Blockade of HERG and Kv1.5 by ketoconazole

Ketoconazole, a widely used fungicide in patients, has been associated with Q-T prolongation and torsade de pointes when co-administered with terfenadine (Seldane). Both compounds use the same cytochrome-P450 metabolic pathway, resulting in an increase in plasma concentration of terfenadine. We previously showed that terfenadine blocked HERG (Human Ether-a-Gogo Related Gene), an important component of the repolarizing cardiac delayed rectifier IK with concentration needed to obtain 50% of the block (IC50) in the therapeutic range (300 nM). Another target is Kv1.5 (delayed outward rectifier potassium current), an important component of human atrial ultrarapid delayed rectifier current. Whether Kv1.5 and HERG proteins are direct targets for ketoconazole has yet to be addressed. We heterologously expressed HERG and Kv1.5 in Xenopus oocytes and compared their sensitivities to ketoconazole. HERG and Kv1.5 currents were reduced comparably with apparent IC50 values of 49 microM and 107 microM, respectively, when measured using the two-microelectrode recording technique. The differences in the IC50 may help explain the preferential ventricular origin of the ketoconazole-associated arrhythmias during overdose. The mechanism of block was different between Kv1.5 and HERG. Cumulative application of terfenadine and ketoconazole at their respective IC50 concentrations resulted in current reductions that suggest an additive rather than a competitive type of block by the two drugs. We conclude that ketoconazole may potentiate the effects of terfenadine first by an indirect pharmacokinetic action to elevate plasma levels and second by a direct pharmacodynamic action on HERG currents. These potential dual actions on HERG currents suggest that precautions should be taken in long-term ketoconazole treatment, particularly for patients who have decreased liver function or are on a drug regimen requiring simultaneous medications that use cytochrome-P450 for breakdown, such as terfenadine or erythromycin, or Class III antiarrhythmic drugs.     

Inhibitory effects of terfenadine on the rising phase of action potentials and sinus rates in isolated guinea-pig myocardium

1. Effects of terfenadine on the ventricular action potential and sinus rate of isolated guinea-pig myocardial preparations were examined to elucidate whether the drug has any cardioinhibitory effect. 2. Terfenadine significantly and concentration dependently decreased the maximum rate of rise (Vmax) of action potentials, the decrease of which was 60% of the control value at 2 x 10(-5) M. 3. Terfenadine decreased the sinus rate concentration dependently at 10(-6) M and higher concentrations; in some preparations, spontaneous beating was abolished at 2 x 10(-5) M (sinus arrest). 4. On the other hand, KW-4679 ((Z)-11-[3-(dimethylamino)propylidene]-6-11-dihydrodibenz[b, e]oxepin- 2-acetic acid hydrochloride), a new antiallergic drug having higher antiallergic potency than terfenadine, exerted a weaker inhibitory effect on the Vmax without affecting the sinus rate. 5. In conclusion, the antiallergic drug terfenadine has inhibitory effects on isolated myocardia. The cardioinhibitory effects of antiallergic drugs seem to be independent of their antiallergic potency.     

Metabolism of epinastine, a histamine H1 receptor antagonist, in human liver microsomes in comparison with that of terfenadine

Epinastine is a non-sedative second-generation antiallergic drug, like terfenadine. In the present study, the metabolism of epinastine in human liver microsomes was investigated and compared with that of terfenadine. Terfenadine was extensively metabolized to terfenadine acid with a Km value of 1.78 microM, a Vmax value of 173.8 pmol/min/mg and a metabolic clearance (Vmax/Km) of 103.9. Epinastine, in contrast, was poorly metabolized by microsomes from the same source with a high Km value of 232 microM. Metabolic clearance of epinastine was only 0.832, which was lower by three orders of magnitude than that of terfenadine. Studies with microsomes expressing recombinant cytochrome P450 (CYP) species revealed that the CYP isoforms responsible for epinastine metabolism are CYP3A4, 2D6 and (to a minor extent) 2B6. Epinastine and terfenadine had no effect on CYP1A2 (theophylline 1-demethylation), 2C8/9 (tolbutamide hydroxylation) or 2E1 (chlorzoxazone 6-hydroxylation) activity, but weakly inhibited CYP2D6 (debrisoquine 4-hydroxylation) activity. CYP3A4 (testosterone 6 beta-hydroxylation) activity was strongly inhibited by terfenadine with a Ki value of 25 microM, whereas epinastine had no effect at up to 100 microM. Thus, epinastine is very poorly metabolized compared to terfenadine in human liver microsomes and does not inhibit CYP3A4 activity in vitro, unlike terfenadine.     

