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Biomedical subjects

D J Edwards

Publications and source records attributed to D J Edwards.

At least 73 records · Page 4Linked to original sources
PubMed1991

Influence of subject age on the inhibition of oxidative metabolism by ciprofloxacin.

Case reports suggest that the magnitude of inhibition of oxidative metabolism produced by ciprofloxacin may be greater in elderly subjects. We examined the effect of oral ciprofloxacin on antipyrine disposition in 13 young (ages, 23 to 34 years) and 9 elderly (ages, 65 to 82 years) healthy volunteers. Ciprofloxacin decreased antipyrine oral clearance in young and elderly subjects (P less than 0.05), with the average decreases being similar in both groups (23.3% for the young subjects and 27.9% for the elderly subjects). Ciprofloxacin concentrations in serum were significantly higher (mean, 57%) in the elderly. The formation clearance of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was also significantly decreased in both groups of subjects; however, norantipyrine formation, accounting for 15 to 20% of antipyrine clearance, was reduced only in the elderly. These results suggest that elderly subjects are not more sensitive to the inhibitory effect of ciprofloxacin on antipyrine metabolism. However, careful clinical monitoring is necessary with all patients, irrespective of age, taking ciprofloxacin concomitantly with drugs primarily eliminated by the cytochrome P-450 system.

Adult↗
PubMed1991

Tarzan swings: a dangerous new epidemic.

Accidental injury in school children was thought to be unpreventable. This series presents the results of 24 consecutive patients with 29 fractures as a result of a fall from a 'Tarzan' rope swing. Twenty-six of the fractures involved the upper limb, 11 patients required hospitalization with operative intervention and 13 required outpatient care only. These types of injury are preventable. The morbidity and pain that these young patients suffer can be avoided.

Accidental Falls↗
PubMed1990

Quinidine does not alter antipyrine metabolism.

Quinidine has been reported to be a potent inhibitor of a specific isozyme of cytochrome P-450 (P-450db 1) that is responsible for the metabolism of a select group of drugs. In order to investigate the potential for quinidine to inhibit other isozymes of cytochrome P-450 and to assess whether or not P-450db 1 plays any role in antipyrine metabolism, we studied the effects of quinidine pretreatment on the pharmacokinetics and metabolism of antipyrine in six healthy, male volunteers. Using a randomized, crossover study design with a 2-week washout period between treatments, subjects received a single 1 gram antipyrine dose alone or with quinidine sulfate 200 mg orally every 8 hours for 24 hours prior to the dose of antipyrine and over the 48 hours following antipyrine administration. Mean serum concentrations, apparent oral clearance (1.93 +/- 0.86 vs 2.06 +/- 1.06 L/hr with quinidine) and half-life (13.5 +/- 3.3 vs 12.4 +/- 3.6 hr with quinidine) were not significantly different between the two treatments. The fraction of the administered dose recovered as antipyrine and measured metabolites (56.7% vs 59% with quinidine) as well as the recovery of each individual metabolite was not altered with quinidine pretreatment. In addition, the mean formation clearances for norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine exhibited no change between treatment phases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Hypoaminoacidemia caused by imipramine but not by clenbuterol is dissociable from hyperglycemia and hyperinsulinemia.

The effects of the tricyclic antidepressant imipramine (20 mg/kg) and the beta-adrenoceptor agonist clenbuterol (0.5 mg/kg) on the serum concentrations of tyrosine, tryptophan, glucose and insulin were compared 30 min after intraperitoneal injection. The drugs had nearly identical effects on serum tyrosine, which was reduced to 73% of control by both drugs, and on tryptophan, which was reduced to 72% by imipramine and to 66% by clenbuterol. In contrast, whereas clenbuterol raised serum glucose to 174% and insulin to 379% of control, imipramine had no significant effects on either glucose or insulin. The results clearly demonstrate that the effects of imipramine on blood amino acid levels are dissociable from effects on glucose and insulin. We conclude, therefore, that hypoaminoacidemia caused by imipramine is not mediated by stimulating insulin release.

