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Biomedical subjects

E F Ellis

Publications and source records attributed to E F Ellis.

At least 109 records · Page 6Linked to original sources
PubMed1982

Steroid-specific and anticonvulsant interaction aspects of troleandomycin-steroid therapy.

Troleandomycin (TAO) is a macrolide antibiotic that has an apparent "steroid-sparing" effect when used in the treatment of severe steroid-dependent asthmatic patients. Recent observations demonstrated the effect of TAO on inhibiting methylprednisolone elimination, possibly contributing to its beneficial effects. Prednisolone and methylprednisolone disposition were studied before and 1 wk after initiation of TAO therapy in three patients. Methylprednisolone elimination was characteristically impaired in the presence of TAO therapy; however, there was no apparent effect on prednisolone elimination. Methylprednisolone elimination was also evaluated before and after initiation of TAO therapy in three patients receiving concomitant anticonvulsant therapy with phenobarbital-1, phenytoin-2. Methylprednisolone clearance before TAO was at least 4 times faster than normal and was probably related to enzyme induction by the anticonvulsant medication. Methylprednisolone clearance was subsequently reduced by approximately 70% in the presence of TAO therapy. The effect of TAO on corticosteroid disposition is steroid-specific and TAO can diminish the effect of certain drugs on the induction of corticosteroid metabolism.

Asthma↗
PubMed1982

Dose- and time-related effect of troleandomycin on methylprednisolone elimination.

Effects of varying doses of troleandomycin (TAO) on methylprednisolone disposition were examined in five steroid-dependent asthmatic patients. The characteristic reduction in methylprednisolone elimination in the presence of TAO after a 40 mg IV methylprednisolone was also present after methylprednisolone doses as low as 4 mg. In patients receiving continuous TAO on an every-other-day basis, inhibition of methylprednisolone elimination was impaired to a greater extent on the "day on" TAO than on the "day off" TAO Methylprednisolone elimination on the day off TAO was still slower than that before TAO, however, TAO on a multiple-dose schedule resulted in greater reduction of methylprednisolone elimination than after a single TAO dose. These results suggest that TAO induces immediate and continued inhibition of methylprednisolone disposition.

Asthma↗
PubMed1982

The effect of tranylcypromine on levels of 6-keto-PGF1 alpha and other prostaglandins in brain and mesentery of the mouse.

Tranylcypromine (TCP), which can inhibit prostacyclin (PGI2) synthesis in vitro, has been shown to facilitate platelet aggregation in damaged cerebral arterioles of the mouse when given intraperitoneally (50 mg/kg) one hour before inducing aggregation. The same dose has no effect on platelet aggregation in damaged mesenteric arterioles. The present experiments used HPLC and GC/MS to analyze PG levels and show that 5 or 50 mg/kg TCP, given intraperitoneally one hour before sacrificing the mouse, moderately reduces the level of 6-keto-PGF1 alpha, the stable metabolite of PGI2, in incubated brain homogenates. This finding supports the hypothesis that TCP's enhancement of platelet aggregation in the brain was affected by a reduction in PGI2 levels. When 500 micrograms/ml TCP was added to the incubate of brain homogenate from mice given 50 mg/kg, PGE2 levels were reduced as well as the levels of 6-keto-PGF1 alpha. In incubated mesentery, the level of 6-keto-PGF1 alpha was also reduced by treating mice with 50 mg/kg TCP. The latter result failed to support the hypothesis that levels of mesenteric 6-keto-PGF1 alpha would be unaltered by TCP in parallel with the inability of TCP to alter platelet aggregation in mesenteric arterioles. Thus our data fails to support an overall hypothesis relating TCP action on platelet aggregation to its inhibitory effect on PGI2 synthesis. At the same time the data do not rule out such a relationship for mouse brain.

Animals↗
PubMed1981

Prostaglandin levels in isolated brain microvessels and in normal and norepinephrine-stimulated cat brain homogenates.

