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Prevention of pelvic adhesion formation by different modalities of treatment.

This prospective study was designed to investigate the effect of glucocorticoids, promethazine (Phenergan), hyskon, heparin, and Ringer's lactated solution in the prevention of pelvic adhesion formation after pelvic surgery. The patients were divided into two groups: The first consisted of 396 patients who had laparotomy for different types of pelvic surgery, and the second group consisted of 546 patients who had operative laparoscopy for different types of pelvic disease. Patients in these two major groups were divided prospectively into different subgroups with different modalities of adjuvant therapy to prevent postoperative pelvic adhesions. A second-look laparoscopy was performed for some of the patients who failed to conceive in each of these subgroups. Pregnancy rate and adhesion formation were compared between these subgroups with no statistical difference noted. It is concluded that glucocorticoids, promethazine, heparin, and hyskon have no therapeutic advantage over Ringer's lactated solution in the prevention of postoperative pelvic adhesion formation.

Adnexal Diseases↗

Studies on the involvement of histamine in the hypothalamic-pituitary-adrenal axis activation induced by nerve growth factor.

Nerve growth factor (NGF) has been shown to stimulate the hypothalamic-pituitary-adrenocortical (HPA) axis. Since NGF induces the release of histamine from mast cells and in consideration of the fact that histamine is an HPA axis activator, we investigated whether NGF adrenocortical stimulation is mediated by histamine. To accomplish with it, the H1 histamine antagonist promethazine and the H2 antagonists metiamide and zolantidine were used in freely-moving cannulated rats. The increase in plasma corticosterone concentration induced by histamine administration was prevented completely by promethazine pretreatment but was unaffected by the H2 antagonists. Neither H1 nor H2 antagonists affected the adrenocortical stimulation induced by NGF administration. Moreover, since mast cells are reportedly present in the rat adrenal gland and the locally released histamine mediates the release of adrenaline which, in turn, stimulates glucocorticoid synthesis and secretion, we studied the effect of NGF on basal and ACTH-stimulated corticosterone release from in vitro isolated quartered adrenal glands and collagenase-dispersed adrenal cells. The results from these in vitro experiments have indicated that NGF modified neither spontaneous nor stimulated corticosterone release. Altogether these observations suggest that endogenous histamine is unlikely to be involved in HPA axis stimulation by NGF and reinforce the previously proposed concept of an active participation of NGF in the control of adrenocortical activity.

Adrenal Glands↗

The effect of therapeutic drugs and other pharmacologic agents on activity of porphobilinogen deaminase, the enzyme that is deficient in intermittent acute porphyria.

Drugs and toxins precipitate life-threatening acute attacks in patients with intermittent acute porphyria. These materials may act by directly inhibiting enzyme activity, thus further reducing porphobilinogen (PBG) deaminase activity below the ca. 50% level that results from the gene defect. To test this, we studied the effects of drugs that precipitate acute attacks (lead, phenobarbital, griseofulvin, phenytoin, sulfanilamide, sulfisoxazole, 17alpha-ethinyl estradiol, 5beta-pregnan-3alpha-ol-20-one), drugs that are safe (lithium, magnesium, chlorpromazine, promethazine), and those with uncertain effects (ethyl alcohol, imipramine, diazepam, haloperidol) on activity of PBG deaminase in vitro and in vivo. In the in vitro studies, of PBG deaminase from human erythrocytes from normals and individuals with IAP, only lead (> or = .01 mM) inhibited enzyme activity. Chlorpromazine (> or = .01 mM), promethazine (> or = .01 mM) and imipramine (1 mM) seemed to increase enzyme activity. In most in vivo experiments, male rats were injected intraperitoneally with test material twice daily for 3 days and once on day four; and erythrocyte and hepatic PBG deaminase activity was assayed thereafter. Effects on enzyme activity were observed only with 17alpha-ethinyl estradiol (0.05 microg/kg/day; reduction of 11% in erythrocyte enzyme [NS], and of 20% in liver enzyme [P=.02]), and imipramine (12.5 mg/kg/day; reduction in erythrocyte enzyme activity of 13% [P<.001]). Rats given lead acetate in their drinking water (10 mg/ml) for the first 60 days of life, resulting in high blood and liver lead levels, had increased erythrocyte PBG deaminase (167% of control; P=.004). Thus, enzyme inhibition by lead in vitro was not reflected in a similar in vivo inhibition. The only inhibitory effects in vivo, with ethinyl estradiol and imipramine, appear to be mild and biologically inconsequential. We conclude that inhibition of PBG deaminase activity by materials that precipitate acute attacks is an unlikely mechanism by which these materials exert their harmful effects in patients with IAP.