Dopamine-secreting glomus vagale: a case report and histopathologic correlation

The effect of atorvastatin, a CYP3A4 substrate, on the pharmacokinetics of terfenadine and its carboxylic acid metabolite, fexofenadine, were evaluated. Single 120-mg doses of terfenadine were given 2 weeks apart to healthy volunteers with 80-mg daily doses of atorvastatin administered from 7 days before through 2 days after the second terfenadine dose. Concentrations of terfenadine and fexofenadine were measured for 72 hours after each terfenadine dose. Administration of terfenadine alone or in combination with atorvastatin produced no alterations in the QTc interval. For terfenadine, atorvastatin coadministration produced an 8% decrease in maximum concentration (Cmax), a 35% increase in area under the concentration-time curve extrapolated to infinity (AUC0-infinity), and a 2% decrease in elimination half-life (t1/2). For fexofenadine, atorvastatin coadministration produced a 16% decrease in Cmax, a 2% decrease in AUC0-infinity and a 51 % increase in t1/2. None of these changes achieved statistical significance. Coadministration of atorvastatin with terfenadine does not result in a clinically significant drug interaction. Because 80 mg is the highest atorvastatin dose used clinically, drug interactions mediated by CYP3A4 inhibition are unlikely in clinical practice.     

Hong Kong''s eastern and western medical history

BACKGROUND: Some clinical studies suggest that a combination of an H1- and H2-antagonist may be effective in the prophylaxis of allergic reactions. OBJECTIVE: The efficacy of pretreatment with an H1/H2-antagonist combination, H1-antagonist alone, or placebo in the prophylaxis of local and systemic adverse reactions to specific immunotherapy with Hymenoptera venom was compared. METHODS: In a prospective, randomized, double-blind, placebo-controlled study, 121 patients with Hymenoptera venom allergy were treated with rush immunotherapy and pretreatment with one of the following: 120 mg of terfenadine plus 300 mg of ranitidine, 120 mg of terfenadine alone, or placebo. The incidence of unwanted systemic adverse and local reactions was recorded for up to 50 weeks. RESULTS: In seven patients (6%), six in the placebo group and one in the terfenadine group, systemic side effects required cessation of therapy (p = 0.005). Subjective symptoms occurred in four patients (10%) in the terfenadine plus ranitidine group and in three patients (7%) in the terfenadine group. Regarding local reactions, significantly fewer patients treated with a combination of terfenadine and ranitidine and with terfenadine alone as compared with placebo had severe local symptoms of erythema (29%, 29%, and 49%), edema (24%, 18%, and 41%), and pruritus (13%, 11%, and 31%) at week 1 (p < 0.05). This therapeutic benefit was limited to the first 4 weeks of treatment. Treatment with a combination of terfenadine and ranitidine was not superior to treatment with terfenadine alone. CONCLUSIONS: Pretreatment with H1-antihistamines with or without H2-antihistamines significantly reduced local and systemic adverse reactions to immunotherapy with Hymenoptera venom and may therefore be helpful in the management of immunotherapy.     

