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Biomedical subjects

J A Boyd

Publications and source records attributed to J A Boyd.

28 records · Page 2Linked to original sources
PubMed1982

Selective activation of some dihydrodiols of several polycyclic aromatic hydrocarbons to mutagenic products by prostaglandin synthetase.

The ability of prostaglandin synthetase (PGS) to cooxidize benzo(a)pyrene, benzo(a)anthracene, chrysene, and several of their dihydrodiol derivatives to mutagenic products was tested with Salmonella typhimurium strains TA98 and TA100. The microsomal fraction of ram seminal vesicles, a known source of PGS, in the presence of the PGS substrate arachidonic acid, metabolized benzo(a)pyrene-7,8-dihydrodiol, benzo(a)anthracene-3,4-dihydrodiol, and chrysene-1,2-dihydrodiol to mutagenic products. This activity was inhibited by the PGS inhibitor indomethacin. Unlike the PGS system, however, a cytochrome P-450-reduced nicotinamide adenine dinucleotide phosphate-dependent system, present in an Aroclor 1254-induced rat liver 9000 x g supernatant fraction, also activated the parent compounds [benzo(a)pyrene, benzo(a)anthracene, chrysene] and several other benzo(a)anthracene dihydrodiols (the 1,2-dihydrodiol, the 8,9-dihydrodiol, and the 10,11-dihydrodiol). The chrysene trans-3,4, trans-5,6, and cis-5,6 diols were not activated to mutagens by either system. Thus, the PGS system appears to be more selective than does the cytochrome P-450 system in the activation of polycyclic aromatic hydrocarbons to mutagenic products, activating only those dihydrodiols with adjacent double bonds in the bay region from which the bay-region diol-epoxides are formed.

Animals↗
PubMed1982

Prostaglandin endoperoxide synthetase-dependent cooxidation of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene in C3H/10T 1/2 clone 8 cells.

(+/-)trans-7,8-Dihydroxy-7,8-dihydrobenzo(a)pyrene (BP-7,8-diol), the proximate form of the carcinogen benzo(a)pyrene, is cooxidized during the oxidation of arachidonic acid to prostaglandins by prostaglandin endoperoxide synthetase (PES). This enzyme can oxidize BP-7,8-diol to the reactive intermediate (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, which binds covalently to macromolecules, is mutagenic in bacterial test systems, and forms 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BP-tetrol) isomers. We have examined the cooxidation of BP-7,8-diol in an intact cell culture system of C3H/10T 1/2 clone 8 mouse embryo fibroblasts, in which both the mixed-function oxidase and PES systems are present. When BP-7,8-diol is incubated for 72 hr with approximately 10(6) confluent cells, high-performance liquid chromatography analysis of the organic extractable products reveals all four pairs of BP-tetrols, with those from (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene predominating. The addition of arachidonic acid (100 microM) produced a 2- to 3-fold increase in the formation of BP-tetrols from (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, while the metabolism of BP-tetrols from (+/-)-7 beta,8 alpha-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10 tetrahydrobenzo(a)pyrene was unchanged. The addition of the PES inhibitor indomethacin (100 microM) completely eliminated this stimulation. Cell transformation assays were carried out under the same conditions. The addition of arachidonic acid resulted in a 10-fold increase in foci formation, while indomethacin inhibited the increase in foci formation by 70%. These results suggest that cooxidation of BP-7,8-diol to reactive intermediates by PES can occur in an intact cell system if stimulated with arachidonic acid. In addition to mixed-function oxidase-dependent activation of carcinogens, the cooxidation of chemicals to reactive metabolites during prostaglandin biosynthesis may also play a role in carcinogenesis.

Animals↗
PubMed1981

Prostaglandin endoperoxide synthetase-dependent cooxidation of acetaminophen to intermediates which covalently bind in vitro to rabbit renal medullary microsomes.

