Charles H. Jarboe

Effects of cimetidine on caffeine disposition in smokers and nonsmokers

The absorption, distribution, and elimination of caffeine, 2 mg/kg by mouth, were evaluated in six smokers and six nonsmokers before and on the fourth day of administration of cimetidine, 300 mg by mouth every 6 hr. Caffeine absorption, assessed by the maximal serum caffeine concentration (Cmax) and the time to reach Cmax (tmax), was very rapid relative to elimination. The total body clearance (TBC) of caffeine was higher (2.49 ± 0.35 and 1.59 ± 0.19 ml/kg/min, P < 0.05) and the elimination half‐life (t½) shorter (190 ± 15 and 276 ± 30 min, P < 0.05) in smokers than nonsmokers, but Cmax, tmax, and the apparent volume of distribution (Vd, app) did not differ (P > 0.05). Cimetidine decreased the TBC of caffeine by 31% (to 1.73 ± 0.28 ml/kg/min, P < 0.05) and by 42% (to 0.92 ± 0.11 ml/kg/min, P < 0.01) in smokers and nonsmokers. The increases in t½ were 45% (to 276 ± 25 min, P < 0.05) and 96% (to 542 ± 123 min, P < 0.05). Cmax, tmax, and Vd, app were unaffected by cimetidine. Caffeine induced similar slight increases in blood pressure and pulse rate in smokers and nonsmokers both before and during cimetidine dosing.

The Effects of Erythromycin on Theophylline Elimination in Normal Males

Abstract: The effects of three erythromycin preparations on theophylline elimination kinetics were examined in 23 male subjects. Subjects received 6 mg/kg of theophylline elixir orally and elimination kinetics were determined. The population was then randomized to receive either a lactose placebo, erythromycin base, erythromycin stearate, or erythromycin ethylsuccinate. Each 250‐mg preparation was given four times a day for six days. On day seven, a repeat kinetic study was performed. The mean theophylline half‐life of controls was 7.8 ± 2.6 hours. The half‐life increased significantly in all erythromycin treatment groups. The increase for the base, stearate, and ethylsuccinate groups was 51.7, 21.3, and 60.3 per cent, respectively. The total body theophylline clearance decreased significantly in all treatment groups. This was not associated with biochemical evidence of hepatitis. Three of four smokers who received erythromycin manifested no increase in theophylline half‐life, in contrast to one of 13 nonsmokers. There was no difference in the percentage theophylline bound to serum protein for any of the erythromycin treatment groups or controls as determined by ultracentrifugation.

Translaryngeal absorption of lidocaine

Our study was conducted to determine the appropriate dose of lidocaine using the larynx and to characterize the onset and duration of therapeutic serum levels. A mean dose of 5.67 +/- 1.2 mg/kg was topically administered to the subglottic region of seven comatose patients through a cricothyroid membrane puncture. Serial serum lidocaine levels showed that therapeutic levels were attained in 5.1 +/- 3.2 minutes with a mean maximum level of 3.16 +/- 1.52 micrograms/ml and were reached at 18.71 +/- 8.71 minutes. Therapeutic serum levels were maintained for 68.4 +/- 29.7 minutes. Absorption of lidocaine via the airway yields sustained levels, although the duration of onset is less rapid and the maximum serum level is lower than that from an equivalent intravenous dose.

Viopudial, a Hypotensive and Smooth Muscle Antispasmodic from Viburnum opulus

Summary The administration of viopudial, a Viburnum opulus component, produces bradycardia, hypotension, and some decrease in myocardial contractility. Experimental evidence indicates that viopudials mechanism of action is partly due to its effects on cholinesterase. In vitro demonstrations of a competitive inhibitory effect on both acetylcholinesterase and butyrylcholinesterase showed viopudial to be relatively weak when compared to the known potent inhibitor, physostigmine. Additional mechanistic effects, such as a direct musculotrophic action, may also be responsible for the overall activity. The authors are grateful to Dr. A. H. Nathan and Mr. C. V. Vanderkolk of the Upjohn Company, Kalamazoo, MI, for extractions. This research was supported by NIH Grants GM 461, GM 33,888 and AM 07147.

Dyphylline Elimination Kinetics in Lactating Women: Blood to Milk Transfer

Abstract: A population of 20 normal lactating females between the ages of 20 and 35 years was treated with a single 5 mg/kg intragluteal dose of dyphylline, 7‐(2,3‐dihydroxypropyl)theophylline. The distribution of the drug between blood and milk and its pharmacokinetics of elimination were determined. The apparent volume of distribution (Vd) of dyphylline was found to be 0.505 ± 0.162 l./kg, the elimination rate constant (kel) was 0.228 ± 0.055 hr−1, the biological half‐life (t1/2) was 3.21 ± 0.76 hr, and the total body clearance (Cl) was 0.109 ± 0.036 l./kg/hr. The ratio described by dyphylline distribution between milk and serum (M/S) was 2.08 ± 0.52. The elimination rate from milk was equivalent to that from blood.