The levels of PGD2, PGE2, PGF2 alpha and 6-keto-PGF1 alpha (6KF1 alpha) produced from endogenous arachidonic acid (AA) were quantitated in cat cerebral cortical homogenates and microvessels isolated from cat cerebral cortex using gas chromatography/mass spectrometry (GC/MS). There was a six-fold enrichment of 6KF1 alpha levels in isolated microvessels, compared to homogenates, suggesting that 6KF1 alpha is of vascular, rather than neuronal origin. In order to further understand any possible role that norepinephrine (NE) might have on modulation of PG synthesis, we studied the effects of 0.5 mM NE on PG synthesis from endogenous AA and from 3H-PGG2, the endoperoxide precursor of PGs. In cat cortical homogenates NE induced a 74% increase in PGD2 and PGF2 alpha, a 62% increase in PGE2, and a 36% increase in 6KF1 alpha, as measured by GC/MS. NE caused a twofold increase in the conversion of 3H-PGG2 to 3H-PGF2 alpha, with a concomitant decrease in 3H-PGE2 and 3H-6KF1 alpha formation, and no change in 3H-PGD2 synthesis. NE had no effect on the total conversion of 3H-PGG2 to 3H-PGs, nor on the breakdown of 3H-PGG2 in the absence of brain tissue. We conclude that NE stimulates extravascular synthesis of PGD2, PGE2 and PGF2 alpha by stimulation of the prostaglandin synthetase complex, in addition to NE's stimulatory effect on the conversion of PGG2 to PGF2 alpha, and that the lack of effect on NE on 6KF1 alpha synthesis reflects either a failure to achieve an adequate concentration at the vascular tissue, or an absence of the mechanism whereby NE stimulates PG synthetase.

Animals↗
PubMed1981

Prednisolone disposition in steroid-dependent asthmatic children.

The pharmacokinetics of a 40-mg intravenous dose of prednisolone were determined in 10 steroid-dependent asthmatic children with highly variable prednisone requirements (5 mg every other day to 40 mg a day). Concentrations of prednisolone and cortisol in plasma over a 24-hr test period were measured by high-performance liquid chromatography. Eosinophil concentrations and the concentration-dependent protein binding of prednisolone were also determined. The mean (+/-SD) apparent half-life of prednisolone in these children was 2.5 +/- 0.5 hr. The mean total volume of distribution was 52.8 +/- 14.5 L/1.73 m2 and mean plasma clearance was 246 +/- 62 ml/min/1.73 m2. These pharmacokinetic parameters, as well as the protein binding and eosinopenic response, were similar to values from healthy and steroid-dependent asthmatic adults. The data were also similar in both responsive and relatively resistant patients. The pharmacokinetics and protein binding of prednisolone are not responsible for the highly variable prednisone requirement and clinical response of these children to prednisone therapy.

Aging↗
PubMed1981

GC/MS analysis of prostaglandins in ventricular cerebrospinal fluid from head injured humans.

The purpose of this study was to determine the levels of prostaglandins in ventricular cerebrospinal fluid (CSF) from severely head injured humans on successive days following injury. Sixteen samples from three patients were purified using XAD-2 and high pressure liquid chromatography and PGE2, PGF2alpha, and 6-keto-PGF1alpha were quantitated utilizing deuterated internal standards and gas chromatography-mass spectrometry. Generally, the levels of PGs in ventricular CSF were found to be higher than has previously been reported for PGs in CSF from spinal taps. PG levels ranged from reported for PGs in CSF from spinal taps. PG levels ranged from nondetectable to 11.8, 3.3 and 27.3 ng per ml for PGE2, PGF2alpha, and 6-keto-PGF2alpha, respectively. However, in one sample, PG levels were much higher than this range and approached the levels found in human cortical tissue. Analysis of red and white blood cell numbers in the CSF showed no relationship between cell numbers and prostaglandin levels. This study confirms a previous report that 6-keto-PGF2alpha is the major prostaglandin in CSF and demonstrates that PG levels in ventricular CSF from head traumatized humans can be greatly elevated.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Cyclooxygenase products of arachidonic acid metabolism in cat cerebral cortex after experimental concussive brain injury.

Previous studies have suggested that following experimental fluid percussion brain injury, increased prostaglandin (PG) synthesis, with its concomitant production of oxygen free radicals, causes functional and morphological abnormalities of the cerebral arterioles. The purpose of this study was to chemically determine if PGs are altered following this injury. To facilitate interpretation of neurochemical measurements the cats were ventilated, blood pressure was measured, and a cranial window, for microscopic observation of pial arteriolar diameter was inserted. PG levels were determined in quick-frozen cortical tissue removed from control and 3 groups of injured cats at 1.5, 8,0, and 60 min after injury. Analysis of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha was performed by HPLC and GC/MS. The control levels of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha were 216 +/- 44, 210 +/- 48, and 48 +/- 12 ng/g wet weight, respectively. Following injury, produced by a 22 ms increase in intracranial pressure, the pial arterioles dilated irreversibly and a transient hypertensive response occurred, thereby producing hyperemia. During the maximum hyperemic response, the total PGs were 75% of control. At 8 min after injury, when blood pressure returned to control level, the PGs were 158% of control and PGs fell to 111% of control at 60 min. These experiments supported our previous studies implicating increased PG synthesis in te genesis of the physiologic and morphologic sequelae of experimental concussive brain injury.