Female exposure to high G: chronic adaptations of cardiovascular functions

The substrate structure-activity relationships described for the major human drug-metabolizing cytochrome P450 (P450 or CYP) enzymes suggest that the H1 receptor antagonist terfenadine could interact with CYP2D6 either as a substrate or as an inhibitor, in addition to its known ability to act as a substrate for CYP3A4. Based on this substrate structure-activity relationship, computer modeling studies were undertaken to explore the likely interactions of terfenadine with CYP2D6. An overlay of terfenadine and dextromethorphan, a known substrate of CYP2D6, showed that it was possible to superimpose the site of hydroxylation (t-butyl group) and the nitrogen atom of terfenadine with similar regions in dextromethorphan. These observations were substantiated by the ease of docking of terfenadine into a protein model of CYP2D6. Experimentally, terfenadine inhibited CYP2D6 activity in human liver microsomes with an IC50 of 14-27 microM, depending on the CYP2D6 substrate used. The inhibition of CYP2D6 was further defined by determining the Ki for terfenadine against bufuralol 1'-hydroxylase activity in four human livers. Terfenadine inhibited bufuralol 1'-hydroxylase activity with a Ki of approximately 3.6 microM. The formation of the hydroxylated metabolite (hydroxyterfenadine) in microsomes prepared from human liver and specific P450 cDNA-transfected B lymphoblastoid cells indicated that only CYP2D6 and CYP3A4 were involved in this transformation. As expected, the rate of formation was greatest with CYP3A4 (Vmax = 1257 pmol/min/nmol of P450), with CYP2D6 forming the metabolite at a 6-fold lower rate (Vmax = 206 pmol/min/nmol of P450). The two enzymes had similar KM values (9 and 13 microM, respectively). These data indicate that, as predicted from modeling studies, terfenadine has the structural features necessary for interaction with CYP2D6.     

Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals

To determine whether the clinical adverse interactions of terfenadine with azole antifungals and macrolide antibiotics may be related to inhibition of terfenadine biotransformation, an in vitro system was developed to follow the metabolism of terfenadine by rat liver S9 or human liver microsomes. When test compounds were coincubated with terfenadine, the metabolites formed and unchanged terfenadine was quantitatively analyzed by HPLC. Five metabolites of terfenadine were formed by rat liver S9: predominantly alcohol metabolite (III), with four minor metabolites--azacyclonol (I), acid metabolite (II), an unidentified metabolite (IV), and a new ketone metabolite (V). By human liver microsomes, two major metabolites were formed: azacyclonol (I) and alcohol metabolite (III). Ketoconazole, fluconazole, itraconazole, erythromycin, clarithromycin, and troleandomycin potently inhibited terfenadine metabolism by human liver (IC50 = 4-10 microM), but inhibition by rat liver was weaker (IC50 = 87-218 microM) and 18% maximally for troleandomycin. Other CYP3A substrates (cyclosporin A, naringenin, and midazolam) also demonstrated potent inhibition of terfenadine biotransformation in human liver microsomes (IC50 = 17-24 microM). Substrates of other P450 families [sparteine (CYP2D6), caffeine (CYP1A), and diclofenac (CYP2C)] only very weakly inhibited terfenadine metabolism. Dixon plot analyses for human liver revealed competitive/reversible inhibition by the azole antifungals and macrolide antibiotics of azacyclonol and alcohol metabolite formations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intranasal fluticasone propionate is more effective than terfenadine tablets for seasonal allergic rhinitis

