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PubMed1998

Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

PURPOSE: Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS: Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS: A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION: Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

Adult↗
PubMed1985

Mouse hypothalamic somatostatin release: roles of calcium and calmodulin.

We employed a short term system of dispersed adult mouse hypothalamic cells, as previously described in the rat, to examine the roles of calcium and calmodulin in SRIF release. Incubation studies were performed 24 h after hypothalamic cell dispersion. SRIF release, as determined by RIA was stimulated in a dose-dependent manner by the membrane-depolarizing agents KCl, ouabain, and veratridine as well as by the calcium ionophore A23187. The stimulation of SRIF release induced by depolarizing agents was abolished or diminished by 1) omission of extracellular calcium, 2) chelation of extracellular calcium by EGTA, and 3) the calcium channel blocker verapamil, indicating calcium dependence of this process. Three chemically distinct groups of calmodulin inhibitors were employed to study the role of calmodulin in stimulus-secretion coupling of hypothalamic SRIF. The neuroleptic calmodulin inhibitors trifluperazine (1 microM), chlorpromazine (10 microM), and promethazine (10 microM) as well as the naphthalene sulfonamide calmodulin inhibitor W7 (1 microM) and compound 48/80 (50 micrograms/ml) were all demonstrated to have an inhibitory effect on the stimulation of SRIF release induced by membrane depolarization. No inhibitory effect of the less potent naphthalene sulfonamide agent W5 was observed at 1 microM, although an inhibitory effect was seen at 10 microM. The stimulation of SRIF release induced by A23187 was not inhibited by omission of extracellular calcium or by verapamil, but was inhibited by EGTA and trifluperazine. These data demonstrate the role of calcium in membrane depolarization-induced stimulus-secretion coupling of mouse hypothalamic SRIF. Inhibition of the stimulatory response by low concentrations of three distinct groups of calmodulin inhibitors, i.e. neuroleptics, naphthalenesulfonamide agents and compound 48/80, suggests a role for calmodulin in this process.

Animals↗
PubMed1980

Histamine receptors on dispersed parathyroid cells from pathological human parathyroid tissue.

The effects of histamine on cAMP accumulation and parathyroid hormone (PTH) release were studied in dispersed cell preparations from pathological parathyroid tissue of 13 patients with primary hyperparathyroidism. Histamine stimulated cAMP accumulation 1.4- to 110-fold in a dose- and time-dependent manner. The increased cAMP content was inhibited by the H2 antagonist cimetidine and the H1 antagonist promethazine, with Ki values of 0.14--0.46 and 0.2--0.37 micrometer, respectively. Moreover, in one cell preparation, the H2 agonist dimaprit stimulated cAMP accumulation 2- to 3-fold, while the H1 agonist 2-pyridylethylamine had no effect on cAMP levels. The potent alpha-and beta-adrenergic antagonists phentolamine and propranolol did not inhibit histamine-stimulated cAMP accumulation significantly. Histamine also caused a dose- and time-dependent increase in PTH release, with a Ka in reasonable agreement with that for cAMP accumulation (0.5--1 vs. 3 micrometer, respectively), indicating that enhanced cAMP accumulation was linked to increased secretion. These results indicate that pathological human parathyroid cells have histamine receptors, probably H2 in subtype, which mediate enhanced cAMP accumulation and PTH release.

Cyclic AMP↗
PubMed1994

Inhibition of presynaptic catecholamine synthesis with alpha-methyl-para-tyrosine attenuates nocturnal melatonin secretion in humans.

The catecholamine dopamine (D) is involved in the regulation of LH and PRL secretion, whereas a dysregulated noradrenergic system may contribute significantly to symptoms encountered in affective disorders. This explains the attraction of using alpha-methyl-para-tyrosine (AMPT) in neuroendocrine and psychiatric research, as it inhibits both neurotransmitters. PRL has been used as a marker of the effectiveness of AMPT in blocking D function, but no good marker for the effectiveness of AMPT in blocking norepinephrine (NE) is available. The purpose of this study was to determine whether melatonin (M) might serve as such a marker, as its production and secretion are regulated by NE. Seven subjects were given either AMPT or promethazine, which does not alter M secretion, in a randomized, double blind fashion, and 24-h M secretion was studied. Two-way analysis of variance revealed a significant difference in M secretion (F = 13.2; df = 17,102; P = 0.0013), with the following time points being different: 22, 23, 24, 1, 2, 3, 4, 5, and 6 h. Also, 24-h urinary 6-sulfatoxymelatonin excretion correlated highly with 24-h M secretion, expressed as the area under the curve in the AMPT experiment (r = 0.93; P = 0.002), which indicates that AMPT does not alter the metabolism of M. These results demonstrate for the first time that AMPT significantly attenuates nocturnal M secretion. It is concluded that M is a good marker for characterizing the effectiveness of AMPT in inhibiting sympathetic NE activity.

