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Biomedical subjects

R B Forney

Publications and source records attributed to R B Forney.

At least 19 recordsLinked to original sources
PubMed1990

The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of cigarette smoking on human hepatic drug metabolism.

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multiple-sample estimates of clearance for quinidine, valproic acid, unbound valproic acid, and lorazepam. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates, CL, corresponded closely to multiple-sample clearance estimates. Best post-dose sampling times were: quinidine, 8 h; valproic acid, 24 h; and lorazepam, 24 h. 2. Single-sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Valproic acid was used to probe microsomal and peroxisomal beta-oxidase activity; antipyrine, phenytoin, quinidine, carbamazepine, and theophylline were used as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely probe CL for smokers divided by probe CL for non-smokers) was calculated for each probe. The effect of cigarette smoking (and presumably polycyclic aromatic hydrocarbon exposure) on all probe CL values was consolidated and plotted as the logarithm of the CI to produce a handprint of drug metabolizing enzyme activity for cigarette smokers. 4. Only theophylline CL was significantly faster among smokers than non-smokers (P less than 0.01). 5. We conclude that the use of multiple probes of MFO activity when given in a single-dose, single-sample protocol for structuring handprints represents a minimally invasive and useful approach to characterize xenobiotic-mediated effects on hepatic MFO.

Antipyrine↗
PubMed1989

Optimal dosing of phenytoin: an evaluation of the timing and appropriateness of serum level monitoring.

The appropriateness of all serum phenytoin concentrations measured at this 294-bed, tertiary care institution over a 7-week period were evaluated. Each serum level was determined to be justified or unjustified based on either pharmacokinetic or clinical criteria. A total of 234 serum levels were measured in 58 patients. Thirty-eight (16%) of the levels were justified on a pharmacokinetic basis, whereas 70 (30%) were justified for clinical assessment of the patient. One hundred thirty (56%) of the serum levels could not be justified on any grounds. Also identified were distinct clinical situations for 13 patients for which monitoring of serum levels was warranted but not performed. Most phenytoin serum level measurements at this institution were not reasonably justified and may have been unnecessary. A yearly reduction in laboratory costs in excess of $9,000 was predicted if such serum levels had been ordered only when clearly indicated.

Adolescent↗
PubMed1988

Postmortem disposition of morphine in rats.

The antemortem and postmortem distribution of morphine was studied in rats for the purpose of establishing whether drug distribution is altered after death. Samples were examined for free and total morphine concentration, pH and water content at 0-96 h after death. Morphine was administered antemortem at various intervals. All groups of rats studied showed a significant (P less than 0.05) increase in postmortem cardiac blood morphine concentrations. These changes, which are detectable within 5 min after death are likely to be related to an observed, rapid decrease in cardiac blood pH from 7.34 +/- 0.02 to 6.74 +/- 0.05. Significant increases in free morphine levels were, also, observed 24 and 96 h after death in liver, heart and forebrain while urine morphine levels decreased. The liver showed the greatest increase (20-fold) in free morphine levels 96 h after death, while hindbrain levels did not significantly change. Bacterial hydrolysis of morphine glucuronides accounted only in part for the observed increase in free morphine concentration. Postmortem fluid movement and pH-dependent drug partitioning was detected. It would appear that several mechanisms are responsible for postmortem drug distribution. Understanding the mechanisms and patterns responsible may eventually lead to better choices of postmortem tissue which may better represent antemortem drug levels.

Animals↗
PubMed1988

Heroin, morphine, and hydromorphone determination in postmortem material by high performance liquid chromatography.

A procedure has been developed for the simultaneous determination of heroin, morphine, and hydromorphone from postmortem tissues by reversed phase high performance liquid chromatography (HPLC) using electrochemical detection. This method permits the direct determination of unmetabolized heroin from antemortem or postmortem urine as evidence of illegal drug use. Presumptive confirmation of heroin was based on the ability to hydrolyze the HPLC heroin fraction to morphine. Heroin was also confirmed in urine by gas chromatographic/mass spectroscopic (GC/MS) analysis of the HPLC fraction. Analysis of postmortem blood, gastric contents, urine, and injection site tissues have revealed the presence of morphine and hydromorphone, while heroin has only been identified in urine.

Body Fluids↗
PubMed1988

Cardiac blood pH as a possible indicator of postmortem interval.

Postmortem changes in the pH of blood and selected tissues in rats were evaluated at intervals ranging from 2 min to 96 h. Cardiac blood pH was significantly and reproducibly decreased in all groups at all postmortem intervals, independent of the method of sacrifice used. A preliminary study using cardiac blood obtained at autopsy from a limited number (n = 11) of human subjects demonstrated a significant negative correlation (r = -0.908, P less than 0.01) between postmortem interval (range 2 to 20 h) and cardiac blood pH.

