ACTIONS OF 4-AMINOPYRIDINE ON THE CARDIOVASCULAR SYSTEMS OF ANAESTHETIZED CATS AND DOGS

The effects of the anti-curare agent 4-aminopyridine on thecardiovascular systems of cats and greyhounds under barbiturate-chloraloseanaesthesia have been studied. In both species, 4-aminopyridineproduced a transient atropine-sensitive decrease in arterialpressure followed by a prolonged adrenergically-mediated increase.In the cat, the cardiac responses to vagal stimulation and thenictitating membrane responses to sympathetic stimulation wereaugmented after injection of 4-aminopyridine, and the evidenceindicated that these effects were the results of increased releaseof neurotransmitters. In the greyhound, 4-aminopyridine producedincreases in left ventricular systolic pressure and dP/dt max,right atrial pressure, stroke volume, myocardial blood flow,myocardial oxygen consumption, external cardiac work, arterialoxygen content and blood haemoglobin. These effects were attributableto facilitation of sympathetic transmission to the blood vessels,heart and spleen. Heart rate was not much affected because facilitationof vagal transmission to the S-A node counteracted the increasedsympathetic effect. In the greyhound, 4-aminopyridine also producedtemporary cardiac arrhythmia which was only partly attributableto facilitated sympathetic transmission. In addition there wasevidence of a central stimulant action of 4-aminopyridine andof a stimulant action on visceral activity. It is concludedthat, while 4-aminopyridine may be useful in certain relativelyrare conditions of neuromuscular transmission failure, its actionsare too widespread for routine use as an antagonist to non-depolarizingneuromuscular blocking drugs.     

EFFECTS OF A NEW NEUROMUSCULAR BLOCKING AGENT (ORG 9426) IN ANAESTHETIZED CATS AND PIGS AND IN ISOLATED NERVE-MUSCLE PREPARATIONS

The effects of Org 9426 (the 2-morpholino, 3-hydroxy, 16N-allylpyrrolidino analogue of vecuronium) were studied in anaesthetizedcats and pigs and in isolated nerve—muscle preparationsusing tension and intracellular recording techniques. In isolatedpreparations, the effects of Org 9426 were antagonized by neostigmine.No contracture of the chick muscle preparation occurred. Org9426 reduced the amplitude of endplate currents (EPC) in ratand snake muscle, but had no major effects on EPC decay characteristics,indicating a lack of endplate channel blocking action. In anaesthetizedanimals, no fasciculations were observed and the neuromuscularblock was associated with tetanic and train-of-four fade andwas antagonized by neostigmine. In anaesthetized cats and pigs,Org 9426 was approximately 20% as potent as vecuronium, itsonset of action was twice as rapid as that of vecuronium inthe cat and its duration of action was similar to that of vecuroniumin both cats and pigs. It blocked the bradycardia produced byvagal stimulation only in doses greater than those necessaryto produce neuromuscular block (ratios 7.2 in the cat and 4.4in the pig—10—14% of the corresponding ratios forvecuronium). Ganglion block was seen only at doses several timesthose producing vagal block. In general the effects of Org 9426on the cardiovascular system were slight, a small depressoreffect occurring at high doses in the cat. The 17-hydroxy analogue,the potential metabolite of Org 9426, was approximately 20 timesless potent than Org 9426 and is thus unlikely to contributeto the neuromuscular block produced by the parent compound.     

The effects of a 16-N-homopiperidino analogue of vecuronium on neuromuscular transmission in anaesthetized cats, pigs, dogs and monkeys, and in isolated preparations

Org 9991, a 16-N-homopiperidinium substituted vecuronium analogue, has been tested for neuromuscular blocking activity in anaesthetized cats, pigs, dogs and monkeys, and in isolated nerve-muscle preparations. Org 9991 exhibited non-depolarizing neuromuscular blocking activity of the competitive type, being reversible by neostigmine and showing no endplate channel blocking action in isolated preparations. In cats, 50% vagal block was observed at doses of Org 9991 approximately 10 times those producing 50% neuromuscular block; no ganglion block was seen at these doses. Effects on blood pressure or heart rate at 90% twitch blocking doses were either minor or absent. The potency and time course of action of Org 9991 remained similar in all four species: i.e. 90% block at ca 200-300 micrograms kg-1; onset time ca 1.2-1.9 min; duration 90% ca 4.5-8.9 min. This study suggests that 16-N-homopiperidinium analogues of vecuronium may provide leads in the quest for a potent non-depolarizing replacement for suxamethonium.     

