Half-life and vitreous clearance of trifluorothymidine after intravitreal injection in the rabbit eye.

To determine the half-life and vitreous clearance of trifluorothymidine, a drug that demonstrates good toxicity against cytomegalovirus (CMV), we injected 200 micrograms of the drug intravitreally in the eyes of nine New Zealand white rabbits. None of the rabbits showed any adverse reactions to the injection or the drug. The rabbits were killed at 3, 6, 12, 24 or 72 hours. High-performance liquid chromatography was used to measure the vitreous trifluorothymidine concentration. The half-life of the drug was found to be 3.15 hours, and the vitreous concentration remained above the ID50 (concentration required to inhibit cytopathic effects by 50% compared with control cultures) for CMV for about 30 hours. We conclude that trifluorothymidine may be of future benefit in the management of CMV retinitis.

Posterior chamber lens implantation following pars plana lensectomy and vitrectomy in severe proliferative diabetic retinopathy.

In two patients secondary cataracts developed after pars plana vitrectomy. In both cases the lens was removed from the pars plana, and the anterior capsule was kept intact. In one patient a posterior chamber lens was placed in the ciliary sulcus 3 months after the lens had been removed, and in the other patient a posterior chamber lens was implanted intraoperatively after pars plana lensectomy and vitrectomy. Improved visual results were obtained in both cases, and there was no evidence of rubeosis or elevated intraocular pressure. In selected cases preservation of the anterior capsule may be important to implant posterior chamber lenses in eyes requiring pars plana lensectomy and vitrectomy. To our knowledge this technique has not previously been reported.

Microencapsulation of bitolterol for controlled release and its effect on bronchodilator and heart rate activities in dogs.

Spheronized cores produced by extrusion and marumerization were microencapsulated with ethylcellulose by organic phase separation to produce beads exhibiting controlled-release characteristics. In vitro dissolution studies indicated that the drug was released as a first-order model and that the release rates were proportional to the amount of film on the bead. The bronchodilator activity in the anesthetized dog and the heart rate effect in the unanesthetized trained dog were evaluated. Microencapsulated beads were prepared which produced controlled release as assayed by bronchodilation. The heart rate increases induced by the controlled-release formulations were gradual in onset, and the total increase in heart rate over a 6-hr period was less than that associated with the plain drug powder.

Studies on bitolterol, di-p-toluate ester of N-tert.-butylarterenol: a new long-acting bronchodilator with reduced cardiovascular effects.

The bronchodilator activity of bitolterol, the di-p-toluate ester of N-tert.-butylarterenol (N-t-B) was evaluated by comparing it with the activity of the parent compound (N-t-B), isoproterenol and in some experiments with salbutamol in the anesthetized, open-chest dog maintained under artificial respiration. Bronchodilation was expressed as percent inhibition of the control bronchoconstriction induced by intravenous carbachol or histamine. At equiactive intravenous bronchodilator doses, the duration of action of bitolterol was 10 times that of N-t-B or isoproterenol. In the cardiovascular studies in anesthetized dogs, chronotropic, inotropic and blood pressure effects of bitolterol were markedly reduced relative to its bronchodilator effect. The bronchodilator/heart rate ratio for bitolterol was 22 times that of isoproterenol and 6 times that of N-t-B or salbutamol suggesting greater selectivity for beta2 adrenoreceptors for bitolterol. A good intraduodenal bronchodilator activity with a prolonged duration of action was obtained with bitolterol when compared with N-t-B and isoproterenol. The intraduodenal/intravenous bronchodilator dose ratio for bitolterol was 2 compared with 240 and 960 for N-t-B and isoproterenol, respectively. Bitolterol showed a significantly less (P less than .01) chronotropic effect than salbutamol at equibronchodilator doses (ED60) by intraduodenal or aerosol administration. A similar difference in chronotropic effect was observed in the unanesthetized dog. The prolonged bronchodilator effect of bitolterol was attributed to high concentration of the ester in lung tissues and to its slow hydrolysis, gradually releasing the active catecholamine, N-t-B.

Pars plana vitrectomy in the management of pupillary block glaucoma following irrigation and aspiration.

Pupillary block glaucoma developed in 3 children treated with irrigation and aspiration using the Cavitron phacoemulsification system. One had a congenital cataract, 1 had blunt trauma, and 1 had a penetrating injury. The factors contributing to pupillary block included excessive retained lens material, severe post-traumatic inflammation with synechia formation in 2 cases, and the lack of iridectomy in a case requiring a membrane discission. The pupillary block was successfully treated by pars plana vitrectomy in all cases; however, vision in 1 eye was lost owing to secondary glaucoma resulting from delay in treatment and the development of 360 degrees peripheral anterior synechiae.

Eye injuries from exploding car batteries.

Explosions of car batteries have become a frequent cause of eye injuries. A total of 62 patients were seen in our clinic during eight consecutive months. A wide range of injuries were discovered that extended from the anterior segment to the retina. The most common injuries were acid-induced conjunctivitis, corneal abrasions, and iridocyclitis. Hospitalization and surgery were required in some cases.

Esters of N-tert-butylarterenol. Long-acting new bronchodilators with reduced cardiac effects.

