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A patient developed papilloedema and hepatic dysfunction while being treated with perhexiline maleate. These later regressed when the drug was withdrawn. Patients should be monitored for these potentially serious side-effects while on this drug.
The effects of timolol maleate administered intravenously on coronary and systemic haemodynamics, myocardial metabolism, and plasma catecholamine concentrations were assessed in 10 patients with confirmed coronary artery disease. Rapid atrial pacing to the onset of angina was performed in all patients. Timolol reduced cardiac output at rest and during pacing and reduced resting heart rate but did not affect arterial blood pressure. Left ventricular stroke work index fell during pacing. Coronary sinus blood flow was unchanged, but pulmonary artery diastolic pressure rose after timolol. The drug produced clinical improvement in nine of the 10 patients with prolongation of the mean pacing time to angina. There was evidence of improved myocardial metabolism with a change from production to extraction of lactate: Arterial noradrenaline concentrations at rest rose after timolol. In these patients with coronary artery disease timolol produced an increased tolerance to atrial pacing stress, which appears to be due to a combination of effects including reduced myocardial contractility and decreased lipolysis.
A patient prescribed timolol maleate for the control of hypertension developed dryness of the eyes. The symptoms improved on withdrawal of the drug. Vigilance for such adverse reactions must be observed in the use of any beta-adrenoreceptor blocking agent.
Systolic blood pressure responses to enalapril maleate (MK 421, a new angiotensin converting enzyme inhibitor (CEI] and hydrochlorothiazide (HTZ) were studied in conscious Dahl salt-sensitive (DS) and salt-resistant (DR) rats maintained on a high salt (8.0% NaCl) and a normal salt (0.4% NaCl) diet. The DS rats were severely hypertensive after 3 weeks on the high salt diet whereas the systolic blood pressure (SBP) of the DR rats were normotensive. Oral treatment with enalapril (15-100 mg X kg-1 X day-1) and HTZ (60-400 mg X kg-1 X day-1) caused a significant reduction of SBP in the DS rats with the high salt diet (P less than 0.001); however, this was not observed until after 4 weeks of treatment when the dosage was 30 and 150 mg X kg-1 X day-1, respectively. Furthermore, enalapril therapy alone significantly reduced the SBP of all groups of rats regardless of diet or Dahl strain (P less than 0.001), but this was not observed until the end of the 7th week of therapy in DR rats on 8.0% NaCl and the end of the 3rd week of therapy for DR and DS rats on 0.4% NaCl. These results suggest that enalapril may lower SBP by mechanisms other than those related to an action as a CEI.
Oxygen-induced retinopathy (OIR) similar to that seen in premature infants can be produced in newborn rats by exposure to 80% oxygen for the first 5 days of life, with subsequent recovery for 7 days in a room air environment. Previous studies have shown that the latter phase is associated with degeneration of retinal astrocytes. In the absence of astrocytes, the vascular endothelial growth factor (VEGF) is produced by the neurons of the inner retina. In this study, immunohistochemical methods were used to assess retinal expression of VEGF protein in ratlings exposed to the above protocol, with and without simultaneous treatment with topical timolol maleate. Intraocular pressure (IOP) and arterial pressure were measured. The severity of OIR was also evaluated in retinal flat mounts after India ink perfusion. The mean IOP was 8.25 +/- 0.32 mm Hg in untreated ratlings and 5.15 +/- 0.24 mm Hg in timolol-treated animals. OIR in retinas from the timolol group was less severe than that seen in untreated ratlings. VEGF protein expression was almost completely absent in the latter group. Retinas from timolol-treated animals expressed VEGF protein, though the level was inferior to that found in controls raised under room air conditions. In conclusion, these data seem to indicate that experimental OIR can be attenuated by a reduction of the IOP during and after oxygen supplementation. It is possible that these effects are due to improved ocular perfusion pressure, which would mitigate the hypoxic insult to the retina during the room air recovery period.
