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PubMed1982

Uncoupling of Na+-dependent solute transport in renal brush border membranes of maleate-treated rats.

The effect of maleate on the Na+-dependent transport of glucose, phenylalanine and phosphate in the renal brush border membranes (BBM) was studied. It was found that maleate as such had no effect on the isolated BBM vesicles. In BBM isolated from kidney cortex slices which were incubated with maleate, as well as in BBM isolated from the kidneys of maleate-treated rats, an inhibition of the Na+-dependent glucose and phenylalanine transport was observed, whereas the Na+-dependent phosphate transport was stimulated. In kidney slices these effects were prevented by the simultaneous addition of acetoacetate to the incubation medium. The permeability to Na+ ions was increased in the brush border membranes isolated from maleate-treated renal tissue. Cyclic AMP level was decreased nearly by half in the kidneys of maleate-treated rats. It is concluded that the formation of maleyl-CoA, which is prevented by acetoacetate, is a prerequisite for the effects of maleate on the BBM. The data suggest that the inhibition of Na+-dependent glucose and phenylalanine transport results from the uncoupling of Na+ and solute transport, due to increased permeability of the BBM to Na+. The stimulation of the phosphate transport system results probably from a decrease of cell cyclic AMP level. It is suggested that the uncoupling of Na+ and solute transport in the BBM is responsible for the generalized impairment by maleate of solute reabsorption in the renal proximal tubules.

Amino Acids↗
PubMed1982

Cerebral metabolic, vascular and protective effects of midazolam maleate: comparison to diazepam.

The effects of midazolam maleate and diazepam on cerebral metabolism and circulation were examined for each drug in six dogs maintained on N2O 70 per cent and halothane less than 0.1 per cent. Midazolam maleate at 0.2 mg/kg and diazepam at 0.3 mg/kg (the ED 100 per cent for induction of anesthesia for each drug in humans) did not decrease metabolic rate for oxygen (CMRO2) but did decrease cerebral blood flow (CBF) to about 55 per cent of control. Additional drug administrations (2.0, 5.0, and 10.0 mg/kg midazolam maleate, and 3.0 and 7.5 mg/kg diazepam) resulted in dose-related decreases in CMRO2 to a maximum of 55 per cent of control after 10.0 mg/kg midazolam maleate. Concomitant with the initial decreases in CMRO2, there was a change in the EEG as reflected by a decrease in frequency and an increase in amplitude. This EEG change suggests that 2.0 mg/kg midazolam maleate and 3.0 mg/kg diazepam represent a comparable canine anesthetic dose. Each additional dose of midazolam maleate decreased CBF to a greater extent than did the added doses of diazepam. Brain biopsies taken at the end of the midazolam maleate studies revealed a normal cerebral energy state (phosphocreatine, ATP, ADP, and AMP) and normal glucose, lactate, and pyruvate concentrations. In a hypoxic mouse model (FIO2 = 0.05), midazolam maleate provided greater protection from hypoxia (2.8 x control survival time) than diazepam (1.6 x control survival time). By comparison barbiturates in this model provide a survival time which is 4.0 x control.

Anesthetics↗
PubMed1998

Effects of monatepil maleate, a new Ca2+ channel antagonist with alpha1-adrenoceptor antagonistic activity, on cholesterol absorption and catabolism in high cholesterol diet-fed rabbits.