Adult↗
PubMed1987

Cefotetan-induced disulfiram-type reactions and hypoprothrombinemia.

A double-blind, placebo-controlled study in eight healthy male volunteers was conducted to study possible disulfiram-type reactions and hypoprothrombinemia associated with cefotetan administration. Three doses of cefotetan (2 g) or of placebo were administered at 12-h intervals. Ethanol (0.5 g/kg of total body weight) was ingested 1 h after the third dose. Blood ethanol, serum acetaldehyde, and prothrombin times were measured throughout the study. Heart rate, blood pressure, and clinical signs as well as symptoms suggestive of a disulfiram-type reaction were also noted. Five of eight volunteers that received cefotetan showed significant flushing. A significant increase in heart rate also was noted. No change in mean arterial pressure was observed during the cefotetan phase, and no one experienced nausea or vomiting. No statistical differences were observed between phases with respect to ethanol area under the time-concentration curve, elimination rate, or serum acetaldehyde concentrations. A slight but statistically significant increase in prothrombin time also was observed with cefotetan. This study suggests that patients receiving cefotetan might be at risk to develop disulfiram-type reactions and hypoprothrombinemia.

Acetaldehyde↗
PubMed1986

Impact of cefaclor on the pharmacokinetics of theophylline.

The influence of cefaclor taken for 8 days (250 mg every 8 h) on the pharmacokinetics of a single intravenous dose of theophylline (2 mg/kg administered on the 8th cefaclor day) was studied in a crossover fashion among 11 healthy adults (10 men and one woman). Theophylline concentrations were measured serially for 12 h by an immunofluorescence polarization technique. No influence of cefaclor was detectable on theophylline clearance, half-life, or volume of distribution. It is concluded that cefaclor and theophylline can be administered together safely.

Adult↗
PubMed1986

Inability of ibuprofen to alter single dose phenytoin disposition.

The effect of ibuprofen treatment (1600 mg day-1 per os for 7 days) on single dose (300 mg per os) dispositional parameters of phenytoin (DPH) was evaluated in 10 healthy males. Ibuprofen slightly increased the free fraction of DPH from mean (+/- s.d.) value of 6.9 (+/- 0.7)% to 7.8 (+/- 0.3)% (P less than 0.01). DPH total clearance (CL/F) was not significantly changed going from a value of 0.027 (+/- 0.009) 1 h-1 kg-1 to 0.032 (+/- 0.014) 1 h-1 kg-1 (0.05 less than P less than 0.1). Intrinsic unbound DPH clearance (CLuint/F) was unaffected by ibuprofen treatment. Neither DPH's apparent volume of distribution (V/F) nor the apparent volume of distribution of unbound DPH (Vunb/F) were significantly altered by ibuprofen treatment. The slight changes in DPH plasma protein binding that are due to concurrent ibuprofen treatment in doses of 1600 mg day-1 are not likely to produce important changes in DPH dispositional parameters.

Adult↗
PubMed1986

Histamine action in paraquat-induced lung injury.

We investigated direct histamine release and its effects in edema formation following paraquat (PQ) injury in a blood-free, perfused rat lung preparation. Under control conditions, perfusate histamine levels from the lung averaged 9.5 +/- 1.4 ng/ml. Lungs perfused with paraquat (1 mM) showed marked increases in pulmonary arterial pressure (133%), airway pressure (74%), alveolarcapillary protein flux (200%), and lung weight (38%). Prior to any detectable lung weight or pressure changes, PQ caused a 300% increase in perfusate histamine. Diphenhydramine (1.0 X 10(-5) M), a specific H1-histamine receptor antagonist, blocked the increased protein flux that followed PQ administration and significantly delayed edema. Furthermore, diphenhydramine attenuated the rise in PGF2 alpha. Conversely, histamine release was partially attenuated by the cyclooxygenase inhibitor, ibuprofen, at 2.4 X 10(-5) M, the same level that we had previously shown to block an early rise in PGF2 alpha and the onset of edema after PQ. These data show that the increased alveolar-capillary protein flux that occurred with PQ injury was attenuated by an H1-receptor antagonist and suggest that histamine is a primary mediator in paraquat-induced injury and that histamine subsequently stimulates prostaglandin release.

Animals↗
PubMed1984

The effect of a single administration of phencyclidine on behavior in the rat over a 21-day period.

