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Biomedical subjects

D J Edwards

Publications and source records attributed to D J Edwards.

At least 37 records · Page 2Linked to original sources
PubMed1998

Choice of anaesthetic and healthcare facility for third molar surgery.

A prospective investigation was carried out to find out which factors affected the choice of anaesthetic for 444 consecutive patients (153 male, 291 female, age range 15-85) listed for extraction of third molars. Two hundred and seventy-two were listed for treatment under general anaesthesia, 120 (44%) as inpatients and 152 (60%) as day cases. The remaining 144 (32%) patients were to be treated under local anaesthesia and 28 (6%) with additional intravenous sedation. Logistic regression analysis showed that difficulty of surgery, patients' anxiety, patients' preferences, medical history, and number of teeth to be removed were important predictors of choice of anaesthetic. From an anaesthetist's perspective, many more patients should have been treated under local anaesthesia with intravenous sedation and fewer should have been listed for inpatient extraction under general anaesthesia.

Adolescent↗
PubMed1998

The effects of lithium on a potential cycling model of bipolar disorder.

1. Although bipolar disorder constitutes a major public health problem, with a high risk of suicide and an economic cost exceeding that of unipolar depression, it has received comparatively little attention, particularly at the basic science level. Perhaps as a result of this neglect, there is currently no animal model able to simulate the cyclicity which is its defining characteristic. 2. Consequently, drug development in this area is meager and has proceeded serendipitously rather than empirically. 3. The authors have recently reported that repeated exposure to cocaine and other stressors can induce an oscillation or cycling in a host of neurochemical and physiological systems. 4. In order to test whether such cycling might be of potential relevance to bipolar disorder, the authors examined whether cocaine-induced cyclicity of amphetamine-evoked efflux of dopamine from slices of rat nucleus accumbens and striatum and/or cocaine induced oscillation of a behavior, stress-induced hypoalgesia, could be prevented by lithium, the agent of choice in treating this disease. 5. The authors report that prophylactic treatment with lithium, completely and specifically prevented oscillations in each instance. This may represent an important initial step toward the development of the first cycling model of bipolar disorder.

Amphetamine↗
PubMed1998

Oscillatory-sensitization model of repeated drug exposure: cocaine's effects on shock-induced hypoalgesia.

1. The authors have recently proposed that the sensitization produced by repeated exposure to drugs or stress may give way to an alternating pattern of increases and decreases in the response to each subsequent exposure (i.e., oscillate), as the limits of the physiological system are approached. 2. Evidence for oscillation has been obtained for 6 drug/non-drug stressors and 9 neurochemical or endocrine endpoints. This paper extends the model to a behavioral outcome. 3. In the first experiment, rats were given 0, 1, 2 or 3 pretreatments with cocaine hydrochloride (COC; 12 mg/kg i.p.), separated by 1-week intervals, and then were tested for footshock-induced hypoalgesia (5-sec, 2-mA), as measured by withdrawal latencies from a hot-plate. 4. The second experiment replicated the first and extended the pretreatment sequence to 5 COC injections. 5. In both experiments, shock significantly increased latencies over the no-shock controls. COC enhanced shock-induced hypoalgesia and this sensitization reached its maximum after 2 COC pretreatments. Thereafter, oscillation developed such that the sensitization was attenuated by 3 as compared to 2 COC injections, enhanced by 4 injections, and reattenuated after 5 COC pretreatments. 6. These data complement other findings by demonstrating that the oscillation model extends to a stress-induced behavioral outcome.

Animals↗
PubMed1997

Adrenal epinephrine and norepinephrine release to hypoglycemia measured by microdialysis in conscious rats.

Experiments were conducted in conscious male rats to determine whether hypoglycemia induced by insulin administration preferentially stimulated epinephrine (Epi) or norepinephrine (NE) adrenal medullary chromaffin cells. The release of Epi and NE from the adrenal medulla was continuously monitored using a microdialysis probe of novel design that had been inserted in the adrenal medulla approximately 16 h before the administration of insulin. Following insulin, 3 U/kg i.v., blood glucose declined and dialysate Epi levels rose. No measurable increment in dialysate NE was obtained. Similarly, plasma Epi increased with no detectable change in NE. Patterns of dialysate and plasma catecholamine changes were similar in two groups of animals that had been fed or fasted overnight before insulin treatment. However, the magnitude of the Epi increase was greater in the fasted animals. After recovery of the blood glucose concentration to preinsulin levels, dialysate and plasma catecholamine concentrations returned to control values. These experiments clearly demonstrate that adrenal medullary chromaffin cells that produce Epi are preferentially stimulated in response to insulin-induced hypoglycemia.

Adrenal Medulla↗
PubMed1997

A model of insulin fibrils derived from the x-ray crystal structure of a monomeric insulin (despentapeptide insulin).

