Marjorie H. Malagodi

STUDIES ON THE MECHANISM OF ACTION OF A NEW Ca2+ ANTAGONIST, 8‐(N,N‐DIETHYLAMINO)OCTYL 3,4,5‐TRIMETHOXYBENZOATE HYDROCHLORIDE IN SMOOTH AND SKELETAL MUSCLES

1 The rabbit aortic strip, guinea‐pig ileum and rabbit skeletal muscle sarcoplasmic reticulum preparations were used to determine at which sites and in what manner 8‐(N,N‐diethylamino)‐octyl 3,4,5‐trimethoxybenzoate (TMB‐8) interferes with Ca2+ availability in smooth and skeletal muscles. 2 TMB‐8 (50 μM) significantly inhibited equivalent responses of the rabbit aortic strip to KCl and noradrenaline. 3 TMB‐8 (65 μM) produced no significant alteration in the extracellular space of the guinea‐pig ileum as measured with [3 H]‐sorbitol. 4 The resting cellular Ca2+ influx as well as the resting 45 Ca2+ efflux in the guinea‐pig ileum preparation were significantly inhibited by TMB‐8 (65 μM). 5 TMB‐8 (5 μM and 50 μM) had no significant effect on the uptake of 45 Ca2+ by the sarcoplasmic reticulum preparation of skeletal muscle; however, TMB‐8 (5 μM) did significantly inhibit the caffeine (20 μ)‐induced release of 45 Ca2+ from this preparation. 6 It is concluded that TMB‐8 reduces Ca2+ availability in smooth and skeletal muscles by stabilizing Ca2+ binding to cellular Ca2+ stores and thereby inhibits the release of this Ca2+ by contractile stimuli.

Pharmacological evaluation of a new Ca2+ antagonist, 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8): studies in smooth muscles.

Abstract The pharmacology of 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) has been studied using guinea pig ileum and vas deferens preparations. TMB-8 inhibited responses to drugs that excite specific receptors (acetylcholine and norepinephrine) as well as to agents whose actions are not mediated via specific receptors (KCl and BaCl2) with ID50s of 3.8 × 10−6 to 1 × 10−4 M. TMB-8 inhibited responses to acetylcholine, norepinephrine, nicotine, dimethylphenylpiperazinium and KCl in an insurmountable manner in the guinea pig ileum, while responses to BaCl2 were inhibited in a competitive manner. Increasing Ca2+ concentrations of the bathing medium from 1.35 to 5.40 mM effectively antagonized the TMB-8 inhibition of responses to KCl in the guinea pig ileum and vas deferens preparations. These results indicate that TMB-8 may produce its inhibitory effects in smooth muscle by interfering with the availability of Ca2+ for muscle contraction by blocking the Ca2+ release from intracellular bound stores.

Pharmacological Evaluation of a New Ca++ Antagonist, 8-(N,N-Diethylamino)Octyl 3,4,5-Trimethoxybenzoate Hydrochloride (TMB-8): Studies in Skeletal Muscles

The pharmacology of 8-(N, N-diethyl-amino)octyl 3,4,5-trimethoxybenzoate (TMB-8) has been studied in several skeletal muscle preparations. TMB-8 inhibited responses of skeletal muscle produced by elec

Etidocaine, Bupivacaine, and Lidocaine Seizure Thresholds in Monkeys

The central nervous system toxicities of etidocaine, bupivacaine, and lidocaine were studied during constant-rate intravenous infusions in rhesus monkeys. Comparison of drug effects was achieved by determining the drug dosages and arterial plasma concentrations that induced electrical seizure activity. The central nervous system toxicity of etidooaine was similar to that of bupivacaine. The toxicity of each was four times greater than that of lidocaine. Since the drug infusion rates were proportional to anesthetic potencies in clinical usage, the therapeutic-toxic ratios of these three drugs are similar.

