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R R MacGregor

Publications and source records attributed to R R MacGregor.

At least 19 recordsLinked to original sources
PubMed1992

Synthesis of carbon-11 labeled iodinated cocaine derivatives and their distribution in baboon brain measured using positron emission tomography.

Three iodine-substituted derivatives of cocaine, methyl esters of 3-[(2'-, 3'-, and 4'-iodobenzoyl)oxy]-8-methyl-[1R-(exo,exo)]-8- azabicyclo[3.2.1]octane-2 carboxylic acid (2a-c), were synthesized and subjected to N-demethylation to give the corresponding noriodococaines 3-[(2'-,3'-, and 4'-iodobenzoyl)oxy]-[1R-(exo,exo)]-8- azabicyclo[3.2.1]-octane-2-carboxylic acid (3a-c). These were remethylated with [11C]CH3I to give the [N-11C-methyl]iodococaines 4a-c which were examined in baboon brain in vivo using positron emission tomography (PET). Compared to [N-11C]cocaine itself the regional distributions were changed from a highly specific localization in the corpus striatum to more diffuse patterns which included the cerebellum and cortex. Peak brain uptakes and clearance kinetics were also changed. [N-11C]-o-Iodococaine (4a) had a peak uptake in the striatum at 4-5 min after injection of only 17% that of cocaine in the same animal. The peak uptake of [N-11C]-p-iodococaine (4c) was 60% of that of [N-11C]cocaine and a clearance half-time of approximately 55 min, twice that of [N-11C]cocaine. [N-11C]-m-Iodococaine (4b) displayed half the uptake of [N-11C]cocaine, buts its clearance was similar to that of the parent molecule. The fractions of unmetabolized tracer in blood plasma at 1-30 min were higher for 4a-c than for [N-11C]cocaine. Plasma protein binding experiments showed 10%, 0.3%, 1.6%, and 6% as the free fraction for cocaine and o-, m-, and p-iodococaines respectively, consistent with the low brain uptake observed for the ortho isomer, and implicated alpha 1-acid glycoprotein as responsible for the low free fraction of o-iodococaine. The potencies of 2a-c to displace tritiated cocaine from striatal membranes were p-iodo approximately cocaine greater than m-iodo approximately o-iodo.

Animals↗
PubMed1992

Determination of the enantiomeric composition of samples of cocaine by normal-phase high-performance liquid chromatography with UV detection.

A high-performance liquid chromatographic method has been developed for the quantitation of the enantiomers of cocaine. Mixtures of the naturally occurring (-)-cocaine and synthetically produced (+)-cocaine were hydrolyzed in water to (+) and (-)-benzoyl ecgonine. Esterification with an optically pure 2-octanol resulted in diastereoisomers that could be separated on bare silica gel using an acetonitrile-aqueous ammonium phosphate mobile phase.

Chromatography, High Pressure Liquid↗
PubMed1992

Comparative PET studies of the kinetics and distribution of cocaine and cocaethylene in baboon brain.

Recent studies have suggested that cocaethylene, an active metabolite of cocaine found in blood and postmortem brain of individuals self-administering cocaine and alcohol, may play a role in the increased toxicity seen when coadministering these 2 drugs. We have used positron emission tomography (PET) and carbon-11 (t1/2:20.4 min) labeled cocaine and cocaethylene to compare the short-term kinetics of cocaine and cocaethylene in baboon brain. The regional uptake of [11C]cocaine cocaethylene in baboon brain. The regional uptake of [11C]cocaine ([11C]COC) and [11C]cocaethylene ([11C]CE), 5-8 mCi and 4-6 micrograms, in baboon brain (n = 7) were similar but clearance from whole brain (global, GL) and from striatum (SR), thalamus (TH), and cerebellum (CB) was slower for cocaethylene. Steady-state distribution volumes (DV) were not significantly different in the striatum but were greater for cocaethylene in the thalamus, cerebellum, and whole brain. Debenzoylation of cocaethylene proceeded at about one-third the rate of cocaine, as determined by in vitro incubation of labeled cocaethylene and labeled cocaine with baboon plasma and with purified horse butyryl-cholinesterase (EC 3.1.1.8). Even though the slower clearance of cocaethylene could lead to longer tissue exposures and potentially accentuated or different physiological effects relative to cocaine, the difference between the 2 drugs is not large. Thus it is more likely that the direct actions of cocaine and alcohol on some organs, rather than cocaethylene, account for this enhanced toxicity.