PURPOSE: To compare the 24-hour efficacy of dorzolamide and timolol maleate administered twice daily to primary open-angle glaucoma patients whose intraocular pressure (IOP) could not be adequately controlled with latanoprost monotherapy. METHODS: In this double-blind prospective crossover clinical comparison trial, 36 primary open-angle glaucoma patients with uncontrolled IOP despite treatment with latanoprost applied once daily were administered timolol and dorzolamide twice daily. The treatment sequence was randomized. All patients underwent measurements for four 24-hour tonometric curves: at baseline and after each 4-week period of treatment. The IOP measurements were taken at 06:00, 09:00, 12:00, 15:00, 18:00, 21:00, 24:00 and 03:00 h. The between-group differences were tested for significance by means of parametric analysis of variance at each time point and circadian curve. The peak values within circadian curve were defined. The mean of the exact amount and percentage of additional IOP reductions from baseline were evaluated and success rates (a minimum of 10% reduction) were determined for both drug regimens. RESULTS: The mean peak/circadian curve IOPs were 23.4 +/- 2.2/21.8 +/- 2.2 mm Hg at dorzolamide baseline, 23.3 +/- 2.2/21.7 +/- 2.1 mm Hg at timolol baseline, and reduced to 20.2 +/- 1.7/18.7 +/- 1.7 mm Hg and 20.7 +/- 2.4/19.4 +/- 1.6 mm Hg, respectively. When added to latanoprost, both dorzolamide and timolol lowered IOP at circadian curve significantly (p < 0.05). Dorzolamide reduced baseline IOP values at each time point. Timolol also significantly reduced baseline IOP values at all time points except at 03:00. The mean of the exact amount and percentage of reduction in IOP at circadian curve and 5 out of 8 time points were significantly greater with dorzolamide add-on treatment (p < 0.05). The successful reduction rates were 86% for the dorzolamide group and 61% for the timolol group (p = 0.016; chi(2) test). CONCLUSION: Both of the combinations are effective in lowering IOP, the exact amount and percentage of reduction is greater with the latanoprost + dorzolamide regimen, especially at night-time.
5 patients treated with perhexiline maleate, 200-400 mg/day for at least 6 months, exhibited evidence of hepatitis. The picture was very similar to acute alcoholic hepatitis, clinically, biologically and histologically with presence of necrosis, Mallory's hyaline, polynuclear infiltration and to a lesser degree, steatosis. Association with peripheral neuropathy, hypoglycemia, and renal failure appears strikingly frequently. The evolution was severe since 3 patients died within 6 months, even after treatment withdrawal. Further studies are to be done to understand the mechanisms of hepatic and neurologic toxicity, and to measure the hazards of this drug. These studies could bring a new insight to alcohol toxicity.
To investigate pattern electroretinogram changes in treated ocular hypertension, we evaluated pattern electroretinogram recordings of 48 hypertensive eyes following an 8-month timolol maleate therapy. During treatment, 27 of 48 eyes had normalized intraocular pressures (15-18 mm Hg), while 21 retained elevated values (21-25 mm Hg). Twenty-eight eyes with untreated hypertension (22-25 mm Hg) lasting at least 8 months, as well as 32 untreated, normotensive eyes served as controls. When compared to untreated normotensive controls, timolol-treated eyes with either elevated or normalized intraocular pressures showed reductions in the mean electroretinographic amplitudes. However, these amplitude reductions were substantially greater in treated eyes with elevated pressures as compared to those with normalized ones. Untreated hypertensive controls showed pattern electroretinogram reductions, with respect to normal values, that were comparable to those of treated hypertensive eyes, but larger than those of treated normotensive ones. These results indicate that, in treated ocular hypertension, pattern electroretinogram losses tend to be associated with moderately increased intraocular pressures in the range of 21-25 mm Hg. Electroretinographic abnormalities may be, at least in part, prevented only by lowering intraocular pressure into a normal range.
The effect of methylergometrine maleate (methergin) on electrical and mechanical activities of pregnant human isthmic myometrium was examined. Methergin (10(-8)-10(-6) g/ml) enhanced plateau potential and contraction, however, the effects were not prominent. Plateau potential and contraction were also potentiated after pretreatment with 10(-7) g/ml phentolamine (alpha-blocker), however 10(-7) g/ml methergin further increased these effects. It is suggested that methergin might potentiate contractions by changing the pattern of action potentials and not by alpha-adrenoceptor.
50 subjects participated in a 4-month study of the effects of an antihistamine on total menstrual loss. During the first 2 periods, no drugs were given; during the last 2 periods, an antihistamine or a placebo was administered according to a double-blind format. The menstrual weights of the first 2 months were averaged and compared with averages from the last 2 months combined. The treated group showed an average decrease in menstrual loss of 11.30 g compared to a decrease of 0.98 g in the placebo group. While the difference in means was not statistically significant, the variance between the 2 groups was significant (p = 0.0002), indicating that the antihistamine, chlorpheniramine maleate, was effective in reducing menstrual loss in certain individuals, but that the effect was neither uniform nor universal.
Metergoline, a prolactin (PRL) lowering drug, is used in the puerperal period to inhibit lactation. Methylergobasine maleate (MEM), widely employed in the puerperium to promote uterine contractions, has also been reported to decrease PRL release and to reduce lactation. To evaluate the possible interactions of the two drugs, groups of 6-11 puerperae each received no treatment, metergoline alone (8 or 12 mg/day for 5 days), MEM alone (0.2 mg i.v. at delivery followed by 0.5 mg/day p.o. for 5 days) and metergoline plus MEM. Metergoline fully prevented lactation and significantly reduced PRL release, the higher dose inducing effects faster. MEM was without effect on PRL release and lactation, and did not modify the effect of metergoline.
