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PubMed1996

Preclinical skin sensitization testing of antihistamines: guinea pig and local lymph node assay responses.

Preclinical test methods for allergic contact sensitivity have been widely used for sensitization hazard identification and, with consideration of human exposure conditions, have also been valuable tools for sensitization risk assessment. For many years, the guinea pig has been the test species of choice with a variety of test methods developed to assess the sensitization response. More recently the local lymph node assay (LLNA) in mice has been developed to provide a more objective index of sensitization potential. The standardized methods have proven to be very well suited to most situations in which potential skin sensitization of a chemical needs to be assessed before human exposure. A potential difficulty with all these relatively limited exposure preclinical test methods, however, is in the ability to detect weak contact allergens that prove to be significant clinical allergens due to chronic topical exposure, exposure to compromised skin, and/or highly exaggerated exposure through transdermal delivery. This has been shown with the transdermal drug clonidine and might also be the case for topical antihistamines. The latter are considered significant clinical contact allergens, although predictive preclinical test data are minimal or lacking. A series of guinea pig (modified Buehler) tests with two common antihistamine compounds (triprolidine and diphenhydramine) and LLNA on these and two other compounds (chlorpheniramine and promethazine) was conducted. Positive Buehler test results required use of penetrating vehicle systems and a modified nine-induction patch regimen. Positive LLNA responses were obtained with all four materials (to varying degrees) only if the application site was pre-abraded or a penetrating vehicle (dimethylformamide) was used. These data support the notion that preclinical sensitization test methods can be modified to increase sensitivity. This may be critical for preclinical assessment of topical/transdermal drugs or other materials with chronic or high-concentration exposures in man.

Animals↗

PubMed1985

Effects of protease inhibitors and calmodulin inhibitors on Ca2+ influx and catecholamine secretion in isolated bovine adrenal medullary cells.

Acetylcholine (ACh) (10(-4) M) induced Ca2+ influx (21.2 nmol/mg cell protein/3 min) and catecholamine (CA) secretion (11.5% of total CA content) in isolated bovine adrenal medullary cells. Both excess K+ (56 mM KCl) and a calcium ionophore (A-23187: 10(-5) M) also induced CA secretion (9.7 and 7.5%, respectively, of total CA content). Protease inhibitors [gabexate mesilate (FOY), TLCK], a synthetic substrate of protease (TAME) and calmodulin inhibitors (W-7, trifluoperazine, promethazine, chlorpromazine) inhibited Ca2+ influx and CA secretion induced by ACh. Protease inhibitors and a substrate of protease had no effect on CA secretion induced by excess K+, and a high concentration of calmodulin inhibitors was required to inhibit excess K+-induced CA secretion. CA secretion induced by A-23187 was not inhibited by these inhibitors and the substrate.

Adrenal Medulla↗

PubMed1996

The impact of gender on alpha-methyl-para-tyrosine mediated changes in prolactin secretion and 6-hydroxymelatonin sulfate excretion.

Prolactin (PRL) and melatonin (ML) secretion are mediated by dopamine (DA) and norepinephrine (NE), respectively. Alpha-methyl-para-tyrosine (AMPT) inhibits the production of CNS catecholamines (CA). The purpose of the study is to determine: (1) if AMPT inhibition of ML has the same gender-dependent effect as on PRL secretion; (2) if there is a post AMPT-induced NE depletion mood change in men and/or women. In a randomized, double-blind cross-over fashion, five healthy young males and five females were either given five doses of AMPT 1 g (active) or promethazine 50 mg (placebo) over a 28 h period, separated by 4-6 weeks. The PRL and ML concentrations were collected at regular intervals via an indwelling venous catheter and concurrently, two 12 h urinary 6-hydroxymelatonin sulfate (6-MS) measurements were made. Mood and anxiety states of subjects at baseline and post drug were assessed with appropriate rating scales at regular intervals. Light exposure beginning at dusk and lasting until dawn was controlled to no more than 200 lux during all phases of the study. The PRL secretion showed a significant interaction of drug x time (p = .0001) in women and a non-significant trend (p = .056) in men. No difference in PRL secretion was found between the two genders in the placebo condition, whereas the PRL secretion was significantly higher in the AMPT condition in women when compared to men (df 17,119, F = 1.9, p = .021). Total 24 h urinary 6-MS secretion highly correlated with ML secretion expressed as area under the curve (AUC) during both active and placebo experiments (r = 0.8, p < .01) and (r = 0.86, p < or = .01), respectively. The ANOVA reveals a significant interaction of drug x time for 6-SM excretion. There was no gender difference in AMPT suppression of 6-MS excretion. No mood changes were detected in men or women. We conclude that urinary 6-MS is a reliable indirect measure of the degree of AMPT-induced decrease in CNS NE activity as part of overall AMPT-induced reduction of central catecholamine activities. The pre and post AMPT-induced changes in 6-MS are not gender dependent, dissimilar to the AMPT-induced changes in PRL secretion. Therefore, 6-MS, in addition to PRL, should be measured when applying the AMPT paradigm in future research.