Animals↗
PubMed1992

Alcohol intoxication does not change [11C]cocaine pharmacokinetics in human brain and heart.

There is increasing evidence that the combined use of cocaine and alcohol produces enhanced behavioral and toxic effects. We have used PET and tracer doses of [11C]cocaine in 7 normal human volunteers to assess if the distribution and clearance of cocaine are altered by alcohol intoxication. Each subject received 2 PET studies with [11C]cocaine (3-11 micrograms), one before and one during alcohol intoxication (1 g/kg). Regions of interest included the brain (n = 3) and heart (n = 4). Arterial plasma was assayed for unchanged cocaine and for labeled cocaethylene, a metabolite of cocaine found in individuals using cocaine and alcohol in combination (Hearn et al., 1991a). Alcohol intoxication did not change uptake and clearance or the steady-state distribution volume of [11C] cocaine in brain (striatum, thalamus, and cerebellum) or in heart. Moreover, labeled cocaethylene was not detected in the 10 minute plasma sample. These results suggest that the acute enhancement of behavior and toxicity associated with the combined use of cocaine and alcohol is not due to an alteration in cocaine's organ distribution or to cocaethylene formation but may be related to an additive effect resulting from the direct actions of each of these drugs.

Adult↗
PubMed1992

Randomized, double-blind study of cefotetan and cefoxitin in post-cesarean section endometritis.

OBJECTIVE: The hypothesis of the study is that cefotetan and cefoxitin will be equally efficacious and safe in the treatment of post-cesarean section endometritis. STUDY DESIGN: In a double-blind, randomized manner 140 patients with post-cesarean section endometritis were treated with cefotetan, 2 gm intravenously every 12 hours, or cefoxitin, 2 gm intravenously every 6 hours. They were followed prospectively for clinical response and side effects. Cure rates between the two groups were compared with the chi 2 test. RESULTS: The cure rates were 83% for cefotetan and 79% for cefoxitin (p = 0.56). No patient required a change in therapy due to adverse effects, and no abnormal bleeding occurred. CONCLUSION: In this study cefotetan and cefoxitin appeared equally effective in treating endometritis with no difference in side effects or complications.

Adult↗
PubMed1992

Niacin-positive Mycobacterium kansasii isolated from immunocompromised patients.

Niacin-positive Mycobacterium kansasii was isolated from three patients, two with respiratory infections and one with a perirectal abscess. The isolates were phenotypically similar to other strains of M. kansasii, differing only in their ability to produce niacin. This phenotype has been reported only twice in the literature, during the 1960s.

Adult↗
PubMed1992

Calcium-regulated secretion of tissue plasminogen activator and parathyroid hormone from human parathyroid cells.

The effects of Ca and other agents on secretion of plasminogen activator (PA) and PTH have been examined and compared, using parathyroid cells obtained from the glands of chronic renal patients. During 2 weeks culture at different [Ca], the secretory rates of PA activity and PTH were parallel; steady-state secretion over 24-h periods was maximal at 0.5-0.9 mM Ca, minimal at 1.5-2.5 mM Ca, and the [Ca] at 50% suppression was 1.1 mM. At 2.5 mM Ca, two inhibitors of cellular proteolysis, 3-methyladenine and chloroquine, stimulated secretion of both PA activity and PTH. The results indicated that secretion of PA from human parathyroid cells is regulated similarly to that of PTH. The characteristics of human parathyroid PA were also examined using human parathyroid adenoma tissue. In homogenates, the highest specific activity of PA was in microsomal fractions. The Mr of PA from tissue and from culture media was 70 kilodalton by sodium dodecyl sulfate gel electrophoresis followed by zymography, or by Western blotting using antisera to human tissue PA (tPA). Enzyme activity was inhibited by incubation with antisera to tPA but not to urokinase. In contrast to bovine parathyroid cells that secrete a urokinase, human parathyroids apparently contain and secrete tPA.

Adenine↗
PubMed1992

GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography.