The mechanism of the prophylactic effect against hyperlipidemia by monatepil maleate was investigated in animal models. Monatepil maleate is an antihypertensive agent with Ca2+-channel antagonistic, alpha1-adrenergic receptor-blocking, and lipid peroxidation inhibitory activity. In high cholesterol diet-fed rabbits, monatepil maleate (30 mg/kg, p.o., once daily for 9 weeks) showed a prophylactic effect against increases in total cholesterol and beta-lipoprotein. Monatepil maleate significantly accelerated the clearance of radioactivity from the blood after intravenous injection of low-density lipoprotein (LDL) labeled with [1alpha,2alpha (n)-3H]cholesterol, increasing biliary excretion of [3H]-bile acids without modifying bile acid composition. Furthermore, monatepil maleate tended to inhibit the absorption of orally administered [1alpha,2alpha (n)-3H]cholesterol from the gastrointestinal tract in these rabbits. In Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of hepatic LDL receptor deficiency, monatepil maleate (30 mg/kg, p.o., once daily for 6 months) did not suppress the increase in plasma lipids. These results suggest that the plasma lipid lowering effect of monatepil maleate requires the presence of hepatic LDL receptors. It is also suggested that monatepil maleate improves plasma lipid metabolism through two mechanisms: enhancement of clearance of plasma LDL, which may be mediated by up-regulation of hepatic LDL receptors, and acceleration of conversion of free cholesterol to bile acids in the liver.

Adrenergic alpha-Antagonists↗
PubMed2001

Systemic bioavailability of nasally applied chlorphenamine maleate (0.4% nasal spray) relative to tablets administered perorally.

AIM: This study investigated the bioavailability of single doses of 1.12 and 2.24 mg chlorphenamine maleate applied intranasally (0.4% nasal spray) relative to a single peroral dose of 8 mg chlorphenamine maleate (tablets). METHODS: Twenty-four (24) subjects were treated with single nasal doses of 1.12 mg and 2.24 mg chlorphenamine maleate (0.4% nasal spray) and two 4 mg chlorphenamine maleate tablets (Piriton) on 3 separate study days according to a 3-way cross-over design with a 7-day wash-out between periods. Blood was sampled before and at 0.25, 0.50, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12, 16 and 24 hours after drug administration. Additional blood samples were obtained 36, 48 and 72 hours after peroral administration only. All subjects were included in the pharmacokinetic analysis. RESULTS: Nasally applied chlorphenamine maleate was readily absorbed, reaching peak plasma levels after 0.25 to 3.0 hours. The dose-normalized estimated mean Cmax values were 1.24, 1.43 and 1.21 ng/ml for the peroral tablet and the 1.12 mg and 2.24 mg nasal dose, respectively. The dose-normalized estimated mean AUC(0-infinity) values were 25.91, 26.44 and 25.56 ng x h/ml for the tablet and the 1.12 and 2.24 mg nasal dose, respectively. The estimated treatment ratios (nasal dose to tablet) of the dose-normalized values for the 1.12 mg nasal dose were 1.15 (900 CI: 1.0-1.32) and 1.02 (90% CI: 0.88-1.18) for Cmax and AUC(0-infinity), respectively, for the 2.24 mg nasal dose they were 0.98 (90% CI: 0.85-1.13) and 0.99 (90% CI: 0.85-1.13) for Cmax and AUC(0-infinity), respectively. The other pharmacokinetic characteristics (tmax, t(1/2), lambda(z), AUC(0-tf), MRTtot, CL/f and Vz/f) were comparable across all treatments. These data indicate that the disposition of chlorphenamine maleate was independent of the route and dose of administration. CONCLUSIONS: Chlorphenamine maleate is readily absorbed after nasal application using a 0.4% nasal spray. The nasal administration showed that the systemic bioavailability at the two dose levels used was comparable to that for the tablet. Maximum concentrations on the low dose, however, were higher and those on the high dose were comparable to those for the tablet. The nasal application of chlorphenamine maleate does not alter the overall systemic exposure compared to the oral route.

Administration, Intranasal↗
PubMed2003

[The safety and efficacy of rosiglitazone maleate in the treatment of patients with type 2 diabetes mellitus in China].

