PubMed Health⌕ Search

Biomedical subjects

S A Hunter

Publications and source records attributed to S A Hunter.

At least 19 recordsLinked to original sources
PubMed1998

Dimethylheptyl-THC-11 oic acid: a nonpsychoactive antiinflammatory agent with a cannabinoid template structure.

OBJECTIVE: To assess the antiinflammatory activity of dimethylheptyl-THC-11 oic acid (DMH-11C), a nonpsychoactive synthetic derivative of tetrahydrocannabinol. METHODS: Acute inflammation was induced by injection of interleukin-1beta and tumor necrosis factor alpha into subcutaneous air pouches formed on the backs of mice. Inflammation was quantified 6 hours later by pouch fluid leukocyte counts. Adjuvant-induced polyarthritis in rats was used as a model of chronic inflammation and joint tissue injury. Animals were either untreated, treated with safflower oil, or treated with DMH-11C in safflower oil. Arthritis was assessed by clinical observation and by histomorphologic evaluation of tibiotarsal joints. RESULTS: Oral administration of DMH-11C reduced the accumulation of pouch fluid leukocytes and significantly reduced the severity of adjuvant-induced polyarthritis. Histopathologic studies of tibiotarsal joints showed that DMH-11C treatment attenuated pannus formation and joint tissue injury. CONCLUSION: DMH-11C suppresses acute inflammation in the subcutaneous air pouch in mice and chronic joint inflammation characteristic of adjuvant disease in rats. These results demonstrate the potential use of this nonpsychoactive cannabinoid as an antiinflammatory agent.

3T3 Cells↗
PubMed1997

Receptor mediation in cannabinoid stimulated arachidonic acid mobilization and anandamide synthesis.

Numerous reports have suggested that increased synthesis of eicosanoids is a significant effect of cannabinoids in several models including the human. To address the question of receptor mediation in this process we have carried out experiments using oligonucleotides that are antisense to the CB1 and to the CB2 receptors. We have synthesized sense, antisense and random oligonucleotide probes to test for receptor involvement in THC stimulation of arachidonic acid release in three cell lines of both central and peripheral origin. Treatment of N18 mouse neuroblastoma cells with the CB1 antisense probe, at two concentrations, resulted in a dramatic decrease of THC stimulated arachidonate release while treatment with antisense CB2 was less effective. Synthesis of the novel eicosanoid, anandamide, was also reduced by antisense CB1 but not by antisense CB2. Western blot analysis indicated a decreased level of CB1 in CB1 antisense treated cells. The CB1 antagonist, SR141716A, was effective in reducing the THC elevated levels of free arachidonate in these cells in agreement with the antisense data. In the macrophage line, RAW 264.7, we found that while the sense, the random and the CB1 antisense oligonucleotides were ineffective, the CB2 antisense probe gave significant reductions of the THC induced response. The CB2 probe was also effective in reducing the release of arachidonate in WI-38 human lung fibroblasts. These findings support the idea of a receptor mediated process for cannabinoid stimulation of eicosanoid synthesis.

Animals↗
PubMed1997

Correlation between frequency of tuberculosis and compliance with control strategies.

OBJECTIVE: To determine if compliance with annual tuberculosis skin testing correlated with the number of cases of tuberculosis seen in patients and healthcare workers. DESIGN: Survey using a written questionnaire. SETTING AND PARTICIPANTS: 159 Veterans' Administration facilities. RESULTS: Hospitals that reported that > 80% of their healthcare workers received annual skin tests saw 12.7 patient cases per 10,000 admissions and 4.0 healthcare worker cases per 10,000 personnel. Facilities in which < 20% of their healthcare workers were given annual skin tests saw 4.5 cases per 10,000 admissions and 1.6 cases in healthcare workers per 10,000 personnel (P < .001 for patients and P = .31 for healthcare workers). The ratio of the median number of patients placed in acid-fast bacilli (AFB) isolation to the median number of patients with confirmed tuberculosis was 12. There was no correlation of this ratio with the number of cases of tuberculosis in patients or healthcare workers seen in each facility. CONCLUSION: Compliance with annual tuberculosis skin testing was related directly to the rate of tuberculosis seen in patients. More standardized policies for placing patients in AFB isolation are needed to control for potentially costly variation among facilities. These measures should have highest priority in the control of tuberculosis in the healthcare setting, before implementing still more expensive interventions.

