Routine monitoring of serum vancomycin concentrations: waiting for proof of its value.
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Drug Administration Schedule↗
Biomedical subjects
D J Edwards
Publications and source records attributed to D J Edwards.
Assay for L-p-tyrosine in plasma and brain by column liquid chromatography with electrochemical detection using m-tyrosine as the internal standard.
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Animals↗
Behavioral effects of a single neuroleptic treatment grow with the passage of time.
The principal finding of this manuscript is that the incidence of catalepsy observed in the rat after a single administration of low, clinically relevant doses of the dopamine receptor antagonists and antipsychotic agents, haloperidol and fluphenazine hydrochloride, grows over time such that one re-exposure to the same compound up to 8 weeks later results in a marked enhancement (i.e. sensitization) of this response. This phenomenon appears to be independent of pharmacokinetic or conditioning factors as well as alterations in dopamine or dihydroxyphenylacetic acid. It suggests that the antidopaminergic influence of acute exposure to a neuroleptic not only persists but continues to sensitize for extraordinary periods of time even after the drug is no longer detectable in the system. Our findings may hold the key to understanding the apparent paradox that although neuroleptics presumably induce their therapeutic actions in disorders such as Tourette syndrome and schizophrenia as well as their parkinsonian effects by blocking dopamine receptors, this antagonism occurs immediately while behavioral changes often require weeks for maximal development.
3,4-Dihydroxyphenylacetic Acid↗
Pharmacokinetics of tranylcypromine in patients who are depressed: relationship to cardiovascular effects.
We investigated the pharmacokinetics of tranylcypromine, as well as the relationship between plasma levels of this agent and its effects on blood pressure and pulse rate. Tranylcypromine was absorbed rapidly after oral dosing, with the peak level being attained within 0.67 to 3.50 hours. Absorption was biphasic in seven of nine subjects. Elimination of tranylcypromine also was rapid, with a t 1/2 between 1.54 and 3.15 hours. From 2 to 7 hours after dosing, standing systolic and diastolic blood pressures were lowered and standing pulse was raised, compared with baseline. Onset of the effect on standing systolic blood pressure was correlated with the time of peak plasma tranylcypromine concentration. Maximum orthostatic drop of blood pressure and rise of pulse rate occurred 2 hours after dosing. Mean plasma tranylcypromine concentrations were correlated with mean orthostatic drop of systolic blood pressure and rise of pulse rate. Patients who have clinically significant hypotensive reactions to this agent may benefit from changes in their dose regimen aimed at minimizing peak tranylcypromine levels.
Administration, Oral↗
The pharmacokinetics of meperidine in acute trauma patients.
Traumatic injury has the potential to alter the hepatic clearance and hence the efficacy and toxicity of drugs by a variety of mechanisms. These include changes in hepatic microsomal enzyme activity, hepatic blood flow rate, and plasma protein binding. Unfortunately, there have been few pharmacokinetic studies in trauma patients. Thus, few data are available to provide guidance in drug regimen design for these individuals. Meperidine clearance was therefore evaluated in patients with traumatic injury and an effort was made to identify physiologic and/or clinical predictors of clearance which could facilitate initial dosage selection. Meperidine total body clearance (TBC) was determined on 12 occasions at steady state following IM administration of meperidine to nine severely injured nonseptic trauma patients with normal renal and hepatic function. TBC of this drug averaged 684 +/- 206 ml/min (mean +/- SD) and was highly correlated with ideal body weight (IBW) (r2 = 0.735; F = 27.75; n = 12; p less than 0.01). The serum concentration of the acute phase reactant protein, alpha 1 acid glycoprotein (AGP), which binds meperidine and many other basic drugs increased strikingly in an apparent linear manner at a rate of 27 mg/dl/day up to 9 days after the traumatic event (r2 = 0.828; F = 42.30; n = 12; p less than 0.01). However, this increase in binding protein concentration was not associated with an alteration in meperidine TBC as has been reported for other drugs. It is concluded that IBW may be a useful guide initial dosage selection of meperidine in acute trauma patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The effect of verapamil on antipyrine pharmacokinetics and metabolism in man.
