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PubMed1975

On the mechanism of maleate action on rat kidney mitochondria. Effect on substrate-level phosphorylation.

1. Maleate inhibits the substrate-level phosphorylation linked to anaerobic dismutation of 2-oxoglutarate in rat kidney mitochondria. 2. Phosphate and magnesium diminish the inhibitory effect of maleate. Arsenate also relieves the inhibition of 2-oxoglutarate consumption but only at low (1 mM) phosphate concentration; at higher concentrations, the action of phosphate and arsenate is competitive. 3. Acetoacetate, malonate and succinate, the substrates of CoA-transferase, relieve the inhibition of 2-oxoglutarate metabolism by maleate both in the respiring mitochondria and in the "anaerobic" system containing antimycin and rotenone. 4. The interference in succinyl-CoA metabolism by maleate is discussed as a possible mechanism of the inhibitory action of this compound.

Animals↗
PubMedDate not supplied

Effects of maleate on CoA metabolism in rat kidney.

CoA transfer from acetoacetyl-CoA to maleate catalyzed by purified CoA transferase was studied. The thioester product of the reaction undergoes further chemical transformations and the final product appeared to be stable CoA derivative showing neither free SH group nor hydrolyzable thio-acyl bond. Similar product was obtained as the result of the reaction of addition of CoA to the double bond of maleic anhydride. This was confirmed by DEAE-chromatography. The decrease of free CoA and acid soluble acyl-CoA in kidney mitochondria respiring in the presence of maleate or in the kidney of maleate-treated rats occured without appreciable changes in acid insoluble acyl-CoA derivatives. As the result substantial loss of total content of CoA was found. The data indicate that maleate binds and removes CoA in the form of stable and metabolically inert compound.

Acetyl-CoA C-Acetyltransferase↗
PubMed1984

Induction of cystine and glutamate transport activity in human fibroblasts by diethyl maleate and other electrophilic agents.

The transport activity for cystine and glutamate in cultured human diploid fibroblasts is enhanced in response to diethyl maleate treatment. The enhancement is time- and dose-related, with a lag of about 3 h, and maximum enhancement (approximately 3-fold increase in the rate of uptake) is attained after 1 to 2 days of incubation of the cells with 0.1 mM diethyl maleate. The enhancement of the transport activity is accompanied by an increase in the Vmax and little change in the Km, and it requires RNA and protein synthesis. Other electrophilic agents, such as cyclohex-2-en-1-one, ethacrynic acid, 1,2-epoxy-3-(p-nitro-phenoxy)propane, and sulfobromophthalein, similarly enhance the transport activity. These electrophiles are known as agents that interact with glutathione. For example, diethyl maleate at high concentrations, i.e. 1 mM, depletes intracellular glutathione and injures the cells. However, at relatively low concentrations diethyl maleate and other electrophilic compounds do cause increases in the intracellular levels of glutathione which we attribute to the enhanced uptake of cystine. It is suggested that the transport system for cystine and glutamate is involved in a protective mechanism of cells against an electrophilic attack.

Biological Transport↗
PubMed1983

Significance of CoA-transferase in the reaction of maleate with amino acids and proteins.

Maleate reacts, in the presence of acetoacetyl-CoA and CoA-transferase with amino acids containing no sulphydryl groups. The physico-chemical properties of the reaction products are the same as those of the derivatives obtained in the reaction of amino acids with maleic anhydride, which indicates that the amino groups became acylated. In the presence of the transferase system, maleate also reacts with such proteins as histone IIA, cytochrome c and albumin. The reaction also occurs after blocking SH groups, thus it could involve amino groups as well. The reacting agent is not maleate itself but a product of the reaction of maleate with acetoacetyl-CoA, catalysed by the transferase, i.e. maleyl-CoA.

Acetyl Coenzyme A↗
PubMedDate not supplied

Pharmacokinetics of repeated single oral doses of enalapril maleate (MK-421) in normal volunteers.