Adult↗
PubMed2002

Preparation, characterization and taste-masking properties of polyvinylacetal diethylaminoacetate microspheres containing trimebutine.

The objectives of this study were to produce acid soluble, polyvinylacetal diethylaminoacetate (AEA) microspheres containing trimebutine (as maleate), using a water-in-oil-in-water (w/o/w) emulsion solvent evaporation method, to characterize their in-vitro release properties, and to evaluate the taste-masking potential of this formulation in human volunteers. The pH of the external aqueous phase was the critical factor in achieving a high loading efficiency for trimebutine in the microencapsulation process; nearly 90% (w/w) loading efficiency was obtained at above pH 10. Trimebutine was completely released from AEA microspheres within 10 min in a dissolution test at pH 1.2, simulating conditions in the stomach, whereas at pH 6.8, the pH in the mouth, only small quantities of trimebutine were released in the initial 1-2 min. The results of a gustatory sensation test in healthy volunteers confirmed the taste-masking effects of the AEA microspheres. Finally, an attempt was made to encapsulate the salts of other basic drugs (lidocaine, imipramine, desipramine, amitriptyline, promethazine and chlorpheniramine) into AEA microspheres using the w/o/w emulsion evaporation method. The loading efficiencies were ranked in almost inverse proportion with the solubility of the drugs in the external aqueous phase. This study demonstrated the possibility of masking the taste of salts of basic drugs by microencapsulation with AEA using a w/o/w emulsion solvent evaporation method.

Algorithms↗
PubMed2006

Anti-allergic properties of Mangifera indica L. extract (Vimang) and contribution of its glucosylxanthone mangiferin.

Vimang is the brand name of formulations containing an extract of Mangifera indica L., ethnopharmacologically used in Cuba for the treatment of some immunopathological disorders, including bronchial asthma, atopic dermatitis and other allergic diseases. However, the effects of Vimang on allergic response have not been reported until now. In this study, the effects of Vimang and mangiferin, a C-glucosylxanthone isolated from the extract, on different parameters of allergic response are reported. Vimang and mangiferin showed a significant dose-dependent inhibition of IgE production in mice and anaphylaxis reaction in rats, histamine-induced vascular permeability and the histamine release induced by compound 48/80 from rat mast cells, and of lymphocyte proliferative response as evidence of the reduction of the amount of B and T lymphocytes able to contribute to allergic response. In these experiments, ketotifen, promethazine and disodium cromoglicate were used as reference drugs. Furthermore, we demonstrated that Vimang had an effect on an in-vivo model of inflammatory allergy mediated by mast cells. These results constitute the first report of the anti-allergic properties of Vimang on allergic models, as well as suggesting that this natural extract could be successfully used in the treatment of allergic disorders. Mangiferin, the major compound of Vimang, contributes to the anti-allergic effects of the extract.

Anaphylaxis↗
PubMed1993

Resistance to decamethonium neuromuscular block after prior administration of vecuronium.

Prior administration of nondepolarizing neuromuscular blocking drugs reduces the potency of subsequently administered succinylcholine. To assess whether this interaction is also observed with the depolarizing drug, decamethonium, the potency of decamethonium alone and decamethonium after vecuronium (10 micrograms/kg) were assessed using a cumulative dose-response technique in two groups of six healthy patients each. Patients were premedicated with meperidine and promethazine and anesthetized with thiopental, isoflurane, and nitrous oxide in oxygen. Twitch tension was monitored using adductor pollicis mechanomyography in response to ulnar nerve stimulation at 0.1 Hz. The mean (SEM) dose of decamethonium producing 80% twitch tension depression (ED80) when administered alone was 37 (4.0) micrograms/kg. After recovery of twitch tension (but persistence of train-of-four fade) from vecuronium, the mean (SEM) ED80 for decamethonium was increased to 89 (4.4) micrograms/kg (P < 0.01). The shift to the right of the dose-response curve for decamethonium was nonparallel. Antagonism is observed when decamethonium is administered after a small dose of vercuronium; this interaction, which is also seen with succinylcholine, is likely to be a feature of depolarizing block. Nonparallel shift of the dose-response curve to decamethonium indicates that this is not likely to be a simple agonist-antagonist effect at a single site.