The effects of phencyclidine (PCP) (7.0, 11.7, 19.5, 32.6, and 54.4 mg/kg) on locomotor activity, stereotyped behavior (circling, backing up, and weaving frequency), and rotarod performance were evaluated. In addition, the frequency of other PCP-induced abnormal behaviors (head in corner, arched back, and cataleptic freeze) was determined. All doses of PCP produced a significant increase in locomotor activity and stereotyped behavior as well as an impairment of rotarod performance. Both the duration and the time to peak effects (with the exception of rotarod performance) of these PCP-induced behavioral changes appeared to be dose dependent. The delay in attaining peak effects for locomotor activity and stereotypy was attributed to PCP-induced gross motor ataxia, which became more severe and long lasting with increasing dose. Although the longest period of time that significant changes were seen in locomotor activity, stereotyped behavior, and rotarod performance was 12 hr, sporadic recurrences of stereotypy and a significant increase in cataleptic freeze were observed in the high-dose groups (19.5, 32.6, and 54.4 mg/kg) up to 21 days postadministration. These persistent behaviors (stereotypy and cataleptic freeze) are not unlike certain of the prolonged behaviors seen in man with PCP overdose (catatonic stupor along with repetitive orofacial and limb movements).

Animals↗
PubMed1984

Pharmacological activity of the basic fraction of marihuana whole smoke condensate alone and in combination with delta-9-tetrahydrocannabinol in mice.

This basic fraction (BF) of marihuana whole smoke condensate was subjected to pharmacological testing in males, Swiss-Webster mice. In a general pharmacological activity screen looking at behavioral, neurologic, and autonomic parameters, BF, at iv doses of 5, 10, and 20 mg/kg, caused impairment of visual placing, increase in tail pinch response, decrease in tail elevation, and induction of piloerection. These effects, although statistically significant, were slight and not consistently dose dependent. In a second study with doses ranging from 10 to 29 mg/kg, BF caused a decrease in spatial locomotion, rearing behavior, and urination incidence. In a third study, body temperatures of mice were measured periodically for 2 hr following administration of BF (1.2, 2.4, and 4.8 mg/kg) alone or in combination with 1.0 mg/kg delta-9-tetrahydrocannabinol (THC). BF did not alter body temperature, nor did it affect THC-induced hypothermia. These results, although suggesting that the basic fraction of marihuana whole smoke condensate has pharmacological activity in mice, offers little evidence for the presence of highly active compounds.

Animals↗
PubMed1984

Single dose phenytoin clearance during erythromycin treatment.

The effects of erythromycin on the single dose kinetics of phenytoin (PHT) were studied in eight healthy, male volunteers in a crossover study. PHT was administered in a single, oral 300 mg dose either alone or after 5 days of a 7 day erythromycin regimen. Erythromycin base (333 mg) was taken orally every 8 hr. PHT concentrations were measured in plasma collected at 0, 2, 4, 8, 12, 24, 36, and 48 hr after PHT administration and in saliva at 48 hr. PHT was assayed by a polarized immunofluorescent technique. Mean (+/- SD) control values for PHT intrinsic clearance, CLint/F; volume of distribution, V/F; and half-life, t 1/2 were 0.028 (+/- 0.009) 1 X hr-1 X kg-1, 0.97, (+/- 0.33) l/kg, and 27.3 (+/- 12.4) hr, respectively. During erythromycin treatment CLint/F was 0.026 (+/- 0.011) 1 X hr-1 X kg-1, V/F was 0.87 (+/- 0.23) l/kg, and t 1/2 was 31.2 (+/- 26.1) hr. None of the mean values changed significantly due to erythromycin treatment (p greater than 0.05). Estimates of intrinsic unbound PHT clearance, CL'int/F, based upon the 48 hr salivary PHT values were 0.403 (+/- 0.170) 1 X hr-1 X kg-1 and 0.352 (+/- 0.152) 1 X hr-1 X kg-1 for the control and erythromycin phases, respectively (p greater than 0.05). When intrinsic unbound PHT clearance, CL'int/F, was calculated from CLint/F using a mean free PHT fraction, fu, of 0.069 a good correlation between CL'int/F and CL'int/F could be shown. Evaluation of the interaction on the basis of multiple plasma sample data and single salivary sample data led to the same conclusion. Even though erythromycin failed to significantly decrease mean PHT clearance, occasionally large changes in PHT clearance accompanying erythromycin treatment provide sufficient incentive to closely monitor patients taking both drugs.

Adult↗
PubMed1983

Analysis of succinylcholine in tissues and body fluids by ion-pair extraction and gas chromatography-mass spectrometry.

The neuromuscular blocking agent succinylcholine (SCh) has been identified and quantitated in biological material using gas chromatography-mass spectrometry. The bisquaternary ammonium compound SCh is extracted from tissue homogenates or body fluids into dichloromethane as an ion pair with hexanitrodiphenylamine (DPA). The evaporated ion pair residue is demethylated with sodium benzenethiolate to form the corresponding tertiary amine which is identified and quantitated by gas chromatography-mass spectrometry using a glass capillary column coated with SE 52. In the quantitative analysis deuterated SCh is used as internal standard. The instrument is focussed on m/z 58 for demethylated SCh and m/z 62 or 64 for the internal standard. Concentrations as low as 5 ng SCh iodide/g tissue or body fluid are easily detected.