Gas chromatographic determination of 1,2-propanediol dinitrate in blood

A method is described for determination of 1,2-propanediol dinitrate in blood at concentrations ranging from 10 ng/ml up to 25,000 ng/ml. It used double ether extraction with manual shaking in order to complete sample preparation within 5 min. Samples are analyzed via gas chromatography-electron-capture detection using a column of 3% base deactivated SP-2250 on Supelcoport. This column provides excellent separation and little 1,2-propanediol dinitrate tailing.

Effect of probenecid on dyphylline elimination.

Dyphylline is a methylxanthine bronchodilator with such a short a biologic t½ that development of practical dosing regimens has been difficult. Because its rapid renal elimination suggests active secretion, the effect of 1 gm probenecid on single‐dose elimination kinetics of dyphylline was determined. Twelve subjects (six male, six female) participated in a crossover design. Subjects were their own controls and received dyphylline, 20 mg/kg orally, alone and after probenecid. The dyphylline t½ increased from 2.57 ± 0.45 to 4.88 ± 1.2 hr, whereas the elimination rate constant decreased from 0.276 ± 0.056 to 0.150 ± 0.037 hr−1 after probenecid. There was no significant change in the dyphylline apparent volume of distribution. Dyphylline total body clearance fell from 173 ± 20 to 95 ± 12 ml/kg · hr. The combined use of these drugs may lead to a practical dyphylline dosage schedule in aminophylline‐hypersensitive patients or those incapacitated by theophylline gastrointestinal side effects.

Clovoxamine kinetics in an early clinical trial

Elimination kinetics of the new antidepressant clovoxamine were determined in a preliminary clinical trial in 10 depressed patients. When final oral doses of 50 mg clovoxamine fumarate were given, the mean peak steady‐state plasma concentration was about 60 ng/ml after 3 hr. Clovoxamine elimination proceeded by an apparent single‐phasic, first‐order decline with a mean t½ of 9.5 ± 2.8 hr. One subject had an unusually long t½ (31.5 hr) and had correspondingly high clovoxamine plasma concentrations. The mean apparent volume of distribution (Vd) calculated from oral dosage was 19.5 ± 6 l/kg, but one atypical subject had an apparent Vd of 96 l/kg. The mean apparent oral clearance was 25.5 ± 12.5 ml/min/kg. These parameters should be of assistance in planning dosage regimens and monitoring therapeutic blood levels according to kinetic principles. Atypical clovoxamine kinetics can be associated with abnormally high or low blood levels and could therefore lead to variability in clinical response.

Reconsideration of a test for dopaminergic stimulation: inability of apomorphine to induce mouse jumping.

Apomorphine was administered parenterally to mice in an unsuccessful attempt to induce amphetamine and L-3,4-dihydroxyphenylalanine-like elicited jumping. The efficacy of jumping behavior as an indicator of dopaminergic overstimulation is criticized in light of the results.

Pharmacology of β-(3,4-dimethoxyphenyl)ethyl amine: Lack of peripheral and central antidopaminergic properties

The diversity of molecular structures capable of antagonizing the central and peripheral actions of dopamine (Goldberg, 1975 a,b; Iversen, 1975) has prompted consideration of the minimum structure to display blockade. Whether structurally simple compounds with selective central or peripheral activity could be developed on the concept of a minimum blocking structure and thus become the basis for probing dopamine receptor chemical topography remains an open question. Successful receptor differentiation using complicated molecules is portended by work suggestive of central dopamine inhibitory and excitatory receptors (cools, Struyker Boudier & van Rossum, 1976). It is also apparent in the pimozide differentiation of peripheral dopamine receptors from apomorphine sensitive central dopamine receptors (Setler, Pendleton & Finlay, 1975). In contrast to the complicated molecular structures presented by most antidopaminergic compounds, dopamine dimethyl ether (DMPEA) has been reported to have been both central (Ernst, 1969) and peripheral (Elie, Barbeau & others, 1969) dopamine blocking activity. It has been implicated in schizophrenia (Friedhoff & Van Winkle, 1962 a,b), reported to induce catalepsy invarious species as a high dose effect (DeJong, 1945; Brown, Lang & Gershon, 1965) and to elicit various autonomic responses including a pressor action, a depressor action and /3-adrenergic blockade (Epstein, Gunn & Virden, 1932; Brown & others 1965). The effects of DMPEA on ~-3,4-dihydroxyphenylalanine (L-dopa) or apomorphine-induced gnawing in the rat have been assessed to determine its ability to block central dopamine receptor systems. It was reported to antagonize stereotypy as measured by a shortened recovery from drug-induced gnawing (Ernst, 1965) and decreased gnawing intensity (Ernst, 1969). Contrary to the reports of dopamine-blocking action, our investigation of DMPEA pharmacology shows the compound to have no antidopaminergic properties. In non-toxic doses the peripheral action of DMPEA is that of an a-adrenergic Rgonist; centrally, DMPEA potentiates apomorphine-induced climbing behaviour as indicated by haloperidol blockable (Protais, Costentin & Schwartz, 1976) climbing in mice. Male Swiss Webster mice (25-30 g), housed in a light controlled environment with free access to food were administered apomorphine hydrochloride (s.c.) or DMPEA (i.p.), dissolved in 0.9% saline (0.2 ml). Apomorphine-induced climbing was used since it has