenergic responsiveness in hypertension. Vascular beta-adrenergic response appears to be regulated selectively in hypertension, not simply by lowering of blood pressure.

Adult↗
PubMed1993

Quinidine interaction with nifedipine and felodipine: pharmacokinetic and pharmacodynamic evaluation.

Conflicting findings suggest that serum quinidine concentrations may be decreased or increased by nifedipine. We performed a double-blind, placebo-controlled trial of Latin-square design. Twelve healthy men received 3 days of pretreatment with nifedipine prolonged action (20 mg twice a day) or felodipine extended release (10 mg every day), another dihydropyridine calcium antagonist, followed by coadministration of quinidine (400 mg). Quinidine pharmacokinetics were not changed by either dihydropyridine. However, 3-hydroxyquinidine area under the concentration-time curve (AUC) and 3-hydroxyquinidine/quinidine AUC ratio were decreased by felodipine, consistent with reduced metabolite formation. Heart rates and adverse events were higher with felodipine, demonstrating lack of bioequivalence with nifedipine. The QTc interval did not deviate from that expected for the observed quinidine concentration, suggesting the pharmacokinetics of active quinidine metabolites were not markedly altered among treatments. Quinidine disposition did not appear to be changed sufficiently to be clinically important by sustained-release nifedipine and felodipine.

Adolescent↗
PubMed1993

Smoking and plasma lipoproteins in man: effects on low density lipoprotein cholesterol levels and high density lipoprotein subfraction distribution.

In a survey of a healthy population (n = 197), LDL cholesterol, plasma triglycerides and VLDL triglycerides were found to be substantially increased and plasma HDL cholesterol decreased in smokers. The lipid-associated atherogenic risk in smokers as assessed by the LDL/HDL ratio was significantly higher [2.89 (SD 1.18, n = 63)] than in non-smokers [2.38 (SD 0.98, n = 86) P < 0.01]. The lower HDL level found in smokers was explained by a lower HDL-2 subfraction as determined by analytical ultracentrifugation. HDL 2b, 2a and 3a, measured by gradient gel electrophoresis, were all lower in the smokers but this was only significant for HDL 2a. Smoking had no effect on Lp(a) levels. HDL cholesterol and HDL-2 were strongly negatively correlated whereas LDL cholesterol and LDL/HDL ratio were strongly positively correlated with the plasma triglyceride concentration. There was a small but significant reduction in plasma CETP activity [non-smokers 49% t/microliter (SD 17, n = 90), smokers 43% t/microliter (SD 17, n = 66) P < 0.05] but CETP activity was not correlated with any measure of HDL in this population. Smoking was found to be an important independent contributor to the variation in plasma triglyceride, HDL, HDL-2 and LDL/HDL ratio. After correcting for sex, age, BMI, alcohol consumption, oral contraceptive use and plasma triglycerides smoking was still found to be significantly associated with HDL and the LDL/HDL ratio. Upon adjustment for covariant factors the mean differences between smokers and non-smokers for HDL cholesterol, HDL-2 and LDL/HDL were 0.15 mM, 16 mg dl-1 and 0.39 respectively. There appeared to be important sex differences in the influence of smoking on plasma lipoproteins. In women the main impact of smoking was on triglyceride levels and they in turn affected LDL and HDL. In contrast, in men, smoking had little impact on triglycerides and affected HDL more directly. We conclude that smoking cigarettes has an important effect on plasma lipoprotein metabolism through multiple mechanisms.

Adult↗
PubMed1991

Pharmacology and pharmacokinetics of cyclosporine.

Cyclosporine (CsA) is a lipophilic, immunosuppressive peptide which selectively inhibits T-lymphocyte activation in response to antigen stimulation. Although it is the drug of choice in organ transplantation, its clinical use is hampered by toxicity and unpredictable pharmacokinetics. CsA absorption from the small intestine is normally incomplete and is further reduced by intestinal dysfunction and low bile flow. That which enters the systemic blood is metabolized almost entirely by the liver and excreted in the bile. Blood CsA levels are altered to a clinically relevant degree by abnormal liver function and by drugs that induce or inhibit hepatic metabolism. Intestinal absorption may also play a role in some drug interactions. The narrow therapeutic range of CsA and the various factors that alter its kinetics underlie the continuing need to monitor this drug in blood.

Animals↗
PubMed1991

Differences in tonsil core bacteriology in adults and children: a prospective study of 262 patients.

The tonsillar microflora of 262 patients with recurrent acute tonsillitis studied in 1989-1990 is presented. The patient population was divided into three age groups to determine any age-related features. One-hundred and forty-nine patients (57%) were in the 2-7-year-old group, 72 (28%) the 8-14-year-old age group, and the remaining 41 (15%) were over 15 years of age. H. influenzae was the single most common bacterium isolated from the centre of the tonsil (referred to as 'tonsil core'), and this was more prevalent in the 2-7-year-old age group. Staph aureus was the next most commonly isolated bacterium and was most frequently seen in the 8-14-year-old age group (29%). Anaerobic bacteriology was performed in 120 patients. Strict anaerobic species were isolated in significant numbers from the tonsil core in 5% but were present in the superficial culture in all. Anaerobes were present in moderate to heavy numbers in 32% of superficial swabs overall and this was more frequently seen in the older age groups. Mixed pathogens were found throughout all age groups and were most prevalent in the 8-14-year-old age group at 46%. The commonest mixture was H. influenzae and Staph aureus. Normal flora only was commonly found in the superficial swab and rarely in the tonsil core. The number of specimens containing a beta-lactamase producer was assessed for each group; this was similar in all of the groups ranging from 43% in the 2-7-year-old group and 53% in the 8-14-year-old group to 39% in the greater than 15-year-old group.

Adolescent↗