Cross Infection↗
PubMed1995

Stimulation of anandamide biosynthesis in N-18TG2 neuroblastoma cells by delta 9-tetrahydrocannabinol (THC).

A concentration-related stimulation of anandamide (arachidonylethanolamide) synthesis by delta 9-tetrahydrocannabinol (THC) was observed in N-18TG2 neuroblastoma cells. Anandamide was detected and measured using an approach in which [3H]arachidonic acid and [14C]ethanolamine were incorporated into the phospholipids of subconfluent monolayers of cells, and the radiolabeled products were analyzed by TLC following agonist exposure. Both precursors showed similar concentration-response relationships and time dependencies consistent with the production of a product containing both the ethanolamine and arachidonyl moieties. The radiolabeled product also migrated together with authentic anandamide on two-dimensional TLC, confirming its identity as arachidonylethanolamide. Approximately two-thirds of the observed synthesis could be inhibited by 1 microM wortmannin, an agent previously reported to inhibit THC-stimulated arachidonic acid release. These findings are in agreement with reports showing that THC can mobilize phospholipid bound arachidonic acid, leading to the production of other eicosanoids.

Arachidonic Acid↗
PubMed1994

Phospholipase participation in cannabinoid-induced release of free arachidonic acid.

The exposure of cells in culture to cannabinoids results in a rapid and significant mobilization of phospholipid bound arachidonic acid. In vivo, this effect has been observed as a rise in eicosanoid tissue levels that may account for some of the pharmacological actions of delta 9-tetrahydrocannabinol (THC), the major psychoactive cannabinoid. Fluoroaluminate pretreatment of mouse peritoneal cells potently reduced the cannabinoid response, while promoting arachidonate release on its own, consistent with earlier observations that this effect may be a receptor/G-protein-mediated process. Further support for receptor mediation was the demonstration of saturable, high-affinity cannabinoid binding in these cells. THC potency was reduced in the presence of ethanol, and was accompanied by significant increases in phosphatidylethanol (PdEt) levels, a unique product of phospholipase D (PLD) activity. THC-dependent arachidonate release was reduced partially in similar amounts by either propranolol or wortmannin, further implicating PLD as a mediator of THC action. A central role for diacylglyceride (DAG), a secondary product of PLD metabolism, in this THC-induced process, both as a source of arachidonate and as a stimulator of protein kinase C (PKC), is supported by the data in this report. Cells exposed to phorbol ester for 18 hr prior to THC challenge became less responsive, indicating a possible role for PKC. The involvement of PKC further suggests participation by phospholipase A2 (PLA2) whose activity may be regulated by the former. Treatment of cells with interleukin-1 alpha, an agent known to elevate PLA2 levels, caused an increase in the THC response, supporting a role for this enzyme in the release reaction. Direct evidence, by immunoblotting, for the activation and phosphorylation of PLA2 by THC was also obtained. In summary, the evidence presented in this report indicates that THC-induced arachidonic acid release occurs through a series of events that are consistent with a receptor-mediated process involving the stimulation of one or more phospholipases.

Animals↗
PubMed1994

Tuberculosis control strategies: the cost of particulate respirators.

