R. E. Gosselin

The tolerance of coffee drinkers to caffeine

To decaffeinated coffee powder was added either caffeine or lactose, each in an amount of 150 mg. per dose. Prepared packets were issued to second‐year medical students, who served as subjects. When consumed at bedtime, this modest dose of caffeine was significantly more effective than the lactose placebo at inducing a reduction in pulse rate in noncoffee drinkers, but not in those who habitually consumed caffeinated beverages. Small but significant differences were demonstrated in both frequency and intensity of response. Only non coffee drinkers reported disturbances in sleep patterns, most consistently a delay in the onset of sleep. The relative insensitivity of coffee drinkers to these actions of caffeine presumably represents an acquired tolerance. Like that previously demonstrated to the diuretic and salivary‐stimulating actions, this tolerance is probably low grade. Some of the cardiovascular effects of caffeine are reviewed. Heightened vagal tone appears to be responsible for the bradycardia, which is reportedly masked after high doses of caffeine by direct excitatory actions on the heart. Bradycardia has not been observed regularly after small doses of caffeine in man, apparently in large measure because most investigators failed to separate the responses of habitual and occasional coffee drinkers.

On the mechanism of sulfide inactivation by methemoglobin

Abstract Methemoglobinemia induced in laboratory mammals protects them against death from inorganic sulfide poisoning. Similarly, an intraperitoneal depot of human methemoglobin prepared in vitro protects mice against a subsequent intraperitoneal injection of sodium sulfide. Human methemoglobin is effective whether in simple solution or in red cells; oxyhemoglobin is inactive under similar circumstances. The prophylactic efficacy of methemoglobin is presumably due to its ability to bind or otherwise inactivate sulfide. From the displacement of the dose-mortality curve in methemoglobinemic mice it is inferred that 2–4 moles of sulfide are inactivated in vivo for each mole of methemoglobin heme. The comparable ratio in poisoning by cyanide is about one, and for high doses of azide the ratio also approaches unity. That the ferric iron of methemoglobin binds (and perhaps otherwise inactivates) sulfide is deduced from the observation that, when methemoglobin is converted to cyanmethemoglobin, its antidotal effectiveness is reduced by the equivalent of at least 1 mole of sulfide per mole of heme. The inference that methemoglobin possesses more binding sites for sulfide than for cyanide is proved by the demonstration that cyanmethemoglobin protects mice against sulfide poisoning. These extra binding sites must be associated with some part of the molecule other than the heme iron, which is known to be occupied by cyanide. To be effective against sulfide poisoning, however, cyanmethemoglobin must be prepared from nitrite-treated hemoglobin, not from ferricyanide-treated hemoglobin. Therefore, the former but not the latter must possess sulfide-binding sites unavailable to cyanide. On the assumption that spectral changes reflect only 1:1 interactions between anion and heme iron, dissociation constants have been calculated from spectrophotometric titration curves. They indicate that the hydrosulfide ion (HS − ) is bound to the ferric iron more tightly in nitrite-treated hemoglobin than in ferricyanide-treated hemoglobin. In contrast, no difference between these two pigments could be demonstrated in their affinities for cyanide or azide. Another difference between nitrite-treated and ferricyanide-treated hemoglobins is the presence of at least one more free sulfhydryl group in the nitrite-prepared pigment.

Comparison of the adsorptive properties of activated charcoal and alaskan montmorillonite for some common poisons

Abstract Activated charcoal and our own preparation of Alaskan montmorillonite have been compared in vitro with respect to their adsorption isotherms at 37° for six common poisons. When evaluated on the basis of the maximum adsorption capacity and dissociation constant in 0.1 N HCl (“artificial gastric juice”), montmorillonite adsorbs d-amphetamine, tripelennamine, ferrous sulfate, and ethyl alcohol about as well as activated charcoal. With substances which are not ionized at the pH of gastric juice, notably salicylic acid and pentobarbital, a 100-fold difference in dissociation constants and a 3- to 13-fold difference in adsorption capacities occur in favor of charcoal. Both adsorbents are expected to dissociate free salicylate if allowed to pass into the intestinal tract. When the pH rises from 1 to 7.4, the dissociation constant of the salicylate-charcoal complex increases 5-fold and the capacity decreases 3-fold. Over the same pH range, however, the montmorillonite-salicylate complex increases its dissociation constant more than 10-fold and decreases its capacity more than 50-fold. Despite its less acceptable appearance, activated charcoal is judged to be superior to montmorillonite as a gastrointestinal adsorbent for general clinical use in acute poisonings.