OBJECTIVE: To assess the clinical safety and efficacy of rosiglitazone maleate in the treatment of patients with type 2 diabetes mellitus. METHODS: A multi-center, open-label and 12-week duration study comprising of three cohorts, rosiglitazone maleate mono-therapy, rosiglitazone maleate plus metformin (Met) or sulphonylurea (SU) was carried out. RESULTS: A total of 2 308 patients enrolled in the study; but 2 134 completed and 174 withdrew from it. The percentages of patients reporting on-therapy adverse events were similar in the three cohorts. The most frequent adverse experiences were hyperlipidaemia (9.77%), upper respiratory tract infection (6.11%) and oedema (5.32%). There were totally 11 patients with serious, on-therapy adverse experiences. All serious adverse events (SAE) were considered by the investigator being not related to study medication except one case of SAE which was considered to be possibly related to the study medication. The mean levels of ALT in the three treatment cohorts were all reduced from baseline (25.5 IU/L) after treatment of 12 weeks (22.8 IU/L). Minor decreases in haemoglobin and haematocrit were observed in all treatment cohorts. Slight increases in total cholesterol, low density lipoprotein cholesterol and triglyceride were observed following 12 weeks of treatment, whereas high density lipoprotein cholesterol remained stable. In the efficacy evaluable population, the fasting plasma glucose reduction following 12 weeks of treatment was 1.70 mmol/L in the rosiglitazone maleate mono-therapy cohort, 1.47 mmol/L in the rosiglitazone maleate plus SU cohort and 1.36 mmol/L in the rosiglitazone maleate plus Met cohort, respectively. CONCLUSIONS: In this 12-week phase IV study, rosiglitazone maleate was found to be safe and well tolerated in all the three cohorts receiving rosiglitazone maleate as monotherapy or in combination with SU or MET for a large sample of population of patients with type 2 diabetes. Statistically significant reduction in fasting plasma glucose was observed in all the treated cohorts.

Adult↗
PubMed2004

Adsorption of organic matter at mineral/water interfaces. 2. Outer-sphere adsorption of maleate and implications for dissolution processes.

The effects of the adsorption of a simple dicarboxylate low molecular weight organic anion, maleate, on the dissolution of a model aluminum oxide, corundum (alpha-Al2O3), have been examined over a range of different maleate concentrations (0.125-5.0 mM) and pH conditions (2-10). In situ attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopic measurements indicate that maleate binds predominantly as an outer-sphere, fully deprotonated complex ([triple bond]AlOH2+ -Mal2-) at the corundum surface over the entire range of maleate concentrations and pH conditions investigated. In accordance with the ATR-FTIR findings, macroscopic adsorption data can be modeled as a function of maleate concentration and pH using an extended constant capacitance approach and a single [triple bond]AlOH2+ -Mal2- species. Outer-sphere adsorption of maleate is found to significantly reduce the protolytic dissolution rate of corundum under acidic conditions (pH < 5). A likely mechanism involves steric protection of dissolution-active surface sites, whereby strong outer-sphere interactions with maleate hinder attack on those surface sites by dissolution-promoting species.

Adsorption↗
PubMed1992

Screening for microorganisms producing D-malate from maleate.

More than 300 microorganisms were screened for their ability to convert maleate into D-malate as a result of the action of maleate hydratase. Accumulation of fumarate during incubation of permeabilized cells with maleate was shown to be indicative of one of the two enzymes known to transform maleate. The ratio in which fumarate and malate accumulated could be used to estimate the enantiomeric composition of the malate formed. Many strains (n = 128) were found to be capable of converting maleate to D-malate with an enantiomeric purity of more than 97%. Pseudomonas pseudoalcaligenes NCIMB 9867 was selected for more detailed studies. Although this strain was not able to grow on maleate, permeabilized cells were able to degrade maleate to undetectable levels, with a concomitant formation of D-malate. The D-malate was formed with an enantiomeric purity of more than 99.97%.

Bacteria↗
PubMed1975

Identity of maleate-stimulated glutaminase with gamma-glutamyl transpeptidase in rat kidney.