Animals↗
PubMed1990

Immobilization 12 days (but not one hour) earlier enhanced 2-deoxy-D-glucose-induced immunosuppression: evidence for stressor-induced time-dependent sensitization of the immune system.

1. Prior exposure to a stressor can either increase or decrease subsequent behavioral, neurochemical, and endocrine reactivity to stress, depending on the pattern of stress exposure. 2. Massed or frequent exposures typically induce a reduction in reactivity whereas intermittent or widely spaced exposures increase subsequent reactivity. 3. In the present study, the authors examined whether a single presentation of a temporally remote stressor would increase the immunosuppressive effects of a subsequent stressor. Specifically, the authors investigated the effectiveness of 2-deoxy-D-glucose (2-DG) in suppressing the responsiveness of splenic lymphocytes in male, Sprague-Dawley rats that received either no prior treatment, or immobilization either one hour or 12 days earlier. 4. Splenic lymphocyte responsiveness to the T-cell mitogens, Concanavalin A (Con-A) and phytohemagglutinin (PHA) was suppressed following a single injection of 2-DG. 5. The group exposed to the stress of immobilization one hour prior to 2-DG demonstrated a comparable level of immune suppression. 6. In contrast, animals immobilized 12 days prior to the administration of 2-DG showed a more pronounced suppression of immune responsiveness which was significantly greater than the other groups injected with 2-DG. 7. Neither the stress-induced elevation in corticosterone, nor the suppression of blood lymphocyte reactivity to Con-A and PHA was enhanced by prior immobilization. 8. The results indicate that the immunosuppressive effects of an acute stressor can sensitize with the passage of time.

Animals↗
PubMed1990

Indices of renal function: values in eight normal foals from birth to 56 days.

A series of blood and urine samples was collected from each of eight normal foals between birth and eight weeks. Blood chemistry relating to renal function was evaluated as well as physical and chemical characteristics of urine. During the first 4d of life it was impractical to suggest meaningful normal values due to wide variation among foals and with time. Serum urea and plasma creatinine fell markedly to levels less than those previously reported for normal adult horses, while urine, mildly hypersthenuric at birth, rapidly became hyposthenuric. There was also a marked proteinuria during the first 48h. After 4d clinicopathological values stabilised. Urea and creatinine remained at subadult levels and hyposthenuria was maintained. While there was some variation with time, generally the urinary activity of gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (AP) was greater in foals than in adults; plasma potassium, the creatinine clearance ratio of potassium (% Cr K), serum inorganic phosphate and the creatinine clearance ratio of phosphate (% Cr PO4) were greater than in adults while plasma chloride and the creatinine clearance ratio of chloride (% Cr Cl) were lower in foals than in adults. Urinary pH was acidic and epithelial cells and calcium oxalate crystals more prevalent in the urine of foals than in that of adults. The information presented here will be useful in the diagnosis and management of renal disease and azotaemia in foals.

Animals↗
PubMed1990

Alternative catecholamine pathways after tyrosine hydroxylase inhibition in malignant pheochromocytoma.

A suppression of norepinephrine, epinephrine, and its metabolites in malignant pheochromocytoma by metyrosine was associated with an increase in tyrosine, plasma DOPA, and sulfate esters of DOPA and dopamine, followed, with continuing metyrosine administration, by a further rise of both DOPA sulfate and dopamine sulfate. Urinary dopamine progressively increased in the course of metyrosine treatment, and this, along with the increase of the dopamine metabolite, dihydroxyphenylethanol, and plasma dopamine sulfate, occurred in the absence of any change in plasma dopamine. The octopamine metabolite para-hydroxyphenylglycol, which was initially elevated at least 10-fold, also increased after metyrosine treatment. The unexpected increase of DOPA (progressively more converted toward DOPA sulfate) in the presence of tyrosine hydroxylase inhibition and increase in tyrosine may result from channeling the excess tyrosine toward DOPA and melanin through tyrosinase. Increases in plasma dopamine sulfate and urinary dopamine suggest that dopamine sulfate may be generated via DOPA sulfate and urinary dopamine may originate from circulating DOPA. Tyrosine hydroxylase inhibition may thus result in DOPA generation in non-catecholamine-producing tissues by an alternative pathway. The resulting progressive increase in DOPA and its sulfate may lead to increased urinary dopamine. DOPA sulfate may be an alternative source of dopamine sulfate.