Enalapril, the ethyl ester of a potent angiotensin converting enzyme inhibitor, enalaprilat, was administered to healthy volunteers as a capsule containing 10 mg of the maleate salt, every 24h for eight doses. Serum profiles show little accumulation of enalaprilat following eight daily doses of enalapril maleate. An average effective half-life for accumulation of approximately 11h was calculated from urine data. Comparison of observed 24-h urinary recoveries of enalaprilat to predicted steady-state recovery indicates that an 'average' steady state for enalaprilat is attained by the third or fourth dose of enalapril maleate. Statistical comparison of daily urinary recoveries, as well as Cmin values for enalaprilat, confirm this. Observed fluctuations in serum and urine data during apparent steady state suggest some day-to-day variability in the absorption of enalapril maleate and/or its hydrolysis to enalaprilat. An accumulation ratio of 1.3 for enalaprilat was calculated from the predicted steady-state urinary recovery and observed urinary recovery for dose one.

Administration, Oral↗
PubMedDate not supplied

Determination of ergometrine maleate by fluorescence detection.

A simple, accurate, sensitive and selective fluorescence analysis method for rapid determination of trace amounts of ergometrine maleate has been developed. The method is based on the fluorescence of ergometrine maleate. The calibration graph was linear in the range of 1 x 10(-4) to 0.2 microg/mL and the detection limit was 4 x 10(-5) microg/mL, with a relative standard deviation of 0.32% at 0.05 microg/mL (n = 11) ergometrine maleate. The influence of foreign compounds was tested. The proposed method was applied successfully to the determination of ergometrine maleate in pharmaceutical preparations and human plasma.

Calibration↗
PubMed1988

Simultaneous determination of pseudoephedrine hydrochloride, chlorpheniramine maleate, and dextromethorphan hydrobromide by second-derivative photodiode array spectroscopy.

The simultaneous determination of the active ingredients in multicomponent pharmaceutical products normally requires the use of a separation technique, such as HPLC or GC, followed by quantitation. Presented here is a rapid, validated, analytical method that does not require prior separation for the simultaneous determination of three drugs, pseudoephedrine hydrochloride, chlorpheniramine maleate, and dextromethorphan hydrobromide, in a tablet formulation. A diode array spectrophotometer, capable of multicomponent analysis, was used for the quantitation. The utility of this method was demonstrated in two ways: the analysis of a chewable pediatric tablet (formulation CP) containing 7.5 mg of pseudoephedrine hydrochloride, 0.5 mg of chlorpheniramine maleate, and 2.5 mg of dextromethorphan hydrobromide, and the dissolution analysis of a hydroxypropyl methylcellulose-based sustained-release tablet (formulation SR) containing 120 mg of pseudoephedrine hydrochloride, 8 mg of chlorpheniramine maleate, and 60 mg of dextromethorphan hydrobromide. The sensitivity of this assay is 7.5 micrograms/mL for pseudoephedrine hydrochloride, 1.0 micrograms/mL for chlorpheniramine maleate, and 5.0 micrograms/mL for dextromethorphan hydrobromide, using the second-derivative spectra of the absorbance with respect to wavelength. Determinations were made in 0.1 M sodium acetate buffer at pH 5.0 using a 1-cm quartz cell. Absorbance spectra, and their first and second derivatives, from 240 to 300 nm were used for the determination. The results obtained by this method compared favorably with the results obtained by a validated HPLC method.

Chlorpheniramine↗
PubMed1988

Modulation of induced resistance to adriamycin in two human breast cancer cell lines with tamoxifen or perhexiline maleate.

