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Biomedical subjects

R R MacGregor

Publications and source records attributed to R R MacGregor.

At least 91 records · Page 5Linked to original sources
PubMed1991

Steady-state pharmacokinetics of intramuscular imipenem-cilastatin in elderly patients with various degrees of renal function.

We studied the concentrations in plasma and pharmacokinetics of imipenem and cilastatin in elderly patients (greater than 65 years old) who had various degrees of renal function and who were hospitalized with soft tissue infections. Three groups of patients received imipenem-cilastatin (500/500 mg) intramuscularly every 12 h: group I consisted of eight patients with a creatinine clearance (CLCR) of greater than 50 ml/min (range, 51 to 84 ml/min; mean, 65.8 ml/min); group II consisted of three patients with a CLCR of 20 to 50 ml/min; and group III consisted of two patients with a CLCR of less than 20 ml/min. Imipenem and cilastatin concentrations were measured at steady state on day 5. Mean peak and trough plasma imipenem concentrations were 5.28 +/- 1.78 and 1.43 +/- 0.76 micrograms/ml in group I, 6.25 +/- 0.78 and 2.50 +/- 0.00 micrograms/ml in group II, and 14.3 +/- 0.71 and 6.85 +/- 1.06 micrograms/ml in group III, respectively. Mean peak and trough plasma cilastatin concentrations were 11.8 +/- 2.85 and 0.31 +/- 0.43 microgram/ml in group I, 15.5 +/- 2.48 and 2.03 +/- 2.05 micrograms/ml in group II, and 24.5 +/- 6.72 and 10.7 +/- 5.94 micrograms/ml in group III, respectively. Mean imipenem AUCss (area under the concentration-time curve over a dosage interval at steady state) values were 38.7 +/- 7.9 micrograms.h/ml for group I, 52.3 +/- 7.3 micrograms.h/ml for group II, and 143.7 +/- 11.9 micrograms.h/ml for group III. Mean cilastatin AUCss values were 45.6 +/- 12.5 micrograms.h/ml for group I, 93.8 +/- 51.2 micrograms.h/ml for group II, and 217.5 +/- 57.8 micrograms.h/ml for group III. Cilastatin mean apparent body clearance values (normalized to weight) were 2.78 +/- 0.67 ml/min for group I, 1.43 +/- 0.81 ml/min for group II, and 0.71 +/- 0.24 ml/min for group III. Imipenem open-lactam metabolite levels were all below the level of detective of the assay (<3.9 micrograms/ml). There was a progressive increase in plasma imipenem and cilastatin levels and AUCss and there was a decline in body clearance as renal function declined.

Aged↗
PubMed1991

Twice daily intramuscular imipenem/cilastatin in the treatment of skin and soft tissue infections.

One hundred and two patients were enrolled in an open-label evaluation of intramuscular imipenem/cilastatin using doses of either 500 or 750 mg every 12 h in the treatment of mild to moderately severe skin and soft tissue infections. Seventy-four of 102 patients were clinically evaluable. Thirty-one patients had abscesses, 20 had cellulitis and 23 had wound infections. One hundred seventy-eight isolates were recovered from these 74 patients (average 2.4 isolates/patient). Sixty of 74 evaluable patients (82%) were cured; 12 of 74 (16%) were improved. Two patients failed to improve. Therapy was well tolerated. Adverse effects occurred in 8 patients. All of these effects were minor, and none required discontinuation of therapy. Eighty-two percent of patients reported no pain with injections. Therapy did not need to be interrupted or discontinued in the remaining 18% of patients reporting moderate local pain with injections. Peak and trough serum imipenem levels were measured in 15 patients receiving a 500-mg intramuscular dose of imipenem/cilastatin. The mean peak imipenem concentration in 15 patients was 10.7 micrograms/ml (range 3.3-17.8); the mean trough concentration was 2.1 micrograms/ml (range 0.8-4.9). The trough levels were higher than those found in healthy volunteers and may reflect the age and mild renal dysfunction in this group of treated patients. Imipenem/cilastatin used for mild or moderate skin and soft tissue infections was both efficacious and well tolerated. Intramuscular therapy with this agent offers advantages over intravenous therapy because of its long apparent half-life and pharmacokinetics.

