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PubMedDate not supplied

Antimutagenicity of phenothiazine-metal co-ordination complexes in chemically induced mutagenesis.

Phenothiazines are heterocyclic organic compounds in which nitrogen and sulfur are incorporated in the tricyclic system, and are known to have antimutagenic activity by shielding DNA-base pairs. Inorganic metals have also been intensively studied for DNA-adduct formation as potential anticancer agents. Phenothiazine, promethazine, promazine and chlorpromazine were complexed either with copper, palladium or gold. The antimutagenicity of twelve phenothiazine-metal complexes, four phenothiazines and three inorganic metals was examined on Salmonella typhimurium TA98 strain treated with a strain-specific, direct-acting mutagen, 4-nitro-o-phenylene-diamine, and the ligand-DNA interaction was analyzed by ultraviolet (UV) spectrophotometry. Phenothiazine-metal co-ordination complexes generally increased their antimutagenic activity, compared to their parent compounds, and the enhanced antimutagenicity was attributed to their interaction with DNA as evidenced by the UV spectra.

Anticarcinogenic Agents↗
PubMed1996

[Clinical use of antiemetic drugs for prevention and therapy of postoperative nausea and vomiting].

The incidence of postoperative nausea and vomiting (PONV) has not decreased significantly for decades. This study was done to evaluate whether there is a standard method or a preferred substance in German hospitals in the prophylaxis and treatment of PONV. Twenty-one randomly selected hospitals were asked to give details about substances, doses and application times and forms in PONV prophylaxis and treatment. Most of the patients with a high risk of emesis were treated prophylactically with droperidol. Dosage and time of application were different in each hospital. Metoclopramide was the second most frequently used substance for both prophylaxis and treatment. Dimenhydrinate, triflupromaxzine, promethazine and acupuncture were used less commonly in prophylaxis. Alizapride and ondansetron were used to treat PONV in only two hospitals. Summarising, this study found no routine standard in the prophylaxis and therapy of PONV. Droperidol and metoclopramide were the most frequently used antiemetics. An overview of the antiemetics involved is given.

Antiemetics↗
PubMed1997

Effect of phenothiazines on activated macrophage-induced luminol-dependent chemiluminescence.

The inhibitory effect of some phenothiazine neuroleptics (chlorpromazine, levomepromazine, thioridazine, promethazine and trifluoperazine) on the ability of rat peritoneal macrophages to produce O2- during phagocytosis was investigated. The superoxide radical release was estimated by measuring the luminol-dependent chemiluminescence (CL). The effect of drugs was studied in the concentration range of 0.1-100 mumol/l. Additional experiments to determine the ability of the drugs to scavenge O2- were carried out. They included measuring the effect of phenothiazines on the luminol-dependent CL in systems with enzymatically (xanthine-xanthine oxidase) and non-enzymatically (KO2) generated O2-. The ability of phenothiazines to scavenge O2- was additionally tested by a "non-luminescence" method in which the superoxide concentration was determined spectrophotometrically by the reduction of nitro blue tetrazolium to formazan. All drugs tested decreased significantly CL of stimulated macrophages at concentrations greater than 1 mumol/l. The C50 values were between 0.45 and 1.74 mumol/l. Also phenothiazines were found to act as scavengers of O2-. However, this effect occurred at significantly higher drug concentrations. The C50 values for 50% scavenging of O2- in systems with different sources of O2- were in the concentration range of 5-160 mumol/l. These results suggested that phenothiazines predominantly affected the ability of macrophages to produce O2- during phagocytosis. The findings may provide some insight into the untoward effects of the drugs tested.

Animals↗
PubMedDate not supplied

[Phenothiazine drugs as photosensitizers and photoprotectors].