The crystal structure of despentapeptide insulin, a monomeric insulin, has been refined at 1.3 A spacing and subsequently used to predict and model the organization in the insulin fibril. The model makes use of the contacts in the densely packed despentapeptide insulin crystal, and takes into account other experimental evidence, including binding studies with Congo red. The dimensions of this model fibril correspond well with those measured experimentally, and the monomer-monomer contacts within the fibril are in accordance with the known physical chemistry of insulin fibrils. Using this model, it may be possible to predict mutations in insulin that might alleviate problems associated with fibril formation during insulin therapy.

Computer Simulation↗
PubMed1997

Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins.

Grapefruit juice increases the oral availability of a variety of CYP3A4 substrates. It has been shown that recurrent grapefruit juice ingestion results in a loss of CYP3A4 from the small bowel epithelium. We now show that the reduction in intestinal CYP3A4 concentration is rapid; a 47% decrease occurred in a healthy volunteer within 4 hr after consuming grapefruit juice. To identify the specific components of the juice responsible for this effect, we used a recently developed Caco-2 cell culture model of human intestinal epithelium that expresses catalytically active CYP3A4. We found that grapefruit oil and two furanocoumarin constituents (6', 7'-dihydroxybergamottin and a closely related dimer) caused a dose-dependent fall in CYP3A4 catalytic activity and immunoreactive CYP3A4 concentration. The effect was selective in that concentrations of CYP1A1 and CYP2D6 did not fall, consistent with previous results obtained in vivo. Assays of various juices confirmed that 6',7'-dihydroxybergamottin is the major furanocoumarin present and, although its concentration varies significantly among types and brands of grapefruit juice, it is consistently present in concentrations exceeding the IC50 (1 microM) for loss of midazolam 1'-hydroxylase activity determined in the Caco-2 cells. Studies with recombinant CYP3A4 revealed that 6', 7'-dihydroxybergamottin is a mechanism-based inactivator, which supports the idea that loss of CYP3A4 results from accelerated degradation of the enzyme. We conclude that the effect of grapefruit juice on oral availability of CYP3A4 substrates can be largely accounted for by the presence of 6',7'-dihydroxybergamottin although other furanocoumarins probably also contribute.

Biological Availability↗
PubMed1996

Pharmacokinetics of ceftriaxone in patients undergoing continuous veno-venous hemofiltration.

Continuous hemofiltration is used widely in the management of patients with acute renal failure, but administration guidelines for many drugs have yet to be established. In this study, the pharmacokinetics of ceftriaxone were compared in patients with normal renal function (n = 9), mild renal insufficiency (n = 5), and acute renal failure receiving continuous veno-venous hemofiltration (n = 6). Pharmacokinetic parameters were determined under steady state conditions. Patients with mild renal insufficiency had a significantly lower renal clearance and longer half-life of ceftriaxone; however, drug recovery in the ultrafiltrate with continuous veno-venous hemofiltration was similar to that in the urine of patients with normal renal function. Pharmacokinetic parameters for renal, nonrenal, and systemic clearance and for volume of distribution and half-life were also similar between patients receiving continuous veno-venous hemofiltration and those with normal renal function. The sieving coefficient (S) of ceftriaxone (0.69) significantly exceeded the expected free fraction in plasma, confirming previous reports that protein binding does not limit the sieving of this compound. The results suggest that a reduction in the usual daily dose of ceftriaxone is not required in patients with acute renal failure receiving continuous veno-venous hemofiltration.

Acute Kidney Injury↗
PubMed1996

Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice.

The effect of various citrus juices and solutions of naringin on CYP3A activity in rat liver microsomes was compared by measuring the formation of 6 beta-hydroxytestosterone from testosterone. Control enzyme activity was reduced by more than 70% by grapefruit juice. Freshly-squeezed sour (Seville) orange juice containing 20% as much naringin was comparable to grapefruit juice in its ability to inhibit microsomal activity. An aqueous solution of naringin at the same concentration as in grapefruit juice produced only a small decrease in 6 beta-hydroxytestosterone formation. Dilution of grapefruit juice with a naringin solution reduced the inhibitory activity of the juice even though naringin concentration did not change. Naringenin did not form under the incubation conditions used indicating that it did not contribute to the inhibition produced by grapefruit juice. Finally, organic extracts of grapefruit juice possessed considerable inhibitory activity even though naringin was not extractable. These data suggest that grapefruit juice inhibits CYP3A activity in vitro and that neither naringin nor naringenin are primarily responsible for this effect. A compound present in both grapefruit juice and Seville orange juice and extractable into organic solvents appears to be responsible.

Animals↗
PubMed1996

The effects of ethanol on striatal dopamine and frontal cortical D-[3H]aspartate efflux oscillate with repeated treatment. Relevance to individual differences in drug responsiveness.

