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PubMed1977

[Electron microscopic study of nerve, muscle and skin lesions induced by perhexiline maleate (author's transl)].

The pathological findings in four nerves and muscles and in one skin biopsies from four patients treated with perhexiline maleate for angina pectoris are reported. In every case, a muscular denervation atrophy and a decrease in the large diameter myelinated fibers were observed. Only one case showed a decrease of the total number of myelinated fibers, on quantitative studies. The electron microscopic study of each nerve displayed findings consistent with a predominant schwannian degeneration, associated with a few onion bulbs formations and, in two cases, with a mild wallerian degeneration. The most striking finding consisted in the presence of polymorphous membrane-bound inclusions reminding the morphology of lysosomal complex lipids. These structures were very abundant in Schwann cells, but they were seen also in fibrocytes, endothelial and pericytic cells. Similar inclusions were present in the single muscle and skin biopsies studied by electron microscopy. In the muscle, they were seen in muscular cells as well as in endothelial and pericytic cells. In the skin, similar inclusions were observed in endothelial, smooth muscle and sweat gland cells. These inclusions were difficult to identify in one micron thick sections, emphazing the need of ultrastructural study for diagnostic purposes.

Aged↗

PubMed1992

Complete disappearance of metastatic abdominal tumors from gastric cancer after treatment with irsogladine maleate.

A 60-year-old woman with gastric cancer had undergone partial gastrectomy in September 1989. Pathological examination revealed a poorly differentiated adenocarcinoma of pT3pN3pM0 (not resected for cure), stage IV. Postoperative adjuvant therapy comprised 1-(tetrahydro-2-furanyl)-5-fluorouracil plus uracil and OK-432. On 11 August 1990, two forefinger-tip-sized tumors were palpated beneath the operation scar. They increase in size, the superior tumor reaching 4x3 cm, the inferior tumor 5x3 cm on 5 September. Then, on 17 September, the inferior tumor was resected but the superior tumor remained; the histological type was poorly differentiated adenocarcinoma. After the operation, from 20 September, she was given 4 mg irsogladine maleate orally every day. On 8 October, there was no increase in the size of the superior tumor. By 29 October, the superior tumor had disappeared and no further tumor appeared thereafter; the patient showed no sign of relapse.

Abdominal Neoplasms↗

PubMed1994

Controlled exposure to mite allergen for a dose-finding of dimethindene maleate (DMM).

The aim of the study was to develop a laboratory system to challenge mite allergic patients with physiological concentrations of Der p I in order to evaluate the efficacy of antiallergic drugs in mite allergic patients. A double-blind, placebo-controlled, cross-over study was designed with three consecutive sessions. Twelve patients with proven sensitivity to dust mite were treated with a single dose of dimethindene maleate in a FOAD formulation (4 and 8 mg vs. placebo) 12 h before a long-term challenge with mite allergen Der p I in the Vienna challenge chamber. Challenge was performed with a constant concentration of 40 ng Der p I per cubic meter of air for 4 h. Nasal parameters were recorded at 15 min intervals during long-term challenge. In comparison to placebo, dimethindene leads to a statistically significant reduction (p < 0.05) of the nasal response at both concentrations tested. The house-dust mite model in the Vienna challenge chamber thus proved to be a useful tool for drug investigations in mite allergies.

Adult↗

PubMed1994

Influences of dimethindene maleate in a new formulation on oculo and psychomotor performance using the oculodynamic test (ODT) in volunteers.

Most antihistamines are assumed to possess a more or less pronounced sedative potential in addition to their antihistaminic properties. Therefore, a single-blind three-way crossover study was designed to assess the influence of single-dose dimethindene maleate (new "once a day formulation") on vigilance and performance vs. loratadine as reference and vs. placebo. Drug effects on performance were tested in 18 healthy volunteers by the oculodynamic test [ODT, i.e. choice reaction task (CRT), combined with recording of electrooculography (EOG) and cardiovascular parameters] and effects on subjective well-being by visual analogue scales (VAS). Main target parameters for evaluation of CNS-effects are latency and subjective perception of sedation (VAS). Neither statistically significant nor clinically relevant differences in all objective and subjective target variables (ODT and VAS) between active drugs and placebo, after single-dose administration were found. The same holds for accessory EOG, CRT and vital parameters under workload.

