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PubMed1998

"Conventional" antihistamines slow cardiac repolarization in isolated perfused (Langendorff) feline hearts.

We examined the effects of "conventional" antihistamines on cardiac repolarization by using the isolated perfused feline heart model. Representative drugs from the major classes of antihistamines were tested. Each of the antihistamines evaluated in this study elicited a dose-dependent slowing of cardiac repolarization, as indicated by the QT prolongations observed from electrocardiogram (ECG) tracings recorded during these experiments. The concentrations of drugs tested ranged from 1 to 30 microM. Of the drugs analyzed, clemastine and hydroxyzine appeared to be the most potent (relative EC50 values, 5.2 and 6.6 microM, respectively), causing the QT to lengthen by as much as 40-50% at a concentration of 10 microM. Brompheniramine, chlorpheniramine, and diphenhydramine displayed intermediate potencies with respect to QT prolongation (relative EC50 values, 11-13 microM), whereas cyproheptadine, chlorcyclizine, and promethazine were the least potent of the antihistamines tested (relative EC50 values, 16-20 microM). It is concluded that the antihistamines evaluated in this study act directly on the heart to slow cardiac repolarization. These findings could have important clinical relevance for patients taking excessive dosages of conventional antihistamines and those at risk of developing cardiac arrhythmias.

Animals↗
PubMed1976

Naloxone in the parturient and her infant.

Eighteen women in labor received analgesia with moderately large total doses of meperidien. Various doses of naloxone (8, 12, 18, 27, 40, or 60mug/kg of body weight) were given intravenously to the mothers before delivery in an attempt to find the dose that would prevent neonatal narcotic depression. Maternal and neonatal blood gas values, Apgar scores, and postnatal neurobehavioral examinations were used to assess the effects. Infants born of mothers who had received neither meperidine, promethazine, nor naloxone served as controls. After the naloxone injection, the mothers showed an improvement in consciousness and blood gas values. When the study infants, as a group, were compared with control infants, there was very little difference in blood gas values or neurobehavioral examination. Infants in the groups receiving naloxone in doses of 18, 27, and 40mug/kg compared most favorably with the control infants, indicating that naloxone may be effective in preventing neonatal narcotic depression.

Adult↗
PubMed1978

Value of fiberoptic gastrointestinal endoscopy in infants and children.

Fiberoptic gastrointestinal endoscopy was performed on 52 patients between the ages of 2 months and 16 years. The procedures were safely and easily done with premedications consisting of meperidine, promethazine, and chlorpromazine, and atropine, with diazepam given at the time of the procedure. Fiberoptic endoscopy was particularly helpful in localizing the site of upper gastrointestinal hemorrhage, in retrieving foreign objects, and in removing colonic polyps. In contrast, endoscopy added little to the clinical history and roentgenographic studies in children with recurrent abdominal pain or vomiting, in whom we believe fiberoptic endoscopy is not indicated unless the symptoms or history appear inconsistent with the diagnosis of functional bowel disease.

Abdomen↗
PubMed2003

Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6.

Bupropion is applied in depression and smoking cessation. Genetic polymorphisms in cytochrome P450 2B6 (CYP2B6) may cause variability in bupropion pharmacokinetics since hydroxylation is known to be mediated by CYP2B6. Bupropion may be a probe drug for CYP2B6 activity in humans. Bupropion pharmacokinetics were studied after a single oral dose of 150 mg in 121 healthy male volunteers. The amino acid polymorphisms R22C, Q172H, S259R, K262R and R487C were analysed by polymerase chain reaction and restriction fragment length polymorphism and plasma concentrations were measured by high-performance liquid chromatography. Pharmacokinetic analysis was performed by non-parametric methods and by population pharmacokinetic modelling. A unimodal distribution of bupropion and hydroxybupropion kinetic parameters was detected with a mean (range) area under the curve (AUC) of 3.64 (0.89-8.14) micromol.h/l for bupropion and 25.5 (6.72-75.3) micromol.h/l for hydroxybupropion. Population kinetic analysis revealed that bupropion total clearance via CYP2B6 alleles *1, *2, *5 and *6 did not differ, but clearance via allele *4 was 1.66-fold higher compared to wild-type allele *1 (P=0.001). Corresponding to the high clearance of bupropion, carriers of the CYP2B6 genotype *1/*4 had significantly higher Cmax of hydroxybupropion compared to all other genotypes (P=0.03). Only a minor fraction of the variability in bupropion and hydroxybupropion kinetics could be explained by the known CYP2B6 amino acid variants, in particular by the CYP2B6*4 allele. The role of this allele should also be studied in other CYP2B6 substrates, including cyclophosphamide, halothane, mianserin, promethazine and propofol.