Intravenous perhexiline maleate in a canine preparation with fixed coronary flow increases coronary diastolic pressure. It also redistributes coronary flow so as to preserve endocardial flow. Myocardial oxygen consumption was reduced and lactate uptake enhanced by the drug. It had no effect upon the threshold for ischemic-induced left ventricular failure.
Despite large gains in the medical and surgical treatment of angina pectoris in the past two decades, many patients are refractory to conventional medical therapy and are unsuitable for a first or, more commonly, repeat coronary revascularization procedure. We evaluated the efficacy of perhexiline maleate, a drug with an antianginal mechanism of action in humans that is as yet unknown, by using a randomized double-blind placebo-controlled crossover design in 17 patients with refractory angina who continued to receive maximal antianginal therapy, typically including nitrates, a beta-blocker, and a calcium channel antagonist. In view of perhexiline's potential for hepatic and neurological toxicity, plasma drug levels were monitored and maintained in the 150-600 ng/ml range. Sixty-three percent of patients were judged perhexiline responders by objective exercise testing criteria, as compared with 18% of patients on placebo (p less than 0.05). By blinded review of subjective measures of anginal frequency and severity, 65% of patients noted an improvement while on perhexiline, whereas no patient identified the placebo phase with improvement. Side effects observed in 29% of patients were minor and related to transient elevations of blood levels of more than 600 ng/ml; no patient suffered hemodynamic or cardiac conduction abnormalities attributable to perhexiline. With attention to the pharmacokinetics of perhexiline's elimination in individual patients, this novel antianginal agent seems to be safe and effective and deserves further evaluation in patients already receiving maximal antianginal therapy who are not candidates for revascularization procedures.
Ergonovine maleate was given to a patient suspected as a case of Prinzmetal's variant angina following demonstration of normal coronary arteries by angiography. Profound shock, heart block, and severe pain accompanied marked spasm of the left coronary artery. Direct infusion of nitroglycerin into the left coronary artery reversed the spasm when sublingual and intraaortic nitroglycerin failed to prevent further hemodynamic and clinical deterioration.
UNLABELLED: The influence of long-term oral administration of enalapril maleate (an angiotensin II-converting enzyme inhibitor) on regional cerebral blood flow (rCBF) was studied in 10 patients with chronic cerebral infarction. The rCBF was measured by a 133Xe inhalation method before and after a mean of sixty-five days' administration of 5 mg of enalapril. RESULTS: Mean arterial blood pressure (MABP) was mildly decreased in 6 patients, but the average change in MABP was not significant (Endtidal partial pressure of carbon dioxide (PeC02) was not changed significantly. The mean rCBF was increased by 8% after administration of enalapril (0.05 less than p less than 0.1) There was no significant correlation between percent change in MABP and the percent change in rCBF. These results indicate that enalapril has not only antihypertensive action but also a beneficial effect on the cerebral circulation in patients with chronic cerebral infarction.
Patients taking oral doses of perhexiline maleate have been examined. Measurement of serum perhexiline concentrations established that different dose requirements between patients were necessary due to the different doses at which drug saturation was achieved. Measurement of serum perhexiline concentrations are essential if side-effects from the drug are to be avoided.
A placebo controlled-blind study performed on new patients presenting with mild to moderate essential hypertension. A once daily combined dose of timolol maleate and bendrofluazide in a 4:1 ratio was administered ot each patient after a four week placebo period. The starting dose was timolol 10 mg and bendrofluazide 2-5 mg and this dose was increased in steps of timolol 10 mg and bendrofluazide 2-5 mg until blood pressure was controlled. Eleven out of twelve patients achieved normotension, the falls in diastolic and systolic blood pressure being highly significant on active treatment compared with placebo. The once daily regimen of timolol and bendrofluazide resulted in good control of blood pressure with no more side-effects than occurred on the placebo. A combination of these two drugs in one tablet would appear to be both practical and advantageous and should increase patient compliance in taking medication.
Dexchlorpheniramine maleate 6 mg b.i.d. was compared with Terfenadine 60 mg b.i.d. for efficacy in controlling Ragweed Hay Fever symptoms, as well as tolerance and occurrence of adverse reactions. The study was a randomized, multicentric, parallel group, blind evaluator design which involved 174 patients equally divided, eighty-seven receiving dexchlorpheniramine and eighty-seven terfenadine, for a period of 2 weeks during the latter half of August and the first half of September 1983. The study indicated that dexchlorpheniramine at the doses tested, was significantly more effective in controlling hay fever symptoms than terfenadine.