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When introduced as a gas into the abdominal cavity of the rat, oxygen above the initial concentration of 10 % provokes vasodilatation, perivascular oedematous infiltrations and fluid formation. These lesions are entirely reversible. Antihistaminics (promethazine and mepyramine 2 mg/100 g completely inhibit vascular lesions.
Study of the type of premedication used in aorto-coronary bypass surgery involved 60 clinical cases of patients operated upon in the department of Professor GALEY (Henri Mondor Hospital, Creteil). The choice of drugs used showed the important role of tranquilisers and anxiolytics: diazepam, dipotassium chlorazepate, to which, in the majority of cases, were added an antihistamine: promethazine and a parasympatholytic: atropine. No accidents or complications were seen during the pre-anaesthetic period, and above all during the induction of anaesthesia in these patients, more than half of whom were in major cardiovascular decompensation. This would appear to confirm the efficacy of the drugs chosen for the premedication of these patients.
Neonatal jaundice is a common problem in Port Moresby. A survey was carried out on 50 consecutive jaundiced neonates in an attempt to delineate the causes of severe neonatal jaundice (bilirubin 15 mg. % or more). ABO blood group incompatibility, G-6-P-D deficiency and infection accounted for 62% of cases while no cause could be found in 38% of cases. Low birth weight, multiple births, male sex, asphyxia, delivery occuring outside the hospital, and vacuum extraction were associated more commonly with jaundiced neonates than with the controls. There was a statistically significant association between the use of promethazine in the mother during and after labour and jaundice in the newborn. The association between the use of sulphonamides in the mother after delivery and neonatal jaundice was suggestive but not statistically significant.
The effects of chlorpromazine and of some metabolites of chlorpromazine on the apomorphine-elicited inhibition of synaptosomal tyrosine hydroxylase activity were investigated. Chlorpromazine, nor1-chlorpromazine and 7-hydroxychlorpromazine reverse the apomorphine-elicited inhibition of tyrosine hydroxylase activity while nor1-chlorpromazine sulfoxide and nor2-chlorpromazine sulfoxide have no effect on this inhibition. 6-Hydroxychlorpromazine and promethazine also reverse the enzyme inhibition by apomorphine but are less potent than chlorpromazine or 7-hydroxychlorpromazine. These results show that chlorpromazine and its metabolites with antipsychotic activity are more effective in reversing the apomorphine-elicited inhibition of tyrosine hydroxylase than those metabolites which are devoid of antipsychotic activity.
Several drugs affecting nerve cell excitability, by opposing ion movements in membranes, were tested in mice rendered tolerant to or dependent on morphine. The purpose of the study was to investigate whether these drugs share the ability to attenuate morphine tolerance and dependence exhibited by tricyclic antidepressants. Tolerance to morphine was decreased by the administration of imipramine, doxepin, promethazine, propranolol, lidocaine and quinidine. Chlorpromazine and carbamazepine were ineffective. The intensity of the abstinence syndrome provoked by naloxone was decreased by chlorpromazine, imipramine, doxepin, lidocaine, quinidine and propranolol. Diphenyl. hydantion and carbamazepine had no effect. The results are discussed in relation with the blockade of ion conductance and their interference with the release of neurotransmitters produced by the drugs assayed.
To clarify the role of electrostatic forces in the binding of phenothiazines to calmodulin, the quaternary methiodide salts of several 10-alkylaminophenothiazines were prepared and examined for anticalmodulin activity. In addition, the methiodide salt of [3H]chlorpromazine was prepared and its binding to calmodulin was studied. Both the hydrochloride and methiodide salts of a variety of 10-alkylaminophenothiazines inhibited the calmodulin-induced activation of phosphodiesterase at concentrations that had no effect on the basal activity of the enzyme. The IC50 values for the inhibition of calmodulin by the methiodide salts were similar to those of the corresponding hydrochloride salts, with the compounds displaying the order of potency: trifluopromazine greater than chlorpromazine greater than promazine greater than promethazine greater than chlorpromazine sulfoxide. The acidic compound 3-(2-chloro-10-phenothiazinyl)propionic acid displayed no anticalmodulin activity at concentrations up to 80 microM; at higher concentrations the compound inhibited both basal and calmodulin-stimulated enzyme activity. Other results showed that both chlorpromazine hydrochloride and chlorpromazine methiodide bound to calmodulin in a Ca++-dependent manner. However, the binding of chlorpromazine hydrochloride decreased markedly at alkaline pHs, whereas the binding of chlorpromazine methiodide was not pH-dependent. The fact that the binding of the nondissociable methiodide salt is not pH-dependent, whereas the binding of the hydrochloride salt decreases at pHs at which the drug would be nonionized, indicates that it is the cationic species of the phenothiazine that binds to calmodulin and inhibits its activity.