Adult↗
PubMedDate not supplied

Safety and cost-effectiveness of outpatient total body irradiation in pediatric patients undergoing stem cell transplantation.

PURPOSE: To determine the feasibility, safety, and cost of delivering total body irradiation (TBI) in an outpatient setting. PATIENTS AND METHODS: The records of 33 pediatric patients with hematopoietic malignancies undergoing TBI in preparation for bone marrow transplantation (BMT) at the Children's Medical Center of Dallas between February 1992 and June 1997 were retrospectively reviewed. Seventeen children received TBI in an outpatient setting, including 7 patients younger than 8 years of age. All patients had a good performance status (Karnofsky index > 90%) and lived or were housed within a 50-mile radius of the hospital. Patients received 1200 cGy or 1350 cGy in 8 or 9 fractions twice daily over 4 to 5 days and were admitted for high-dose chemotherapy after the last TBI fraction. Mean age was 9 years (range 13 months to 16 years). Close contact was maintained with the BMT staff during outpatient TBI. RESULTS: Eleven patients (65%) received oral ondansetron for nausea and vomiting, 6 received promethazine and ondansetron, and 3 required dexamethasone. Only 2 of the 17 children (12%) required admission during TBI for persistent vomiting and poor oral intake. Two other children (12%) required outpatient administration of intravenous fluids. The other 13 patients (76%) tolerated the outpatient TBI regimen well. Taking into account hospitalization and ambulance transport charges, outpatient TBI represented a savings of approximately $3250 per patient compared with inpatient TBI. CONCLUSIONS: Fractionated TBI delivered in an outpatient setting to selected children of all ages is a safe and cost-effective practice.

Acute Disease↗
PubMed1995

Ocular toxicology.

In this review of recent articles on ocular toxicology, the author concentrates on undesirable effects on the eye induced by systemically used xenobiotics. These effects include increased tear flow elicited by systemic cyclosporine; uveitis associated with inactivated influenza vaccine, intravenous immunoglobulins, or skin tattoos; iritis associated with intravenous streptokinase; corneal epithelial erosion associated with the use of an alcohol-based antimisting spray; decreased color vision associated with workplace exposure to perchloroethylene, or to digoxin; myocardial ischemia induced by topical atropine; and systemic exposure to cyclopentolate after topical instillation. Ocular irritation associated with systemic use of 5-fluorouracil may be attenuated with prophylactic ice packs. At doses evaluated for treatment of choroidal neovascularization, systemic alpha interferon leads to toxicity in multiple organ systems. Promethazine precipitates when injected into intravenous lines with fluorescein. No drug achieves ultimate efficacy or ultimate safety. Thus, the decision to employ a given therapy involves a physician's evaluation of its therapeutic index-the ratio between efficacy and toxicity.

Drug-Related Side Effects and Adverse Reactions↗
PubMed1984

Control mechanisms governing the infectivity of Chlamydia trachomatis for HeLa cells: the role of calmodulin.