Abscess↗
PubMed1991

Overall clinical utility of the intramuscular preparation of imipenem/cilastatin.

Imipenem is the broadest-spectrum antibiotic currently available but requires frequent intravenous dosing for efficacy. A recently formulated finely milled preparation can be given intramuscularly in small volumes and demonstrates kinetics favorable for 12-hourly intramuscular administration. The intramuscular imipenem formulation has been proven to be effective for mild to moderate infections of many body sites, as demonstrated by other papers in this symposium. The advantages of intramuscular administration include: less frequent dosing, avoidance of the complications of intravenous administration (phlebitis, bacteremia, fluid overload, nursing time), ability to use the drug in settings where intravenous administration is either undesirable or impossible and, surprising to medical personnel, greater patient satisfaction.

Bacterial Infections↗
PubMed1991

Effects of insulin on the synthesis, intracellular degradation, and secretion of parathormone.

Bovine parathyroid organoids were maintained for up to 12 days of culture in the presence or absence of insulin. Insulin-treated organoids secreted more PTH and secretory protein-I (SP-I) than did untreated organoids at both 1.4 and 1.8 mM Ca, concentrations chosen to promote partially elevated and suppressed secretion rates, respectively. The insulin effect was dose dependent and reversible. To determine whether insulin might increase secretion by reducing degradation of cellular PTH, its effects on several parameters related to degradative processes were examined. Compared to control cultures maintained at either 1.4 or 1.8 mM Ca, insulin did not induce changes in the relative levels of intact hormone and COOH-terminal peptide fragments secreted into culture medium, nor did it decrease the total cellular levels of three lysosomal enzymes or mute the effects of 3-methyladenine (an agent that decreases formation of autophagosomes) to increase PTH secretion. Thus, insulin did not appear to increase PTH secretion by reducing the latter's cellular degradation. Synthesis of total proteins and of the secreted proteins SP-I and PTH was examined using short incubations of control and insulin-treated organoids with [3H] leucine. Incorporation of 3H into total acid-precipitable proteins was not elevated in insulin-treated organoids; that into PTH/pro-PTH and SP-I, however, was significantly greater in insulin-treated than in control organoids. The results suggested that the insulin-mediated increase in PTH and SP-I secretion is largely due to its regulation of PTH and SP-I biosynthesis.

Acid Phosphatase↗
PubMed1991

Toxicities of antimicrobial agents used to treat osteomyelitis.

This article presents an overview of the toxicities associated with the antibiotics more commonly used for the treatment of osteomyelitis. Included in each drug monograph are major and minor side effects, significant drug-drug and drug-food interactions, and the relative safety of the antimicrobial during pregnancy and in breast-feeding women.

Anti-Bacterial Agents↗
PubMed1990

Age-related decreases in muscarinic cholinergic receptor binding in the human brain measured with positron emission tomography (PET).

Muscarinic cholinergic M1 and M2 receptors in young and aged adult male volunteers were studied using [N-11C-methyl]-benztropine, a specific muscarinic cholinergic receptor ligand, and high resolution positron emission tomography (PET). A regionally specific pattern of decreased binding was observed in aged volunteers. Using two separate methods of data analysis, thalamic, hippocampal and cerebellar regions showed no decreases in the apparent specific binding of [N-11C-methyl]-benztropine while frontal, parietal, temporal and occipital cortices as well as the corpus striatum showed age related changes in binding that declined (in 82 yrs old subject) to about 50% of the value obtained from the youngest volunteer (19 yrs). These data suggest that regions high in muscarinic receptor density, the corpus striatum and the cortical mantle, show a greater rate of decline than those areas that have a relatively low number of muscarinic receptors. Furthermore, this study demonstrates the usefulness of PET and [N-11C-methyl]-benztropine for assessing age related regional changes in muscarinic cholinergic receptor binding in the living human brain.

Adult↗
PubMed1990

Mapping muscarinic receptors in human and baboon brain using [N-11C-methyl]-benztropine.