Adult↗

PubMed1984

Prevention of radiation emesis in dogs by combinations of drugs.

Male mixed-breed dogs were used to evaluate the effectiveness of cimetidine (Cim), promethazine (Pro), and thiethylperazine (Thi), singly and in combination, to raise the threshold for radiation-induced emesis. Cim was chosen as an H2 antihistamine, Pro as an H1 antihistamine, and Thi as a phenothiazine derivative dopamine blocker. Doses were: 167 mg/m2 i.v. for Cim; 13.9 mg/m2 i.m. for Pro; and 5.6 mg/m2 i.m. for Thi. These doses were calculated on a mg/m2 basis to approximate doses for an average human (1.8 m2) of 300 mg Cim, 25 mg Pro, and 10 mg Thi. Exposure was to 60Co at 60 rad (midline) per min. The dogs were fed 0.4 kg canned dog food 1 hour before exposure, and injected with the appropriate drugs 30 minutes prior to exposure. Emesis onset times, number of episodes, and time to last episode were recorded. The radiation dose (midline tissue rad) to cause a 50% incidence of emesis (ED50) was calculated using an up-and-down procedure. The ED50 (95% confidence limits) were: 258 (212-315) for controls; 240 (151-380) for Cim; 313 (256-384) for Pro; 405 (319-514) for Thi; 334 (284-394) for Cim + Pro; 446 (365-546) for Cim + Thi; 347 (306-399) for Pro + Thi; and 478 (428-539) for Cim + Pro + Thi.

Animals↗

PubMed1983

Case vignettes of movement disorders.

This paper reports five movement disorders cases to serve as a basis for discussion of the problems encountered in the clinical management of these cases, and the pathophysiological mechanisms involved in these disorders as presented. Case 1 is a description of the subjective experience of a patient with acute orofacial dystonia from promethazine. Case 2 is the use of clonazepam is post-head injury tics. Case 3 is the complication from discontinuation of haloperidol and benztropine mesylate treatment. Case 4 is myoclonus in subacute sclerosing Panencephalitis, and Case 5 is rebound tremor from withdrawal of a beta-adrenergic blocker.

Adult↗

PubMed1993

Protective effect of calmodulin inhibitors against acute cyanide-induced lethality and convulsions in mice.

The ED50 value of cyanide as measured by induction of convulsions (tonic seizure) was significantly increased by 80% or 69% when trifluoperazine (TFP) or chlorpromazine (CHP), a specific calmodulin inhibitor was preinjected intracerebroventricularly (i.v.t.) at a dose of 0.09 mumol/body of mice. However, the ED50 of cyanide was not significantly changed by the same dose of promethazine (PMZ), another calmodulin inhibitor. Since it is known that the inhibitory effect of TFP or CHP against calmodulin-dependent enzymes such as phosphodiesterase is 100-400-fold higher compared to PMZ, it is speculated that the inhibitory effect of TFP or CHP against cyanide-induced convulsions may be based on its strong inhibitory properties into calmodulin-dependent enzymes. On the other hand, the LD50 value of cyanide was significantly increased by i.v.t. preadministration of TFP or CHP (0.045 mumol/body). Furthermore, the LD50 value of cyanide was also significantly increased by the same dose of PMZ. These results suggest that there is no positive correlation between mortality and convulsions induced by cyanide.

Animals↗

PubMed2006

Fasting duration influences the inhibition of food intake by histamine in chickens.