The photosensitizing properties of eight N-alkylated phenothiazine neuroleptic drugs were studied. The experiments were carried out in a model system based on photooxidative chemiluminescence of Gly-Trp peptide in aqueous solution. Under irradiation with light longer than 280 nm, all the studied phenothiazine derivatives decrease the chemiluminescence intensity at low concentrations and enhance it at high concentrations. Phenothiazine derivatives is likely to be due to superoxide and/or Gly-Trp free peroxide radicals. Photosensitization begins to dominate over protection at concentrations which are different for various phenothiazine derivatives compounds and lie in the range 10(-6)-10(-5) M. The photosensitizing efficiency decreases in the order: Thioproperazine, Trifluoperazine Hydrochloride, Alimezine, Thioridazine Hydrochloride, Levomepromazine Hydrochloride, Promethazine Hydrochloride, Periciazine, Chlorpromazine Hydrochloride. It was shown that photooxidation of Gly-Trp sensitized by phenothiazine derivatives occurs via singlet oxygen formation.

Light↗
PubMed1998

In vitro characterization of cytochrome P450 2D6 inhibition by classic histamine H1 receptor antagonists.

Classic antihistamines, namely diphenhydramine, chlorpheniramine, clemastine, perphenazine, hydroxyzine, and tripelennamine, share structural features with substrates and inhibitors of the polymorphic cytochrome P450 (CYP) isozyme CYP2D6. Therefore, the current study was undertaken to characterize the in vitro inhibition of CYP2D6 by these commonly used, histamine H1 receptor antagonists. Microsomal incubations were performed using bufuralol as a specific CYP2D6 substrate and microsomes derived from human cells transfected with CYP2D6 cDNA. Reaction velocities were assessed in the absence and presence of antihistamines (20 microM) at 11 substrate concentrations (1, 2.5, 5, 7.5, 10, 15, 20, 25, 50, 75, and 100 microM), as well as at three nonsaturating substrate concentrations (2.5, 5, and 20 microM) and three inhibitor concentrations (5, 20, and 50 microM). In the presence of all antihistamines, the Vmax and KM of bufuralol 1'-hydroxylation were significantly altered, compared with the uninhibited reaction (p < 0.05). Lineweaver-Burke plots suggested competitive inhibition of the reaction by diphenhydramine and mixed inhibition by all other antihistamines tested. Diphenhydramine and chlorpheniramine, with estimated Ki values of approximately 11 microM, were the weakest inhibitors of CYP2D6 in vitro. Whereas tripelennamine, promethazine, and hydroxyzine were similar in their inhibitory capacities (Ki approximately 4-6 microM), clemastine appeared to be significantly more potent, with a Ki of approximately 2 microM. These data demonstrate that classic histamine H1 receptor antagonists, available in over-the-counter preparations, inhibit CYP2D6 in vitro. Furthermore, the CYP2D6-inhibitory concentrations of these antihistamines are in the range of their expected hepatic blood concentrations, suggesting that, under specific circumstances, clinically relevant interactions between classic antihistamines and CYP2D6 substrates might occur.

Cytochrome P-450 CYP2D6 Inhibitors↗
PubMedDate not supplied

Multidrug resistance reversal in mouse lymphoma cells by heterocyclic compounds.

Due to the close homology between bacterial and tumor cell transporter proteins, some antiplasmid and anticancer compounds were tested for their ability to reserve the multidrug resistance (mdr) of lymphoma cells. Some known anticancer medicines such as platidiam, novantron, fluorouracil, bleomycin and methotrexate were ineffective/while vinca alkaloids exerted a strong reversal effect on the mdr of lymphoma cells. The structurally related reserpine and yohimbine do not affect the activity of efflux pump. Some selected antitumor phenothiazines and benzo[a]phenothiazines, including trifluoperazine inhibit the P-glycoprotein (pgp) function. This fact is independent from the antiproliferative- or differentiation inducing effects. Since the polylactosamine specific tomato lectin prevents the action of the chemosensitizers tested, it is supposed that the site of action of phenothiazines can be at the 1st loop in the transmembrane glycoprotein. The efflux pump activity of the pgp in brain capillary endothel which is responsible for blood brain barrier (BBB) was also inhibited by some phenothiazines. However, the tomato lectin sensitivity of pgp was different in mouse lymphoma and human brain capillary endothelial cells. The mdr-gene expression of the mouse lymphoma cells (which were transfected with the human mdr-1 gene) could be reduced by phenothiazines such as promethazine and trifluoperazine, when the cells were cultured in the presence of 0.5 microgram/mL phenothiazines. Further synergism was found between two resistance modifiers i.e. verapamil and trifluoperazine on the inhibition of mdr-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Tomato lectin labels the 180 kD glycoform of P-glycoprotein in rat brain capillary endothelia and mdr tumor cells.