Animals↗
PubMed1983

The effects of an in vivo administration of phencyclidine on sodium-dependent high affinity choline uptake in rat hippocampus and striatum in vitro.

The effect of phencyclidine and other drugs on sodium-dependent high-affinity uptake of choline in the rat hippocampus and/or striatum was investigated and related to the behavioral changes induced by these agents. In contrast to atropine (40.0 mg/kg), which increased the uptake of choline in synaptosomes from both the rat hippocampus and striatum, the administration of phencyclidine (54.4 mg/kg), 30 min prior to sacrifice, caused a significant decrease in the uptake of choline in synaptosomes from rat striatum (but not hippocampus). This effect of phencyclidine could be seen up to 1 hr after administration of drug, but by 3.5 hr the uptake of choline was essentially back to normal. The inhibition of striatal uptake of choline occurred at a time when brain levels of phencyclidine and its metabolites were at their highest, and the animals were essentially immobile; it did not appear to correlate with behavioral changes (including stereotypy and catalepsy) seen at later times after this dose of phencyclidine (54.4 mg/kg), or at earlier times after smaller doses. Amphetamine (6.0 mg/kg) also decreased the uptake of choline in the striatum. Haloperidol (2.0 and 3.0 mg/kg) blocked both the phencyclidine and amphetamine-induced inhibition of the uptake of choline but only the behavioral effects of amphetamine. The data suggest that phencyclidine may be exerting an indirect effect on the uptake of choline in the striatum via its interaction with the dopaminergic system. However, this neurochemical effect of phencyclidine could not be related in any simple way to the immobility, stereotypy or catalepsy caused by this drug.

Amphetamine↗
PubMed1983

Selective action of prostaglandin F2 alpha during paraquat-induced pulmonary edema in the perfused lung.

Lung prostaglandins (PGs) play a key role in normal pulmonary vascular regulation. We investigated PG metabolism during edema formation following paraquat-induced damage with an isolated perfused rat lung preparation. Lungs perfused with paraquat (PQ), 1 X 10(-7) M to 1 X 10(-2) M, showed significant increases in PGF2 alpha prior to detectable functional and pathological changes (increases in airway resistance, vascular resistance, and edema). No changes in PGE were observed. PGF2 alpha in perfused lungs showed a dose-related response following PQ exposure (up to 300% increase over control values). Lungs perfused with PQ and ventilated with high oxygen (95% O2-5% CO2) instead of air-5% CO2 showed a dramatic potentiation in the selective increase of PGF2 alpha, with levels reaching over 1 ng/ml (a 2600% increase over control values). The addition of exogenous PGF2 alpha to the perfusate without PQ initiated edema in a dose-related fashion, indicating the potential of PGF2 alpha as a causative agent in lung edema formation from PQ injury. The addition of ibuprofen (a nonsteroidal anti-inflammatory agent) to the perfusion medium blocked endogenous release of PGF2 alpha in lungs linked to oxidant-induced edema. These data show that in the perfused lung: (1) PQ caused a selective increase of PGF2 alpha; (2) this selective increase occurred prior to the onset of edema; (3) exogenous PGF2 alpha alone induced pulmonary edema; and (4) ibuprofen, in doses which blocked PGF2 alpha, also prevented edema formation.

Animals↗
PubMed1983

Combined effects of propranolol and ethanol on human psychomotor performance.

Twelve male subjects were given placebo or 160 mg propranolol, in divided doses, during a 24-hr period before drinking a beverage containing 0 or 50 ml ethanol/70 kg body weight. Tests designed to measure mental and motor performance were administered 75 min after the last dose of propranolol. The tests performed included the wobble board (WB), pursuit meter (PM), delayed auditory feedback (DAF), pegboard (PB), tapping, time estimation (TE), and a modified Cornell medical index (CMI). A mean blood ethanol concentration of 48.0 +/- 9.1 mg/dl and a mean plasma propranolol level of 33.1 +/- 13.1 ng/ml were achieved. Ethanol alone significantly impaired performance in 12 out of 20 tests (p less than 0.05). Propranolol significantly (p less than 0.05) antagonized the decrement in psychomotor performance induced by ethanol on the PM. In all other tests, there was no significant interaction between ethanol and propranolol. Propranolol alone had no significant effect on the psychomotor tests. When the drugs were combined, the subjective symptoms, as measured by the CMI, showed a trend toward being additive. This study suggests that no adverse interaction occurs between therapeutic doses of propranolol and minimum impairment doses of ethanol.

Adult↗