The clinical utility of adriamycin in the treatment of patients with metastatic breast cancer is often-limited by the development of drug resistance. It has been recognized that in addition to the development of primary resistance against adriamycin, malignant cells can simultaneously develop cross-resistance to other agents. An adriamycin-resistant human breast cancer cell line (MCF 7Ad) was developed by exposing the parent line (MCF 7) to gradually increasing concentrations of adriamycin while the cells were being grown in monolayer. Using these lines in a clonogenic assay, the relative drug sensitivities to adriamycin, vinblastine, melphalan, 5-fluorouracil and methotrexate were studied. MCF 7Ad was 12.5-fold more resistant to adriamycin than MCF 7 and 500-fold cross-resistant to vinblastine. There was no cross-resistance to melphalan, 5-fluorouracil or methotrexate. The resistance of MCF 7Ad was decreased by simultaneous exposure to tamoxifen (by a factor of 3.33) or perhexiline maleate (by a factor of 7.50). This decreased resistance was evidenced by a shift to the left of the sensitivity curves. However, there was no consistent change in the sensitivity curves of MCF 7. At the selected concentration of tamoxifen and perhexiline maleate, the cloning efficiency of MCF 7 and MCF 7Ad was 80%-90% of control values in medium without tamoxifen, perhexiline maleate or cytotoxic drugs. The resistance of MCF 7Ad to adriamycin was associated with a lower accumulation of [14C]adriamycin than exhibited by the sensitive MCF 7 line. There was no consistent change in [14C]adriamycin accumulation in MCF 7 or MCF 7Ad when tamoxifen was added, but when perhexiline maleate was added the [14C] accumulation increased. These results suggest that the tamoxifen-induced change in MCF 7Ad adriamycin resistance was not due to an increase in the amount of cell-associated adriamycin, but rather to some other mechanism that increased the cytotoxicity of the adriamycin.

Breast Neoplasms↗
PubMed1999

The effect of trimebutine maleate on gastric emptying in patients with non-ulcer dyspepsia.

The study was designed to investigate the effect of trimebutine maleate, a drug used in both hyperkinetic and hypokinetic motility disorders, on gastric emptying in patients with non-ulcer dyspepsia having prolonged gastric emptying rates and to compare the parameters used for the determination of the lag period observed during the emptying of solid foods from the stomach. Gastric emptying was measured by the radionuclide technique. Twenty normal volunteers and 43 patients with non-ulcer dyspepsia participated in the study. Radionuclide imaging was performed by using a solid meal labeled with 99mTc-tin colloid. Of the patients with non-ulcer dyspepsia, 20 had prolonged gastric emptying. They were given three weeks of oral treatment with trimebutine maleate and had their radionuclide gastric emptying study repeated. Treatment with trimebutine maleate resulted in reduction in duration of the lag period and less retention of food at 100 minutes (p < 0.0005). After treatment with trimebutine maleate, no significant difference has been observed in the mean symptom score of patients with prolonged gastric emptying. Among the parameters used for the determination of the lag period, lag period determined by a mathematical equation (TLAG) has been found to be longer than the lag period determined by visual inspection of the images (VLAG) and there was correlation between the two parameters when the lag time was short.

Administration, Oral↗
PubMed2005

A new fluorescent assay for enalapril maleate.

A new spectrofluorimetric method for the enalapril maleate monitoring was studied. Enalapril maleate was found to be highly photolabile. This drug was evaluated according to photodegradation assay at pH 2.5 and 6. Enalapril maleate was exposed to UVA-UVB radiations. Under these specific conditions was found as degradation product, the diketopiperazine. The modification of the fluorescent properties of enalapril maleate in solution after exposure UV-radiation and the degradation mechanisms were studied. The photodegradation was followed by the developed spectrofluorimetric assay.

Antihypertensive Agents↗
PubMed1979

Corneal anesthesia after timolol maleate therapy.

Symptomatic superficial punctate keratitis associated with complete corneal anesthesia occurred in three patients after they had been taking timolol maleate for glaucoma. After discontinuation of the timolol maleate and substitution of conventional antiglaucomatous collyria, the keratitis gradually cleared with restoration of normal corneal sensitivity. Corneal sensitivity, measured in 25 additional patients taking timolol maleate, was markedly diminished in four patients, all of whom were elderly and had been using the drug for a minimum of three months. Timolol maleate does appear to have some local anesthetic properties in human cornea after chronic use by susceptible individuals.