The preparation of various esters of N-tert-butylarterenol is described. Esterification of the phenolic OH groups has increased bioavailability, prolonged bronchodilation, and reduced tachycardia. The substitution of aromatic esters compared with simple aliphatic esters improved markedly these pharmacological properties. Of a number of esters tested, compound 45 (bitolterol) demonstrated the most favorable pharmacological properties as a bronchodilator. Its long duration of action and significant bronchodilator-cardiovascular separation are briefly described.

Comparison of animal models for predicting bronchodilator efficacy in man.

In vitro and in vivo models of bronchodilation were compared to assess their relative usefulness for predicting clinical efficacy. Drugs studied were isoproterenol, isoetharine, salbutamol, hexoprenaline, terbutaline, ephedrine and aminophylline. In vitro preparations were guinea pig perfused lung, tracheal strip and spontaneously beating right atria. In vivo, drugs were compared by three routes in conscious guinea pigs and anesthetized dogs and relative potency estimates and separations of bronchodilator and heart rate effects of these agents were determined. The Spearman rank correlation coefficient was statistically significant when the effects of the drugs were compared for guinea pig perfused lung and tracheal responses, in vivo guinea pig and dog intravenous and oral (or intraduodenal) responses. Aerosol results did not correlate, most likely due to differences in experimental techniques. Relative potency estimates were in general agreement with human data in the literature and support the use of these tests for the study of bronchodilator agents.

The role of bronchoconstrictors in evaluating smooth muscle relaxant activity.

Several bronchoconstrictor and smooth muscle relaxant agents were studied in a dog preparation (in vivo) and on guinea pig tracheal strips (in vitro). Isoproterenol, isoetharine and N-t-butylnorepinephrine, individually, had similar dose-response curves and ED50 values when tested as antagonists of histamine and carbamylcholine-induced bronchoconstriction in dogs. Diphenhydramine, cyproheptadine, thenyldiamine, atropine and suloxifen each exhibited more selective antagonism. A ratio of anticholinergic and antihistamine ED50s was obtained in dogs and on guinea pig tracheal strips. The rank order correlation coefficient of this ratio for each drug in the two species (rs = 0.93) was highly significant. Dose-responses to smooth muscle relaxant effects of isoproterenol were obtained with several different constrictors and experimental conditions on guinea pig tracheal strips. The choice of a constrictor and experimental conditions was found to affect EC50 values. The influence of resting tension, temperature, season, dibenamine-pretreatment and manner of performing the dose-response was evaluated. Both Ba and carbamylcholine were found to be suitable constricting agents under various conditions, whereas histamine, serotonin, potassium and rubidium had more limitations and eight other inorganic ions were not suitable.

Cardiovascular effects and blood concentrations of ajmaline and its 17-monochloroacetate ester in cats.

The antiarrhythmic drugs ajmaline and its 17-monochloroacetate ester (MCAA; Rtimos-Elle) were studied in cats. MCAA was less than half as toxic as ajmaline. Non-lethal doses of MCAA decreased blood pressure before heart rate, whereas ajmaline initially decreased heart rate. Both drugs prolonged the PR, QRS and QT intervals of the EKG. Recovery of these effects was within one hr. MCAA (10 mg/kg) and ajmaline (4.05 mg/kg) were studied separately by a one and 10 min infusion in the same cat. The dose of MCAA was ten times the usual dose in man and that of ajmaline four times the usual clinical dose. More marked effects were observed with the one min infusion. Arrhythmias were usually observed with ajmaline, but not with MCAA, even though it was rapidly converted to ajmaline. Maximal cardiovascular effects of MCAA and ajmaline were observed within 3 min of the end of infusion, which was also the time of peak blood levels. The elimination of MCAA resembled the kinetics of a multi-compartment system after a one min infusion. Peak blood levels declined by one-half in 3 min. Ajmaline blood levels declined linearly, with a half-life of 100 min, after a one min infusion. The peak blood level of MCAA after an intraduodenal dose of 25 mg/kg occurred at 20 min, whereas the peak blood level of the ajmaline formed occurred at 4 hr. In conclusion, MCAA has some different pharmacological properties and different kinetics of elimination than ajmaline.

Lack of cardiac or bronchodilator tachyphylaxis to isoprenaline in the dog.

1. Tachyphylaxis to heart rate and bronchodilator effects of (plus or minus)-isoprenaline was studied in anaesthetized open-chest dogs by 5 procedures. 2. Heart rate responses to a series of intravenous injections of isoprenaline were essentially unchanged before and after a 15 min infusion of isoprenaline (at 3 doses). 3. Heart rate and bronchodilator responses in the same animal to an intravenous injection of isoprenaline were not significantly different before and after a 30 min infusion of isoprenaline (at 2 doses). 4. Heart rate responses were relatively constant to an isoprenaline injection given every 30 min during a 4 h infusion of isoprenaline (at 3 doses), but the magnitude of the response was smallest for the largest infusion dose (highest background heart rate) and greatest for the smallest infusion dose (lowest background heart rate). 5. Heart rate and bronchodilator responses in the same animal to isoprenaline were relatively constant during a 5 h infusion of isoprenaline (at 2 doses). 6. Bronchodilator responses to intratracheally administered isoprenaline aerosol were essentially unchanged during a 4-5 h period using various doses and procedures. 7. Tachyphylaxis to the heart rate of bronchodilator effects of isoprenaline was not observed. The present data give no support to the hypothesis that tachyphylaxis to isoprenaline aerosols is an important mechanism in asthma mortality.