Numerous inconsistencies in the reported effects of drugs that can be found in both the human clinical and animal experimental literatures have prompted attempts to identify the basis of this variability. Our data suggest that one source may derive from the tendency of many systems to oscillate in their response to repeated drug or stress exposure. In the first experiment a single administration of ethanol to male rats, either 2 or 30 minutes or 2 weeks before sacrifice suppressed amphetamine-induced dopamine efflux from striatal slices. However, when ethanol was given both 2 weeks and 30 minutes before sacrifice, the two treatments significantly attenuate each other's effects. In Experiment 2, the stress of a novel environment (black box) 30 minutes before sacrifice decreased fractional D-[3H]aspartate efflux from the medial frontal cortex. When a single injection of ethanol 1 week earlier was added to black box exposure, it depressed efflux still further. However, adding a third treatment (ethanol at 2 weeks and 1 week + black box at 30 minutes) significantly reversed the effects of the two treatments (ethanol + black box). When a four-treatment chain was used (ethanol at 3, 2, and 1 week + black box at 30 minutes), the attenuation of efflux was reinstated. These data complement other findings from this laboratory showing that repeated stress or drug exposure can lead to an oscillatory pattern of change in the effects of future exposures and, in this way, contribute to variability in drug responsiveness.

Amphetamine↗
PubMed1996

Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice.

Grapefruit juice inhibits the metabolism of substrates for enzymes of the CYP3A subfamily. However, the identity of the inhibitor has not been established. Grapefruit juice was extracted into methylene chloride and chromatographed by HPLC, and the effect of the HPLC eluent on CYP3A activity was assessed by measuring 6beta-hydroxytestosterone formation in rat liver microsomes. Significant inhibition was associated with a fraction of HPLC eluent containing a single peak, with a retention time of 16 min. The substance producing this peak was isolated using TLC and identified, using NMR and MS, as 6',7'-dihydroxybergamottin (C21H2406; molecular weight, 372), a furanocoumarin (psoralen) compound. The concentration of 6',7'-dihydroxybergamottin required to inhibit 6beta-hydroxytestosterone formation by 50% was 25 microM. Grapefruit juice reduced CYP3A activity to a significantly greater extent (p < 0.05) than did orange juice, which contained no measurable 6',7'-dihydroxybergamottin (28.6% vs. 62.2% of control activity). The addition of 6',7'-dihydroxybergamottin (30 microM) to orange juice decreased CYP3A activity to values comparable to those observed with grapefruit juice. 6',7'-Dihydroxybergamottin is a potent inhibitor of CYP3A activity, accounts for the difference in inhibition between grapefruit juice and orange juice in vitro, and may be primarily responsible for the effects of grapefruit juice on cytochrome P450 activity in humans.

Animals↗
PubMed1995

Itraconazole and hydroxyitraconazole serum concentrations are reduced more than tenfold by phenytoin.

OBJECTIVE: To study the disposition of single doses of phenytoin and itraconazole when administered alone and after chronic treatment with the other drug. METHODS: Healthy male volunteers were randomized to two groups and studied in parallel. In group 1, a single 200 mg oral dose of itraconazole was administered on two occasions (alone and after 15 days of 300 mg oral phenytoin once daily). Subjects in group 2 were given a single 300 mg oral dose of phenytoin before and after 15 days of itraconazole (200 mg once daily). Blood was collected for 96 hours after each single dose of phenytoin or itraconazole. Serum was assayed for itraconazole and hydroxyitraconazole concentration by HPLC and for phenytoin concentration by fluorescence polarization immunoassay. RESULTS: Phenytoin decreased the area under the concentration-time curve (AUC) of itraconazole by more than 90%, from 3203 to 224 ng.hr/ml, accompanied by a decrease in half-life from 22.3 to 3.8 hours. Similar changes were observed for hydroxyitraconazole AUC (decreased from 6224 to 315 ng.hr/ml) and half-life (11.3 versus 2.9 hours). Itraconazole increased the AUC of phenytoin (10.3%; p < 0.05), with no change in any other pharmacokinetic parameter. CONCLUSIONS: The striking decrease in itraconazole concentrations with phenytoin is due to induction of metabolism combined with a reduction in the degree of saturable metabolism normally exhibited by itraconazole at this dose. The magnitude of interaction likely accounts for reports of therapeutic failures in patients with fungal infections who are receiving both itraconazole and phenytoin.

Adult↗
PubMed1995

Disposition of intravenous and oral cyclosporine after administration with grapefruit juice.