This work was performed to investigate the effect of duration of fasting in the responses of chickens peripherally injected with histamine on the regulation of food intake. The animals were 16-week-old male chickens from layer-strain and the doses of histamine used were 500 and 1000 microg/kg of body weight. The non fasted chickens showed no effect of histamine on the food intake. When the animals were fasted during 4 h, injected with the histamine and immediately refed, the results showed a reduction of food intake only the first 15 min of the experiments with the dose of 1000 mug. In chickens fasted during 16 h or 26 h and refed, the histamine inhibited significantly the food intake at all time with the two doses. When the animals were fasted 16 h and refed during 60 min before the administration of the histamine, there is no inhibition of food intake. No effect on water intake has been registered in all the experiments. The blockade of the action of histamine injected in chickens fasted during 16 h by cimetidine and promethazine, show that the inhibition of food intake occurs through the H1 but not through H2 receptors. The fasting used in paradigm to investigate the effect of drugs such as histamine on the appetite, can affect differently the responses according to its duration, as observed here in chickens.

Animals↗

PubMed1985

Is intraperitoneal dextran 70 safe for routine gynecologic use?

The routine use of intraperitoneal 32% dextran 70 has been suggested as an adjuvant to prevent postsurgical pelvic adhesions. Two hundred thirty-four women received an antiadhesion regimen consisting of intraperitoneal 32% dextran 70, dexamethasone, and promethazine. Ten women (4%) experienced spontaneous leakage of the dextran-peritoneal fluid mixture through their abdominal incisions. Painless bilateral swelling of the labia was noted in 18 women (8%). Mild abdominal bloating and weight gain of from 2.5 to 11 pounds were common. No anaphylactic reactions, peritonitis, or wound infections were experienced by any woman. Intraperitoneal dextran 70 appears to be a safe, well-tolerated antiadhesion adjuvant for routine use in gynecologic operations.

Anti-Bacterial Agents↗

PubMed2002

Recovery, enrichment and selectivity in liquid-phase microextraction comparison with conventional liquid-liquid extraction.

Mathematical descriptions for extraction recovery and enrichment were applied for liquid-phase microextraction (LPME) and comparison with conventional two- and three-phase liquid-liquid extraction techniques (LLE) was made. The LPME theoretical calculations were verified by experimental determination of actual partition coefficients and by data obtained with LPME in a robust hollow fibre formate. With hollow fibre LPME operated in the two-phase mode, analytes were extracted from 1 to 4 ml aqueous samples into 25-50 microl of an organic solvent present in the pores and in the lumen of the porous hollow fibres. Compared with conventional two-phase LLE, two-phase LPME provided substantially higher enrichments for compounds with relatively large partition coefficients (K(org)/d>500). In contrast, because of the large volume of organic solvent relative to the sample volume, LLE provided high recovery and moderate enrichment even for compounds with relatively low partition coefficients (K(org)/d>5). Thus, two-phase LPME may be used for substantially enhanced extraction selectivity and enrichment of relatively hydrophobic analytes as compared with LLE whereas conventional two-phase LLE is superior for more hydrophilic analytes. Similar results were found for three-phase LPME where analytes where extracted from 1 to 4 ml aqueous samples through approximately 20 microl organic solvent immobilized within the pores of the hollow fibre and into 25 microl of an aqueous acceptor solution inside the lumen of the hollow fibre. The fundamental differences of LPME and LLE were further demonstrated with practical experiments on extraction of the basic drugs promethazine, methadone, and haloperidol from human plasma and urine.

Chromatography, Gas↗

PubMed1991

Analgesia in anesthesia-free extracorporeal shock wave lithotripsy: a standardized protocol.

We treated 101 patients at our stone facility with the Dornier HM3 lithotriptor modified with the anesthesia-free design upgrade. A protocol designed by our anesthesiologists consisting of intravenous and intramuscular injections for sedation was used without any general or regional anesthesia required. Pre-medication with intramuscular meperidine and promethazine, and oral diazepam was sufficient sedation in 43 patients, while 37 required additional intravenous meperidine and/or midazolam during the procedure, 16 were treated with intraprocedural medication alone and 5 required no medication at all. Care before, during and after the procedure was rendered by the urology staff for patients in American Society of Anesthesiologists risk category I or II. Treatment was successfully completed in all patients without complications. We compared this group to the 99 patients treated consecutively before the modification. Voltage used, number of shocks and stone burden were comparable in the 2 groups but average treatment time was prolonged with the upgraded equipment (39.2 versus 27.1 minutes) to a significant degree (p less than 0.001).