Aged↗
PubMed1976

Direct dopaminergic action of lisuride hydrogen maleate, an ergot derivative, in mice.

Lisuride hydrogen maleate induced stereotyped behaviour in normal as well as in reserpinized mice. It antagonized the motor depression and hypothermia induced by reserpine. On i.p. administration the compound was about as effective as apomorphine and D-amphetamine. As with apomorphine and in contrast to D-amphetamine the effects of lisuride hydrogen maleate in reserpinized mice were not impaired by additional treatment with alpha-methyl-p-tyrosine methylester. In untreated mice, the substance was very potent in lowering body temperature with significant hypothermia measured after dosages as low as 0.10 mg/kg i.p. Occurrence of stereotyped behaviour and hypothermia could be prevented by the dopaminergic antagonist haloperidol. From these data it is concluded that lisuride hydrogen maleate in addition to its interaction with serotoninergic systems is a potent dopaminergic agonist with a probably direct action on dopaminergic receptors. Further arguments in support of such an action of lisuride hydrogen maleate are, in addition to biochemical data, its serum prolactin lowering effect in rats, its strong emetic action in dogs and its effects on rat behaviour.

Animals↗
PubMed1989

Colorimetric methods for the assay of nomifensine maleate.

Two colorimetric methods are reported for the assay of nomifensine maleate. The methods are based on coupling between the diazotised form of nomifensine maleate and (i) N-(1-naphthyl)-ethylene diamine dihydrochloride (Bratton-Marshall reagent) and (ii) p-aminosalicylic acid (PAS). The optimum conditions for the reactions were investigated. The coupled products exhibit maximum absorbance at 470 and 435 nm for the Bratton-Marshall and PAS reagents, respectively. With PAS, a linear relationship has been established between absorbance (Amax) and concentration of nomefensine maleate over the range 2-12 micrograms ml-1. Similarly, with the Bratton-Marshall reagent, a linear relationship exists in the concentration range 2-16 micrograms ml-1. The calculated mean percent recoveries for nomifensine maleate in the commercial capsules (Merital 25 mg) respectively. Similarly, for the added recoveries, the percentage obtained were 99.01 +/- 0.46 and 100.03 +/- 1.03, respectively.

Aminosalicylic Acid↗
PubMed2006

A randomized, investigator-masked, 4-week study comparing timolol maleate 0.5%, brinzolamide 1%, and brimonidine tartrate 0.2% as adjunctive therapies to travoprost 0.004% in adults with primary open-angle glaucoma or ocular hypertension.

OBJECTIVE: The objective of this study was to assess the hypotensive efficacy of timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2% ophthalmic solution, administered in conjunction with travoprost 0.004%, in patients with primary open-angle laucoma (OAG) or ocular hypertension (OHT) whose intraocular pressure (IOP) did not meet the treatment target using travoprost 0.004% monotherapy. METHODS: This was a randomized, comparative, investigator-masked study. Patients with OAG or OHT treated with travoprost 0.004% monotherapy were randomized to receive 1 of the 3 adjunctive therapies (timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2%), 1 drop BID in each randomized eye, in addition to 1 drop QD of travoprost for a period of 4 weeks. IOP was measured on days 0 (travoprost 0.004%) and 28 (travoprost 0.004% and adjunctive treatment). Adverse events were monitored on days 0 and 28 by patient interview. RESULTS: Twenty-nine patients with OAG (46 eyes) and 3 patients with OHT (6 eyes), with a total of 52 eligible eyes, completed the study; 28 eyes were from male patients and 24 were from female patients. In addition to continuing travoprost treatment, 20 eyes received timolol, 16 eyes received brinzolamide, and 16 eyes were treated with brimonidine. There were no significant differences among the groups in the mean (SD) IOP at baseline on day 0 (19.0 [4.1], 17.2 [3.5], and 17.0 [3.1] mm Hg, respectively; P=NS). On day 28, the reduction in mean (SD) IOP in eyes treated with brimonidine tartrate 0.2% was significantly smaller (2.3 [1.8] mm Hg vs 3.9 [1.8] mm Hg [P=0.01]) and the mean (SD) percentage reduction in IOP was significantly smaller (13.4% [9.1%] vs 20.2% [7.5%] [P=0.01]) when compared with timolol maleate 0.5%, and likewise when compared with brinzolamide 1% (4.0 [2.1] mm Hg [P=0.02] and 22.7% [8.6%] [P=0.006], respectively). The group treated with brinzolamide was associated with a similar reduction in IOP to timolol (P=NS for both mean [SD] IOP and percentage reduction in IOP compared with timolol monotherapy). Barring the occasional conjunctival hyperemia, which was excluded as an adverse event for the purposes of this study, no adverse events were recorded. CONCLUSION: Brinzolamide 1% and timolol maleate 0.5% treatment were both associated with a significantly greater reduction in IOP compared with brimonidine 0.2% when administered as a nonfixed adjuvant to travoprost 0.004% in the treatment of patients with OAG and OHT whose IOP was inadequately controlled with travoprost monotherapy. All treatments were well tolerated.