OBJECTIVE: To assess the cost of the mandatory use of high-efficiency particulate respirators to treat patients with known or suspected tuberculosis. DESIGN: A questionnaire was used to determine the number of high-efficiency particulate respirators required and the number of cases of tuberculosis in employees that could potentially be prevented. Indirect costs included the training and fitness testing of employees. The clinical efficacy of respirators is not known. To provide a best-case scenario, it was assumed that the respirators could prevent as many as 25% of tuberculosis cases in health care workers. SETTING: 159 acute care facilities administered by the Department of Veterans Affairs. PARTICIPANTS: Quality improvement, infection control, and employee health specialists. MEASUREMENTS: Cost of the respirators compared with their maximum predicted efficacy. RESULTS: The use of the respirators would cost $7 million per case of tuberculosis prevented and $100 million per life saved. CONCLUSIONS: High-efficiency particulate respirators are a costly means of trying to prevent tuberculosis. Costs could be reduced by reusing masks or by restricting the number of health care workers allowed to have contact with potentially infectious patients. As the health care budget undergoes further restrictions, specific means of accommodating the cost of new regulations must be found.

Cost-Benefit Analysis↗
PubMed1991

Detection of cannabinoid receptors by photoaffinity labelling.

A novel [125I]-labelled photoaffinity ligand designed to detect cannabinoid binding sites has been used in mouse brain preparations and in cultured S49 mouse lymphoma cells. The ligand, 2-iodo-5'-azido-delta 8-THC, shows a high affinity for sites in both brain (Kd = 5.60 pM) and whole cell (Kd = 9.38 pM) systems. Photolabelling studies with brain samples revealed the existence of four ligand-protein adducts, of estimated molecular weights 85.5, 62.1, 30.0 and 25.5 kDa, that were diminished by prior exposure to 8 microM THC. A similar study with S49 cells gave adducts with apparent molecular weights of 62.1, 34.4, 16.9 and 13.5 kDa. The ligand produces a typical cannabinoid cataleptic response in mice suggesting that possibly one or more of the binding sites may be involved in some of the receptor mediated actions of THC.

Affinity Labels↗
PubMed1991

G-protein mediation of cannabinoid-induced phospholipase activation.

The release of arachidonic acid from mouse peritoneal and S49 cells induced by delta 1-tetrahydrocannabinol was found to be altered by prior exposure of the cells to either pertussis toxin or cholera toxin. The stable analogs of GTP and GDP, GTP-gamma-S and GDP-beta-S, were also effective in changing the extent of arachidonate release in saponin-treated cells. GDP-beta-S essentially abolished the THC response, while GTP-gamma-S showed effects mainly on vehicle-treated cells. The cataleptic action of THC in intact mice which is mediated by eicosanoids was also attenuated by pertussis toxin pretreatment. It is suggested that the THC receptor is coupled to phospholipases through one or more G-proteins and that adenylate cyclase probably does not have a role in this mechanism.

Adenylate Cyclase Toxin↗
PubMed1991

Elevation of brain prostaglandin E2 levels in rodents by delta 1-tetrahydrocannabinol.

An isotopic dilution procedure using specific prostaglandin E2 (PGE2) brain receptors was utilized to determine the changes in brain PGE2 levels subsequent to drug exposure. Delta-1-tetrahydrocannabinol (delta 1-THC) stimulated PGE2 synthesis resulting in increased brain concentrations when compared with vehicle treated rats and mice. Indomethacin markedly inhibited the delta 1-THC elevated rise in PGE2 levels presumably by inhibition of prostaglandin synthetase. The delta 1-THC-induced increase in PGE2 brain levels was also suppressed by i.v. administered rabbit PGE2-antiserum. This suggests that one of the sites of delta 1-THC action is extracerebral and from here a portion of the released prostaglandins are transported to the brain. These results add further support to previous data that delta 1-THC given orally results in an increase in brain PGE2 levels.

Animals↗
PubMed1990

Appropriateness of admissions and discharges among readmitted patients.