Adrenal Gland Neoplasms↗
PubMed1990

Plasma tranylcypromine: relationship to pharmacokinetic variables and clinical antidepressant actions.

Because the clinical actions of psychotherapeutic agents can be influenced by their pharmacokinetics, we investigated plasma tranylcypromine in relation to treatment outcome in 26 patients with bipolar depression. After oral administration of a tranylcypromine dose, plasma drug levels were measured hourly from 5-8 hours (N = 16) or 0-8 hours (N = 10) postdose, and pharmacokinetic parameters were calculated. Depressive symptoms were rated using the Hamilton Rating Scale for Depression (HAM-D), and subjects were categorized as responders, partial responders, or nonresponders, based on end-pair ratings. Twelve subjects were responders, seven were partial responders, and seven were nonresponders (mean scores = 3.2, 13.1, and 24.9, respectively); pretreatment HAM-D scores did not differ among the three groups. Tranylcypromine elimination (t1/2) was unrelated to clinical outcome. However, plasma tranylcypromine measured 5 hours postdose (5hTCP) was correlated with the end-pair HAM-D scores (r = 0.48, p less than 0.015) and was significantly higher in nonresponders than in responders (ANOVA, F = 4.7, p less than 0.02; Newman-Keuls test, p less than 0.05). For subjects who were studied from 0-8 hours postdose, the time to peak absorption (Tpeak), the area under the plasma tranylcypromine-versus-time curve, and the volume of distribution (Vd) were determined. Two subjects having delayed (3-4 hours) Tpeak also manifested elevated mean 5hTCP (63.9 vs. 34.1 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Effects of the beta 2-adrenoceptor agonist clenbuterol on tyrosine and tryptophan in plasma and brain of the rat.

The beta 2-adrenoceptor agonist, clenbuterol (initially 5 mg/kg), was found to significantly reduce plasma tyrosine and raise brain tryptophan levels (P less than 0.01). By comparison, decreases in plasma tryptophan and increases in brain tyrosine were small and often nonsignificant. Amino acid levels measured in different brain regions revealed that the elevations were similar among the cerebellum, striatum, and cortex. These effects were partially blocked by propanolol but not by atenolol. The ED50 was estimated from dose-response curves to be about 0.05 mg/kg for both the decrease in plasma tyrosine and the increase in brain tryptophan. The effects of low doses of clenbuterol were prevented completely by propranolol. Peripheral organs displayed strikingly different patterns of change in amino acid concentrations. Only the spleen had any accumulation of tryptophan, but that was much less than in brain. In contrast, tyrosine and tryptophan were decreased in heart and unaltered in liver; tyrosine was decreased in lung. The elevation in brain tryptophan levels was attenuated by the beta 2-antagonist, ICI 118,551, but not by the beta 1-antagonist, betaxolol; but the reduction in plasma tyrosine was unaffected by either drug. The serotonin antagonist, methysergide, failed to block the effects of clenbuterol. We conclude that changes in amino acid concentrations produced by clenbuterol are mediated by beta 2-adrenoceptor stimulation. Although the increases in brain tyrosine and tryptophan were similar to increases in the plasma ratios of these amino acids to the sum of the other large neutral amino acids competing for transport into the brain, the disparity between the effects of ICI 118,551 in brain and plasma suggests that clenbuterol may also have a direct action in brain to regulate levels of aromatic amino acids. Since clenbuterol has been purported to have an antidepressant effect and since other antidepressants also increase brain tryptophan, this may be a common feature of antidepressant drug action.

Amino Acids↗
PubMed1989

Persistent sensitization of clonidine-induced hypokinesia following one exposure to a stressor: possible relevance to panic disorder and its treatment.

