Age-related changes in hippocampal drug facilitation of memory processing in SAMP8 mice.

SAMP8/TaJf(P8) mouse strain has an inherited age-related impairment of learning and memory, while age-matched subjects of the closely related SAMR1/TaJf(R1) show no impairment. After training on footshock avoidance, P8 and R1 received a drug injection into the hippocampus. Retention was tested 1 week later. The results indicate that bicuculline (GABA antagonist), SKF38393 (DA agonist), and ST587 (NE agonist) facilitated retention with little change in the dose-response curves for P8 mice 4, 8, and 12 months of age. L-glutamate, acting at the NMDA receptor, showed a modest decline in ability to improve retention with increasing age. Arecoline, a muscarinic agonist, had the strongest trend for an age-related decline in potency. The same drug treatments yielded dose-dependent facilitation of retention but no age-related changes in R1 mice. Reduced cholinergic activity in the hippocampus may be, in part, responsible for age-related decline in memory retention in P8 mice.

Comparison of intravenous mexiletine and lidocaine for the treatment of ventricular arrhythmias.

The efficacy and safety of intravenous loading of mexiletine was compared to lidocaine in patients with ventricular premature depolarizations (VPDs). Seventeen men and five women, average age 63 years, completed this randomized parallel study. Twelve patients received mexiletine intravenously at (5 to 10 mg/min) until greater than or equal to 95% VPD suppression was achieved or a total of 450 mg of drug was given. The average loading dose of mexiletine was 4.4 mg/kg, at an infusion rate of 0.1 mg/kg/min. Ten patients received lidocaine (1 mg/kg) given over 3 minutes, with a second similar bolus given if after 10 minutes greater than or equal to 95% VPD suppression was not achieved. Total VPDs were determined for the 60 minutes before drug administration, during drug infusion, and 60 minutes thereafter. Eleven of 12 (92%) patients receiving mexiletine were full responders (greater than or equal to 95% suppression) and one was a partial responder (greater than or equal to 75% greater than or equal to 95% suppression). Five of 10 lidocaine patients (50%) were full responders, three (30%) were partial responders, and two failed to respond. At peak suppression, mexiletine reduced mean VPD from 37 +/- 33/5 minutes (mean +/- S.D.) to 0.8 +/- 0.9/5 minutes (p less than 0.01) and lidocaine decreased mean VPDs from 28 +/- 47/5 minutes to 4.7 +/- 2.2/5 minutes (p less than 0.01). Mexiletine resulted in greater suppression of VPDs than lidocaine in terms of mean percent reduction (96% vs 68%, p less than 0.01). All lidocaine patients had therapeutic plasma levels (range 1.6 to 3.5 micrograms/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Antianginal efficacy and improved exercise performance with timolol. Twice-daily beta blockade in ischemic heart disease.

Antianginal efficacy and improved exercise performance with timolol, a new beta-adrenergic blocking agent, was assessed in 23 patients with chronic stable angina pectoris in an 11-week double-blind, placebo-controlled study. Twenty-two of the 23 subjects completed the open-label phase of this investigation (weeks 0 to 6) while receiving 10 to 30 mg of timolol twice daily to optimize exercise capacity. Weekly anginal episodes and nitroglycerin consumption declined from 8.9 +/- 9.1 episodes/week and 8.1 +/- 10.6 tablets/week, respectively, with placebo to 2.7 +/- 5.2 episodes/week and 2.6 +/- 6.0 tablets/week with optimal timolol dose (p less than 0.05). Resting heart rate (HR) and systolic blood pressure (SBP) also decreased from 75.2 +/- 14.0 beats/min and 139.1 +/- 15.7 mm Hg with placebo to 55.1 +/- 8.9 beats/min and 130.5 +/- 15.9 mm Hg with timolol (p less than 0.05). Peak exercise HR, peak exercise SBP, and peak exercise double product (HR X SBP) were significantly (p less than 0.05) reduced when evaluated 12 to 13 hours after administration of timolol compared with placebo (101.5 +/- 21.1 beats/min verus 193.3 +/- 96.2 beats/min, 161.5 +/- 26.7 mm Hg versus 175.6 + 20.8 mm Hg, and 16.6 +/- 5.1 X 10(-3) versus 21.7 +/- 5.4 X 10(-3), respectively). Exercise duration was prolonged from 263.3 +/- 90.2 seconds to 330.3 +/- 73.9 seconds (p less than 0.05), while time to onset of 1 mm S-T segment depression was delayed in 15 patients from 231.8 +/- 86.4 seconds to 298.7 +/- 68.4 seconds (p less than 0.05). During the double-blind phase (weeks 7 to 10), 8 subjects received timolol and 11 patients received placebo. Nitroglycerin consumption at weeks 8 and 10 and anginal frequency at week 8 were unchanged compared with initial placebo treatment. Resting HR, peak exercise HR, and peak exercise double product were significantly attenuated at weeks 8 and 10 in timolol patients compared with their initial placebo exposure. However, these variables were unchanged in placebo subjects compared with their initial placebo therapy. Exercise duration was again prolonged at week 8 in timolol subjects compared with initial placebo results (315.1 +/- 61.2 seconds versus 261.3 +/- 68.8 seconds, p less than 0.05), but not at week 10. Placebo patients demonstrated no difference at week 8 or 10 in exercise performance compared with initial placebo treatment. Timolol twice daily, therefore, is potentially useful in some patients with angina pectoris. Other patients may, however, require a shorter dose interval for optimal angina control and maximal improvement in exercise capacity.

Short- and long-term therapy of mild essential hypertension with timolol.

The short and long-term antihypertensive action of timolol, a beta blocker, was assessed in 36 mild hypertensives in a 32-wk, double-blind, placebo-controlled study followed by an additional 96 wk of timolol in 17 responders. Diastolic blood pressure (DBP) and heart rate (HR) declined during the first phase from 103 to 93 mm Hg and from 73 to 61 bpm (P less than 0.01) but there was long-term timolol subjects (DBP 89 mm Hg at 32 wk and 88 mm Hg at 96 wk [NS] and HR 62 and 65 bpm [NS]). Although stimulated plasma renin activity in the entire group decreased from 1.08 to 0.28 ng/ml/hr (P less than 0.001), blood pressure reduction did not correlate with this decline (r = 0.29) or with serum timolol level (r = 0.29). In 20 patients who underwent treadmill was not altered. Thus, timolol is effective in reducing mild high blood pressure during short-term therapy and in maintaining this effect over the long term in responsive subjects. It is therefore potentially useful in chronic essential hypertension.