Gamma-Glutamyl transpeptidase was purified from rat kidney by a procedure involving Lubrol extraction, acetone precipitation, ammonium sulfate fractionation, treatment with bromelain, and column chromatography on DEAE-cellulose and Sephadex G-100. The final preparation (enzyme III), which exhibits a specific activity about 8-fold higher than that of the purified rat kidney transpeptidase previously obtained in this laboratory (enzyme I), was apparently homogeneous on polyacrylamide gel electrophoresis. Enzyme III is a glycoprotein containing 10% hexose, 7% aminohexose, and 1.5% sialic acid; a tentative molecular weight value of about 70,000 was obtained by gel filtration. Enzyme III has a much lower molecular weight and a different amino acid and carbohydrate content than the less active rat kidney transpeptidase preparation previously obtained, but obtained, but the catalytic properties of these preparations are virtually identical. It is suggested that bromelain treatment may liberate the transpeptidase from a brush border complex that contains other proteins. An improved method is described for the isolation of the higher molecular weight form of the enzyme (enzyme I) in which affinity chromatography on concanavalin A-Sephrose is employed. The purified transpeptidase (enzyme III) is similar to the phosphate-independent maleate-stimulated glutaminase preparation obtained from rat kidney by Katunuma and colleagues with respect to amino acid and carbohydrate content, apparent molecular weight, and relative transpeptidase and maleate-stimulated "glutaminase" activities. Both of these enzyme preparations are much more active in transpeptidation reactions with glutathione and related gamma-glutamyl compounds than with glutamine. In the absence of maleate, the enzyme catalyzes the utilization of glutamine (by conversion to gamma-glutamylglutamine, glutamate, and ammonia) at about 2% of the rate observed for catalysis of transpeptidation between glutathione and glycylglycine; the utilization of glutamine occurs about 8 times more rapidly in the presence of 0.1 M maleate. The transpeptidation and maleate-stimulated glutaminase reactions catalyzed by both enzyme preprations are inhibited by 5 mM L-serine in the presence of 5 mM sodium borate. Studies on gamma-glutamyl transpeptidase and maleate-stimulated glutaminase in the kidneys of fetal rats, newborn rats, and rats after weaning showed parallel development of these activities. The evidence reported here and earlier work in this laboratory strongly support the conclusion that maleate-stimulated glutaminase activity is a catalytic function of gamma-glutamyl transpeptidase. The studies on the ontogeny of gamma-glutamyl transpeptidase and other data are considered in relation to the proposal that this enzyme is involved in amino acid and peptide transport. Its possible role in renal formation of ammonia is also discussed.

Aging↗
PubMed1999

Myocardial ischemia due to vasospasm of small coronary arteries detected by methylergometrine maleate stress myocardial scintigraphy.

BACKGROUND: Recently, several case reports have implicated vasospasm of small coronary arteries in vasospastic angina pectoris. Vasospasm of small coronary arteries was also considered from angiographic findings in patients with atypical chest pain. In Syrian hamster, vasospasm in small coronary arteries was considered to be the cause of dilated cardiomyopathy. HYPOTHESIS: This study was undertaken to determine whether vasospasm in small coronary arteries can be induced by methylergometrine maleate stress thallium-201 (201Tl) myocardial scintigraphy. METHODS: Twenty-five patients with chest pain, all of whom had intact coronary arteries, were studied. After intracoronary methylergometrine maleate injection, coronary arteriograms also looked normal in all cases. Thallium-201 myocardial scintigraphy was carried out immediately after intracoronary methylergometrine maleate injection in four patients with chest pain. In the remaining 21 patients with chest pain, methylergometrine maleate was given intravenously within up to 2 weeks before 201Tl myocardial scintigraphy. RESULTS: In the intracoronary injection study, one patient had chest discomfort after methylergometrine maleate injection, and ST-segment elevation was observed on electrocardiogram (ECG). Of the 21 patients with chest pain, 11 patients felt angina-like chest pain after intravenous injection of methylergometrine maleate, but their ECGs showed no ischemic changes. Stress 201Tl myocardial scintigrams showed methylergometrine maleate-induced perfusion defects with complete redistribution in 3 of 4 patients in the intracoronary injection study and in 12 of 21 patients in the intravenous injection study. These findings suggest that vasospasm in small coronary arteries caused myocardial ischemia in 15 of 25 patients (60%) with chest pain. CONCLUSION: Vasospasm in small coronary arteries may be involved in the myocardial ischemia of some patients with chest pain who do not show any large coronary artery vasospasm.