Analgesia↗

PubMed1998

No development of tolerance to analgesia by repeated administration of H1 antagonists.

The effect produced by repeated administration of the H1-antihistaminics diphenhydramine, promethazine and pyrilamine on their ability to induce antinociception was evaluated in the mouse hot-plate and abdominal constriction tests. Contrary to morphine, baclofen and oxotremorine, the three H1 antagonists investigated did not promote the development of tolerance to the analgesic effect after 14 days of repeated treatment. H1 antagonists could, therefore, represent a promising pharmacological approach to the management of chronic pain.

Analgesia↗

PubMed1992

Central effects of tricyclic compounds on the endocrine system--an in vitro study.

The present study involves the effects on corticotropin (ACTH) release of neuro- and thymoleptic tricyclic antidepressant compounds (TrcACs: chlorpromazine, promethazine, haloperidol, imipramine, amitriptyline) and their interactions with lysine-8-vasopressin (LVP) and corticosterone (B). As an in vitro model, 14-day monolayer pituitary cell cultures of Wistar rats were employed. The ACTH concentrations of the supernatant media were measured by radioimmunoassay. TrcACs augmented ACTH release; their combination with LVP, however, did not result in further stimulation; moreover, when combined with TrcACs + LVP, B did not inhibit, but rather paradoxically increased their ACTH-releasing action. As none of these phenomena were followed by relevant changes in intracellular cyclic adenosine monophosphate content, the mechanism of action may be proposed to involve a protein kinase C route.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

A new goldfish model to evaluate pharmacokinetic and pharmacodynamic effects of drugs used for motion sickness in different gravity loads.

This paper proposes a new goldfish model to predict pharmacodynamic/pharmacokinetic effects of drugs used to treat motion sickness administered in differing gravity loads. The assumption of these experiments is that the vestibular system is dominant in producing motion sickness and that the visual system is secondary or of small import in the production of motion sickness. Studies will evaluate the parameter of gravity and the contribution of vision to the role of the neurovestibular system in the initiation of motion sickness with and without pharmacologic agents. Promethazine will be studied first. A comparison of data obtained in different groups of goldfish will be done (normal vs. acutely and chronically bilaterally blinded vs. sham operated). Some fish will be bilaterally blinded 10 months prior to initiation of the experiment (designated the chronically bilaterally blinded group of goldfish) to evaluate the neuroplasticity of the nervous system and the associated return of neurovestibular function. Data will be obtained under differing gravity loads with and without a pharmacological agent for motion sickness. Experiments will differentiate pharmacological effects on vision vs. neurovestibular input to motion sickness. Comparison of data obtained in the normal fish and in acutely and chronically bilaterally blinded fish with those obtained in fish with intact and denervated otoliths will differentiate if the visual or neurovestibular system is dominant in response to altered gravity and/or drugs. Experiments will contribute to validation of the goldfish as a model for humans since plasticity of the central nervous system allows astronauts to adapt to the altered visual stimulus conditions of 0-g. Space motion sickness may occur until such an adaptation is achieved.

Animals↗

PubMed1979

Survival of heart allografts in rats treated with azathioprine and sodium salicylate.

In a rat heart transplant model representing a severe mismatch, median survival time (M.S.T.) with no treatment was 6 days. M.S.T. with azathioprine was 6 days, and with azathioprine and methylprednisolone 7 days. Azathioprine with promethazine hydrochloride gave an M.S.T. of 15 days. In rats treated with sodium salicylate alone M.S.T. was 16 days, and when azathioprine was administered for 12 days in a group continuously treated with sodium salicylate, all hearts were beating normally at 50 days.

Animals↗

PubMed2002

Antihistamine antinociception is mediated by Gi-protein activation.

The effect of the i.c.v. administration of antisense oligodeoxynucleotides directed against the alpha subunit of different Gi-proteins (anti-Gi alpha(1), anti-Gi alpha(2), anti-Gi alpha(3)) on the antinociception induced by the H(1)-antihistamines was evaluated in the mouse hot-plate test. The administration of diphenhydramine (20 mg kg(-1) s.c.), pyrilamine (15 mg kg(-1) s.c.) and promethazine (6 mg kg(-1) s.c.) produced an increase of the pain threshold which peaked 15 min after injection. Pretreatment with anti-Gi alpha(1) (12.5 microg per mouse i.c.v.), anti-Gi alpha(2) (25 microg per mouse i.c.v.) and anti-Gi alpha(3) (25 microg per mouse i.c.v.), administered 24 and 18 h before test, prevented the antihistamine-induced antinociception. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test. These results suggest an important role played by the Gi-protein pathway in the transduction mechanism involved in the enhancement of the pain threshold produced by H(1)-antihistamines.