The effect of verapamil pre-treatment on the pharmacokinetics and metabolism of antipyrine was studied in eight healthy male volunteers. The oral clearance of antipyrine was decreased from 2.18 to 1.95 l h-1 (P less than 0.01) by verapamil (80 mg three times daily for 2 days prior to antipyrine administration and 2 days following) while half-life was increased from 13.2 to 15.6 h (P less than 0.01). The urinary excretion of norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was decreased by 19.2%, 23.1% and 16.7% respectively (P less than 0.05) in the presence of verapamil. In addition, the rate constants for formation of each of these metabolites were significantly decreased by an average of approximately 30%. These results suggest that verapamil is capable of inhibiting oxidative metabolism, a finding which could be of clinical significance for drugs highly dependent upon pathways such as those inhibited in this study for elimination.
Adult↗
Specific 125I radioimmunoassay for morphine.
In this specific radioimmunoassay procedure for morphine, samples are first subjected to an extraction procedure to remove the major metabolite of morphine (morphine-3-glucuronide), then quantified by use of a commercial radioimmunoassay kit with 125I-labeled morphine. Concentrations between 10 and and 100 micrograms/L are routinely measured with a within-run CV of less than 2.0% and a between-run CV of 3.5%. This rapid, specific, and sensitive method requires minimal technical skills and analytical equipment that is common to most laboratories.
Humans↗
Determination of tranylcypromine in plasma using gas chromatography-chemical-ionization mass spectrometry.
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Gas Chromatography-Mass Spectrometry↗
Effects of debrisoquin on the excretion of catecholamine and octopamine metabolites in the rat and guinea pig.
The effects of debrisoquin, administered daily for 4 days to rats (40 mg/kg, i.p.) and guinea pigs (4 mg/kg, i.p.), were determined for urinary excretion of several acidic and neutral amine metabolites, including the norepinephrine metabolites, 3-methoxy-4-hydroxyphenethylene glycol (MHPG) and vanillylmandelic acid (VMA), the dopamine metabolites, 3,4-dihydroxyphenethanol (DHPE), 3-methoxy-4-hydroxyphenethanol (MHPE), and homovanillic acid (HVA), and the octopamine metabolite, p-hydroxyphenylglycol (pHPG). The excretion of MHPG was reduced to 32% of control in rats and to 46% in guinea pigs, HVA was reduced to 64 and 80% in these two species, respectively, and MHPE was lowered to 59% of control in the rat but was not affected in the guinea pig. DHPE and pHPG were not altered significantly in either species. VMA was a minor metabolite in both species, being less than 6% of MHPG, and its formation was blocked only partially (rat) or not at all (guinea pig) by debrisoquin. The data refute the idea based on previous in vitro studies that VMA is a major metabolite of norepinephrine in the periphery of the guinea pig as it is in man.
3-Methoxy-4-hydroxyphenylethanol↗
Effects of intraventricular injections of 6-hydroxydopamine on amine metabolites in rat brain and urine.
The effects in rats of intraventricular injections of 6-hydroxydopamine (6-OHDA) on the urinary excretion 1-3 weeks later of 3-methoxy-4-hydroxyphenethylene glycol (MHPG), 3,4-dihydroxyphenethanol (DHPE), 3-methoxy-4-hydroxyphenethanol (MHPE), p-hydroxyphenylglycol (pHPG), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were examined. The excretion of MHPG was decreased to 63 and 71% of control on days 7 and 14, respectively, but had returned to control levels by day 23, even though the brain levels were decreased by 87%. Free and total HVA excretion was reduced on both days 7 and 23, but free and total DOPAC was reduced only on day 7. Based on these data, it can be estimated that about 39% of the free and 46% of the total HVA in urine originates in the CNS. The excretion of conjugated HVA was decreased by 70-80%, but this decrease does not support the notion that the conjugated form of HVA is derived principally from the brain and thus serves as a better marker of brain dopamine metabolism, since the level of this metabolite in the brain was not correspondingly decreased but was instead increased. Urinary DOPAC levels were generally more variable and derived to a greater extent from the periphery; therefore, DOPAC appears to be less suitable than HVA as a marker of brain dopamine. The results also indicate that as much as 35% of the urinary MHPG may originate in the CNS, although compensatory changes in catecholamine metabolism in either the brain or in the periphery may have somewhat influenced this estimate. The results also suggest that at least as much pHPG as MHPG in urine derives from the CNS. The data are consistent with the idea that the neutral dopamine metabolites largely derive from the brain, but the relatively small depletion in their brain levels produced by 6-OHDA prevented the exact proportion being determined accurately.