Adult↗
PubMed2001

Brimonidine 0.2% given two or three times daily versus timolol maleate 0.5% in primary open-angle glaucoma.

PURPOSE: To evaluate the efficacy and safety of brimonidine 0.2% two or three times daily versus timolol maleate 0.5% solution twice daily. METHODS: Patients with primary open-angle glaucoma were randomized by Latin square technique to one of the three treatment sequences in this crossover, prospective double-masked trial. Each treatment period consisted of 6 weeks of chronic dosing followed by a diurnal curve for the intraocular pressure measured at 08:00, 10:00, 16:00, 18:00, 20:00, 22:00, and 24:00 hours. Intraocular pressure was measured by applanation tonometry. RESULTS: Thirty patients completed this trial. The average diurnal intraocular pressures in the trial were measured for timolol maleate (17.7 +/- 2.7 mm Hg), brimonidine given three times daily (18.0 +/- 2.2 mm Hg), and brimonidine given twice daily (19.2 +/- 2.4 mm Hg). There was a statistical difference between groups (P <.005). When groups were compared by pairs, three times daily dosing with brimonidine and timolol maleate both reduced the pressure more than twice daily brimonidine at every time point past 10:00 hours and for the diurnal curve (P <.05). In contrast, three times daily brimonidine and timolol maleate were statistically similar for the diurnal pressure, and each time point, except timolol maleate, decreased the pressure more at 16:00 (P =.042). Safety was similar between groups. CONCLUSIONS: This study demonstrated that both timolol maleate twice daily and brimonidine three times daily provide a similar intraocular pressure reduction to each other. Timolol maleate twice daily and brimonidine three times daily provide a greater decrease in pressure in the late afternoon and nighttime hours, compared with brimonidine twice daily.

Adrenergic alpha-Agonists↗
PubMed1996

Timolol hemihydrate vs timolol maleate to treat ocular hypertension and open-angle glaucoma.

PURPOSE: We compared the therapeutic efficacy and safety of timolol hemihydrate to timolol maleate in patients with ocular hypertension and chronic open-angle glaucoma. METHODS: We conducted this three-month study as a multicentered, masked, parallel group comparison. Both the 0.25% and 0.5% concentrations were evaluated against similar concentrations of timolol maleate. Dosing was twice daily. An open-label, nine-month study followed the masked portion of the protocol, in which all patients received either 0.25% or 0.5% timolol hemihydrate. A total of 371 patients were included in both the 0.25% and 0.5% studies. RESULTS: We found statistically similar intraocular pressures with both the 0.25% (18.3 and 18.6 mm Hg for the hemihydrate and maleate groups, respectively) and 0.5% (19.9 and 19.5 mm Hg for the hemihydrate and maleate groups, respectively) concentrations of timolol hemihydrate and timolol maleate after three months of masked treatment. Likewise, peak intraocular effect at two hours after taking the medication was statistically similar between medicines at both concentrations. Likewise, both ocular and systemic safety were similar between the maleate and hemihydrate preparations at both concentrations. In the nine-month open-label protocol, therapeutic efficacy (19.9 and 19.1 mm Hg for the 0.25% and 0.5% concentrations, respectively) and safety of timolol hemihydrate were similar to effect and safety of the three-month protocol. CONCLUSIONS: This study suggests that timolol hemihydrate had an ocular hypotensive efficacy and safety profile statistically equivalent to that of timolol maleate for up to three months of therapy. Timolol hemihydrate showed efficacy and safety similar to that observed within the first three months, for up to one year of therapy.