Adult↗

PubMed1990

Trimebutine maleate has inhibitory effects on the voltage-dependent Ca2+ inward current and other membrane currents in intestinal smooth muscle cells.

We examined effects of trimebutine maleate on the membrane currents of the intestinal smooth muscle cells by using the tight-seal whole cell clamp technique. Trimebutine suppressed the Ba2+ inward current through voltage-dependent Ca2+ channels in a dose-dependent manner. The inhibitory effect of trimebutine on the Ba2+ inward current was not use-dependent. It shifted the steady-state inactivation curve to the left along the voltage axis. Trimebutine also had inhibitory effects on the other membrane currents of the cells, such as the voltage-dependent K+ current, the Ca2(+)-activated oscillating K+ current and the acetylcholine-induced inward current. These relatively non-specific inhibitory effects of trimebutine on the membrane currents may explain, at least in part, the dual actions of the drug on the intestinal smooth muscle contractility, i.e. inhibitory as well as excitatory.

Animals↗

PubMed1980

Perhexiline maleate-induced lipidosis in cultured human fibroblasts: cell kinetics, ultrastructural and biochemical studies.

Perhexiline maleate reduced the growth of human skin fibroblasts in cell culture at a concentration range of 0.3-3 micrograms/ml. At the highest concentration, the cells survived only four days. Pleomorphic inclusions characteristic of drug-induced phospholipidoses appeared in cultured cells. Analysis of the major lipid classes was performed on cells exposed to 3 micrograms/ml at four days. Gangliosides, phospholipids and cholesterol levels four to six times above controls were found. No major qualitative abnormalities were detected in phospholipids. On the contrary, an abnormal pattern of gangliosides was seen by densitometry of silica gel thin-layer plates with increases of GD3 and of an unknown ganglioside. Drug induced lipidosis may involve other lipids than phospholipids, particularly gangliosides.

Cell Division↗

PubMed1981

The pharmacokinetics of lisuride hydrogen maleate in rat, rabbit and rhesus monkey.

The pharmacokinetics of lisuride hydrogen maleate (LHM) were investigated in rat, rabbit and rhesus monkey. Experiments were designed to meet not only the requirements of drug registration but also to serve other preclinical disciplines (toxicology, pharmacology). LHM is absorbed almost completely at a dose level of 100-250 micrograms/kg. During absorption and first liver passage (FPE) LHM is metabolized. The FPE was highest in the rhesus monkey and lowest in the rat. Calculated on bioavailability during chronic tolerance studies, in the highest dose group rats were burdened with 180-fold and rhesus monkeys with 70-fold the highest human dose (parkinsonism). Total clearance values indicated the presence of extrahepatic metabolism in all animal species. Terminal half-lives of unchanged drug in plasma were in the range of a few hours. Therefore, no accumulation of unchanged drug was expected to occur following daily repeated administration in the animal species investigated. Elimination of 14C-radioactivity proceeded mainly via the liver in rat and rabbit. The rhesus monkey excreted most of the dose administered in the urine. Enterohepatic circulation of 14C-material was demonstrated in the rat. In the rat but not in the other two species a small part of the dose (about 2%) accumulated in blood cells in the form of metabolites. Unchanged lisuride is able to cross membranes very rapidly, this was shown in distribution studies (whole-body autoradiography of rat, direct measurements in rat and rabbit). Transfer of lisuride into fetuses and brain is governed by its concentration in plasma. Drug level decrease in fetuses and brain was shown to somewhat slower than in plasma. Detailed evaluation of the distribution pattern in the brain of rat and rabbit showed a high affinity of lisuride for its preferential target tissue, the pituitary.

Absorption↗

PubMedDate not supplied

The pharmacokinetics and biotransformation of 14C-lisuride hydrogen maleate in rhesus monkey and in man.