Adult↗
PubMed1993

Metabolic formation of dimethylamine and methylamine from basic drugs containing N-methyl group: a newly established chromatographic assay and its application to the determination of deaminase activity.

A new method of assaying deaminase activity was established in which methylamine and/or dimethylamine formed from drugs containing N,N-dimethyl or N-methyl group were derivatized with phenylisothiocyanate to phenylthiourea derivatives. After purification with Sep-PAK C18 cartridge, the derivatives were separated by a reversed phase high-performance liquid chromatography monitored by ultraviolet absorption. The recoveries and determination limits of methylamine and dimethylamine were over 55% and about 0.4 nmol/ml of incubation mixture, respectively. The method was used to measure the deaminase activities of liver microsomes of rats, rabbits and guinea pigs for 11 drugs. Of the compounds tested, diphenhydramine and diltiazem are deaminated with microsomes from all the above animal species; rat and rabbit liver microsomes also well deaminated promethazine. Most other drugs such as chlorpromazine, promazine, imipramine, amitriptyline and tetracaine were found to be poor substrates. In general, dimethylamine but not methylamine was the predominant metabolite formed from drugs containing N,N-dimethylamino group. The results also suggested that the deamination of these compounds takes place mainly via a one step mechanism, thus implying that the sequential reaction consisting of N-demethylation and elimination of ammonia is of minor importance. The relation between in vitro deaminase activity and the extent of the in vivo deamination for drugs is discussed.

Aminohydrolases↗
PubMed1994

Effect of cumene hydroperoxide on lipid peroxidation in cultured rat hepatocytes supplemented with eicosapentaenoic acid.

The present study was undertaken to examine whether the oxidative effect of organic hydroperoxide on cultured rat hepatocytes is enhanced by eicosapentaenoic acid (EPA). The cells were pretreated with 0.8 mM EPA which was complexed to bovine serum albumin (EPA-BSA) for 4 h, and then challenged to cumene hydroperoxide (CMHP). By the addition of CMHP to the cell culture, lipid peroxidation estimated as production of malondialdehyde (MDA) was provoked to a much greater extent in the EPA-loaded hepatocytes than in the non-loaded cells. The CMHP treatment also resulted in more severe cell injury in association with the decrease in intracellular levels of glutathione and protein thiols in the EPA-loaded cells as compared with results in the non-loaded cells. The addition of antioxidants such as N,N'-diphenyl-p-phenylenediamine (DPPD), promethazine and gamma-tocopherol to the culture medium prevented the CMHP-induced oxidative injury effectively for the EPA-loaded cells but had little effect for the non-loaded cells. The potency of other unsaturated fatty acids with different numbers of double bonds in enhancing the CMHP-induced lipid peroxidation and injury was also examined. The deleterious effects of CMHP were little affected by unsaturated fatty acids with one or two double bonds but were markedly intensified by those with more than 4 double bonds. These data showed that the supplementation with highly unsaturated fatty acids makes the cells susceptible to the drug-induced oxidative stress.

Albumins↗
PubMed1999

Inflammatory action of 8-methoxypsoralen-spermine photoproduct (8-MOP-Spm-P(GFC)) and effects of various drugs on rat paw edema induced by 8-MOP-Spm-P(GFC).

The photoproducts produced by irradiating 8-methoxypsoralen (8-MOP) in the presence of spermine (Spm) were fractionated using gel filtration chromatography (GFC) on a Sephadex G-25 column. As a result, two bands which were characterized by the effects on hyaluronidase activity were obtained. The first band strongly activated the hyaluronidase, but a second band did not exhibit any effect on the enzyme activity. The first and second bands contained photoproducts with molecular weights (MW)>2700 and MW<728, respectively, determined by the GFC method. The photoproducts, 8-MOP-Spm-P(GFC) obtained from the first band, but not the photoproducts with lower MW from the second band, showed enzyme activating action. 8-MOP-Spm-P(GFC) induced paw edema, which was stronger in the first phase than the second one in rats, differing from that induced by carrageenin. This photoproduct was a substance with lower cell toxicity because it did not cause hemolysis on red blood cells or the release of lactic dehydrogenase from mast cells in rats. The effects of various drugs on 8-MOP-Spm-P(GFC)-induced edema were investigated. As a result, edema formation was inhibited by drugs with an anti-histaminic action, such as alimemazine, dl-chlorpheniramine, promethazine, ketotifen and azelastine, and with anti-serotonin action such as cyproheptadine. On the other hand, tranilast did not show significant inhibition and indomethacin showed a tendency to increase its formation. These results suggested that 8-MOP-Spm-P(GFC) is a new inflammatory substance and is very useful as an agent to develop new anti-inflammatory drugs without cyclooxygenase inhibitory action.