Adolescent↗
PubMedDate not supplied

Efficacy and tolerability of 0.5% timolol maleate ophthalmic gel-forming solution QD compared with 0.5% levobunolol hydrochloride BID in patients with open-angle glaucoma or ocular hypertension.

We compared the efficacy of timolol maleate ophthalmic gel-forming solution 0.5% QD with that of levobunolol hydrochloride 0.5% BID, as measured by change in intraocular pressure (IOP), effect on heart rate, and ocular tolerability. The study had a positive-controlled, double-masked, randomized, multicenter, 12-week, two-period (6 weeks each), crossover design. One hundred fifty-two patients with open-angle glaucoma or ocular hypertension were randomized to receive either timolol maleate gel-forming solution QD or levobunolol BID for 6 weeks, followed by a crossover to the alternate treatment. IOP and heart rate were measured at morning trough and peak during weeks 3, 6, 9, and 12. Timolol maleate gel-forming solution QD was comparable to levobunolol BID in reducing IOP at peak and trough. Although the effects on peak heart rate were similar between the two medications, the effect on trough heart rate of timolol maleate gel-forming solution QD was significantly less than that of levobunolol BID (P = 0.001). The incidence of ocular burning and stinging was comparable between the two treatments. Patients experienced significantly more blurred vision when using timolol maleate gel-forming solution than when using levobunolol (P = 0.013). Overall, more patients experienced at least one adverse event when using timolol maleate gel-forming solution. Timolol maleate gel-forming solution QD is as efficacious in reducing IOP as levobunolol BID.

Adrenergic beta-Antagonists↗
PubMed1998

Attenuation of ischemia--reperfusion injury by enalapril maleat.

1. The aim of this study was to investigate the effects of enalapril maleate on ischemia-reperfusion injury of the myocardium, after cardioplegic arrest in isolated guinea pig hearts, in a modified Langendorff model. 2. Animals were subjected to 90 min of normothermic global ischemia, followed by 30 min of reperfusion. Cardioplegic arrest was achieved by administering St. Thomas Hospital cardioplegic solution (STHCS). 3. The hearts were randomly allocated into four groups (n=8 in each group). The first group was utilized as control. In the second group, oral pretreatment was made (0.2 mg/kg enalapril maleat was given twice a day for 10 days). In the third group, enalapril maleat (1 micromol/l) was added to STHCS. In the fourth group, hearts were arrested with enalapril maleat-enriched STHCS, and enalapril maleat-enriched (1 micromol/l) Krebs-Henseleit solution was applied during the reperfusion period. 4. Although the study groups showed better recovery of contractility than did the control group, in the last group, the hearts had the best recovery of left ventricular systolic function, where dp/dt maximum was 89.7+/-6.9% of the preischemic values. Group 1, group 2 and group 3 achieved 44.2+/-4.5%, 79.4+/-5.8% and 68.1+/-6.7% of their preischemic dp/dt values. A similar observation was found for left ventricular developed pressure (LVDP); LVDP values were 52.4+/-2.1% (in group 1), 79.6+/-2.8% (in group 2), 72.8+/-4.6% (in group 3) and 86.7+/-5.8% (in group 4) of control after reperfusion. Creatine kinase leakage was significantly lower and postischemic coronary flows were significantly higher in group 4. 5. We concluded that usage of enalapril maleat in the reperfusion period was more effective for improving myocardial recovery after cardioplegic arrest. The additional protective effects of enalapril maleat not only were by angiotensin-converting-enzyme-inhibition-dependent coronary vasodilation and thiol-dependent limitation of oxidative injury, but could also be related to an oxygen-free-radical-scavenging effect.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Effect of the drug-matrix on the stability of enalapril maleate in tablet formulations.