Animals↗

Usefulness of the hydrogen--deuterium exchange method in the study of drug metabolism using liquid chromatography-tandem mass spectrometry.

The usefulness of the hydrogen-deuterium (H-D) exchange method in the study of drug metabolism was investigated. Metabolite samples of denopamine and promethazine prepared in vitro were introduced to a triple stage quadrupole tandem mass spectrometer via a high performance liquid chromatography (HPLC) system using a deuterated mobile phase. Mass spectra by various ionization modes and collisionally induced dissociation (CID) mass spectra were obtained. A metabolite of denopamine was observed to have a shift of 7 mass units by the H-D exchange method, and this shift proved to be a glucuronidated metabolite. Discrimination between N- or S-oxide formation and hydroxylation observed in the metabolism of promethazine was also easily accomplished by this method. In this manner, the structures of the metabolites were elucidated unequivocally by determining the number of labile hydrogen atoms by the use of the H-D exchange method, since various reactions in drug metabolism are accompanied by an increase or a decrease in the number of labile hydrogen atoms. Additional information on the structures was obtained by analysis of the CID spectra of the molecular ion species. Thus, the combination of the H-D exchange method and tandem mass spectrometry was found to be very useful for the study of drug metabolism.

Animals↗

Interaction between antibiotics and non-conventional antibiotics on bacteria.

The individual activity of antibiotics such as ampicillin, tetracycline, erythromycin and gentamicin in combination with compounds known to modify bacterial resistance to given antibiotics was studied using the checkerboard method. The combination of promethazine with either ampicillin, tetracycline or erythromycin or the combination of methylene blue and erythromycin produced significant synergistic activity against Escherichia coli. Verapamil, however, in combination with ampicillin reduced the activity of ampicillin against E. coli. Combinations of clomipramine with either tetracycline or erythromycin, promethazine and erythromycin or verapamil and ampicillin were synergistic against Staphylococcus epidermidis that was resistant to these antibiotics. The only synergy against Pseudomonas aeruginosa was shown by the combination of methylene blue and gentamicin.

Ampicillin↗

The role of macrophages on the expression of sex difference in the susceptibility to Brugia pahangi infection in C57BL/6 mice.

The role of macrophages or eosinophils on the expression of sex difference in the susceptibility to a primary Brugia pahangi infection in C57BL/6 mice was investigated by using a macrophage blockade technique (carbon treatment) or a histamine type 1 (H1) receptor antagonist (promethazine). Carbon treatment remarkably inhibited macrophage exudation, reduced the resistance of female mice, and completely abolished sex difference in the susceptibility to B. pahangi infection. Although promethazine treatment inhibited eosinophil exudation, it caused only a little increase (not significant) in the recovery rate of worms. These results suggest that macrophages have more important role(s) than do eosinophils on the expression of sex difference in the susceptibility to a primary B. pahangi infection in C57BL/6 mice.

Animals↗

Comparison of three outpatient regimens in the management of nausea and vomiting in pregnancy.

OBJECTIVE: This study compares pyridoxine-metoclopramide combination therapy to prochlorperazine and promethazine monotherapies in the outpatient treatment of nausea and vomiting in pregnancy. STUDY DESIGN: In total, 174 first trimester, singleton pregnancies were evaluated for nausea and vomiting. Patients were prospectively randomized into three treatment groups: pyridoxine-metoclopramide, prochlorperazine, or promethazine. Prior to, and on the third day, patients recorded their subjective responses to the given treatment and their number of emesis episodes. The three treatment groups were compared for therapy response. RESULTS: There were no differences in the number of emesis episodes prior to treatment. Both subjective and objective responses to treatment differed among the three groups when comparing the combination therapy to the monotherapies (p<0.05). CONCLUSION: Combination therapy with pyridoxine and metoclopramide appears to be superior to either monotherapy in the treatment of nausea and vomiting in pregnancy.

Adult↗

Mast cells mediate acid-induced augmentation of opossum esophageal blood flow via histamine and nitric oxide.