14C-labelled lisuride hydrogen maleate was administered intravenously (25 micrograms) and orally (200 micrograms) to three male and three female elderly volunteers. Following i.v. injection radioimmunologically determined plasma levels of unchanged lisuride showed a three-phasic decline with half-lives of 3 minutes, 16 minutes and 2.9 hours. The total clearance was 16 +/- 9 ml/min/kg. Bioavailability was estimated to be 14% of oral dose. Determination of 14C-radioactivity did not show any specific enrichment of lisuride metabolites in cellular components of blood. The drug was almost totally metabolized and its degradation products were eliminated equally via the kidney and liver. Total recovery was about 90% of dose. The elimination half-life was 10 hours. Small parts of the dose administered were renally excreted with a half-life of 23 hours. Lisuride is metabolized extensively. HPLC radiochromatograms of freely extractable metabolites from urine did not show marked differences between both routes of administration. More than 15 compounds were freely extractable, only one of them represented more than 5% of dose. Phase II reactions were quantitatively unimportant. From rhesus monkey urine 6 metabolites were isolated. Chemical structures were proposed for 5 of them. They were assigned to the pattern of freely extractable human urinary metabolites and covered about 50% of radiolabel corresponding to about 13% of dose. The main freely extractable urinary metabolite was thought to be the 2-keto-3-hydroxy-lisuride derivative. Structures of the other four metabolites and earlier observations on the stability of the N'-ethyl-3H label led to the interpretation of independent changes of lisuride by different enzymatic processes such as oxidative N-deethylation, hydroxylation of the benzene system, monooxygenation at C2 and C9, and oxidation of double bonds at C2/C3 and C9/C10.

Animals↗

PubMed1998

Effects of trimebutine maleate on gastric motility in patients with gastric ulcer.

The effects of trimebutine maleate (TM), a prokinetic drug, on gastrointestinal motility in patients with gastric ulcer were investigated. Twenty patients with active gastric ulcers were allocated to two groups; 10 patients received a proton pump inhibitor alone (PPI group), given orally, and 10 patients received oral TM in combination with a PPI (PPI + TM group), each for a period of 8 weeks. Electrogastrography (EGG) and gastric emptying were measured before and after the treatment period. During the active ulcer stage, tachygastria (more than 0.06 Hz) or bradygastria (less than 0.04 Hz) in the EGG frequency were observed in 9 patients either before or after meals. During the healed ulcer stage, tachygastria or bradygastria was observed in 4 of 10 patients in the PPI group, while in the PPI + TM group, 1 patient had tachygastria and none had bradygastria. Postprandial dip (PD) was observed in 3 of the 20 patients during the active stage, while after treatment, PD was observed in 3 patients in the PPI group and in 6 patients in the PPI + TM group, respectively. Gastric emptying in the PPI group did not show any change between before and after treatment, while that in the PPI + TM group improved significantly after treatment. These results suggest that TM may have an ameliorative effect on abnormal gastric motility in patients with gastric ulcer.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1980

Coronary hemodynamic effects of ergonovine maleate in human subjects.

The coronary hemodynamic effects of ergonovine maleate were examined in 15 patients with a chest pain syndrome not thought to be variant angina. Ergonovine was given intravenously in sequential doses of 0.05, 0.1 and 0.25 mg while measurements were made of systemic hemodynamic variables, coronary sinus blood flow and coronary arteriovenous oxygen difference at intervals during the protocol. Coronary arterial diameters were measured from the 35 mm cineangiogram. Despite an increase in myocardial metabolic demand, as estimated with the heart-rate-blood pressure product, there was no apparent increase in coronary vascular resistance. In addition, there was a significant widening of the coronary arteriovenous oxygen difference in five of the seven patients in whom it could be measured. However, neither chest pain nor ischemic electrocardiographic changes were evoked. Although ergonovine also produced a diminution in epicardial coronary arterial diameters, this effect was not sufficient to explain the absence of appropriate coronary vasodilation. These results suggest that ergonovine may limit the normal vasodilatory response of the arteriolar bed to increases in myocardial metabolic demand.