Trends in the therapy of acute poisonings

Attention has been focused on many new and old techniques for preventing and treating poisonings arising from the ingestion of substances against which no specific antidotes are established. Aside from symptomatic and general supportive care, the nonspecific measures of value in clinical toxicology are of two types: those employed to minimize absorption by terminating the toxic exposure and those designed to promote the excretion of poisons already absorbed. In the first category, the induction of emesis, gastric lavage, the ingestion of adsorbents, and the administration of cathartics are recognized. In the second category are techniques for accelerating renal and biliary excretion, as well as extracorporeal hemodialysis, peritoneal dialysis, gastric dialysis, and related procedures. Considerably more information is desirable about each of these measures, how and when it should he used, and what advantages and disadvantages can be anticipated in its adoption. On the basis of recent studies, specific topics of promise for future investigation are suggested. Developments in these areas will probably prove to be more important than new systemic antidotes in terms of improving patient care in clinical toxicology.

Toxicologic studies on the avicide 3-chloro-p-toluidine.

Abstract 3-Chloro- p -toluidine (3-CPT) [also known as 3-chloro-4-methylaniline (3-CMA)] induces methemoglobinemia when given in lethal doses to mice and rats, but not when given to chickens. Death in laboratory rodents, however, appears to be unrelated to the methemoglobinemia. Peak concentrations of methemoglobin were lower than those generated by other compounds such as sodium nitrite or p -aminopropiophenone. Peak values were reached within the first hour but death occurred after several hours in rats, or several days in mice, when circulating methemoglobin concentrations declined toward normal. Methylene blue attenuated the methemoglobinemic response to 3-CPT, but increased the mortality. Hyperbaric oxygen increased methemoglobin concentrations after 3-CPT, but had no effect on mortality. Pretreatment with α-naphthylisothiocyanate (ANIT) decreased methemoglobin concentrations in mice after 3-CPT, but had no effect on mortality. Mortality in mice after 3-CPT was increased by cold stress or contemporaneous administration of Dial-Urethan. A profound and persistent hypothermia in mice and rats occurred after 3-CPT, and mice showed a dramatic but transient decrease in pulmonary ventilation. Elevated ambient temperatures partially blocked the hypothermic response, but, at least in mice, warming did not prevent death. Blood concentrations of 3-CPT in fatally poisoned mice appeared to decrease linearly with time. The half-life was estimated as 6.6 hr. Low concentrations of methemoglobin persisted for at least 24 hrs, after which time Heinz bodies were found in peripheral erythrocytes. Rats appeared to be more sensitive to 3-CPT than mice, and in contrast to the latter exhibited a significant hemoconcentration. In species resistant to 3-CPT-methemoglobinemia, death appears to be due to an uncharacterized blocking of energy metabolism.

Sodium Azide Poisoning

Excerpt To the editor: Since we (RS, RG) were responsible for the suggestion that the therapeutic induction of methemoglobinemia might be of value in acute azide poisoning (1, 2), we are naturally ...

Effects of Oxygen on Determination of Thiocholine by 5,5′-Dithiobis (2-Nitrobenzoic Acid) .

Summary The DTNB (5,5′-dithiobis-2-nitrobenzoic acid) method has been recommended for measuring the hydrolysis of thiocholine esters. During studies on the alkaline hydrolysis of benzoylthiocholine, however, analytical errors have been encountered and traced to the presence of molecular oxygen. Although oxygen does not influence the rate of benzoylthiocholine hydrolysis, it does compete with DTNB for the hydrolysis product thiocholine. Furthermore it produces fading of the chromogen on which the assay is based by oxidizing the monothiol TNB back to the DTNB. Thus the amount of thiocholine released is significantly underestimated if hydrolysis periods of 30 minutes or more are employed. In the absence of oxygen DTNB can be added at any time during the hydrolysis, but in the procedure recommended here it is present throughout. This modified DTNB method was used to determine rate constants for auto-oxidation of thiocholine and for spontaneous alkaline hydrolysis of acetyl- and benzoylthiocholines. Unlike acetylthiocholine, benzoylthiocholine proved to be so unstable in various buffered solutions at pH 8 that it appears to have only limited usefulness as an enzyme substrate.