BACKGROUND & AIMS: Increased esophageal blood flow during reflux episodes may play an important role in mucosal resistance to injury, although the mechanism remains unclear. Decreased stainable mast cells and increased luminal histamine release during acid exposure has been previously documented. Therefore, the role of mast cells, nerves, histamine, and nitric oxide in mediating increased blood flow during acid challenge of the distal esophagus was investigated. METHODS: The effects of the mast cell stabilizers disodium cromoglycate and doxantrazole, the neurotoxin tetrodotoxin, the histamine H1 receptor antagonist promethazine, and the NO synthase inhibitor N omega-nitro-L-arginine methyl ester were examined by monitoring opossum esophageal histamine release and blood flow during perfusion with 100 mmol/L HCl. RESULTS: Luminal acid challenge significantly increased both histamine release and blood flow (P < 0.05). Disodium cromoglycate, promethazine, and N omega-nitro-L-arginine methyl ester attenuated the increase in blood flow to basal (saline-perfused) levels. Tetrodotoxin did not prevent an acute increase in blood flow that rapidly returned to baseline, likely from the ensuing hypotension. CONCLUSIONS: These findings provide evidence that mast cell-derived histamine, acting through an NO-dependent mechanism, plays a central role in the response of the esophageal microcirculation to luminal acid.

Animals↗

[Effect of premedication and barbiturate hypnotics on motor evoked potentials induced by magnetic cortex stimulation].

OBJECTIVE: The aim of this study was to investigate the influence of the premedication and the influence of the two barbiturates methohexital and thiopental on magnetically evoked compound muscle action potentials (magnet MEP) in humans. METHODS: 40 Patients (ASA-PS I-II) undergoing lumbar nucleotomy were included in this study after obtaining written informed consent. The study was approved by the local ethical committee. All patients were premedicated with 0.5 mg atropine, 25 mg promethazine and 50 mg pethidine. For induction of anaesthesia patients randomly received methohexital or thiopental by continuous infusion with increasing infusion rates every 15 seconds up to a minimal anaesthesia level in 15 minutes. Transcranial magnetic stimulation was delivered by the magstim 200 magnetic stimulator. Magnetic MEPs were recorded from the surface of the short abductor pollices muscle. MEP-examination was performed preoperatively, after premedication and every two minutes during the induction of anaesthesia. Every other two minutes the patients level of consciousness were assessed and documented. Statistical calculations were performed with the U-test. RESULTS: No statistical differences were found for the mean induction time in the two groups. No statistical difference in amplitude and latency could be observed between the preoperative values and the values measured after premedication. During anaesthesia induction the amplitude decreased in both groups. In 25 of the 40 cases, the MEP disappeared completely before the patients fell asleep. The thiopental group showed a significantly lower incidence of MEP preservation (20%) compared to methohexital (50%). CONCLUSIONS: Premedication with atropine, promethazine and pethidine has no influence on magnetic MEP. Methohexital allows the highest incidence of successful MEP recordings with sufficient anaesthesia. A success rate of only 50% even in cases without motorpathway affection makes the application of magnetic MEP an unreliable tool for intraoperative monitoring.

Adjuvants, Anesthesia↗

Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology.

Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury.

Animals↗

Peripheral nerve injection injury with antiemetic agents.

Antiemetics are widely used drugs, frequently administered to alleviate postoperative and postchemotherapeutic nausea and vomiting. While antiemetics do not induce peripheral neurotoxicity when administered systemically, it is not known whether peripheral nerve injury can occur as a result of inadvertent intraneural injection during intramuscular administration. The purpose of this study was to characterize the neurotoxic effect of three commonly used antiemetic agents (promethazine, dimenhydrinate, and prochlorperazine) as compared to saline in the rat sciatic nerve model. Intrafascicular and extrafascicular injection as well as direct application of the antiemetic drugs were performed. Nerves were harvested at 2 weeks postoperatively for histology and morphometry, with an additional sacrifice point at 8 weeks for the intrafascicular injection group. Injection injuries caused by antiemetic drugs differed depending on the agent injected and the location of injection. Extrafascicular injection and direct application caused no damage. Intrafascicular injection caused diffuse axonal injury in the promethazine and dimenhydrinate groups, while prochlorperazine caused only focal injury. Regeneration was prominent at 8 weeks in all intrafascicular injection groups in this rat model. Prochlorperazine thus appears to be less neurotoxic when injected intraneurally and should preferentially be used for intramuscular injections.

Animals↗

Morphine decreases peripheral vascular resistance and increases capacitance in man.