Two main isoforms of P-glycoproteins can be distinguished according to their solubility in ionic and non-ionic detergents. Studies on mdr cell lines and brain capillary vessels support the evidence that tomato lectin reveals high affinity binding to the oligosaccharide chains of the SDS soluble isoform of P-glycoprotein, but not to the non-ionic detergent soluble isoform. Thus the SDS-soluble isoform represents a glycoform having polylactosamines in its oligosaccharide chains. The function of these oligosaccharides is still unknown, although the carbohydrate chains of P-glycoprotein were believed to take part in correct protein folding only. We also demonstrated that lectin binding to the extracellular lactosamine sequences of drug efflux pump does not change its efficiency on mdr cell lines, but interferes with the inhibitory action of some drugs, such as verapamil and promethazine. In accordance with earlier findings we assume that carbohydrate chains might be involved in stabilization of the active conformation of efflux pump. The possible role of lectin treatment in maintaining P-glycoprotein mediated blood-brain barrier functions has to be proved in further investigations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

The cardiovascular, coagulation and haematological effects of tiger snake (Notechis scutatus) prothrombin activator and investigation of release of vasoactive substances.

The cardiovascular, coagulation and haematological effects of prothrombin activator from Tiger Snake (Notechis scutatus) venom were investigated in anaesthetized mechanically ventilated dogs. Infusion caused dose-related systemic hypotension, marked decreases in cardiac output and stroke volume, marked increases in pulmonary artery pressure, pulmonary artery occlusion pressure and pulmonary vascular resistance. Effects occurred within several minutes but abated over 30 to 40 minutes. Evidence of procoagulation included prolongation of prothrombin and partial thromboplastin times and depletion of serum fibrinogen. Thrombocytopenia and leucopenia occurred. All effects were prevented by prior administration of heparin but none by inhaled nitric oxide. Oesophageal echocardiography during infusion identified thrombi within the heart, right ventricular dilatation and dyskinesia. Electrocardiography suggested myocardial ischaemia. Pulmonary thromboemboli were identified histologically post mortem. Cardiovascular effects of the activator were not due to a variety of endogenous substances as indicated by use of antagonists to platelet activating factor and thromboxane A2 indomethacin, dexamethasone, serotonin, ketanserin, histamine, promethazine and ondansetron. Tiger Snake prothrombin activator causes bilateral ventricular failure by thrombotic obstruction of the pulmonary vasculature and possibly by coronary ischaemia.

Animals↗
PubMed1975

[Nonhemodynamic pulmonary edema due to toxins].

Lesional pulmonary edema caused by substances which are directly caustic for the gastrointestinal pathways (strong acids and bases, inhaled vomit) are opposed by their immediate and long-term gravity with those due to cardiotropic medicamentatous toxins or volemic overloading which lead to curable pulmonary edema. Material and human factors, in favour of accidental intoxication are compensated for by the fact that many toxins produce vapours which are strongly irritant for the upper respiratory pathways: this prevents prolonged exposure and therefore wards off edema. Drug intoxication by ingestion can lead to pulmonary edema by relative or absolute volemic overload, by allergic accidents or by immaturity of the enzyme degradation systems. It seems to us that the notions of "neurological" and "metabolic" toxic edema should be abandoned. In lesional edema the treatment is that of the acute respiratory failure. The combination of pethidine, promethazine, and chlorpromazine gives good immediate results. Owing to careful follow-up, hemodynamic pulmonary edema should most frequently be avoided.

Acute Kidney Injury↗