This study examined the relationships between appropriateness of readmission within two weeks of discharge and appropriateness of previous admission and discharge, bed section, type of readmission, and patient demographic, medical condition, and hospital stay characteristics. Using the Department of Veterans Affairs (VA) Patient Treatment File and medical records, 445 readmissions to a highly affiliated midwestern VA Medical Center in fiscal year 1984 were examined. Appropriateness was determined by four trained medical record abstractors using InterQual admission and discharge standards. Type of readmission was based on a pilot-tested flowchart. Appropriateness of readmission was significantly associated with that of the previous admission and discharge, with the relationship varying by admission, discharge, and readmission bed sections. Reasons for inappropriate admissions, discharges, and readmissions also varied by bed section. For the majority of inappropriate readmissions, there was clear written evidence in the medical record during the previous hospital stay that the patient was directed to return for readmission. Inappropriate readmissions were more likely than appropriate readmissions to have a primary diagnosis of neoplasm or digestive disorder. These results indicate the importance of examining both the operational efficiencies during the previous admission and the clinical criteria for admitting, discharging, and readmitting patients in assessing the appropriateness of readmissions.

Adult↗
PubMed1989

Immunization against prostaglandins reduces delta 1-tetrahydrocannabinol-induced catalepsy in mice.

Immunization of mice with a thyroglobulin-prostaglandin E2 (PGE2) conjugate produced animals with measurable blood levels of anti-PGE2 antibodies. When these mice were challenged with delta 1-tetrahydrocannabinol (THC) (20 mg/kg), they showed a greatly diminished cataleptic response as compared with control animals. This observation further supports a hypothesis on the mechanism of action of THC in which eicosanoids, such as PGE2, are early mediators. Based on the likelihood that antibodies were not present in the central nervous system, it is suggested that the initial site of action of THC may be at one or more peripheral locations. The transport of peripheral PGE2 or other eicosanoids to the brain would result in the eventual manifestation of THC action at this site.

Animals↗
PubMed1989

Antagonism to the actions of platelet activating factor by a nonpsychoactive cannabinoid.

A recent report from our laboratory gave evidence showing that tetrahydrocannabinol (THC)-7-oic acid has antinociceptive activity in the mouse. We also pointed out that this substance, which is a major metabolite of THC in most species including humans, is probably responsible for the well known analgesic properties of the parent drug. The present report contains findings that suggest THC-7-oic acid may have considerable activity as an antagonist to platelet activating factor, which may also explain the known properties of THC as a bronchodilator, antipyretic and antirheumatic agent. In the mouse ear edema test, THC-7-oic acid appeared to be about as efficacious as phenidone; however, its potency was less than either phenidone or indomethacin. When compared with the parent drug, THC, in the platelet activating factor-induced paw edema assay, it acted more quickly and produced a greater reduction of edema. This is consistent with the possibility that THC must be metabolized to the 7-oic acid for activity to be seen. Its activity in preventing platelet activating factor-induced mortality was comparable to naproxen. In vitro studies suggest that THC-7-oic acid can inhibit both cyclooxygenase and 5-lipoxygenase activities in intact cells.

Animals↗
PubMed1988

Cannabinoids and pain responses: a possible role for prostaglandins.

The principal metabolite of delta 1-THC, delta 1-THC-7-oic acid exhibits significant analgesic action in the mouse hot plate test. The parent delta 1-THC has a similar effect when measured at later time points; however, 10 min after drug administration, a pronounced hyperalgesia is seen. This hyperalgesia can be inhibited by prior administration of either indomethacin or delta 1-THC-7-oic acid, presumably because of their ability to inhibit eicosanoid synthesis. Administration of prostaglandin E2 (PGE2), at doses that were a small fraction of the delta 1-THC given, resulted in a strong hyperalgesic response. Unlike delta 1-THC, the metabolite does not produce a cataleptic state in the mouse, which eliminates this as a basis for the hot plate response. The evidence presented is consistent with a mechanism in which the metabolite inhibits eicosanoid synthesis whereas the parent drug elevates tissue levels of prostaglandins.