Adult↗

PubMed1982

The effects of timolol maleate and acetazolamide on the rate of aqueous formation in normal human subjects.

We used a double-masked, randomized, placebo-controlled study of the effect of acetazolamide alone and timolol maleate alone and of the two in combination on the rate of aqueous humor flow in 21 normal subjects. The rate of aqueous flow was measured by fluorophotometry over an eight-hour period. Timolol decreased the flow by 33%, acetazolamide by 27%, and the drug combination by 44%, compared to the placebo treated eye (P less than .01). Timolol produced a 26% decrease in intraocular pressure. Timolol decreased the intraocular pressure in the fellow eye by 16%, acetazolamide by 21%, and the two drugs together by 35% (P less than .01). Neither drug significantly affected the anterior chamber volume, the endothelium's permeability, or the estimated endothelial pump rate.

Acetazolamide↗

PubMed1988

Impairment of bromosulfophthalein hepatic transport and cholestasis induced by diethyl maleate in the rabbit.

The present study was designed to investigate the effect of hepatic glutathione depletion induced by intraperitoneal administration of diethyl maleate (DEM) on the maximum biliary transport (Tm) and on the biliary excretion of bromosulfophthalein (BSP) in anaesthetized rabbits when the dye was perfused endovenously at doses exceeding Tm. The Tm of total BSP (BSPt) and that of conjugated BSP (BSPc) were significantly reduced after DEM administration whereas that of unconjugated BSP (BSPu) was markedly increased. A reduction in the biliary excretion of BSPt and BSPc, in the percentage of BSPc, in the cumulative excretion of BSPt and in the percent-dose recovery were also observed. However, no change in hepatic glutathione S-transferase activity was noted after DEM. The cholestasis observed following DEM administration coursed with falls in the biliary secretion of sodium, chloride and bicarbonate.

Animals↗

PubMed1983

Inhibition of histamine-induced nasal symptoms by the H1 antihistamine chlorpheniramine maleate: demonstration of topical effect.

To study whether a histamine H1 receptor antagonist inhibits allergic rhinitis symptoms by a peripheral or a central mode of action 21 normal volunteers were challenged with 500 micrograms histamine chloride in the right nasal cavity on four occasions after bilateral pretreatment with an H1 antihistamine spray and a placebo spray in various combinations. The H1 antihistamine (chlorpheniramine maleate, 0.5 mg) significantly inhibited histamine-induced tickling (P less than 0.01), sneezing (P = 0.01) and discharge (P less than 0.01), but only when it was given on the same side as histamine. This is highly suggestive of a local effect on sensory nerve endings, which prompts further studies on the topical use of antihistamines in the nose.

Administration, Intranasal↗

PubMed1979

Lisuride hydrogen maleate: an ergoline with beta-adrenergic antagonist activity.

Lisuride hydrogen maleate is identified as a potent beta-adrenergic antagonist using a hormone-sensitive adenylate cyclase system and [3H]dihydroalprenolol binding in cell free homogenates of rabbit cerebellum. Lisuride and two other ergolines, lergotrile and bromocriptine, and the phenothiazine, fluphenazine, all interact with spiroperidol binding sites (dopamine receptors) in the anterior pituitary; however, among these compounds lisuride is unique in its ability to antagonize the beta-adrenoceptor.

Adenylyl Cyclases↗

PubMed1982

The actions of cimetidine hydrochloride and mepyramine maleate in rat adjuvant arthritis.