The muscarinic cholinergic system has been mapped in vivo in human and baboon brain using [N-11C-methyl]-benztropine and high resolution positron emission tomography (PET). [N-11C-methyl]-benztropine uptake was observed in frontal, parietal, occipital, and temporal cortices as well as in subcortical structures including the corpus striatum and thalamus. Uptake continued to increase in baboon and human brain in all areas over an 80 minute experimental period with the exception of the cerebellum where the accumulation of radioactivity began to decrease by 25 minutes postinjection. The ratio of incorporation of [N-11C-methyl]-benztropine between corpus striatum/cerebellum was 1.53 and 1.46 in humans and baboons, respectively, at 60 minutes. Blocking studies in baboons using the muscarinic cholinergic antagonists scopolamine and benztropine and the muscarinic cholinergic agonist pilocarpine combined with blocking studies in humans using benztropine indicate that the binding of this compound is specific for the muscarinic cholinergic system. Pretreatment with the potent dopamine reuptake blocker nomifensine produced no effect on the incorporation of radioactivity in any baboon brain region examined. Analysis of labelled plasma metabolites indicates that in humans, the rate of metabolism of [N-11C-methyl]-benztropine is slow (83.0% unchanged at 30 minutes postinjection) differing quite dramatically from the rate of metabolism observed in baboons (43.4% unchanged at 30 minutes postinjection). These data combined with postmortem studies in humans and primates demonstrate that [N-11C-methyl]-benztropine is a suitable muscarinic cholinergic ligand for use in humans and baboons with PET.

Adult↗
PubMed1990

Positron emission tomography (PET) studies of dopaminergic/cholinergic interactions in the baboon brain.

Interactions between the dopaminergic D2 receptor system and the muscarinic cholinergic system in the corpus striatum of adult female baboons (Papio anubis) were examined using positron emission tomography (PET) combined with [18F]N-methylspiroperidol [( 18F]NMSP) (to probe D2 receptor availability) and [N-11C-methyl]benztropine (to probe muscarinic cholinergic receptor availability). Pretreatment with benztropine, a long-lasting anticholinergic drug, bilaterally reduced the incorporation of radioactivity in the corpus striatum but did not alter that observed in the cerebellum or the rate of metabolism of [18F]NMSP in plasma. Pretreatment with unlabelled NMSP, a potent dopaminergic antagonist, reduced the incorporation of [N-11C-methyl]benztropine in all brain regions, with the greatest effect being in the corpus striatum greater than cortex greater than thalamus greater than cerebellum, but did not alter the rate of metabolism of the labelled benztropine in the plasma. These reductions in the incorporation of either [18F]NMSP or [N-11C-methyl]benztropine exceeded the normal variation in tracer incorporation in repeated studies in the same animal. This study demonstrates that PET can be used as a tool for investigating interactions between neurochemically different yet functionally linked neurotransmitters systems in vivo and provides insight into the consequences of multiple pharmacologic administration.

Animals↗
PubMed1990

Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects.

A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes requiring the simultaneous measurement of plasma and tissue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time t after which a plot of integral of t0ROI(t')dt'/ROI(t) versus integral of t0Cp(t')dt'/ROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume,.Vp. For a two-compartment model, the slope is given by lambda + Vp, where lambda is the partition coefficient and the intercept is -1/[kappa 2(1 + Vp/lambda)]. For a three-compartment model, the slope is lambda(1 + Bmax/Kd) + Vp and the intercept is -[1 + Bmax/Kd)/k2 + [koff(1 + Kd/Bmax)]-1) [1 + Vp/lambda(1 + Bmax/Kd)]-1 (where Bmax represents the concentration of ligand binding sites and Kd the equilibrium dissociation constant of the ligand-binding site complex, koff (k4) the ligand-binding site dissociation constant, and k2 is the transfer constant from tissue to plasma). This graphical method provides the ratio Bmax/Kd from the slope for comparison with in vitro measures of the same parameter. It also provides an easy, rapid method for comparison of the reproducibility of repeated measures in a single subject, for longitudinal or drug intervention protocols, or for comparing experimental results between subjects. Although the linearity of this plot holds when ROI/Cp is constant, it can be shown that, for many systems, linearity is effectively reached some time before this. This analysis has been applied to data from [N-methyl-11C]-(-)-cocaine ([11C]cocaine) studies in normal human volunteers and the results are compared to the standard nonlinear least-squares analysis. The calculated value of Bmax/Kd for the high-affinity binding site for cocaine is 0.62 +/- 0.20, in agreement with literature values.

Brain↗
PubMed1990

Neutrophil function in healthy elderly subjects.