Adhesion of the obligate intracellular bacterium Chlamydia trachomatis to host cells is associated with a flux of Ca2+ across the cell membrane, and infection is enhanced by treatment of host cells with Ca2+ ionophore. The possibility that Ca2+ might interact with host cell Ca2+ regulatory proteins to promote chlamydial infection was investigated. Treatment of HeLa 229 cells with the calmodulin inhibitors pimozide, trifluoperazine, chlorpromazine, promethazine or haloperidol reduced chlamydial infectivity as measured by inclusion counting or the specific incorporation of [3H]threonine. The inhibitory effect was reversible, dose-related and shown to be associated with impairment of chlamydial adhesion and uptake by the host cells. This effect was clearly distinguished from the delayed maturation of chlamydiae due to continuous exposure to calmodulin inhibitors which may result from a decrease in the availability of high energy compounds from the host cells necessary for chlamydial growth. The possible mechanisms for calmodulin-mediated chlamydial endocytosis are discussed.

Adhesiveness↗
PubMed2025

Integrating explainable AI with multiomics systems biology and EHR data mining for personalized drug repurposing in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by region- and patient-specific molecular heterogeneity, which hinders therapeutic design. In this study, we introduce PRISM-ML (PRecision-medicine using Interpretable Systems and Multiomics with Machine Learning), an open-source integrated analysis pipeline that combines interpretable machine learning with systems biology and electronic health record (EHR) data mining to elucidate the molecular diversity of AD and predict promising drug repurposing opportunities. First, we integrated and harmonized transcriptomic (bulk RNA-seq) and genomic (genome-wide association study) data from 2105 brain samples, each with matched data from the same individual (1363 AD patients, 742 controls; nine tissues), sourced from three independent studies. Random forest classifiers with SHapley Additive exPlanations (SHAP) identified patient-specific biomarkers; unsupervised clustering resolved 36 molecularly distinct "subtissues" (clusters of samples); and gene-gene co-expression networks prioritized 262 high-centrality bottleneck genes as putative regulators of dysregulated pathways. Next, knowledge graph-based drug repurposing predicted six FDA-approved drugs that simultaneously target multiple bottleneck genes and multiple AD-relevant pathways. Notably, in a large U.S. de-identified insurance-claims database (n = 364733), exposure to promethazine, one of the candidate drugs, was associated with a 57-62 % lower incidence of AD versus an active antihistamine comparator (adjusted hazard ratio 0.38; inverse-probability weighted 0.43; both p < 0.001), providing real-world support for its repurposing potential. In summary, PRISM-ML, as an explainable multi-omics analysis pipeline, is readily transferable to other complex diseases, advancing precision medicine.

Computational Biology↗
PubMed1977

Assessment of topical anti-inflammatory activity in rats with cantharidin-induced inflammation.

Topical application of 400 mug of cantharidin to the rat's ear caused an approximate doubling in the mean weight of uniform ear punch samples when compared to vehicle-treated controls at 72 hr, and produced a maximal response at 7 days. Dexamethasone reduced the increase in weight when applied topically, but was ineffective when given subcutaneously or orally at the same doses. Hydrocortisone, prednisolone, triamcinolone, betamethasone, flurometholone, paramethasone acetate, fluocinolone acetonide, fluocinonide, and flurandrenolide showed significant suppression of cantharidin-induced inflammation. Cholesterol, diphenhydramine, tripelennamine, chlorpheniramine, promethazine, cyproheptadine, epinephrine, phenylephrine, alpha-tocopherol, indomethacin, and bufexamac were inactive. It is suggested that the procedure employed may be useful in the screening and evaluation of topical anti-inflammatory agents.

Administration, Topical↗
PubMed1976

Effect of ketamine on intracranial pressure in hydrocephalic children.

Intracranial pressure changes were observed in 10 children with hydrocephalus after ketamine administration. Three patients showed an elevation of pressure and a fall was observed in 7 patients. Two more patients who were given ketamine while under general anaesthesia and IPPV also showed a fall in pressure. No explanation is forthcoming at present for such an unusual response, but an altered cerebral vascular response in the presence of promethazine and general anaesthesia has been postulated.