In experiments in vivo, the derivatives of quinuclidylarylcarbinol, possessing an antihistaminic activity, fencarol, its di(o-tolyl)- and di(o-methoxyphenyl)-derivatives activate histamine oxidative deamination by diaminoxidase of the rat lungs and increase the histamine tissue level. Quinuclidyl-3-dithienyl carbinol inhibits the activity of diaminoxidase, but decreases the histamine tissue level. On the contrary, dimedrol (diphenhydramine), pipolfen (promethazin), pyrilamine and cyproheptadin exerted no effect on the activity of diaminoxidase or the histamine tissue level. All the compounds studied did not alter oxidative deamination of the rat brain serotonin by monoamine oxidase or the serotonin content in brain tissues.
The new antihistaminic and antiallergic drug phencarol (quinuclidy-3-diphenylcarbinol hydrochloride) in contradistinction to dimedrol (diphenhydramine) and diprazine (promethazin) exerts no pronounced depressant effect on the central nervous system. It does not significantly influence the period of action of hypnotic drugs, the effects produced by alcohol, spontaneous motor activity, summation capacity of the central nervous system, conditioned reflexes or electroencephalogram. That phencarol possesses no marked central action may be accounted for by its low lipophilic activity and little permeability of the blood brain barrier by this drug.
The content of neurotensin immunoreactive material (neurotensin-IR) of nucleus accumbens increases 16 hr after a single injection of 2 mg/kg i.p. of haloperidol; this increase persists for 8 hr or longer. Repeated injections of 2 mg/kg/day of haloperidol i.p. cause a gradual and progressive increase of neurotensin-IR. From 0.32 pmol/mg of protein, it increases to 0.57 pmol/mg (1 week) to 0.62 pmol/mg (2 weeks) and reaches 0.68 pmol/mg (3 weeks). A significant increase of neurotensin-IR content of nucleus accumbens is obtained with 0.5 mg/kg i.p. daily for 2 weeks. Maximal responses are obtained with 1 mg/kg/day in 3 weeks. The striatal neurotensin-IR content of rats injected for 2 weeks with 1 mg/kg/day of haloperidol is also increased. In these rats, the neurotensin-IR content of preoptic area hypothalamus, septum and amygdala failed to increase. The increase of neurotensin-IR material of nucleus accumbens was elicited also by chloropromazine (6 mg/kg), trifluoroperazine (2 mg/kg) and pimozide (1.5 mg/kg) while promazine (10 mg/kg) and promethazine (25 mg/kg) were ineffective. The increase of neurotensin-IR content caused by haloperidol chloropromazine, trifluoroperazine and pimozide in accumbens and striatum suggests a modulation of neurotensin metabolism, synthesis or utilization directly or indirectly through dopaminergic synapses.
The usefulness of determining aminopyrine demethylation kinetics via monitoring of metabolite exhalation rats had been assessed. In rats receiving [N-dimethyl-14C]aminopyrine, a biexponential decline in the 14CO2 exhalation rate is apparent when monitoring is continued over a 5 to 6-hr period. Both the fast phase (representing the first demethylation) and the slower phase (representing the second demethylation) are markedly influenced by phenobarbital and promethazine pretreatment. These changes are consistent with enhanced mixed-function oxidase activity. Examination of the urinary excretion products of aminopyrine obtained in these studies support this claim. The sensitivity of the above index of mixed-function oxidase activity is increased considerably by the use of crossover experimental designs. Considerable interanimal variation is observed in the metabolite production in both exhaled air and urine from rats administered aminopyrine.
A single dose of promethazine or of betamethazone, either alone or compounded with dexchloropheniramine, was found to inhibit skin wheal formation in onchocerciasis patients challenged with Onchocerca supernatants. The mean wheal diameter developing 24 hours after drug administration ranged between 40-60% less than the original pre-treatment diameter but this effect had been abolished or was significantly less by 48 hours. Diethycarbamazinecitrate had only a 20% inhibitory effect on the wheal diameter of the skin reaction. It is concluded that antihistamines and corticosteroid derivates may interfere with the immunodiagnostic skin test for onchocerciasis based on skin reactivity to Onchocerca supernatants, unless measures are taken to ensure that these drugs are not consumed within the 48 hours preceding the skin test.