3,4-Dihydroxyphenylacetic Acid↗
The effect of dietary precursors on the excretion of amines and their metabolites in the rat.
The influence of diet on the excretion of catecholamines, some of their metabolites, and pHPG, an octopamine metabolite, was examined. Two groups of rats were fed either a cereal-containing standard laboratory Purina rat chow or a cereal-free casein diet. Use of the standard chow resulted in significant increases in the urinary values for total MHPG, pHPG, DHPE, MHPE, and free and total DOPAC by the seventh day in comparison to the casein diet. No changes were noted in the excretion of free and total NE, DA, and HVA. The data indicate that it is necessary to place the animals on the casein diet several days before determining the excretion of the aforementioned metabolites.
3,4-Dihydroxyphenylacetic Acid↗
Opposite effects of chronic imipramine treatment on brain and urine MHPG levels in the rat.
Acute imipramine (IMI; 20 mg/kg, ip) in rats decreased the brain concentration of 3-methoxy-4-hydroxyphenethylene glycol (MHPG), a metabolite of norepinephrine (NE), to 85% of control 24 hr after injection. In contrast, chronic IMI (20 mg/kg, ip, daily for 14 days) significantly raised brain MHPG levels to 123% of control, while reducing brain NE levels. Urinary MHPG levels were reduced by both acute and chronic IMI treatments, to 52% and 51%, respectively. These data suggest that the brain turnover of NE is reduced after acute IMI, but is elevated after chronic treatment. Although urinary levels of MHPG changed in parallel with brain levels following an acute administration of IMI, such was not the case after chronic administration. We conclude that caution must be used in extrapolating drug-induced changes in urinary metabolite levels to brain amine function.
Animals↗
The effects of imipramine and iprindole on the metabolism of octopamine in the rat.
Acute injections of imipramine and iprindole in rats produced significant decreases in the concentration of p-hydroxyphenylglycol (pHPG), a neutral metabolite of octopamine in brain at 6 and 24 hr after the administration of drugs. The 24-hr urinary levels of both free and total pHPG were reduced to 25-29% of control with acute administration of imipramine, while iprindole produced a 30% decrease in free pHPG. With chronic administration of imipramine, concentrations of pHPG in brain returned to normal, while the 24-hr urinary levels were still decreased (to 24%). Octopamine in brain was unaltered after both single and repeated injections of imipramine. Thus, these data suggest that the turnover of octopamine in brain is reduced after acute administration of imipramine and iprindole, while after chronic treatment with imipramine, turnover of octopamine in brain has returned to control levels.
Animals↗
Applicability of capillary gas liquid chromatography to the measurement of free fraction of disopyramide in human plasma.
A sensitive and specific capillary gas liquid chromatographic nitrogen/phosphorus selective detection technique was used to measure unbound disopyramide in human plasma. The concentration dependent protein binding of disopyramide was examined. Various concentrations of disopyramide alone ranging from 0.5 to 10.0 micrograms/ml in 0.4 ml of isotonic phosphate buffer (pH 7.4) were dialyzed for 6 hours at 37 degrees C, against 0.4 ml blank plasma from five healthy volunteers. The concentration-dependent binding of disopyramide was confirmed. The average free fraction for disopyramide at concentrations of 0.5, 1.0, 2.0, 3.0, 4.0, 5.0 and 10.0 micrograms/ml were 0.14, 0.15, 0.20, 0.27, 0.30, 0.34 and 0.53, respectively.
Chromatography, Gas↗
Simultaneous quantitation of disopyramide and its mono-dealkylated metabolite in human plasma by fused-silica capillary gas chromatography using nitrogen-phosphorus specific detection.
