Postsynaptic antagonism by 4-aminopyridine of ketamine effect in frog (Hyla crepitans) neuromuscular junctions.

The action of ketamine (50 microM) and 4-aminopyridine (4-AP) (50 microM) on the frog (Hyla crepitans) neuromuscular junction using standard intracellular recording techniques was investigated. In our experiments the amplitude of evoked end plate potential was decreased by ketamine and increased by 4-AP, which is similar to the effects reported by other investigators. However, novel effects of the drugs on postsynaptic acetylcholine receptors were detected when miniature end plate potential (MEPP) amplitude and time-course were analyzed. The experiments were performed and registered in presence of 1% dimethylsulfoxide to augment frequency of MEPP's. When ketamine was added to the saline solution, MEPP amplitude control values were reduced from 226 (214, 240) microV (n = 529, median and its 95% confidence interval) to 140 (130, 151) microV (n = 143) by 50 microM ketamine. 4-AP alone also depressed MEPP amplitude to 129 (70, 152) microV (n = 91). The two drugs are partial antagonists, when they were applied together, MEPP amplitude was 180 (172, 188) microV (n = 207). The effect of ketamine on time course of MEPP's, expressed as time to peak, reduced the control values of 4.74 (4.61, 4.88) msec (n = 529) to 3.84 (3.72, 4.01) msec (n = 143) (P less than 0.001); the effect of 4-AP was to reduce the control values to 1.93 (1.79, 2.10) msec (n = 91). The time to peak after adding ketamine and 4-AP was 3.25 (3.12, 3.38) msec (n = 207), expressing an antagonistic effect of the drugs. All values are statistically distinct (P less than 0.001). Thus, our results show that a postsynaptic mechanism is responsible for a significant part of the antagonism of ketamine effects by 4-AP.

Comparison of midazolam (Ro 21-3981) and diazepam as complement of ketamine-air anesthesia in children.

A single-blind, randomized, prospective, comparative clinical trial was performed in 90 (30 X 3) pediatric patients, comparing a new water-soluble benzodiazepine, midazolam (Ro 21-3931) and ketamine-air (8 mg . kg-1) by intramuscular or intravenous routes at equipotent dose (0.2 mg . kg-1) with the standard anesthesia technique with diazepam (0.3 mg . kg-1) as an intravenous complement, during anesthesia for diagnostic urological procedures on an out-patient basis. Comparison between the three series of the mean values of maximal variation of hemodynamic parameters (systolic and diastolic blood pressures, and heart rate) during maintenance of anesthesia revealed no statistical significant difference in their values. Apnea was not observed in any patient. Local tolerance was excellent after i.v. administration, while good in the ketamine-midazolam i.m. series, 5 patients reported slight pain under pressure at the site of injection 24 hours after the end of anesthesia. No serious adverse reactions were observed in this clinical trial. We concluded that the efficacy of midazolam (Ro 21-3981) was excellent and comparable to that of the standard drug (diazepam), with the added advantage of better tolerance after both the intramuscular and intravenous administration, due to the rapid intramuscular absorption of midazolam, which starts simultaneously with that of ketamine.

Effect of 4-aminopyridine on cardiovascular functions in the dog.

The drug 4-aminopyridine (4-AP) at a dose of 0.2 mg . kg-1 body weight intravenously is an effective antagonist of non-depolarizing neuromuscular blockade. We studied its cardiovascular effects in the canine heart using a right-heart bypass with extracorporeal circulation in seven dogs. This study demonstrates that 4-aminopyridine significantly augments arterial blood pressure, left ventricular dp/dt maximum, as well as left ventricular pressure at dp/dt mx. The highest values were obtained between two and 20 minutes after administration of 4-AP. Left ventricular end-diastolic pressure diminished slightly, but this was not statistically significant. Although the exact mechanism of action of 4-AP is not known, its positive inotropic effects may be of value in the reversal of non-depolarizing neuromuscular blockade in patients with impaired myocardial function of diverse aetiologies and it would be contra-indicated in patients with arterial hypertension and/or coronary artery disease.

Effect of tetrahydroaminoacridine and 4-aminopyridine on recovery from ketamine-diazepam anesthesia in the macacus rhesus monkey.

Tetrahydroaminoacridine (T.H.A., Tacrine) 1 mg/kg, and 4-aminopyridine (Pymadin) 0.2 and 1.0 mg/kg i.v., significantly reduced the recovery time when the were administered after ketamine-diazepam anesthesia in Maccacus Rhesus monkeys. Anesthesia was induced with ketamine (50 mg), diazepam (1.2 mg) and sodium glycopyrrolate (0.02 mg) as a secretiondrying agent, as a single bolus injection. Anesthesia was continued with ketamine by constant infusion of a solution of 5 mg/ml, at a speed of 20 mg/ml, at a speed of 20 ml/hour, during 30 minutes. The 5 monkeys in the control group were allowed to recover spontaneously. The test series consisted of the same monkeys, with an adequate rest period of one or more weeks between anesthesias. Recovery was indicated by production of nystagmus, and by an awake pattern in the EEG. Clinical signs, restlessness and purposeful movements, were also used.

Regional ketamine-induced depression of neuromuscular transmission in man.

The intravenous injection of ketamine in the human arm with isolated circulation, using the same technique as for intravenous regional anesthesia, produces a dose-related depression of neuromuscular transmission, as evidenced by the evoked response to supramaximal stimulation of the ulnar nerve with a nerve stimulator. The dose range of ketamine was 200, 25, 10, 5, 1, 0.5 and 0.25 mg, in 20 ml of 5% dextrose in water. The exact mechanism of this effect is discussed. This depression may have clinical significance under certain circumstances.

Ro21-3981/ketamine anesthesia for the treatment of poor risk patients.

Two consecutive anesthetics were given to a young severely debilitated patient, who had recently had bone marrow transplantation. On both occasions a combination of a new benzodiazepine, Ro21-3981, and ketamine was used, the first with the patient breathing oxygen spontaneously, and the second under relaxation and artificial ventilation with pure oxygen. The findings suggest that this technique provides cardiovascular stability during anesthesia and rapid return to consciousness, free from emergence phenomena. The technique facilitated the early transport of the patient away from the recovery facilities.

Ascending aorta-right pulmonary artery anastomosis in children with complex cardiac malformations. Long-term results in 30 cases.

In this report, we shall analyze the results obtained with palliative treatment in 30 patients with congenital heart disease who were operated upon at the University Hospital of Caracas during the period 1968 to 1972. In all cases, an ascending aorta-right pulmonary artery anastomosis was performed. Although we believe that the Blalock-Taussig and Potts shunt are satisfactory operations in some cases, at the present time we prefer the aorta-right pulmonary branch anastomosis in Fallots tetralogy and other congenital heart diseases such as single ventricle. In Fallot's tetralogy, particularly, this procedure provides better results, because the anastomosis can be closed through the aorta when these patients are later subjected to total correction with extracorporeal circulation.