Extracellular single unit recording techniques were used to study the effects of both acute and repeated oral neuroleptic administration on the in vivo activity of rat A9 and A10 dopaminergic (DA) neurons. All antipsychotic drugs examined acutely (haloperidol, l-sulpiride, chlorpromazine, and clozapine) increased the number of spontaneously firing DA neurons in both A9 and A10 compared to controls. Repeated (21 day) treatment with haloperidol, l-sulpiride, and chlorpromazine (antipsychotic drugs which can cause extrapyramidal side effects) markedly reduced the number of active DA cells below control levels in both regions. The "silent" DA neurons were in an apparent state of tonic depolarization inactivation since they could be induced to discharge by the microiontophoretic application of the inhibitory neurotransmitter gamma-aminobutyric acid, but not the excitatory amino acid glutamate. The depolarization inactivation observed may be specific for antipsychotic drugs since a non-neuroleptic phenothiazine (promethazine), the inactive isomer of sulpiride (d-sulpiride), and a tricyclic antidepressant (desmethylimipramine) neither increased DA activity when given acutely nor induced depolarization inactivation when administered repeatedly. In contrast to the other drugs tested, repeated treatment with clozapine (an effective antipsychotic drug which does not produce extrapyramidal side effects) resulted in the depolarization inactivation of A10 neurons but not A9 cells. These data suggest that neuroleptics which can induce extrapyramidal side effects produce depolarization inactivation of both A9 and A10 neurons whereas antipsychotic drugs which lack this property inactivate only A10 neurons. It is suggested that the time-dependent development of A9 DA neuron inactivation induced by repeated neuroleptic treatment may provide a mechanism for understanding the delayed onset of extrapyramidal side effects often observed with these drugs.
It was recently proposed that yohimbine (YOH), an indole alkaloid with multiple pharmacological effects, is an antagonist of the D2 dopamine (DA) receptor. Because the pituitary DA receptor involved in the inhibition of prolactin (PRL) secretion is the prototypic D2 receptor, we examined the effect of YOH on PRL secretion in male rats. YOH produced marked, dose-dependent and sustained increases in plasma PRL levels. However, YOH did not block the inhibitory effect of DA on PRL release from rat pituitary glands in vitro, did not displace [3H]spiperone from bovine pituitary membranes and had no effect on the concentration of DA in pituitary stalk plasma of anesthetized rats, suggesting that the stimulation of PRL release by YOH is not due to its antidopaminergic effects. Clonidine, an alpha-2 adrenergic agonist, produced a partial, non-dose-dependent inhibition of the YOH-induced rise in serum PRL levels. Two antagonists of the H1 histamine receptor, diphenhydramine and promethazine, markedly antagonized the PRL-releasing effect of YOH, but another H1 blocker, chlorpheniramine, and an H2 antagonist, metiamide, had no effect. Serotonin receptor blockers, cyproheptadine, mianserin and pizotifen, and the opiate antagonist, naloxone, also had no effect on the PRL response to YOH. Nevertheless, the PRL-releasing effect of YOH was potentiated 24 hr after the administration of reserpine or para-chlorophenylalanine, an inhibitor of serotonin synthesis. Thus, the mechanisms by which YOH stimulates rat PRL secretion has has not been fully elucidated. It is possible that YOH may stimulate PRL secretion by a novel mechanism, possibly through the intervention of a PRL-releasing factor.
Binding of (3H)-imipramine to F'lac plasmid-carrying E.coli was studied. The binding was saturated at 500 mM imipramine in the case of F'lac cells, and the imipramine binding of plasmid-carrying bacteria was inhibited by several tricyclic compounds, such as acridine orange, desimpramine and promethazine. Methylene blue enhanced the (3H)-imipramine binding of bacteria. Binding of radioactively labelled pBR322 plasmid DNA to the internal membrane was more efficient in the presence of plasmid-eliminating drugs than in that of their ineffective derivatives. It is concluded that a structural association exists between imipramine binding and plasmid replication sites in bacteria. The plasmid DNA is assumed to bind irreversibly to its replication site in the presence of the drug and this process can lead to plasmid elimination.
