Paul R. Finley

Lidocaine elimination: Effects of metoprolol and of propranolol

The effects of administration of metoprolol and propranolol on lidocaine elimination were studied in six healthy young men who did not smoke. Each received three single intravenous doses of lidocaine (2.5 to 3.0 mg/kg injected over 10 min): one alone, one after 1 day pretreatment with propranolol (40 mg orally every 6 hr), and one after 1 day pretreatment with metoprolol (50 mg orally every 6 hr). Lidocaine clearance was 0.88 ± 0.28 l · hr−1 · kg−1 before beta blockade, 0.61 ± 0.20 l · hr−1 · kg−1 during metoprolol dosing, and 0.47 ± 0.16 l · hr−1 · kg−1 during propranolol dosing. There was no correlation between the change in lidocaine elimination and the steady‐state concentrations of metoprolol or propranolol, nor between the change in lidocaine clearance and the change in resting heart rate produced by either beta blocker. Metoprolol and propranolol reduce lidocaine elimination significantly.

Amitriptyline plasma protein binding: Effect of plasma pH and relevance to clinical overdose☆

Reversing ventricular ectopy with plasma alkalinization following acute tricyclic antidepressant overdose is a recognized mode of therapy. The mechanism responsible for this effect is unclear. Changes in plasma protein binding of free drug, effects of the sodium ion on the myocardium, and alterations of plasma concentrations of alpha-1-acid glycoprotein may all interact to alter toxicity of tricyclics in overdose. An in vitro investigation using equilibrium dialysis was designed to examine the effect of altering plasma pH on percentage of free amitriptyline at clinical overdose plasma concentrations. A 1973 report on this effect lacked adequate controls and was faulty in experimental protocol. The current investigation used plasma concentrations typically present in amitriptyline overdose, a sensitive gas liquid chromatographic assay to detect total and free drug, and adequate control of plasma pH. The results of two separate experiments demonstrated a significant decrease in percentage of free amitriptyline of 20% over a pH range of 7.0-7.4 (P less than 0.05) and 42% over a pH range of 7.4-7.8 (P less than 0.05). The rate of change in slope in both experiments was not significantly different (P less than 0.01) indicating similar effects of pH change on plasma protein binding of amitriptyline within the two groups.

Cimetidine decreases theophylline clearance.

Excerpt Cimetidine, an H-2 receptor antagonist, was introduced in the United States in 1977 for the treatment of duodenal ulcers. Since its introduction, approximately 11 million patients worldwide...

Influence of ascites on tobramycin pharmacokinetics.

Abstract: The influence of ascites on the disposition of tobramycin was examined in eight subjects with cirrhosis of the liver. Five of these subjects had resolution of ascites so they could be used as their own controls. While there was no significant effect of ascites on the clearance and half‐life of tobramycin, the volume of distribution of tobramycin was significantly larger when ascites was present, 0.32 versus 0.26 liter/kg (P < 0.01). There was a trend for the volume of distribution to be larger in those patients with larger ascitic fluid volume.

Gonadotropin deficiency in tourette's syndrome: A preliminary communication

Plasma baseline levels of gonadotropins and sex steroids were measured in 17 patients with Tourettes Syndrome (TS). In addition, a Gonadotropin Stimulation test, using a synthetic Gonadotropin releasing factor analogue (GnRH, 100 micrograms, i.v.), was performed in 7 patients. Plasma levels of Luteinizing Hormone (LH) were uniformly low in all patients, while those of Follicle Stimulating hormone (FSH) and sex steroids were less depressed in some patients and in the normal range in others. In all patients, stimulation with GnRH analogue produced a marked rise in LH levels, but the FSH responses were much less dramatic and did not significantly exceed that of normal controls. Our findings indicate reduced gonadotropin release in patients with TS, and support the hypothesis of hypothalamic involvement in the disease.