Anesthesia, General↗
PubMed1988

Nifedipine prevents the pressor response to laryngoscopy and tracheal intubation in patients with coronary artery disease.

The efficacy of sublingual nifedipine, administered one minute before anaesthetic induction, in order to minimise the pressor response to laryngoscopy and tracheal intubation was studied in a group of 15 patients who underwent coronary artery bypass surgery. Another group of 15 similar patients served as control. Premedication consisted of oral diazepam 5-10 mg, intramuscular morphine 0.2 mg/kg and promethazine 0.4 mg/kg. Anaesthesia was induced with morphine 0.1-0.15 mg/kg and thiopentone 3-5 mg/kg. Laryngoscopy and tracheal intubation were facilitated with suxamethonium 1.5 mg/kg. A significant increase in blood pressure occurred during and after laryngoscopy and tracheal intubation in the control group. This increase was absent in the patients pretreated with nifedipine. The nifedipine group also maintained a lower rate-pressure-product than the control group during the period of study. It is concluded that nifedipine 10 mg is a useful pretreatment to prevent the pressor response to laryngoscopy and tracheal intubation in patients with coronary artery disease.

Adult↗
PubMed1993

Topical nitroglycerin prevents the pressor response to tracheal intubation and sternotomy in patients undergoing coronary artery bypass graft surgery.

Thirty adult patients who underwent coronary artery bypass graft surgery were allocated randomly to one of two equal groups to receive either 2% nitroglycerin, or a placebo ointment, applied topically over an area of 5 cm by 10 cm, in a double-blind manner, 1 h before induction of anaesthesia. Premedication consisted of oral diazepam 5-10 mg, intramuscular morphine 0.2 mg.kg-1 and promethazine 0.4 mg.kg-1. Anaesthesia was induced with morphine 0.15-0.2 mg.kg-1 and thiopentone 3-5 mg.kg-1. Laryngoscopy and tracheal intubation were facilitated by suxamethonium 1.5 mg.kg-1, and pancuronium 0.1 mg.kg-1 was used for subsequent muscle relaxation. Anaesthesia was maintained with 0.5% halothane and 40% oxygen in nitrous oxide. A significant increase in blood pressure occurred during and after laryngoscopy and tracheal intubation, and following midline sternotomy in the control group. These changes were absent in patients pretreated with topical nitroglycerin. The nitroglycerin group also maintained a lower rate-pressure product than the control group. We conclude that topical nitroglycerin is a simple and useful pretreatment to prevent the pressor response to tracheal intubation and midline sternotomy in patients undergoing coronary artery bypass graft surgery.

Adult↗
PubMed1981

Evaluation of drug phototoxicity by photosensitization of Trichophyton mentagrophytes.

Long wave ultraviolet radiation to suspensions of T. mentagrophytes, in the presence of photosensitizing chemicals, resulted in death of the fungus as measured by loss in colony-forming ability. Photosensitization could be demonstrated, with appropriate exposures and concentrations, with chlorpromazine, promethazine, perphenazine, anthracene, sulphanilamide, trimethylpsoralen, tolbutamide, tetrachlorosalicylanilide, and tribromosalicylanilide. No phototoxicity was detected with demethylchlortetracycline and thiazides. The present system seems to be simple, reproducible, and sensitive as an in vitro screening test for the photosensitizing potential of chemicals.

Drug Evaluation, Preclinical↗
PubMed1996

Photodermatoses in a Singapore skin referral centre.