Analgesics↗

PubMed1997

Conscious sedation with combined hypnotic agents for implantation of implantable cardioverter-defibrillators.

OBJECTIVES: The objective of this study was to evaluate the feasibility, safety and efficacy of placing implantable cardioverter-defibrillators (ICDs) in the electrophysiology laboratory using conscious sedation with combined hypnotic agents and deep sedation with etomidate. BACKGROUND: Implantable cardioverter-defibrillators with transvenous leads permit the use of simplified implantation techniques similar to those used for the insertion of permanent pacemakers. However, implantation of ICDs without general anesthesia has thus far gained limited acceptance. METHODS: In 162 patients, conscious sedation during ICD placement was achieved with combined intravenous midazolam, morphine and promethazine (Phenergan). Intravenous etomidate was administered to induce deep sedation for defibrillation threshold testing. First-time implantations were in the prepectoral position (n = 142), but some patients with preexisting devices received abdominal implants (n = 20). The results were compared with those of concurrent patients (n = 56) who received prepectoral implants under propofol anesthesia administered by an attending anesthesiologist. RESULTS: The anesthetic protocol was implemented without major intraoperative complications. During deep sedation with etomidate, episodes of apnea, hypoxia or arterial hypotension requiring therapeutic intervention did not occur. During a mean (+/-SD) follow-up period of 257 +/- 140 days (median 227, range 14 to 482), there were, among the 162 patients, a total of two nonsudden cardiac deaths-one 71 days and the other 157 days after the operation. There were two nonsudden deaths in the concurrent control subjects (n = 56)-one 13 days and the other 110 days after the operation. CONCLUSIONS: Implantation of ICDs under conscious sedation with combined hypnotic agents and deep sedation with etomidate is a safe and effective procedure with low perioperative morbidity and low long-term complication rates.

Aged↗

PubMed2002

Toxicity of ethacrynic acid in isolated rat hepatocytes.

Ethacrynic acid, a loop diuretic drug, caused lipid peroxidation in isolated rat hepatocytes. The thiobarbituric acid reactive substances (TBARS) formation showed a good correlation with the leakage of glutamic-oxaloacetic acid transaminase (GOT) from the hepatocytes. The addition of antioxidants such as N, N'-diphenyl-p-phenylenediamine (DPPD) and promethazine to the isolated rat hepatocyte suspension containing ethacrynic acid prevented the lipid peroxidation and decreased the GOT leakage to some extent. SKF-525A inhibited the oxidative metabolism of ethacrynic acid and decreased the TBARS formation, suggesting that the lipid peroxidation was caused by the oxidative metabolism. The intracellular reduced glutathione markedly decreased in the hepatocyte suspension containing ethacrynic acid and the hepatocellular protein sulfhydryls were decreased, which was negatively correlated with the GOT leakage. Thus the ethacrynic acid-induced hepatotoxicity was found to be related to the lipid peroxidation and the decrease of cellular protein sulfhydryls.

Animals↗

PubMed2001

Enhancement of antibiotic activity against poly-drug resistant Mycobacterium tuberculosis by phenothiazines.

Phenothiazines have been shown to inhibit the in vitro growth of multi-drug resistant (resistant to rifampicin and isoniazid) Mycobacterium tuberculosis (MDRTB). They have been considered as potential adjuvants to regimens employing four or more antibiotics for the management of freshly diagnosed infections of M. tuberculosis in patients from areas known to have a high prevalence of MDRTB. Chlorpromazine has been shown to enhance the activity of antibiotics (except ethambutol) to which M. tuberculosis is susceptible. This might result in a reduction in the dose of some or all of the antibiotics employed without sacrificing the integrity of treatment. Chlorpromazine, thioridazine and promethazine were shown to enhance the activity of rifampicin and streptomycin when used in combinations at concentrations that are minimally effective when employed separately against clinical strains of M. tuberculosis resistant to two or more antibiotics (poly-drug resistant MTB). The phenothiazines had no effect on the activity of isoniazid against poly-drug resistant MTB.

Antibiotics, Antitubercular↗