Based on previous findings of this laboratory that a single exposure to a stressful stimulus can induce a very long-lasting, sensitizing influence on the actions of drugs of multiple clinical and structural classes, the hypothesis was tested that a single stressful event might exert such an action on the alpha-2 norepinephrine agonist clonidine. Male rats received a single injection of the highly stressful convulsant stimulant pentylenetetrazole (PTZ; 40 mg/kg, IP) and were tested for locomotion after treatment with clonidine (25 micrograms/kg, IP) 1 h, 1 week or 2 weeks later. As expected, clonidine itself induced the hypokinesia typically associated with low doses of this compound. More importantly, all groups pretreated with PTZ showed a significant enhancement of this effect. The influence of PTZ 1 or 2 weeks prior to clonidine cannot be explained as simply due to a lingering impairment of locomotion by PTZ, since no hypokinesia was observed when activity in these groups was examined immediately prior to clonidine administration. Such impairment appears, however, to have been a factor in the heightened hypokinesia observed in the group receiving PTZ only 1 h before clonidine. Mass spectrometric analysis of norepinephrine and 3-methoxy-4-hydroxyphenylglycol levels in hippocampus and cortical areas failed to reveal any changes which could explain the persistent behavioral sensitization we observed. Plasma corticosterone determinations confirmed the stressful nature of PTZ but similarly failed to provide an explanation for the observed behavioral sensitization. The major finding of a long-term sensitizing influence on clonidine of an acute stressful experience is consistent with what is known of the precipitants and treatment of panic disorder.

Animals↗
PubMed1989

Prior stress attenuates the analgesic response but sensitizes the corticosterone and cortical dopamine responses to stress 10 days later.

This study demonstrates that pre-exposure to stress influences subsequent effects of stress on pain sensitivity (stress-induced analgesia) and on plasma corticosterone and brain catecholamine activity. Animals exposed to a 30 min shock session (S1 = 8, 5.0 s shocks) 10 days earlier showed a significant attenuation of shock-induced analgesia, as measured by increased latency of tail withdrawal from a hot water bath immediately after a 40 s, 1.6 mA footshock (S2). Animals exposed to shock 10 days before testing also exhibited a higher plasma corticosterone response to testing than did all other groups. Norepinephrine (NE) levels in the frontal cortex and dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels in the frontal cortex and nucleus accumbens were not altered in any group. However, the DOPAC/DA ratio in the frontal cortex was increased by analgesia testing, and this increase was enhanced only by the combination of shock 10 days before testing and shock immediately before the test (S1 + S2). These results are consistent with previous reports from this laboratory which indicate that an animal's acute response to stress is strongly influenced by its past history of stress.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Anticonvulsant and other effects of diazepam grow with time after a single treatment.

The hypothesis was tested that some of the effects in rats of the prototypical benzodiazepine, diazepam, would grow (i.e., sensitize) with the passage of time after acute administration as we had previously observed following stimulants, antidepressants, neuroleptics and other compounds. Our principal findings indicate that: 1) A single pretreatment with 0.5 mg/kg of diazepam significantly enhances the anticonvulsant effect of this same dose administered again two weeks later. 2) One injection of 2.5 mg/kg of diazepam significantly sensitizes the catalepsy and ptosis observed following the administration of haloperidol two weeks but not two hours later. These data provide the first evidence for time-dependent sensitization after benzodiazepines and perhaps by implication, of GABA neurons. They may also suggest that acute stimulation of GABA neurons triggers the progressive development of a long-term, antidopaminergic influence. Finally, they raise the question of whether the progressive anxiolytic influence seen during the first week or so of benzodiazepine therapy depends on the passage of time rather than repeated drug treatment.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Indices of renal function: reference values in normal horses.

Urine and blood samples were taken at the same time from normal adult horses presented for routine investigations to establish reference values for a variety of parameters reported to be useful in the clinical evaluation of renal function. Blood biochemical values were consistent with previous studies and had well-defined normal ranges. Parameters representing urine concentration and electrolyte excretion however, varied widely reflecting the ability of the healthy kidney to change the composition of urine in response to differences in environment and management. Percent creatinine clearance ratios for potassium in particular were lower than those reported in normal horses in previous studies. Rational interpretation of these latter measurements should accept a wide range of normal values and management conditions must be considered in this interpretation.