The chemical stability of enalapril maleate in tablet dosage forms consisting of different formulation excipients has been studied in this work. The influence of various parameters such as heat, moisture, light and the drug-matrix was investigated. The degradation of enalapril maleate has been followed by using an HPLC method, which was demonstrated to be specific, stability indicating, accurate and precise. The degradation kinetics of enalalpril maleate in phosphate buffer solutions of pH values in the range of 2.2-10.5 were observed to be psuedo first order throughout the whole pH range studied. Enalapril maleate alone showed high stability for temperature under dry and humid conditions, however it became unstable when mixed with the drug-matrix in its tablet formulations and exposed to the same conditions. The pathway of degradation of enalapril maleate was found to be pH dependent. The extent of degradation of two different enalapril maleate tablet formulations (product A of a basic drug-matrix and product B of an acidic drug-matrix) has been investigated. The degree of degradation of the product with acidic matrix was significantly less than that of the basic matrix under same temperature and humidity conditions. In fact, diketopiperazine and enalaprilat degradants were mainly associated with the degradation of the product with the acidic matrix and that with the basic matrix, respectively. Dry enalapril maleate powder showed some photolysis, which was more significant with daylight (3.3%) compared with that under UV light (0.2%). Although the product with the acidic matrix showed some photolysis but the effect was not pronounced and the % recovery of enalapril was almost complete and within the acceptable experimental errors. However, the product with the basic matrix showed almost no response for photolysis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

The comparative ocular hypotensive effect of apraclonidine with timolol maleate in exfoliation versus primary open-angle glaucoma patients.

PURPOSE: To compare the effect of adding apraclonidine 0.5% to timolol maleate 0.5% in patients with exfoliation versus primary open-angle glaucoma. Since exfoliation glaucoma is known to demonstrate higher pressures than primary open-angle glaucoma on timolol maleate therapy alone, the authors wished to determine whether apraclonidine equalised the intraocular pressure (IOP) between these two glaucomas when added to timolol maleate. METHODS: We age-matched 30 consecutive exfoliation and 30 primary open-angle glaucoma patients who had an IOP > or = 22 mmHg on timolol maleate alone. Patients underwent IOP diurnal curve testing on timolol maleate twice daily alone and, 2 months later, following the addition of apraclonidine 0.5% three times daily. Statistical analysis of the IOP at each time point was by an unpaired t-test between groups. A paired t-test was used to evaluate the reduction in IOP from baseline within groups after the addition of apraclonidine. RESULTS: On timolol maleate alone, exfoliation patients had a higher mean IOP at 06:00 and 10:00 hours as well as a higher peak, range and standard deviation of the IOP compared with primary open-angle glaucoma patients (p < 0.05). Following the addition of apraclonidine the mean, peak and range of IOP were statistically similar between groups and only the standard deviations remained higher in the exfoliation glaucoma group (p < 0.001). The mean diurnal IOP after apraclonidine was added was 20.5 +/- 7.0 mmHg in the exfoliation glaucoma group and 20.0 +/- 3.4 mmHg in the primary open-angle glaucoma group, which was not significantly different between groups (p = 0.73). CONCLUSIONS: This study suggests that apraclonidine 0.5% used adjunctively with timolol maleate 0.5% solution is associated generally with similar IOP control in exfoliation and primary open-angle glaucoma patients.

Adrenergic alpha-Agonists↗
PubMed1979

Cardiovascular responses to diazepam and midazolam maleate in the dog.