The inducing or exacerbating effect of sunlight on skin diseases is often not appreciated in tropical countries, perhaps because of the perennial presence of sunlight, and a retrospective review of photodermatoses seen in a referral skin clinic was therefore carried out. The photodermatoses seen were secondary photoaggravation of primary skin diseases (32.2%), systemic drug photosensitivity (11.3%), polymorphic light eruption (13%), chronic actinic dermatitis (5.3%), solar urticaria (5.3%), actinic prurigo (4%), photoallergic contact dermatitis (2.6%), porphyria (1.3%) and xeroderma pigmentosum (1.3%). Compared with the results of Western studies, there were more photoaggravated underlying skin diseases and systemic drug photosensitivity, and fewer idiopathic photodermatoses and photoallergic contact dermatitis; the common photoallergens were chlorpromazine, promethazine and musk ambrette, very similar to those seen in the West.

Adolescent↗
PubMed1979

Differential effects of fibroblast and leucocyte interferon in HBsAg positive chronic active hepatitis.

Six patients with hepatitis B surface antigen, hepatitis B 'e' antigen positive chronic active hepatitis, and elevated hepatitis B specific DNA polymerase activity were treated sequentially with fibroblast and leucocyte interferon. Fibroblast interferon induced a fall in serum transaminase activities in all patients, whereas a consistent decline in DNA polymerase activity was observed during leucocyte interferon administration only. After treatment one patient remained persistently DNA polymerase and hepatitis B 'e' antigen negative, whereas relapse to initial values occurred in others. Side effects included severe but reversible granulocytopenia, and chills responding to promethazine treatment. The differential biologies with their non-identity in in vitro studies.

Chronic Disease↗
PubMed1986

Dermal reactivity to histamine, serotonin and bradykinin in relation to allergic skin reactions of the horse.

The reactivity of horse skin to intradermal inoculation of histamine, serotonin and bradykinin was investigated, and the resulting reactions compared with those produced in the same horses by a 1% whole-body extract of Culicoides. Both histamine and bradykinin produced large reactions, but there was no significant correlation between the dermal responsiveness to insect allergen and either histamine or bradykinin. Two anti-histamine drugs (promethazine hydrochloride and tripelennamine hydrochloride) were effective in reducing the reaction produced by the insect extract.

Animals↗
PubMed2004

Periodic painful purpura: fact or factitious?

A 60-year-old woman with multiple psychosocial issues presented with a history of spontaneous painful bruising on her left upper arm. Extensive investigations did not reveal any abnormality apart from an elevated activated partial thromboplastin time as a result of factor XII deficiency. An autoerythrocyte sensitization test reproduced the tender bruises on her back. Our patient reported relief of pain with promethazine injections. She was subsequently referred to the psychiatric team for ongoing assessment and management. Having an awareness of this rare condition will assist in the prevention of unnecessary investigation of such cases and will allow the early referral of patients for appropriate psychological counselling.

Diagnosis, Differential↗
PubMed1985

Histidine transport into rat brain synaptosomes.

Histidine transport and metabolism in rat brain synaptosomes were investigated to study the possible role of histidine uptake in the synthesis of the putative neurotransmitter histamine (HA). Histidine uptake was found to be regionally distributed and temperature sensitive, and was not totally independent of sodium or potassium ions. Transport was inhibited by metabolic inhibitors, as well as by promethazine and quinacrine. A number of other HA-related agents and several histidine metabolites had no effect. Kinetic analyses of histidine transport revealed the presence of both high- and low-affinity systems in cerebral cortex. Histidine uptake increased following preexposure of synaptosomes to depolarizing concentrations of potassium. This effect was dependent on the presence of calcium ions during the preincubation. No newly formed [3H]HA was detectable in rat brain synaptosomes following [3H]histidine transport. Lesions of the medial forebrain bundle did not alter histidine uptake in the hippocampus or cerebral cortex. Ontogenic studies indicated that the histidine uptake system developed rapidly and reached a peak during postnatal days 12-17. Overall, the present findings do not support a role for histidine transport in the regulation or maintenance of neurotransmitter pools of HA in rat brain.

Animals↗