A nitrogen-specific detector gas-liquid chromatographic assay method is reported which provides improved selectivity and sensitivity for disopyramide and its mono-N-dealkylated metabolite using a crosslinked fused-silica capillary column. The quantitation of disopyramide and mono-N-dealkylated disopyramide was accomplished by injecting trifluoroacetic anhydride-treated samples containing derivatized internal standard p- chlorodisopyramide , into a gas chromatograph equipped with a nitrogen--phosphorus detector and an automatic liquid sampler. A 25 m X 0.31 mm crosslinked, 5% phenylmethyl silicone-coated fused-silica column was utilized and samples were injected using the splitless injection mode. Linearity was observed in the range 0.05-5.00 micrograms/ml for disopyramide and 0.02-3.00 micrograms/ml for the mono-N-dealkylated metabolite. The coefficient of variation was found to be within 10% for both compounds in the concentration range studied.
Chromatography, Gas↗
Factors affecting quinidine protein binding in humans.
The free (unbound) concentration of drug in plasma is often an important determinant of pharmacological and toxicological effects. Unfortunately, studies examining the factors influencing the free fraction of quinidine in plasma have yielded inconsistent results. It is probable that differences in the type of blood collection tubes utilized and the analytical procedure employed biased some of these estimates of quinidine binding. The present study was executed in a manner free of factors now known to introduce artifacts into estimates of the free fraction of quinidine. In healthy volunteers, the free fraction of quinidine (1.0 microgram/mL) was 0.129 +/- 0.019 (mean +/- SD) and was constant throughout the therapeutic range. A high-affinity, low-capacity binding site (K = 1.17 X 10(5) M-1; nP = 3.49 X 10(-5) M) and a low-affinity, high-capacity binding site (K = 1.33 X 10(3) M-1; nP = 3.14 X 10(-3) M) were identified. The characteristics of quinidine binding in a 4.5-g/dL solution of human serum albumin (K = 3.05 X 10(3) M-1; nP = 1.36 X 10(-3) M) suggested that the low-affinity, high-capacity binding site was on this quinidine free fraction increased from 0.114 to 0.231. A lidocaine concentration of 250 micrograms/mL caused a similar increase. Patients suffering traumatic injury had a significant increase in alpha 1-acid glycoprotein concentration (197 mg/dL) and a decreased quinidine free fraction (0.075 +/- 0.019). Patients with hyperlipidemia had free fractions similar to those observed in healthy individuals (0.118 +/- 0.019).(ABSTRACT TRUNCATED AT 250 WORDS)
Binding, Competitive↗
Evidence favoring the venous equilibrium model for hepatic clearance of (S)-(--)-propranolol.
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Humans↗
Some effects of parathyroidectomy on cell-mediated immune responses in the rat.
Xenografts of mouse tail skin to the rib cages of normal and sham-parathyroidectomized rats caused an increase in plasma calcium concentration and concomitant increase in bone marrow mitosis. Neither was elicited in aparathyroid rats and graft survival was prolonged in these animals. No hypercalcaemic episode was associated with the delayed hypersensitivity response induced by painting rat ears with oxazolone. Compared with the response in sham-parathyroidectomized rats, that in parathyroidectomized rats was enhanced although both responses were less than that in normal rats. Parathyroidectomy of parental donors did not affect the ability of their splenic lymphocytes to mount a graft-versus-host response in F1 hybrid recipients. When sham-operated and aparathyroid parents were sensitized with F1 hybrid lymphocytes no differences were observed in a subsequent graft-versus-host response in F1 recipients. However, when aparathyroid F1 recipients were employed a marked reduction in the graft-versus-host reaction was observed. Thus the clonal expansion of cells with specific reactivity to certain antigens in secondary lymphoid tissue, which is driven by those same specific antigens, is not affected or only moderately affected by the parathyroid status of the animal. However, the more general increase in lymphocyte numbers promoted by non-specific mitogenic lymphokines is markedly impaired in the hypocalcaemic parathyroidectomized rat. Furthermore, the parathyroid gland is essential for the development of a hypercalcaemic episode which follows antigenic challenge and causes cell proliferation in primary lymphoid tissues. This surge of mitosis could serve to replenish the depleted pools of virgin T and B lymphocytes in the secondary lymphoid tissue which occur as a result of their response to antigens.
Animals↗