Animals↗
PubMed1986

Interaction of tertiary amines and quaternary ammonium compounds with gastrointestinal mucin.

The binding property of some tertiary amines (chlorpromazine, promethazine and imipramine) and quaternary ammonium compounds (propantheline, mepenzolate and butylscopolamine) for gastric mucin was investigated. All tertiary amines tested bound gastric mucin to varying extents, and the binding of chlorpromazine was especially strong. Moreover, the absorption behaviors of chlorpromazine in rat intestinal loops was significantly inhibited in the presence of gastric mucin. On the contrary, all quaternary ammonium compounds tested did not bind gastric mucin and the absorption of propantheline was not affected in the presence of gastric mucin. These results suggested that gastrointestinal mucin produced a significant effect on the bioavailability of these tertiary amines after oral administration.

Amines↗
PubMed1989

Effect of phenylhydrazine-induced structural alterations of human erythrocytes on basic drug penetration.

The phospholipid organization, lipid fluidity and spectrin degradation were measured in human erythrocytes oxidized with phenylhydrazine, and the contribution of these structural alterations to the penetration of perazine and promethazine into the membrane was estimated. It was found that exposure of erythrocytes to phenylhydrazine (0.2--0.4 mg/ml) produced a 35--40% decrease in the amount of spectrin, with resultant gross morphological changes to the echinocyte conformation. The phosphatidylethanolamine content in the treated erythrocytes was greatly lowered compared with that in the untreated cells. Treatment with phenylhydrazine (0.05--0.2 mg/ml) dramatically diminished the lipid fluidity of the membrane, as estimated by electron spin resonance (ESR) spectrometry, and the ESR study revealed increased restriction of the molecular motion of the hydrophobic core in the treated membrane. These results suggest a drastic alteration of the erythrocyte membrane structure. The amount of drugs which penetrated into the treated erythrocytes increased markedly with increasing phenylhydrazine concentration, suggesting enhanced membrane permeability and facilitated localization of the drugs in the hydrophobic regions due to the structural changes and partial disturbance of the lipid organization.

Erythrocytes↗
PubMed1977

Possible involvement of cyclic AMP in inflammation induced by a surfactant.

Alkyldimethylbenzylammonium chloride (alkyl-DBAC), a cationic surfactant, produces acute exudative inflammation accompanied by an enhancement of energy metabolism. The mechanism of metabolic changes, consequently the cyclic AMP level and the effects of certain drugs were determined in the gastrocnemius muscles of rats in which acute exudative inflammation had been induced by intramuscular injections of alkyl-DBAC. A transient increase in the cyclic AMP level was noted at 15 to 30 minutes after the injection of alkyl-DBAC, and this elevation was antagonized by chlorpromazine, diphenhydramine, promethazine, aspirin and indomethacin. The time course of increasing tendency in the cyclic AMP level after the injection of histamine closely paralleled that of alkyl-DBAC. These results suggest that cyclic AMP may be involved in the metabolic changes with inflammation induced by alkyl-DBAC.

Animals↗
PubMed1979

Histamine-induced ACTH secretion and inhibitory effect of antihistaminic drugs.

Concentration of adrenocorticotropic hormone (ACTH) in the serum increased and reached the maximum level 10 min after the injection of histamine (dihydrochloride, 0.5 or 1 mg/100 g) i.p. into rats. The maximum concentration of ACTH in the serum was dependent on the dose of histamine. The ACTH concentration then decreased and was close to the normal level 30 to 60 min after the injection. The ACTH secretion induced by histamine (0.5 mg/100 g) was inhibited completely by the pretreatment with the antagonists of H1-receptor, diphenyhydramine (hydrochloride, 0.2--0.5 mg/100 g), promethazine (hydrochloride, 0.1--0.2 mg/100 g) and d-chlorpheniramine (maleate, 0.02--0.05 mg/100 g). The antagonist of H2-receptor, metiamide (2--4 mg/100 g) inhibited the ACTH secretion significantly but not completely. These results suggest that H1-receptor plays a major role in the histamine-induced ACTH secretion, although H2-receptor is also involved in this ACTH secretion.

Adrenocorticotropic Hormone↗
PubMed1981

Enhancement of drug withdrawal convulsion by combinations of phenobarbital and antipsychotic agents.