Adjuvant arthritis in rats was induced by a single subcutaneous injection of Freund adjuvant into a hind paw. The injected paws' mean volume increased continuously by 80 +/- 26% after 6 h (acute local response). The injected paw displayed a biphasic response peaking at day 1-2 decreasing to day 5, then increased to day 14 by 123% while the contralateral non-injected paw showed little increase until day 10 and increased by 42% at day 14. The lateral diameter of both knee-joints also increased biphasically, peaking at day 4, decreasing to day 6, then increasing to day 14 (early and late systemic phase). Mepyramine maleate, 1 mg.kg-1 (i.p.) daily, suppressed only the early systemic phase by 50%. Daily cimetidine hydrochloride, 1 mg.kg -1.day-1, almost completely abolished the inflammatory response in the knee joints up to day 12, while at day 14 the suppression was 71%. The increase in mean paw volume was also suppressed by orally administered cimetidine. Intraperitoneal doses of cimetidine (3.5 mumol.kg-1) totally suppressed paw oedema produced by subplantar injection of histamine (1.8 mM) but had no action on equiactive dose of the specific H1-agonist, 2-pyridylethylamine. Mepyramine at 3.5 mumol.kg-1 or greater produced no more than 50% suppression of the histamine response. A component of both adjuvant and histamine-induced responses thus appears to be histamine H2-receptor mediated.

Aminopyridines↗

PubMed1987

Effect of trimebutine maleate on sinus node pacemaker activity of the rabbit.

The electrophysiological effects of trimebutine maleate were studied on rabbit sinus node cells with the two-microelectrode voltage clamp method. Trimebutine (above 10 microM) produced a negative chronotropic effect accompanied by decreases in the maximum upstroke velocity at phase 0, slope of phase 4 depolarization and action potential amplitude. The effects on the current systems were depression of the slow inward current and a decrease in the current oscillations induced by elevating [Ca]0. It is concluded that trimebutine exerts a Ca2+ channel blocking effect on the sinus node pacemaker cells.

Action Potentials↗

PubMed1993

Zaldaride maleate, an intestinal calmodulin inhibitor, in the therapy of travelers' diarrhea.

BACKGROUND: The therapeutic value of zaldaride maleate (Zm), an intestinal calmodulin inhibitor, was examined in patients with travelers' diarrhea, known to be caused by enterotoxigenic Escherichia coli (ETEC) and other bacterial agents. METHODS: One hundred seventy-six American students acquiring diarrhea in Mexico during the summer of 1991 were given Zm in doses of 5 mg, 10 mg, or 20 mg, or a matching placebo, four times a day for 48 hours. RESULTS: The duration of diarrhea was reduced by 53% in the group given the 20-mg Zm dose (overall P < 0.01). Curative antibiotics were required post-treatment only in the placebo and 5-mg Zm groups (P < 0.01). The number of unformed stools passed during 0-48 hours of therapy with the highest Zm dose was reduced compared with placebo by 36% for all subjects (P < 0.05), by 39% for ETEC diarrhea (NS), by 45% for those with any bacterial agents (NS), and by 38% for those without an identifiable bacterial agent (NS). CONCLUSIONS: The fact that a calmodulin inhibitor decreases the severity and duration of travelers' diarrhea has therapeutic implications and suggests that calmodulin and intracellular calcium may serve as mediators of diarrhea in bacterial enteric infection.

Adolescent↗

PubMed1979

Analysis of the major lipid classes in human peripheral nerve biopsies. Age group differences and abnormalities of ganglioside level in perhexiline maleate therapy.

We report here the results of a simple and reproducible technique which can be used in semi-routine analysis of peripheral nerve biopsy specimens, so as to have a quantitative analysis of the major lipid classes, i.e. cholesterol, cerebrosides, ethanolamine phospholipids, phosphatidyl-choline, phosphatidyl-serine + phosphatidylinositol, sphingomyelin and gangliosides. Glycolipid hexoses, cholesterol and total phospholipids have been compared in different age groups. Although all lipid classes increased from the younger to the older age group, the molar ratio of cholesterol to phospholipid differed less than the glycolipid to phospholipid ratio. Both increased significantly, even between age group 10--16 and older patients (36, 54, 61, 68, 72 and 73 years old). Although individual variations in lipid content are noteworthy, it must be emphasized that evolution with age of the lipid composition must be taken into account. Furthermore, this study confirms and extends earlier findings of increased ganglioside levels in some cases of peripheral neuropathies observed during perhexiline maleate therapy where characteristic lipid-like polymorphous inclusions have been demonstrated.

Adolescent↗