Extensive neuroanatomical, neurophysiological, and behavioral evidence demonstrates that GABAergic neurons inhibit endogenous dopamine release in the mammalian corpus striatum. Positron emission tomography (PET) studies in adult female baboons, using the dopamine D2-specific radiotracer 11C-raclopride, were undertaken to assess the utility of this imaging technique for measuring these dynamic interactions in vivo. 11C-raclopride binding was imaged prior to and following the administration of either gamma-vinyl-GABA (GVG), a specific suicide inhibitor of the GABA-catabolizing enzyme GABA transaminase, or lorazepam, a clinically prescribed benzodiazepine agonist. Striatal 11C-raclopride binding increased following both GVG and lorazepam administration. This increase exceeded the test/retest variability of 11C-raclopride binding observed in the same animals. These findings confirm that changes in endogenous dopamine concentrations resulting from drug-induced potentiation of GABAergic transmission can be measured with PET and 11C-raclopride. Finally, this new strategy for noninvasively evaluating the functional integrity of neurophysiologically linked transmitter systems with PET supports its use as an approach for assessing the multiple mechanisms of drug action and their consequences in the human brain.

Aminocaproates↗
PubMed1992

Treatment of cryptosporidiosis with paromomycin. A report of five cases.

Cryptosporidiosis continues to be one of the most devastating complications of the acquired immunodeficiency syndrome, causing severe, chronic diarrhea that is largely refractory to treatment. More than 60 drugs have been tried in the treatment of cryptosporidiosis, none of which have been consistently successful. We describe the successful treatment of cryptosporidiosis in five patients with acquired immunodeficiency syndrome with oral paromomycin at a dose of 1500 to 2000 mg/d. All five patients had resolution of symptoms and normalization of bowel movements, although one patient later relapsed while receiving paromomycin. Three of five patients cleared Cryptosporidium from the stool. Paromomycin is a promising therapy for cryptosporidiosis in acquired immunodeficiency syndrome and further prospective clinical trials are warranted.

AIDS-Related Opportunistic Infections↗
PubMed1992

Is [1-11C]putrescine useful as a brain tumor marker?

Our experience with 11C-putrescine underscores the difficulty of finding a selective brain tumor tracer, uniquely incorporated by neoplastic glia or metastatic cells within brain, but not by the proliferating, nontransformed cells which constitute a normal pathophysiological reaction to various disease processes. Thirty-three patients with 36 lesions were studied with 11C-putrescine to determine the specificity of labeled putrescine for tumor tissue. The uptake of 11C-putrescine was correlated with local cerebral glucose metabolic rate in various lesions, including different types of tumors, to assess the relationship between 11C-putrescine uptake and tumor biology. Carbon-11-putrescine uptake was similar in malignant tumor and benign, non-neoplastic lesions with blood-brain barrier breakdown, illustrating the lack of tumor specificity of this tracer. Carbon-11-putrescine was not well incorporated into poorly enhancing lesions, regardless of their pathology, emphasizing the requirement of a disrupted blood-brain barrier for 11C-putrescine uptake. The ratio of 11C concentration within lesions, compared to that in a region of interest in the contralateral brain, weakly correlated with an analogous ratio for local cerebral glucose metabolic rate in various lesions. Physiological processes not unique to tumors are associated with polyamine active transport and metabolism and contribute to the lack of tumor specificity of 11C-putrescine. Carbon-11-putrescine appear to have less diagnostic utility than 18FDG in brain tumors. The potential of 11C-putrescine for evaluating the effect of antineoplastic therapy and providing prognostic information on brain tumors remains to be investigated.

Biomarkers, Tumor↗
PubMed1991

Successful foscarnet therapy for cytomegalovirus retinitis in an AIDS patient undergoing hemodialysis: rationale for empiric dosing and plasma level monitoring.

Foscarnet is an investigational antiviral agent that has been used effectively in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. However, it has not been readily available to AIDS patients with renal insufficiency because its major side effect is nephrotoxicity. In this report, the efficacy, safety, and dosing requirements of foscarnet in a hemodialysis-dependent patient with CMV retinitis are presented. Foscarnet was administered for 14 weeks, at an initial dosage of 60 mg/kg after each dialysis session. Plasma concentrations were monitored weekly, and the dosage was adjusted to maintain peak plasma levels in the range of 500-800 microM. Although some laboratory abnormalities occurred (a preexisting anemia continued, serum calcium and phosphorus decreased, and ionized calcium increased), they did not limit therapy. Foscarnet is a potentially useful alternative treatment for CMV retinitis in hemodialysis-dependent AIDS patients.

Acquired Immunodeficiency Syndrome↗
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↗