It was previously reported that [3H]nitrendipine binding to a microsomal fraction from intestinal smooth muscle was dependent upon the presence of divalent metal cations (Bolger et al., J. Pharmacol. Exp. Ther. 225: 291-309, 1983). The effects of cations and calmodulin antagonists on [3H]nitrendipine binding in smooth and cardiac muscle have been studied further. Treatment of ileal and aortic smooth muscle and cardiac muscle with EDTA reduced specific [3H]nitrendipine binding by 70 to 95%. Microsomes from rabbit ventricle were more resistant to EDTA treatment than were those from ileal smooth muscle, but low concentrations of Ca++ (less than 10(-5) M) produced half-maximal restoration of binding in both tissues. The ability of cations at a concentration of 10(-3) M to restore binding to membranes from guinea-pig ileum was in the sequence, Ca++ = Sr++ greater than Mg++ = Mn++ = Co++ greater than Ba++ = Ni++ greater than Zn++ = Cd++ greater than La = Sm = Tm . In contrast to the activation of calmodulin-dependent processes, the ability of these cations to restore [3H]nitrendipine binding did not correlate linearly with ionic radius. However, calmodulin antagonists were found to inhibit [3H]nitrendipine binding with the order of potency: pimozide greater than less than calmidazolium (R 24571) greater than trifluoperazine greater than chlorpromazine greater than promethazine greater than chlorpromazine sulfoxide, that correlates quite well with the potency of these drugs as inhibitors of calmodulin-dependent processes. The results suggest that calmodulin antagonists bind to a protein associated with the [3H]nitrendipine binding site that has a hydrophobic domain similar to that exposed on calmodulin by Ca++, but that this protein is not calmodulin itself.
Human polymorphonuclear leukocytes (PMNs) were found to contain a mean +/- S.E.M. of 21.7 +/- 7.9 ng of immunoreactive calmodulin (CaM)/10(6) PMNs, which represents 0.032 +/- 0.001% of the total cellular protein. The functional role of CaM in the control of lysosomal enzyme release from human PMNs was investigated using several CaM antagonists. Trifluoperazine (TFP) (10(-6)-2 X 10(-5) M), pimozide (10(-6)-1.5 X 10(-5) M), chlorpromazine (CPZ) (10(-5)-10(-4) M) and promethazine (2 X 10(-5)-10(-4) M) inhibited in vitro lysosomal enzyme release from human PMNs induced by immunological (serum-treated zymosan, concanavalin A and formyl-L-methionyl-L-leucyl-L-phenylalanine) and nonimmunological (Ca++ ionophore A23187) stimuli. Trifluoperazine sulfoxide (TFP-S) and chlorpromazine sulfoxide (CPZ-S), which have very low affinity for CaM, had practically no inhibitory effect on lysosomal enzyme release. The inhibitory effect of TFP could be made irreversible by irradiating the cells with UV light. A sulfonamide derivative, W-7, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (10(-5)-2 X 10(-4) M), which selectively binds to CaM, inhibited the release of lysosomal enzymes from PMNs. In contrast, the chloride-deficient analog, W-5, N-(6-aminohexyl)-1-naphthalenesulfonamide hydrochloride, which interacts only weakly with CaM, had practically no inhibiting effect. The IC50 for enzyme release by a series of eight CaM antagonists was closely correlated (r = 0.89; P less than .001) with their affinity for binding to CaM, supporting the concept that these agents act by binding to CaM and thereby inhibiting lysosomal enzyme release.(ABSTRACT TRUNCATED AT 250 WORDS)
Anticholinergic and antiserotonergic activities of the psychotropic drugs chlorpromazine, fluphenazine, imipramine and promethazine have been investigated quantitatively on the guinea-pig isolated ileum. Additional experiments were made to assure the comparability of receptor activity with human intestinal (ileum) preparations. Each of the four compounds exhibited a marked blocking potency both on muscarinic and serotonergic receptors. The antagonism was found to be slowly reversible and non-competitive in higher drug concentrations. Sodium sulfate often recommended in cases of poisoning with these drugs was nearly ineffective for evoking contractions in model investigations with drug concentrations which can be found in practical clinical conditions.
The tone of the ductus arteriosus of the rabbit fetus near term constricted by oxygen (PO2 = 20 kPa) was relaxed reversibly by the drugs chlorpromazine, promethazine, drotaverine, papaverine, diazepam, propanidid, isoxsuprine, pethidine, 5-ethyl-5-(1-methyl-propyl) 2-thiobarbituric acid, and furosemide. Ethyl alcohol, on the other hand, caused constriction of the fetal ductus arteriosus. These drugs if used in obstetrics may disturb the newborn's adaptation to extrauterine life by inhibiting the postnatal closure of the ductus arteriosus. On the other hand, the constrictive effect of alcohol may adversely affect the fetus. The results make it necessary to investigate the effect of the drugs applied during the perinatal period on the adaptation of newborns to extrauterine life.