The metabolism of acetaminophen during prostaglandin biosynthesis was studied in vitro. [3H]Acetaminophen was rapidly metabolized by ram seminal vesicle microsomes to an intermediate(s) which covalently binds to microsomal protein. Arachidonic acid, a substrate for the fatty acid cyclooxygenase component of prostaglandin endoperoxide synthetase (PES), was required to support binding. The cyclooxygenase inhibitor indomethacin inhibited binding. Cumene hydroperoxide, a substrate for the hydroperoxidase component of PES, supported covalent binding which was not inhibitable by indomethacin. Acetaminophen also stimulated oxygen uptake during prostaglandin biosynthesis in a dose-dependent manner. By using a purified PES preparation with bovine serum albumin as the acceptor protein, similar results were obtained. Binding was dependent upon the presence of PES and arachidonic acid and was inhibited by indomethacin. Experiments were then carried out by using microsomes prepared form the rabbit kidney medulla, a possible target organ of acetaminophen-induced toxicity. Arachidonic acid and cumene hydroperoxide supported covalent binding, whereas indomethacin inhibited binding supported by the former but not the latter. Reduced glutathione prevented covalent binding to protein when added to the incubation mixture and NADPH did not support binding. The results suggest that the cooxidation of acetaminophen during prostaglandin biosynthesis may play a role in the renal metabolism and possible nephrotoxicity of this compound.

Acetaminophen↗
PubMed1980

Minilaparotomy under local anesthesia for outpatient sterilization: a preliminary report.

An outpatient sterilization program was started at Silas B. Hays Hospital, Fort Ord, California, and later extended to Malcolm Grow USAF Medical Center and the Walter Reed Army Medical Center. From January 1976 to June 1978, two hundred and eight outpatient minilaparotomy Pomeroy tubal ligations were performed under local anesthesia. The minilaparotomy technique, using standard operating room equipment, is described. The average operating time was 31.8 minutes and the complication rate was 2.5%.

Adult↗
PubMed1980

Enhanced thromboxane B2 release from challenged guinea pig lung after oxygen exposure.

The effects of exposure to 100% oxygen (O2) on the release of thromboxane B2 (TXB2) and prostaglandins (PG) from guinea pig lungs during anaphylaxis were studied. Lungs from sensitized guinea pigs were isolated, perfused, and challenged. Serologic examination of the perfusate showed that larger amounts of TXB2, 6-keto-PGF1 alpha, PGE2, and PGF2 alpha were released from the lungs of animals previously exposed to 100% O2 for 72 h. Conversely, these lungs released smaller amounts of 13, 14-dihydro-15-keto-PGF2 alpha. Histamine release, measured spectrofluorometrically, was unchanged. 15-hydroxyprostaglandin dehydrogenase (PGDH) was inhibited by 83% after O2 exposure, as measured by an in vitro enzyme assay. These results suggested that the reported enhancement of systemic anaphylaxis in the guinea pig in vivo after exposure to oxidant gases may be due in part to inhibition of pulmonary PGDH resulting in increased half-lives of primary PG and TX released from the lung.

Anaphylaxis↗
PubMedDate not supplied

Mechanical vibration in neonatal transport: a randomized study of different mattresses.

OBJECTIVE: To test the hypothesis that a gel mattress is most effective in attenuating mechanical vibration in neonatal transport, we performed a randomized block study of four mattress combinations (none, foam, gel, gel on foam) using mannequins and an ambulance traveling on fixed routes (city, highway). STUDY DESIGN: Mechanical vibration was assessed by measuring vertical accelerations at two locations: the forehead of a 2000-gm mannequin and the transport incubator base. From time histories of these accelerations, root mean square (RMS) values and power spectral density functions were calculated. The effect of the mattress on the transmission of vibration was determined from ratios of the RMS values at the two locations. An RMS ratio of < 1.0 indicates attenuation, whereas a ratio of > 1.0 indicates accentuation of vibration. From the power spectral density functions, the natural frequency of the system was determined for each mattress combination in relation to the natural frequencies of the ambulance. To determine the effect of the weight of the mannequin on vibration, additional measurements were performed using a 300-gm mannequin. RESULTS: All the observed RMS ratios were > 1. The highest ratios were observed on the city route in the absence of the gel mattress. The gel mattress, used alone or with the foam mattress, in contrast to foam or no mattress, shifted the natural frequency of the system away from the natural frequencies of the ambulance, avoiding a large amplification of vibration. A decrease in the weight of the mannequin caused the gel mattress to be less effective in attenuating vibration. CONCLUSION: A gel mattress, used alone or with a foam mattress, results in the least accentuation of vibration, but vibration in ambulance transport is not attenuated by any of the mattress combinations. The hazard of vibration may be particularly relevant when transporting extremely low birth weight neonates. These findings indicate a need for study and design of more effective devices that can reduce the vibratory stress.