The response of the human peripheral circulation to morphine in large doeses independent of cardiac and respiratory influences has not been delineated. In 28 patients during cardiopulmonary bypass, alterations of peripheral vascular resistance (PVR) and capacitance in response to rapid arterial injection of morphine, 0.5 mg/kg or 1 mg/kg alone, or preceeded by promethazine, 1 mg/kg, naloxone, 10 mug/kg, or naloxone, 20 mug/kg, were recorded over 15 min at a constant perfusion rate. Both doses of morphine decreased PVR by 46 percent at 2 min, with values returning to control at 9 min. When promethazine preceded morphine, the decrease in PVR after morphine was 25 percent. Naloxone did not alter the response. An increase in capacitance of 600 ml observed 5 min after morphine administration did not revert to control after 15 min, and was unaltered by prior administration of naloxone.

Blood Pressure↗

Randomized study of premedication for esophagogastroduodenoscopy in children and adolescents.

In order to compare three premedication regimens, 58 children and adolescents were randomized to three groups: Group I, meperidine intramuscular; Group II, atropine intramuscular and diazepam intravenous; and Group III, meperidine, promethazine, and chlorpromazine intramuscular. Almost all patients required supplemental intravenous diazepam or meperidine to obtain adequate sedation. An endoscopist without knowledge of the medication group scored each patient for adequacy of sedation. Sedation was more effective in Group III than in Groups I and II (p less than 0.005); however, Group III patients were less arousable at completion of the procedure (p less than 0.0005) and had a greater duration of sedation (220 min compared with 56 and 88 min for Groups I and II, respectively, p less than 0.001). Complications were minor and not associated with any specific treatment. The evidence from this study supports the following conclusions: (a) adequate sedation for esophagogastroduodenoscopy in pediatric patients requires sedation with more than one of the drugs used in this study; and (b) the regimen meperidine, promethazine, and chlorpromazine, with diazepam supplement, was superior in providing sedation, but patients required a longer period of recovery than did patients sedated with one of the other regimens.

Adolescent↗

THE EFFECT OF SOME NEW ANTIHISTAMINES ON THE ANAPHYLACTIC MICROSHOCK OF THE GUINEA-PIG.

The dose/response curves for the protective effects of the new antihistamine compounds trimeprazine, 10-(3-diethylamino-2-methylpropyl)phenothiazine 1,1-dioxide hydrochloride (oxomemazine hydrochloride), cyproheptadine, homochlorcyclizine and methotrimeprazine against the anaphylactic microshock of the guinea-pig were similar to that of promethazine. The first three compounds, however, protected at lower doses than promethazine (5 to 10 mug/kg). The protective effect of cyproheptadine lasted longer than 24 hr.

Anaphylaxis↗

Alpha 4-2 beta 2 and other nicotinic acetylcholine receptor subtypes as targets of psychoactive and addictive drugs.

1. Xenopus oocytes were injected with various muscle and neuronal nicotinic acetylcholine receptor (ACh receptor, cholinoceptor) subunit RNA combinations and their pharmacological properties studied using two-electrode voltage clamp. The functional expression of one of these combinations, rat alpha 4-2 beta 2, has not been previously described. The alpha 4-2 mRNA is a splicing variant transcribed from the alpha 4 gene. In the experiments reported here, the alpha 4-2 beta 2 subtype was functionally indistinguishable from the alpha 4-1 beta 2 subtype. 2. For each subtype, the relative potency of nicotine compared with acetylcholine was obtained by estimating the relative concentration of nicotine which would elicit the same current response as 0.1 microM Ach. The ratios of these concentrations (nicotine: ACh) for the mouse muscle ACh receptor-(alpha 1 beta 1 gamma delta) was 96.1:1. In contrast, the ratios for the rat neuronal subtypes were: alpha 2 beta 2, 1.01:1; alpha 3 beta 2, 2.01:1; alpha 4 beta 2, 0.76:1 and alpha 4-2 beta 2, 0.76:1. The much greater relative nicotine sensitivity of the neuronal subtypes as compared with muscle receptors illustrates their potential to mediate the psychoactive and addictive effects of nicotine. However, it does not appear that the differences in relative nicotinic sensitivity among the neuronal receptors themselves can be used as a simple discriminative tool in neuronal tissue. 3. The slopes of the log dose-log response curves at low ACh concentrations were all greater than 1 but less than 2, suggesting that at least two agonist binding sites mediate the functional response of each hetero-oligomer. 4. The response of all the neuronal subtypes to ACh could be inhibited by the psychoactive drugs mecamylamine, amitriptyline, phencyclidine, trifluoperazine and promethazine. With the exception of the very potent antagonist, mecamylamine, the degree of block of the peak current to ACh produced by 10 microM concentrations of these drugs was remarkably similar (around 50%). 5. The degree of inhibition produced when the antipsychotic drug, trifluoperazine, was co-applied with ACh increased as the duration of application increased. Such an effect was not observed with promethazine, a related phenothiazine derivative which does not have antipsychotic actions.