Previous clinical studies establishing the efficacy of midazolam maleate (RO 21-3981), a new water-soluble benzodiazepine for induction of anesthesia, have not critically evaluated the effects of this agent on the cardiovascular system. The present study compares the cardiovascular effects of midazolam maleate and diazepam in conscious dogs. Systemic arterial, pulmonary arterial and central venous pressures, cardiac output, LVmax dP/dt, heart rate and regional coronary blood flow were measured 3 min following intravenous administration of diazepam (0.5, 1.0, and 2.5 mg/kg) or midazolam maleate (0.25, 1.0, and 10.0 mg/kg). Midazolam maleate increased heart rate 10--20 per cent with all three doses and decreased mean arterial blood pressure approximately 10--20 per cent at 1.0 and 10 mg/kg. Cardiac output was increased 10--12 per cent with all three doses of midazolam maleate, and LVmax dP/dt was decreased 13--16 per cent at the two higher doses. Diazepam at all three doses did not alter heart rate or mean arterial blood pressure. Diazepam, 1.0 and 2.5 mg/kg, produced significant (17 per cent) decreases in LVmax dP/dt, and 2.5 mg/kg produced a significant (10 per cent) increase in cardiac output. Neither drug in any dosage altered regional coronary blood flow, systemic or coronary vascular resistance, stroke volume, or stroke work. Maximum alterations in cardiovascular variables occurred with doses of midazolam maleate that are 10--15 times the recommended clinical induction dosage. It is concluded that in concentrations necessary for induction of anesthesia midazolam maleate has minimal effects on cardiovascular function.

Animals↗
PubMed1990

LY277359 maleate: a potent and selective 5-HT3 receptor antagonist without gastroprokinetic activity.

Several 5-hydroxytryptamine (5-HT3) receptor antagonists have been described. In addition to 5-HT3 receptor antagonist activity, many of these agents also possess gastroprokinetic activity. In the present report, we identify compound LY277359 maleate as a potent, p.o. active, highly selective 5-HT3 receptor antagonist lacking gastroprokinetic effects. LY277359 maleate was a potent and selective antagonist of 2-methyl 5-HT-induced contraction in the guinea pig ileum (KB = 1.6 nM), a response mediated by activation of 5-HT3 receptors. Given both i.v. (0.0003, 0.001 and 0.003 mg/kg) and p.o. (0.01 and 0.03 mg/kg), LY277359 maleate inhibited the bradycardic response to i.v. administered 5-HT in urethane-anesthetized rats. The duration of antagonism of 5-HT-induced bradycardia persisted beyond 6 hr after p.o. administration of LY277359 maleate (0.03 mg/kg p.o.). In contrast to its potent 5-HT3 receptor antagonist activity, LY277359 maleate, in doses up to 1 mg/kg p.o., did not affect gastric emptying in rats, suggesting minimal, if any, gastroprokinetic activity of LY277359 maleate. This is in contrast to another 5-HT3 receptor antagonist, zacopride, which did produce a marked increase in gastric emptying in rats at doses of 0.1 mg/kg p.o. and higher. LY277359 maleate (0.03 and 0.1 mg/kg i.v. and 0.07, 0.1, 0.3 and 1.0 mg/kg p.o.) did have effects consistent with other 5-HT3 antagonists, to inhibit cisplatin-evoked emesis in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by perhexiline maleate.

The effects of perhexiline maleate on growth and drug sensitivity were studied in the P388 murine leukemia cell line and in an anthracycline-resistant subline (P388/ADR). At noninhibitory concentrations, perhexiline maleate markedly increased the sensitivity of P388/ADR cells to doxorubicin but did not have such an effect on anthracycline-sensitive cells. The effects of perhexiline maleate on P388/ADR cells were reversible. Perhexiline maleate also increased the accumulation of another anthracycline, daunorubicin, in P388/ADR cells but did not increase its accumulation in the anthracycline-sensitive cells. Perhexiline maleate did not affect the sensitivity of either cell line to methotrexate or to 6-mercaptopurine. However, its effects on the sensitivity and on drug accumulation of vinblastine, a drug to which P388/ADR cells are cross-resistant, were similar to those observed for the anthracyclines. Although perhexiline maleate has been reported to be a calcium antagonist in other systems, our data do not suggest that this mechanism is involved in its enhancement of the sensitivity of P388/ADR cells to doxorubicin. We suggest instead that this effect might be associated with alterations of cell lipid metabolism induced by perhexiline maleate.

Animals↗