A rapid gas chromatographie procedure for the analysis of oxalate ion in urine

A specific, precise, rapid and sensitive method for the analysis of oxalic acid in urine is described. This microanalytical procedure can detect concentrations of urinary oxalic acid as low as 4 mg/l with a relative standard deviation of replicates of less than 5% (24-h urine collections). 10% BCl3:2-chloroethanol is used to derivatize 0.1 ml of urine after evaporation to dryness or lyophilization. The bis-2-chloroethyl ester of oxalic acid formed is extracted into ethyl acetate/isopropyl ether (1:3, v/v) and is detected by electron capture gas chromatography at the 50 pg level. The total analysis time for 35 samples in 8 h per GC column. A series of determinations of urinary oxalic acid in 21 kidney stone-forming patients resulted in values ranging from 10.6 to 42.0 mg/24 h with a mean recovery of added oxalic acid of 98.2% (range 84.0-111.3%).

Fluroxene toxicity induced by phenobarbital

Because of reports of fluroxene toxicity in man, the effect of phenobarbital treatment on the toxicity and metabolism of fluroxene was studied in 9 rhesus monkeys. Six monkeys that were exposed to a mean calculated alveolar fluroxene concentration of 5.8% for 4‐hr periods up to a total of 16 hr showed no evidence of toxicity. Two animals were sacrificed after a single 4‐hr exposure to obtain control measures of fluroxene metabolites in tissues. Four monkeys that had previously survived received exposures to fluroxene and 3 monkeys that had no exposure to fluroxene died during fluroxene anesthesia after treatment with phenobarbital (mean time, 3 hr). Toxicity was manifested by arterial hypotension, pulmonary edema, and arterial hypoxemia. Phenobarbital treatment enhanced production of fluroxene metabolites, including the highly toxic trifluoroethanol. Concentrations of trifluoroethanol in mixed‐expired gas, blood, and urine, and of total nonvolatile fluorine in blood, urine, and tissues of animals treated with phenobarbital were 2 to 10 times as high as in control animals. The results suggest that the rhesus monkey is a valuable model for the study of fluroxene pharmacology and that inclusion of an enzyme‐inducing challenge in the evaluation of potential toxicity of other anesthetics seems warranted.

Venous air embolism prophylaxis with a surface-active agent.

The protective effect of a nonionic surface-active polyol agent (Pluronic F-68) against bolus injection and constant-rate IV infusion of air was studied in 21 dogs anesthetized with pentobarbital. Aortic, pulmonary artery and right ventricular pressures, cardiac output, end-tidal CO2 concentration, wasted ventilation, and blood surface tensions were measured before and after the IV administration of this surfactant. The magnitudes of change in the cardiorespiratory responses measured after venous air embolism were significantly (p<0.05) reduced in the treated animals. This agent may be advantageous for surgical patients when an increased risk of venous air embolism exists.

Urinary Excretion of Amino Acids by Subjects with Renal Calculi

Idiopathic calcareous calculi remains a disorder of unknown cause, or causes. However, this affliction occurs predominantly in nonblack men, is affected by undefined geographic or climatic factors, and may be influenced by dietary habits1. In addition, the familial occurrence of idiopathic calculi has suggested that hereditary factors may exist that increase susceptability to this disorder2. Searching for a possible index of renal tubular dysfunction, McGeown3 investigated the amino acid excretion of 110 patients with calcareous calculi. She reported that, except for 30 patients with some increase in urinary cystine, the amino acid excretion was reduced in the calculous patients as compared with the amino acid excretion of normal subjects. Of these 110 patients, twenty-three had hyperparathyroidism and the mean excretion of amino acid nitrogen was less in these than in the group as a whole. Subsequently, Hum and associates4 reported the urinary amino acid values of 15 patients with calcareous calculi, but they found a reduced excretion only in those patients with impaired renal function.

Effect of vitamin D in fluoride-treated rats.

Fluoridated drinking water (30 mg and 100 mg F per liter) was used to induce rachitic changes in rats fed a vitamin D free diet containing calcium and phosphorus in a ratio of 1 : 1. Supplements of vitamin D3 (70 IU of cholecalciferol per week) completely prevented the rachitogenic effects of fluoride. This protective effect occurred despite evidence that vitamin D enhanced the intestinal absorption of fluoride.