Ten healthy elderly volunteers (mean age: 78.9) underwent a battery of neutrophil function tests. Resting adherence to endothelium, random and directed migration, phagocytosis-induced chemiluminescence, and granule secretory behavior were all indistinguishable from young healthy controls. However, in vivo delivery of neutrophils into skin abrasions was significantly reduced: 8.4 X 10(5), versus 2.7 X 10(6) in the young. In addition, their neutrophils showed a smaller increase in the surface adhesion glycoprotein CD11 and in adherence to endothelium in response to stimulation with FMLP than did cells from young controls. Inversely, baseline CD11 expression was higher in elderly subjects, suggesting that their cells may have an in vivo defect in mediator responsiveness. Serum immunoglobulin and complement concentrations were also compared. The mean IgM level of 106.3 mg/dl in the elderly was significantly below the 154.4 mg/dl in the young. In contrast, concentrations of C3, C4, and total hemolytic complement were significantly higher in the elderly.

Adult↗
PubMed1990

Rapid stereoselective hydrolysis of (+)-cocaine in baboon plasma prevents its uptake in the brain: implications for behavioral studies.

The naturally occurring enantiomer of cocaine, (-)-cocaine, has been previously labeled with 11C on the N-methyl group and used in conjunction with positron emission tomography to show that cocaine is rapidly taken up in the striata of human and baboon brain. In the present study, the behaviorally inactive (+)-cocaine was similarly labeled, with a view to its use for measuring the nonspecific binding of cocaine. No brain uptake was seen, although transport of cocaine into the brain is not expected to be stereoselective. The explanation for the lack of uptake was determined to be very rapid metabolism of (+)-cocaine in the blood. By 30 s after administration of labeled (+)-cocaine, it was undetectable in plasma. In vitro studies demonstrated that (+)-cocaine is 50% debenzoylated to (+)-ecgonine methyl ester within 5 s of exposure to baboon plasma but not to washed erythrocytes. The hydrolysis of (-)-cocaine is at least 1,000 times slower. Serum butyrylcholinesterase (EC 3.1.1.8) appears to be responsible for this hydrolysis, as evidenced by its inhibition by physostigmine and catalysis by commercially available pseudocholinesterase from horse and human blood.

Animals↗
PubMed1990

In vivo neutrophil delivery in men with alcoholic cirrhosis is normal despite depressed in vitro chemotaxis.

Ten patients with far-advanced Laennec's cirrhosis were studied for in vitro polymorphonuclear (PMN) chemotaxis and in vivo PMN delivery into modified skin windows. Random motility was similar for patient and control cells, but the patients' cells' mean chemotaxis to endotoxin-activated homologous serum was only 38% of control. The poor response was due to a serum inhibitor which reduced chemotactic activity of control serum by 75.6% but had no effect on chemotaxis to N-formyl-methionyl-leucyl-phenylalanine. The level of inhibitor activity in each patient did not correlate with the severity of liver dysfunction. In spite of the universal presence of the chemotactic factor inhibitor in all patients' sera, their in vivo PMN delivery into skin chambers was similar to controls. Thus, patients with alcoholic cirrhosis appear able to deliver PMNs normally in response to local tissue injury.

Adult↗
PubMed1990

Secretion of plasminogen activator from bovine parathyroid cells.

The characteristics and secretion of plasminogen activator (PA) were examined in fresh and cultured bovine parathyroid cells. Release of PA activity was maximal at low Ca concentrations ([Ca]) and suppressed at physiological [Ca]. PA secretion at high [Ca], like that of PTH, was increased by treatment of cells with chloroquine and/or 3-methyladenine. Secretion from organoids was not affected by hydrocortisone hemisuccinate, but was strongly increased by 1,25-dihydroxyvitamin D3. In cell homogenates, PA specific activity was highest in microsomes, from which less than 50% could be solubilized by Triton X-100. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of microsomes and media followed by zymography on fibrin-agarose gels showed that PA from both sources had an apparent mol wt of 44,000. No inhibitors of PA were detected by reverse zymography. PA activity was inhibited by placental urokinase (uPA) inhibitor and amiloride, which indicated that it was a uPA, but the secreted form required tissue-type PA stimulator (fibrin peptides) or denatured microsomes for full activity. Neither the microsomal nor the secreted forms of PA were active with S-2444, a substrate specific for active uPA. By comparison with the characteristics of human activators, the results suggested that parathyroid cells secrete uPA that is primarily in the precursor form single chain urokinase or scuPA.