Acetylcholine↗

Increased permeability of the capillaries of the rat heart to plasma albumin with asphyxiation and with perfusion.

1. Studies on the rate of efflux from the isolated perfused rat heart of plasma albumin conjugated with Evans Blue showed the conjugate to have penetrated extensively the extravascular compartment of the organ during a period of 2 min. This was confirmed by direct analysis of hearts for Evans Blue after perfusion.2. Exposure of the hearts to Evans Blue-albumin conjugate for 8 min in vivo showed no significant penetration of the interstitial space.3. With the isolated preparation inclusion of promethazine in the perfusing medium significantly diminished the rate of penetration of the extravascular compartment by the conjugate as did injection of the animals with either reserpine 2 days before, or bretylium immediately before the experiment.4. Penetration of the interstitial compartment in vivo could be induced by repeated asphyxiation. This penetration could also be diminished by promethazine but was not influenced by mepyramine maleate. The increased permeability of capillaries to plasma proteins can be readily demonstrated in the whole animal by detecting the leakage from the vasculature of the plasma proteins conjugated with a dye (Menkin & Menkin, 1930; Miles & Miles, 1952). Evans Blue, which has been widely used as a vascular marker because of the stability of its conjugate with plasma albumin, is the most suitable dye for this purpose. In the present work this method has been applied to the isolated rat heart, to determine if changes in capillary permeability occur in the perfused tissue. When plasma albumin conjugated with Evans Blue was used as a vascular marker in this preparation, its rate of clearance was very much less than that of erythrocytes, and the amount contained in the heart corresponded to a space approaching that occupied by extracellular markers such as raffinose and inulin. It was concluded, therefore, that there was a failure of a considerable number of the cardiac capillaries to retain the plasma albumin, and subsequent work was directed towards the identification of the condition that gives rise to these changes and the possible involvement of a permeability factor.A preliminary account of part of this work was given to the Physiologcal Society (Sutherland & Young, 1961).

Animals↗

Reduction of reaction due to iron dextran infusion using chloroquine.

The use of promethazine and chloroquine sulphate to reduce reaction to total dose infusion of iron dextran (Imferon) is described. The patients chosen for the investigation were anaemic pregnant African women living in the coastal region of East Africa where malaria due to Plasmodium falciparum is holoendemic. The results show that promethazine has little value in the reduction of reactions whereas chloroquine appears to be effective.

Anemia↗

Phototoxic properties of neuroleptic drugs.

BACKGROUND: Photo-induced eruptions are well-known adverse effects of some neuroleptic drugs, particularly chlorpromazine. OBJECTIVE: By a photohemolysis test we assessed in vitro the phototoxic properties of 12 phenothiazines (chlorpromazine, dixyrazine, fluphenazine, levomepromazine, perazine, perphenazine, promazine, promethazine, prothipendyl, thioridazine, trifluoperazine, triflupromazine) and 5 thioxanthenes (chlorprothixene, clopenthixol, flupenthixol, thiothixene, zuclopenthixol). METHODS: Human erythrocytes from 3 donors were incubated with the compounds and irradiated with light sources rich in UVA or UVB, respectively. Doses were up to 100 J/cm2 UVA or up to 1,600 mJ/cm2 UVB. Photo-induced hemolysis was calculated as percentage of complete hemolysis. RESULTS: Photo-induced hemolysis >10% due to radiation rich in UVA was found with chlorpromazine (maximal median: 98%), dixyrazine (100%), fluphenazine (84%), perazine (100%), perphenazine (100%), promazine (16%), promethazine (25%), prothipendyl (96%), trifluoperazine (100%), triflupromazine (76%), chlorprothixene (100%) and thiothixene (31%). UVB-rich radiation induced hemolysis only with chlorpromazine (73%), dixyrazine (45%) and perazine (60%). CONCLUSION: Most neuroleptics are strongly phototoxic in vitro indicating a potential risk for photo-induced reactions also to occur in patients treated with these drugs.

Antipsychotic Agents↗