Acceleration↗
PubMedDate not supplied

Local cyclosporine immunotherapy of heart transplants in rats enhances survival.

High-dose systemic cyclosporine (CyA) administration frequently results in severe side effects. To evaluate a means of limiting the adverse effects of CyA, we implanted CyA-collagen matrices (0.2 or 1 mg/kg/day released) around the cardiac homografts at the time of rat heterotopic (neck) heart transplantation. Control animals received empty collagen (nondrug) matrix implants. A fourth group received CyA matrix (1 mg/kg/day released), implanted in a distal subdermal leg pouch at the time of heart transplantation. Rejection was determined by the absence of contraction in the transplanted heart. No animal received any other immunosuppression. Parallel groups of animals had whole blood, heart, and kidney CyA levels measured on the sixth posttransplant day. Local immunosuppression with high-dose CyA in a controlled-release matrix resulted in a significant survival advantage (mean survival time, 17.1 days; control, 6.9 days; p less than 0.001). The lower dose of CyA also demonstrated significant survival benefits (10.1 days), with clinically negligible blood CyA levels and very low kidney CyA levels. Both doses of epicardial local release CyA were well absorbed locally, resulting in very high CyA levels in cardiac tissue. Local immunotherapy of transplanted hearts with CyA was shown to be an effective means of preventing rejection. If this technology can be developed, this approach may prove advantageous clinically, both in extending transplantation and in minimizing systemic side effects of immunosuppression.

Animals↗
PubMedDate not supplied

Local controlled release of 1-hydroxyethylidene diphosphonate using silicone-rubber matrices. Effects of sterilization on in vitro release and in vivo efficacy.

Calcification (CALC) is the most frequent cause of the clinical failure of bioprosthetic heart valves (BHVs). Controlled release of disodium ethanehydroxydiphosphonate (EHDP) has been demonstrated to inhibit subdermal BHV calcification at effective low local doses, avoiding adverse effects. However, the eventual circulatory use of controlled release EHDP necessitates addressing several critical issues that may affect efficacy. These include the effects of sterilization on EHDP release and the efficacy of sustained release matrices containing CaEHDP, which is less soluble than NaEHDP. The effects of CaEHDP-NaEHDP incorporation and steam sterilization on controlled release of EHDP from silicone-rubber matrices was studied both in vitro and in vivo using a rat subdermal model and sheep tricuspid valve replacements. Autoclaved EHDP matrices (20% wt/wt) released 88.9% +/- 7.84 of contained drug after 140 days in vitro, compared with control (87.6% +/- 10.3 cumulative release). Autoclaved EHDP matrices completely inhibited BHV CALC in 60 day rat subdermal implants (8.84 +/- 3.68 micrograms Ca++/mg tissue), comparable to nonsterilized EHDP-loaded matrices (7.06 +/- 2.00 micrograms Ca++/mg tissue). Nontreated CALC levels were 183 +/- 7.60 micrograms Ca++/mg tissue. Na-CaEHDP co-incorporation into silicone rubber matrices markedly prolonged controlled release with the 1:1 Na-CaEHDP mixture demonstrating an extrapolated release duration of approximately 20 years, assuming the total amount of dispersed drug was released. Data from tricuspid valve replacements in sheep demonstrate erratic control calcification (41.3 +/- 14.9 micrograms Ca++/mg tissue), but complete suppression of BHV calcification with Na2EHDP controlled release (5.74 +/- 1.35 micrograms Ca++/mg tissue) after 150 days.

Animals↗