Adenine↗
PubMed1990

Oral ciprofloxacin for osteomyelitis.

Ciprofloxacin is a new, oral, broad spectrum fluoroquinolone antibiotic which has a long serum half-life, a low incidence of significant adverse reactions, and is administered twice daily. Eighteen patients with osteomyelitis were treated with ciprofloxacin, 750 mg orally twice daily. The mean age of the patients was 43 years (range, 21 to 73 years); 12 were men. The duration of treatment ranged from 5 to 52 weeks (mean, 20.0 +/- 15.7 weeks). At follow up (mean, 18 +/- 8.5 months; range, 4 to 34.5 months), 11 patients (61.6%) achieved arrest of infection, 4 (22.2%) had improved with therapy, and 3 (16.6%) failed to improve. Ciprofloxacin was well tolerated. Four case histories are given.

Administration, Oral↗
PubMed1989

Inhibitors of cellular proteolysis cause increased secretion from parathyroid cells.

The secretion but not the biosynthesis of parathyroid hormone and secretory protein 1 is strongly, negatively regulated by extracellular [Ca2+]. In order to examine the hypothesis that decreased degradation might directly cause increased secretion, we tested the effects of agents that suppress cellular degradation via different mechanisms: 3-methyladenine, chloroquine, and 1-deoxynojirimycin. When secretion was inhibited by high [Ca2+], all agents caused increased secretion, but at low [Ca2+] only deoxynojirimycin was effective. Results derived from the use of two radioimmunoassays for parathyroid hormone suggested that the increased secretion was due to reduced destruction of secretory vesicles by lysosomes, and to reduced proteolysis of their contents by secretory vesicle proteases.

1-Deoxynojirimycin↗
PubMed1989

Modulation of endothelial fibronectin synthesis by polymorphonuclear granulocytes.

The attachment of polymorphonuclear granulocytes (PMNs) to vascular endothelial cells occurs continually in normal tissues; however, knowledge of the factors that control leukocyte margination is incomplete. In the present study, we used cell cultures of pulmonary artery endothelium to study their interaction with PMNs. Endothelial cells were seeded in Costar 24-well plates following which PMNs were inoculated onto the endothelial monolayers and incubated for 2 to 20 hours. During this period, fibronectin synthesis by endothelial cells was estimated by ELISA. In wells to which PMNs had been added, supernatant fibronectin concentration was increased at all time points during the 20 hour incubation. At 20 hours, supernatants from wells to which PMNs had been added contained approximately 2 1/2 times the control level of fibronectin. Since the amount of fibronectin, as determined by ELISA, adsorbed onto the added PMNs was negligible, these data suggest that PMNs can modulate the synthesis of fibronectin by pulmonary artery cells. Pulse labeling experiments and measurements of endothelial intracellular fibronectin also suggest this possibility. The endothelial response does not appear to be owing to nonspecific physical interaction since similarly sized polystyrene beads did not cause any change in supernatant fibronectin levels while glutaraldehyde-fixed PMNs caused only a 20-25% increase in fibronectin levels.

Adult↗
PubMed1988

Serial [18F]N-methylspiroperidol PET studies to measure changes in antipsychotic drug D-2 receptor occupancy in schizophrenic patients.

An indirect approach to the relationship among drug dose, plasma level, and the competition between a labeled neuroleptic drug [18F]N-methylspiroperidol (18F-NMS) for binding sites in striatal tissue in normal and schizophrenic subjects is described. The slope of the line plotting the ratio of activity in the striatum (As) to activity in the cerebellum (Ac) versus time up to 5 hr postinjection of 18F-NMS is taken as a marker of site occupancy. An inverse relation between labeled competitor uptake and drug plasma level has been demonstrated for the classes of antipsychotic drug studied. Striatal uptake studies showed a progressive increase in all subjects following drug withdrawal up to 156 hr postwithdrawal. Uptake and clearance of 18F-NMS in cerebellar tissue was not appreciably affected by antipsychotic medication or drug withdrawal.

Adult↗