Comparison of Energy Estimation Equations with Measured Energy Expenditure in Obese Adolescent Patients with Cancer

Obesity is increasing in the US adolescent population. As the number of obese adolescents increases, obesity is becoming a more frequent problem in the hospital setting, sometimes causing patients to have complicated and prolonged hospital stays. Calculation of the energy requirements of obese adolescent patients with chronic diseases such as cancer is complicated by increased energy requirements as a result of disease state and growth. This study examined the accuracy of the commonly used equations for calculating energy requirements. Estimated energy expenditure was compared with measured energy expenditure determined by indirect calorimetry. All energy estimation equations were inaccurate, which indicates the need for a specific equation for determination of energy needs in this special patient population. Until further research is done, indirect calorimetry is recommended for all obese adolescent patients with cancer who require nutrition support.     

Cost, Correlates and Effects of Malpractice Litigation in Family Practice Residency Programmes in the United States

A survey of family practice residency programme directors inthe United States was undertaken to look at the impact of malpracticeand malpractice insurance on residency education. Of 385 programmes276 (71.7%) responded to the 20 question survey. The resultsindicated a mean rate of 0.043 claims per resident or facultymember in the previous year. One-fifth of the respondents didnot report the type of malpractice insurance retained for residentsand over half did not report the cost of insurance for residents.Current problems with liability were most often related to theregion of the country, number of visits to the family practicecentre, the number of residents, the number of faculty, thetype of faculty employer and the type of resident employer.Programmes which anticipated future problems with liabilitywere most likely to be those with current problems. The areasidentified as most concerning to residents included: obstetrics,cost of malpractice insurance, difficulty obtaining coverage,and the general anxiety created by malpractice litigation.     

Swine as an In Vivo Model for Electrophysiologic Evaluation of Cardiac Pacing Parameters

Pre-clinical studies of cardiac pacemakers and new electrodes, materials, and designs are for the most part conducted in dogs. Dogs, however, have electrophysiological differences which may preclude accurate translation to clinical trials. The purpose of this study was to develop normal electrophysiological parameters for an animal whose cardiovascular system more closely resembles that of man than any nonprimate animal. The threshold (voltage and current) strength-duration curves of the pig showed the same inverse relationship between the pulse duration and threshold requirements as other species. At 0.5 ms the atrium had 3.5-5.5 times greater energy requirements, over twice the current (2.04 mA vs 0.72 mA) and twice the voltage (0.75 mV vs 0.32 mV) requirements when compared to the ventricles. The pig's S-A nodal P-wave was superior in amplitude (7.80 +/- 1.80 mV vs 4.28 +/- 2.27 mV) and the slew rate was faster (1.30 +/- 0.56 mV/ms vs 0.44 +/- 0.50 mV/ms) compared to that of the atrial appendage. The pig's left ventricular myocardial R-wave had significantly greater amplitude (19.00 +/- 6.44 mV vs 10.70 +/- 4.34 mV) and faster slew rate (1.60 +/- 0.62 mV/ms vs 0.90 +/- 0.30 mV/ms) compared to the right ventricular endocardial R-wave. The electrophysiological parameters of the pig were more similar to those of man than the dog; therefore, the pig is a useful animal model for electrophysiological studies and the testing of pacemaker equipment.     

A Family with Hemoglobin I

Hemoglobin I was recently found in a Negro family. The amino acidsubstitution was shown to occur in the sixteenth residue of the chain (lys asp) and to be identical with hemoglobin I described by Murayama.¹⁰ Theminor component, I₂, was demonstrated by agar gel electrophoresis.

Submitted on January 9, 1963 Accepted on April 3, 1963