Alterations in creatine kinase, ornithine decarboxylase, and transglutaminase during muscle regeneration

Creatine kinase (CK), transglutaminase (TGase) and ornithine decarboxylase (ODC), enzymes implicated in the regulation of growth processes, were studied during muscle regeneration subsequent to the injection of bupivacaine into rat tibialis anterior. Within 2 days, the percent BB isozyme of CK detected in the muscle was elevated 70-fold coincident with a marked decrease in total CK activity. The MB isozyme also increased and was 15-fold of control at 4-5 days postinjection. TGase activity was increased significantly to greater than 2-fold of control within 2 days of injection and significantly decreased at days 3 through 7 compared to controls. ODC activity was elevated significantly to 2- to 3-fold of control from 2-7 days after injection. These results suggest an early alteration in the expression of a coordinated battery of genes in this model of muscle degeneration-regeneration. The increased expression of MB and BB isozymes of CK in various human neuromuscular diseases may be a manifestation of an ongoing process of degeneration-regeneration.

Kinetics of the digoxin-aspirin combination

Digoxin interacts kinetically with many drugs in man. These interactions may result in digoxin toxicity. Aspirin has been shown to raise serum digoxin levels in the dog. We evaluated the effect of aspirin on digoxin single‐dose kinetics in eight healthy adults. Aspirin induced no change in digoxin total body clearance, volume of distribution, elimination half‐life, or renal or creatinine clearance. Trough serum salicylate levels ranged from 93 to 163 μg/ml. We conclude that no alteration is required in digoxin dosing when aspirin is used.

Serum Cpk Isoenzyme Bb as an Indicator of Brain Tissue Damage following Head Injury

In a study of 209 patients who had serum drawn for assay of creatine phosphokinase (CPK) isoenzymes, an attempt was made to correlate elevation of CPK brain fraction (BB) with occurrence of brain injury and to evaluate its sensitivity as an indicator of the presence of brain damage. Thirty-three patients had suffered serious head trauma. However, of the ten patients in coma, only three had elevated serum CPK-BB levels. Twenty-four of the other 176 patients who had no history and head injury also had positive BB fractions. Serum CPK-BB level was therefore an unreliable indicator of the extent of brain damage.

Increased activities of MB and BB isozymes of creatine kinase in denervated neonatal and adult rat muscle

Creatine kinase (CK) activity and isozyme patterns were assessed in newborn and adult rat anterior tibial muscle in response to denervation. Total CK activity was low in the control neonatal muscle, gradually increasing to the adult level within 1 month. Denervation prevented this normal increase, and, therefore, CK activity was reduced to 25% of control at 2 months. In the denervated adult muscle, total CK activity decreased to 50% of control within 3 weeks and remained at that level. Denervation of neonatal muscle resulted in a greater conservation of MB isozyme compared with controls. The alteration in BB isozyme expression was even more dramatic with a 33-fold difference expressed at 2 months in terms of percent total CK in denervated vs. control muscle. In denervated adult muscle, MB and BB isozyme activities increased gradually, attaining levels 3-fold and 13-fold, respectively, above control muscle at the end of the experimental period.

Regulation of Tumor Necrosis Factor Secretion in Leukocytes from Alpha-1-Antitrypsin Deficient Humans

Alpha-1-antitrypsin (AT) is one of several alpha-globulins which have been shown to be inhibitors of human peripheral blood monocyte TNF secretion in vitro. AT deficiency states exist, within which individuals of either the PiSS or PiZZ phenotype have reduced hepatocyte and mononuclear phagocyte AT secretion when compared to normal PiMM subjects. Here we have compared the capacity of peripheral blood monocytes of all three phenotypes to respond to both enhancers and inhibitors of TNF secretion. All monocytes exposed to lipopolysaccharide (LPS), interferon-gamma (IFN-gamma) and endotoxin, PGE2, transforming growth factor-beta 1, whole plasma alpha-globulins, purified AT and IL-6 responded equally with respect to the secretion of TNF. Our findings show that the regulation of TNF secretion in leukocytes from AT deficient humans is normal and suggest that defective AT secretion alone does not result in the aberrant regulation of TNF secretion.