OBJECTIVE: To examine the effect of grapefruit juice on the disposition of cyclosporine after administration of oral and intravenous doses to healthy male subjects. METHODS: Subjects received two oral doses of cyclosporine (7.5 mg/kg) and two intravenous doses (2.5 mg/kg infused for 3 hours), with each dose separated by a 1-week washout period. Grapefruit juice (250 ml) was ingested immediately before one oral and one intravenous dose and again 2 hours later. Blood samples were collected for a 24-hour period, and whole blood concentrations of cyclosporine were measured with use of a specific monoclonal radioimmunoassay. RESULTS: Grapefruit juice had no effect on any pharmacokinetic parameter when given with intravenous cyclosporine. After oral administration, grapefruit juice significantly increased peak concentration (936 versus 1340 ng/ml), as well as area under the curve (6722 versus 10,730 ng . hr/ml) but had no effect on elimination half-life. Absolute bioavailability of cyclosporine was increased from 0.22 to 0.36 (average increase, 62%) by grapefruit juice. CONCLUSIONS: The lack of effect on systemic clearance after intravenous cyclosporine suggests that grapefruit juice improves oral bioavailability by increasing absorption or reducing gut wall metabolism. The latter is more likely in view of studies that suggest significant gut wall metabolism of cyclosporine by CYP3A enzymes known to be inhibited by components of grapefruit juice.

Administration, Oral↗
PubMed1995

Neurochemical and physiological effects of cocaine oscillate with sequential drug treatment: possibly a major factor in drug variability.

Variability in response to drug treatment is a poorly understood problem with severe consequences for both the individual and the health care delivery system. Our data suggest that one source of variability may be inherent in the way physiological systems normally respond to repeated drug exposures. We report that for a wide array of endpoints-amphetamine-evoked, in vitro striatal dopamine efflux, amphetamine and K(+)-evoked efflux of heart norepinephrine and nonevoked plasma levels of corticosterone and glucose-repeated, in vivo cocaine (15 mg/kg IP) administration to male rats precipitated successive oscillations in the magnitude or direction of the organism's responsiveness to subsequent cocaine administration. This capacity of cocaine to produce oscillations in response to successive administrations appears to be due to its foreign/stressful aspect rather than its specific pharmacological properties.

Amphetamine↗
PubMed1995

Recent advances: the cytochrome P450 enzymes.

Successful application of information on cytochrome P450 to prevent drug interactions and improve the therapeutic risk: benefit ratio can occur only if we know which enzyme is responsible for the metabolism of a drug. Until recently, this information was not usually available when new drugs reached the market. It is not enough to know the fraction of a dose metabolized versus excreted unchanged or the metabolic pathways by which a compound is degraded. Studies conducted during drug development must identify the enzyme or enzymes involved in the metabolism of new drugs. In addition, the ability of new drugs to inhibit or induce the activity of the key P450 enzymes must be known if we are to take full advantage of our current knowledge of how the cytochrome P450 system works.

Aryl Hydrocarbon Hydroxylases↗
PubMed1995

The role of the adrenal medulla in neural control of blood pressure in rats.

The role of the adrenal medulla in the regulation of blood pressure was assessed in rats. In conscious intact (SHAM) and adrenal demedullated (DEMED) animals, baseline blood pressures and heart rates were not different. Moreover, equivalent pressor and depressor response curves to norepinephrine and sodium nitroprusside were obtained. Plasma concentration and 24 hr urinary excretion of norepinephrine were not altered by demedullation. However, epinephrine was undetectable in the urine of the DEMED rats. The effectiveness of the demedullation was further evidenced by a greater than 99% decrease in the epinephrine and norepinephrine content of the adrenal glands of DEMED animals. In pithed SHAM rats, electrical stimulation of preganglionic sympathetic neurons (.5 to 16 hz) elicited marked increases in plasma epinephrine indicating adrenal stimulation, whereas in DEMED rats there were no increases. Furthermore, increments in plasma norepinephrine were significantly reduced in DEMED rats, yet the blood pressure increases were greater than in SHAM rats. Thus, adrenal catecholamine release did not contribute to the blood pressure responses, but in fact, may have had an opposite action due to the vasodilatory actions of epinephrine. The results demonstrate that the adrenal medulla is not essential for reflex compensation to a hypotensive challenge or to the blood pressure increases produced to direct neural stimulation.

Adrenal Medulla↗
PubMed1995

Diagnosis of the painful hip by magnetic resonance imaging and arthroscopy.

We have compared the findings of MRI with those of hip arthroscopy in 23 hips in young adults with hip pain. Large deep cartilage deficiencies on the acetabulum or femoral head, the percentage of femoral head cover, and the presence of marginal osteophytes seen on MRI correlated well with those seen at arthroscopy, but chondral softening, fibrillation, or partial-thickness defects less than 1 cm in diameter were less consistently detected by MRI. Osteochondral loose bodies and labral tears were not well demonstrated by MRI, but were readily identified and treated at arthroscopy. Arthroscopy of the hip is a useful investigation for hip pain in young adults especially when standard non-invasive MRI fails to provide a clear diagnosis.

Adult↗