Antipsychotic agents which are considered to depressive to the central nervous system (CNS) but free of dependence liability were used in combination with barbiturates or tranquilizers to study the physical dependence liability in the so-enhanced CNS depression. In the study of physical dependence formation, when CNS depression was maintained in an enhanced stage during the continuous application of the drug combinations, the withdrawal convulsions were enhanced in both frequency and severity. In the crossphysical dependence study, two-drug combinations, i.e., phenobarbital (PhB)-chloropromazine (CPZ), PhB-diphenhydramine (DPH) and nitrazepam-chlorprothixene, and 3-drug combinations (i.e., PhB-CPZ-promethazine and PhB-CPZ-DPH were evaluated. The 2-drug combinations suppressed some of the withdrawal signs, but those at high dosages showed a tendency to aggravate the signs. The 3-drug combinations differed from the 2-drug combinations in that the suppression of withdrawal signs was synergistically enhanced and the barbital withdrawal signs were weak. In conclusion, when CNS depression with PhB was enhanced with combinations of dependence liability-free drugs the drug combinations enhanced withdrawal convulsions both in frequency and severity. The sedation enhanced by the combinations did not always parallel the suppression of barbital withdrawal.

Animals↗
PubMed1982

Effects of anti-inflammatory drugs on triple vaccine-induced pleurisy in rats.

Effects of various anti-inflammatory drugs on triple vaccine-induced pleurisy, a model of delayed hypersensitivity, were examined and compared with those on carrageenin-induced pleurisy in rats. Steroidal drugs depressed markedly the volume of exudate and the number of leucocytes in both types of pleurisy. Gold compounds also depressed both types of pleurisy. Non-steroidal anti-inflammatory drugs were apt to show depressive effects on carrageenin-induced pleurisy, especially on increased exudate volume. BW755C produced a depressive effect on carrageenin-induced pleurisy, but on triple vaccine-induced pleurisy, BW755C produced only a slight depressive effect. Cyproheptadine produced a slight depressive effect on carrageenin-induced pleurisy, but not on triple vaccine-induced pleurisy. Promethazine had a slight depressive effect on both types of pleurisy. D-penicillamine and levamisole did not show any depressive effects on triple vaccine-induced pleurisy. The results show that reported mediators in carrageenin-induced pleurisy (prostaglandin, serotonin, leukotriene B, etc.) are not relevant to triple vaccine-induced pleurisy. Specific lymphokines and/or degradated products of complement may participate in the latter. This triple vaccine-induced pleurisy seems to be a good model for screening non-steroidal anti-inflammatory drugs which have steroidal-like activity.

Animals↗
PubMed1984

Effects of histaminergic drugs on muricide induced by thiamine deficiency.

Male Wistar rats maintained on a thiamine deficient diet showed mouse-killing aggression (muricide). On the 30th day of experimental feeding, the incidence of this muricide was about 70%. Intracerebroventricular histamine suppressed the muricide induced by thiamine deficiency in a dose-dependent manner. Histamine H1-receptor blocking agents such as diphenhydramine, promethazine and chlorpheniramine also showed muricidal suppression, but astemizole which lacks central effects did not show muricidal suppression. Mianserin and iprindole showed muricidal suppression, but metiamide i.p. did not. On the 20th day of experimental feeding, the incidence of this muricide was 45.5%. Histamine synthesis inhibitors such as brocresine or alpha-fluoromethylhistidine could not enhance the muricide on non-killer-rats, but really suppressed the thiamine deficient killer-rats. The results of this paper suggested that muricide induced by thiamine deficiency is not mediated by the central histaminergic system, but pharmacologically characterized by antidepressants, antihistamines and histamine synthesis inhibitors.

Aggression↗
PubMed1984

Determination of chlorpromazine in the blood and brain of mice by high performance liquid chromatography combined with electrochemical detection.

A simple and sensitive procedure was developed for determining the concentration of chlorpromazine (CPZ) in the blood and brain of mice with promethazine as the internal standard. The procedure involves (1) primary extraction by a mixture of heptane and isoamyl alcohol (99:1) in an alkaline condition and (2) determination by means of high performance liquid chromatography with electrochemical detection. The detection limit of CPZ was 0.5 ng for one chromatographic injection. The drug was detectable in a 100 microliters sample of the blood by 6 hr after an intravenous injection of 0.25 mg/kg. The concentration of CPZ was about 40 times higher in the brain compared with that in the blood. The biological half life was estimated to be 87 and 65 min, in the blood and brain, respectively. The proposed method is also applicable for the determination of other phenothiazine derivatives and effective for pharmacokinetic study of the compounds in clinics and laboratories.

Animals↗