Animals↗
PubMed1989

The nephrotoxic potential of neomycin in the horse.

Neomycin was administered intramuscularly to four normal adult horses at a dose rate of 10 mg/kg bodyweight every 12 h for 10 days (21 doses). The pharmacokinetic behaviour of neomycin with multiple dosing was characterised and a range of blood chemical and urinary parameters examined for evidence of nephrotoxicity. There was evidence of physical renal tubular injury (enzymuria and cylindriuria) within four days of neomycin administration but this subsided following cessation of treatment. No significant functional nephrotoxicity was detected. More severe nephrotoxicity might be expected in ill horses and it is recommended that several clinicopathological results be monitored serially in those horses receiving parenteral neomycin.

Alkaline Phosphatase↗
PubMed1989

Effects of ciprofloxacin on testosterone and cortisol concentrations in healthy males.

Several inhibitors of oxidative drug metabolism inhibit the synthesis of endogenous compounds such as testosterone and cortisol. Since ciprofloxacin is a potent inhibitor of the metabolism of a number of drugs, we studied its effect on serum testosterone and cortisol concentrations in eight healthy male subjects. Blood samples were collected over a 12-h period under baseline conditions and following the first and final doses of ciprofloxacin (500 mg orally every 12 h for 4 days). No significant differences in concentrations or area under the concentration-time curve were found when baseline values were compared with those observed for either testosterone or cortisol after ciprofloxacin administration. These results suggest that ciprofloxacin is unlikely to have either antiandrogenic side effects or clinical utility in lowering testosterone or cortisol concentration.

Adult↗
PubMed1989

Protein binding characteristics of bumetanide.

The association constants (k) and binding capacities (np) of bumetanide were determined in pooled venous blood obtained from adults, venous cord blood of healthy full-term infants, and critically ill neonates using ultrafiltration. Bumetanide was highly bound to plasma proteins (approximately 97%) in all three populations studied. Two classes of binding sites were identified, a high-affinity, low-capacity site with k and np in the order of 10(3) M-1 and 10(-3) M, respectively, and a low-affinity, high-capacity site with k and np in the order of 10(2) M-1 and 10(-2) M, respectively. Binding capacities were similar between the three groups studied and were larger than the 'presumed' therapeutic concentration following intravenous administration of the drug, which is on the order of 10(-6) M (less than or equal to 0.5 microgram/ml).

Adult↗
PubMed1988

On the mechanism of imipramine's influence in lowering p-hydroxyphenylglycol concentrations in the brain. The role of tyrosine.

Administration of imipramine (IMI) to rats was shown to lower after 4.5 hr the brain concentration of the octopamine metabolite p-hydroxyphenylglycol (pHPG) in a dose-dependent manner over the range of 10-40 mg/kg of IMI. Assay of plasma and brain levels of tyrosine revealed that IMI produced a reduction in both but with a shorter time-course than for the depletion in pHPG, with the maximal decreases occurring at 1.5 hr, before there was any loss of pHPG. The reductions in tyrosine and pHPG levels could not be explained by an effect of IMI on food intake, since the levels were diminished even in 24-hr fasted animals. When rats were injected with IMI 4.5 hr before 200 mg/kg of tyrosine and 5.5 hr before being killed, the elevation in brain pHPG levels were attenuated by about 50%, as compared to the animals that received tyrosine alone. These data suggest that the ability of IMI to lower brain pHPG probably involves two distinct mechanisms: (1) a lowering of brain and plasma tyrosine concentrations, and (2) an inhibition of the conversion of tyrosine to pHPG. It is unclear whether these effects are due to IMI itself or to one of its metabolites, such as desmethylimipramine or didesmethylimipramine, which were found in the plasma in amounts equal to or greater than IMI.

Animals↗