Adrenergic alpha-Agonists↗
PubMed2000

Stability indicating HPTLC determination of timolol maleate as bulk drug and in pharmaceutical preparations.

Timolol was the first beta blocker to be used as an anti-glaucoma agent and to date remains as the standard because none of the newer beta blockers were found to be more effective. The high performance thin layer chromatographic method of analysis of timolol maleate is reported. The mobile phase selected was ethyl acetate-methanol-isopropyl alcohol-ammonia (25%) (80:20:2:1, v/v/v/v). The calibration curve of the drug was linear in the range of 100-600 ng. The spectrodensitometric analysis was carried out at 294 nm. The mean (+/- RSD) values of slope, correlation coefficient and intercept were 2487.5 (+/- 0.9), 0.996 (+/- 0.081) and 90463 (+/- 1.1), respectively. The system precision and the method precision were excellent with an RSD of 2.8 and 1.004, respectively. The limits of detection and quantitation were 10 and 40 ng, respectively. The mean percent recovery was found to be 98.6. Timolol maleate was degraded by exposing the drug to heat, acid and base. The degraded products were found to be well separated from the pure drug with significantly different Rf values suggesting a stability indicating analysis method for quantification of timolol maleate in pharmaceutical preparations and as bulk drug. The method was utilized to analyze timolol maleate from conventional eye drops and novel sustained release solid polymeric ocular inserts and oral preparations. The reported method is simple, selective, precise, accurate, time saving and economic as compared to reported HPLC methods.

Adrenergic beta-Antagonists↗
PubMed2002

Simultaneous determination of dorzolamide HCL and timolol maleate in eye drops by two different spectroscopic methods.

Two-component mixtures of dorzolamide hydrochloride and timolol maleate were assayed by first derivative and ratio derivative spectrophotometric methods. The first method, derivative spectrophotometry, by the zero-crossing measurements, was used due to the drugs closely overlapping absorption spectra. Linear calibration graphs of first derivative values at 250.3 nm for dorzolamide hydrochloride and 315.8 nm for timolol maleate. The second method, is based on ratio first derivative spectrophotometry, the amplitudes in the first derivative of the ratio spectra at 242.9 and at 223.5 nm were selected to determine dorzolamide and timolol maleate in the binary mixture. Calibration graphs were established for 8.0-30.0 microg ml(-1) for dorzolamide hydrochloride and 3.0-24.6 microg ml(-1) for timolol maleate in binary mixture. Good linearity, precision and selectivity were found, and the proposed methods were applied successfully to the pharmaceutical dosage from containing the above-mentioned drug combination without any interference by the excipients. Vierordt's method was also developed for a comparison method.

Adrenergic beta-Antagonists↗
PubMed2003

HPLC determination of aminophylline, methoxyphenamine hydrochloride, noscapine and chlorphenamine maleate in compound dosage forms with an aqueous-organic mobile phase.