Animals↗
PubMed1981

Mechanism of cerebral arteriolar abnormalities after acute hypertension.

Acute severe hypertension induced by intravenous norepinephrine or angiotensin in anesthetized cats equipped with a cranial window caused prolonged arteriolar vasodilation associated with reduced responsiveness to arterial hypercapnia or hypocapnia and passive response to changes in arterial blood pressure. Scanning and transmission electron microscopy of such pial arterioles showed discrete destructive endothelial lesions the density of which correlated with the degree of vasodilation. Abnormalities of the vascular smooth muscle were seen in all dilated arterioles but affected only a small number of smooth muscle cells. The oxygen consumption of pial arterioles from cats subjected to hypertension was significantly reduced in comparison to that of vessels from normal animals. The arteriolar abnormalities induced by hypertension were inhibited by pretreatment with inhibitors of cyclooxygenase (indomethacin or AHR-5850) or by topical application on the brain surface of scavengers of free oxygen radicals (mannitol or superoxide dismutase). The results suggest that the mechanism of the arteriolar abnormalities from acute hypertension involves a sudden increase in prostaglandin synthesis that leads to generation of free oxygen radicals.

Animals↗
PubMed1981

Inhibition by free radical scavengers and by cyclooxygenase inhibitors of pial arteriolar abnormalities from concussive brain injury in cats.

We studied the role of prostaglandins and free radicals in the induction of the functional and morphological pial arteriolar abnormalities produced by concussive brain injury. Anesthetized cats equipped with a cranial window for the observation of the pial microcirculation were subjected to concussive brain injury using a fluid-percussion device following administration of cyclooxygenase inhibitors (indomethacin or AHR-5850) or the vehicle for the solution of these agents (NaCl or Na2CO3 solution). Pial arterioles from vehicle-treated animals displayed sustained dilation, reduced responsiveness to the vasoconstrictor effect of arterial hypocapnia, and a high density of endothelial lesions. Animals pretreated with cyclooxygenase inhibitors showed less pronounced vasodilation, normal responsiveness to hypocapnia, and a significantly reduced number of lesions. The vasodilation and reduced responsiveness to the vasoconstrictor effects of hypocapnia after brain injury also were inhibited by topical application of free radical scavengers (nitroblue tetrazolium, superoxide dismutase, or mannitol). The vessels from cats pretreated with free radical scavengers also had a lower density of endothelial lesions than controls. The results support the view that the immediate cause of cerebral arteriolar damage in concussive brain injury is the generation of free oxygen radicals associated with increased prostaglandin synthesis.

Animals↗
PubMed1981

Beta-adrenergic receptors of human polymorphonuclear leukocytes.

125I-iodohydroxybenzylpindolol (IHYP) is a beta-adrenergic antagonist used as a ligand for the characterization of beta-adrenergic receptors in various cell preparations. Since IHYP may be adsorbed to surfaces such as test tubes and pipet tips, it is necessary to measure the actual free concentration of IHYP in the incubation solution. With this modification, the number of beta-adrenergic receptors in human peripheral PMNs can be determined with greater precision.

Humans↗
PubMed1981

Prostaglandins in physiological and in certain pathological responses of the cerebral circulation.

The most abundant prostaglandin produced by brain tissue varies from species to species. The most abundant prostaglandin produced by brain microvessels is PGI2, PGG2, PGH2, PGI2, PGE2, PGD2, and arachidonic acid dilated cerebral arterioles. Cyclooxygenase inhibitors (indomethacin, AHR-5850), in doses that reduced prostaglandin synthesis substantially, did not affect resting vascular caliber and did not influence the responses of cerebral arterioles to arterial hypoxia, arterial hypercapnia, or arterial hypocapnia, suggesting that prostaglandins are not involved in the mediation of these responses. The vasodilator action of vasoactive intestinal peptide on cerebral arterioles was blocked by these cyclooxygenase inhibitors. The cerebral arteriolar damage induced by fluid-percussion brain injury was inhibited by pretreatment with cyclooxygenase inhibitors, or with free radical scavengers. Topical application of arachidonic acid or PGG2, reproduced the damage seen with brain injury. These findings show that prostaglandins are mediators of the cerebral arteriolar damage due to brain injury and that their mechanism of action is dependent on the generation of free oxygen radicals.