Analgesia↗
PubMed1987

A major metabolite of delta 1-tetrahydrocannabinol reduces its cataleptic effect in mice.

The results described here demonstrate that THC-induced catalepsy in mice can be substantially inhibited by the prior administration of delta 1-THC-7-oic acid, the major metabolite of THC in most species including humans. This raises the possibility that the intensity and duration of action of THC may depend to a large degree on the levels of this metabolite at the sites of action.

Animals↗
PubMed1986

Prostaglandins and cannabis XV. Comparison of enantiomeric cannabinoids in stimulating prostaglandin synthesis in fibroblasts.

Stereospecificity has been reported for a number of actions of the cannabinoids in a variety of systems. In the present report, we have shown that this effect can also be demonstrated when human lung fibroblasts in monolayer culture are stimulated by cannabinoids to produce prostaglandin E2 (PGE2). Three enantiomeric pairs of cannabinoids, (+) and (-)-delta 1-tetrahydrocannabinol (THC), (+) and (-)-delta 6-THC and (+) and (-)-delta 6-dimethylheptyl (DMH) THC were tested. In each case the (-) isomer was significantly more potent in agreement with the findings of others using different systems. Interestingly, very little stereospecificity was found in fibroblasts when the release of arachidonic acid, the precursor of PGE2, was monitored. This suggests that cannabinoids may act at several sites within the cell some of which show comparatively greater stereoselectivity for these agonists.

Arachidonic Acid↗
PubMed1986

Prostaglandins and cannabis--XVI. Antagonism of delta 1-tetrahydrocannabinol action by its metabolites.

Prior exposure of cells in vitro to delta 1-tetrahydrocannabinol-7-oic acid (delta 1-THC-7-oic acid) reduced the degree of stimulation of prostaglandin synthesis incurred by subsequent treatment with delta 1-THC. The site of action of this inhibitory effect seemed to be on cyclooxygenase and not at the earlier step involving the phospholipase-mediated release of arachidonic acid. delta 1-THC-7-oic acid is a major metabolite of delta 1-THC and has no psychoactivity in humans. Our findings raise the possibility, however, that it may influence the in vivo activities of delta 1-THC by antagonizing its stimulatory action on cellular prostaglandin synthesis.

Animals↗
PubMed1986

Effects of cannabinoids on the activities of mouse brain lipases.

Cannabinoids were found to augment phospholipase activities and modify lipid levels of mouse brain synaptosomes, myelin and mitochondria. Delta-1-tetra-hydrocannabinol (delta 1-THC) and several of its metabolites induced a dose-dependent (0.32-16 microM) stimulation of phospholipase A2 (PLA2) activity resulting in the increased release of free arachidonic acid from exogenous [1-14C]phosphatidylcholine (PC). The potencies of the cannabinoids in modulating PLA2 activity were approximately of the order: 7-OH-delta 1-THC greater than delta 1-THC greater than 7-oxo-delta 1-THC greater than delta 1-THC-7-oic acid = 6 alpha OH-delta 1-THC much greater than 6 beta-OH-delta 1-THC. The hydrolysis of phosphatidylinositol (PI) by synaptosomal phospholipase C (PLC) was enhanced significantly by delta 1-THC and promoted diacylglyceride levels by greater than 100 percent compared to control values. In contrast, arachidonate was the major product resulting from phospholipase activities of a 20,000 g pellet. Synaptosomal diacylglyceride lipase activity was inhibited by delta 1-THC. [1-14C]Arachidonic acid was readily incorporated into subcellular membrane phospholipids and after exposure to cannabinoids led to diminished phosphoglyceride levels and concomitant increases in released neutral lipid products. These data suggest that cannabinoids control phospholipid turnover and metabolism in mouse brain preparations by the activation of phospholipases and, through this mechanism, may exert some of their effects.

Animals↗