A high-performance liquid chromatography procedure for the simultaneous determination of aminophylline, methoxyphenamine hydrochloride, noscapine and chlorphenamine maleate in commercially available compound capsule dosage forms has been developed and validated. The separation and quantification were achieved on an Ultrasphere C18 column using a mobile phase of dichloromethane-methanol-0.25% (v/v) diethylamine aqueous solution (20:60:20, v/v/v) at a flow rate of 1 ml min(-1) with detection of all analytes at 264 nm. The separation was achieved within 6 min for each drug mixture. The method showed good linearity for the aminophylline, noscapine, chlorphenamine maleate and methoxyphenamine hydrochloride mixture in the 125-750, 35-210, 10-60 and 62.5-375 microg ml(-1) ranges, respectively. The intra- and inter-day R.S.D.s ranged from 0.4 to 0.5%, 0.4-0.6%, 0.5-0.7% and 0.4-0.6% for aminophylline, noscapine, chlorphenamine maleate and methoxyphenamine hydrochloride, respectively. The recoveries (mean+/-S.D.) of low, middle and high concentrations were 99.9+/-0.9, 100.4+/-1.3 and 99.7+/-0.7% for aminophylline; 99.9+/-1.1, 100.4+/-0.7 and 100.1+/-0.8% for noscapine; 99.8+/-1.1, 99.7+/-1.0 and 100.7+/-0.8% for chlorphenamine maleate; and 99.8+/-0.9, 100.4+/-1.6 and 99.9+/-0.9% for methoxyphenamine hydrochloride, respectively.

Adrenergic beta-Agonists↗
PubMed2000

Efficacy and tolerability of intranasally applied dimetindene maleate solution versus placebo in the treatment of seasonal allergic rhinitis.

The aim of this study was to investigate the efficacy and tolerability of a 0.1% dimetindene maleate spray (Fenistil Nasal Dosierspray) compared to placebo when applied intranasally. Dimetindene (dimetindene maleate, CAS 3614-69-5, DMM) is a very potent and well established H1-receptor antagonist. A total of 36 asymptomatic patients (17 female, 19 male), suffering from seasonal allergic rhinitis from grass pollen, were randomly assigned to treatment with matching topicalnasal sprays with either dimetindene maleate 0.1% or placebo as control in a double-blind, randomised, cross-over-design, with 2 weeks wash-out periods between. The trial period was chosen in a pollen-free time from 20th October to 5th November 1998 to guarantee asymptomatic patients. The patients being allergic to grass pollen, verified by positive case history, positive skin prick test and positive nasal provocation test, were challenged under controlled conditions with purified airborne grass pollen in the Vienna Challenge Chamber. The nasal spray were applied as single doses (1 puff = 0.14 ml of the respective solution with or without 0.14 mg dimetindene maleate) in the evening before at 7.30 p.m. and in the morning at 7.30 a.m. to each nostril exactly 15 min before the onset of allergen provocation. The dosage scheme relates to a daily dose of 0.56 mg DMM in the active treatment group. Subjective nasal and ocular symptoms were measured on-line in time intervals of 30 min during the 4 h allergen provocation. The statistical analysis was a priori sequentially ordered to account for multiple testing and keep the 5% level of significance. All measured primary criteria, Total Nasal Symptom Score (p < 0.0001) calculated from the three single symptoms running of the nose (p = 0.0032) sneezing stimulus (p < 0.0001) and nasal itching (p < 0.0001), as well nasal secretion (p = 0.0031), resulted consistently in a statistically significant and clinically relevant superiority of 0.1% DMM compared to placebo. The same superior treatment effect was observed for all the other criteria, despite the nasal flow, but including the ocular variables. This can be interpreted as a positive efficacy also in secondary allergic conjunctivitis. No systemic or topical adverse events were reported. The results of the study demonstrate that 0.1% DMM as nasal spray is an efficient and safe application form for patients suffering from seasonal allergic rhinitis.

Administration, Intranasal↗