Animals↗
PubMed1980

Cerebral arteriolar damage by arachidonic acid and prostaglandin G2.

Application of arachidonic acid or prostaglandin G(2) to the brain surface of anesthetized cats induced cerebral arteriolar damage. Scavengers of free oxygen radicals inhibited this damage. Prostaglandin H(2), prostaglandin E(2), and 11,14,17-eicosatrienoic acid did not produce arteriolar damage. It appears that increased prostaglandin synthesis produces cerebral vascular damage by generating free oxygen radicals.

Animals↗
PubMed1980

The effect of troleandomycin on methylprednisolone elimination.

Troleandomoycin (TAO), a macrolide antibiotic, has an apparent "steroid-sparing" effect when used in the treatment of severe steroid-dependent asthma. This study was designed to investigate the effect of TAO on methylprednisolone elimination. Pharmacokinetic studies were performed before and 1 wk after starting TAO in 10 severe steroid-dependent asthmatics. Baseline total body clearance of methylprednisolone was 406 +/- 139 (mean +/- SD) ml/min/1.73 m2 and decreased significantly (p < 0.001) to 146 +/- 57 ml/min/1.73 m2 1 wk after TAO therapy was initiated. Methylprednisolone half-life was 2.46 +/- 0.75 hr before TAO and increased significantly (p < 0.01) to 4.63 +/- 1.35 hr after 1 wk on TAO therapy. A follow-up evaluation of methylprednisolone pharmacokinetics in three patients after at least 1 mo on TAO therapy demonstrated continuation of the reduced methylprednisolone elimination. TAO inhibition of methylprednisolone clearance may contribute to the beneficial effects observed initially with combined methylprednisolone-troleandomycin therapy in severe steroid-dependent asthma.

Adolescent↗
PubMed1980

Role of prostaglandins in pial arteriolar response to CO2 and hypoxia.

The effect of inhibition of prostaglandin synthesis on the pial arteriolar responses to arterial hypercapnia, hypocapnia, and hypoxia was studied in anesthetized cats equipped with a cranial window for the observation of the pial microcirculation of the parietal cortex. Inhibition of prostaglandin synthesis was achieved by intravenous administration of indomethacin (3 mg/kg) or AHR-5850 (2-amino-3-benzoylbenzeneacetic acid, 50 mg/kg). It was shown that the administration of these agents inhibited substantially the vasodilation in response to topical application of arachidonic acid (100--200 micrograms/ml). Inhibition of prostaglandin synthesis did not modify significantly the vasodilator responses to arterial hypercapnia or arterial hypoxia, nor the vasoconstrictor response to arterial hypocapnia. We conclude that endogenous prostaglandins are not mediators of these vascular responses in the pial microcirculation.

Animals↗
PubMed1980

Aspirin and indomethacin enhance platelet aggregation in mouse mesenteric arterioles.

The cyclooxygenase inhibitors aspirin and indomethacin enhanced platelet aggregation in mesenteric vessels, suggesting that the normal mesentery produces an antiaggregatory prostaglandin. Testing of mesentery incubate in mouse platelet-rich plasma disclosed an antiaggregatory material with the properties of prostacyclin. Chromatography showed that mesentery made several radiolabeled products from [3H]arachidonic acid, including one that cochromatographed with 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), the stable hydrolysis product of prostacyclin. Gas chromatography-mass spectrometric analysis of mesentery incubate showed the presence of 6-keto-PGF1 alpha, synthesized from the mesentery's endogenous arachidonic acid. The enhancement of platelet aggregation in mesenteric vessels contrasts with earlier data showing that in similarly injured mouse cerebral vessels aggregation was retarded by both aspirin and indomethacin. This divergent effect of cyclooxygenase inhibitors in different vascular beds may depend on the relative importance of prostacyclin in the different beds or on the capacity of cyclooxygenase inhibitors to influence this prostacyclin production in different beds. Caution is urged before acceptance of a central role for PGI2, however, because of the capability of microvasculatures and adjacent tissue to synthesize a number of other products whose interaction with platelets and with aspirin and indomethacin remains to be elucidated.

Animals↗