BACKGROUND: We compared the efficacy and tolerability of the intranasal corticosteroid fluticasone propionate with that of the antihistamine terfenadine in patients with seasonal allergic rhinitis. METHODS: Two hundred thirty-two adults and adolescents with seasonal allergic rhinitis received intranasal fluticasone propionate (200 micrograms once daily), terfenadine tablets (60 mg twice daily), or placebo for 2 weeks in a double-blind, randomized, parallel-group study. Main outcome measures were clinician- and patient-rated individual and total nasal symptom scores (based on ratings of nasal obstruction, sneezing, nasal itching, and rhinorrhea); clinician-rated overall response to therapy; changes in nasal inflammatory cell counts; adverse events; and morning plasma cortisol concentrations. RESULTS: Both clinician- and patient-rated total and individual nasal symptom scores were significantly lower in the fluticasone group than in either the terfenadine group or the placebo group at nearly every measured time point throughout the treatment period. After 2 weeks of therapy, clinician-rated total nasal symptom scores decreased by 49% in the fluticasone group compared with 27% in the terfenadine group and 19% in the placebo group. In general, therapy with terfenadine was not statistically distinguishable from that with placebo based on patient-rated total or individual nasal symptom scores. According to clinician ratings, 64% of fluticasone-treated patients compared with 49% and 44% of patients treated with terfenadine and placebo, respectively, experienced significant or moderate improvement. A greater percentage of fluticasone-treated patients compared with either terfenadine- or placebo-treated patients experienced reductions in intranasal eosinophil and basophil counts after 2 weeks of therapy. No unusual or serious drug-related adverse events were reported. Morning plasma cortisol concentrations after 2 weeks of therapy did not differ among groups. CONCLUSION: Fluticasone aqueous nasal spray, a well-tolerated corticosteroid preparation that can be administered once daily, is more effective than terfenadine tablets or placebo in controlling symptoms of seasonal allergic rhinitis.     

Comparative effects of nonsedating histamine H1 receptor antagonists, ebastine and terfenadine, on human Kv1.5 channels

The effects of ebastine and terfenadine, long-acting nonsedating histamine H1 receptor antagonists, were studied on hKv1.5 channels using the whole-cell voltage-clamp configuration of the patch-clamp technique in Ltk- cells transfected with the gene encoding the hKv1.5 channel. Upon depolarization to +60 mV, terfenadine, 1 microM and 3 microM, inhibited the hKv1.5 current by 42.4 +/- 6.4% and 69.3 +/- 4.2% (P < 0.01). In contrast, at the same range of concentrations, ebastine-induced inhibition of this K+ current averaged 6.5 +/- 2.0% and 13.0 +/- 2.0 (P < 0.05). At the highest concentration tested (3 microM) neither terfenadine carboxylate nor carebastine significantly modified hKv1.5 current. All these results suggest that ebastine could represent a safer alternative to terfenadine in the clinical practice.     

The effect of terfenadine on unilateral nasal challenge with allergen

To investigate the role of H1 receptor-mediated effects in allergic rhinitis, we challenged 12 allergic volunteers with allergen 2 hours after administration of either placebo or 60 mg of terfenadine. Filter paper discs were used for the unilateral administration of allergen and the collection of nasal secretions. Secretion weights, levels of histamine in recovered nasal secretions, and nasal airway resistance (NAR) were measured for each nostril separately, and the number of sneezes was counted. After placebo treatment, allergen challenge led to significant increases in ipsilateral and contralateral secretion weights, ipsilateral histamine levels, ipsilateral NAR, and sneezing. Contralateral histamine levels were not elevated. H1 antagonism with terfenadine markedly reduced the number of sneezes and partially decreased ipsilateral and contralateral secretion weights, without affecting the increase in NAR. Terfenadine premedication also lowered the amount of histamine in ipsilateral secretions after allergen challenge. Performing identical nasal challenges with a 10-fold lower dose of antigen produced similar results. Previous studies showed that terfenadine had no effect on methacholine provocation and completely abolished ipsilateral and contralateral secretion weights after histamine challenge. We conclude that sneezing after allergen challenge is caused almost exclusively by a reflex initiated through H1 receptors and that H1 antagonism has no influence on allergen-induced increases in NAR. Unilateral allergen challenge leads to bilateral increases in secretion weights, which are only partially inhibited by terfenadine, suggesting the involvement of mediators other than histamine in the nasonasal reflex. As reported earlier, terfenadine also decreases allergen-induced histamine release after challenge with the highest dose of antigen.     

The effects of topical doxepin on responses to histamine, substance P and prostaglandin E2 in human skin

The tricyclic antidepressant, doxepin, is known to have H1 and H2 antihistaminic effects. Recently, 5% doxepin cream has been marketed in the U.S.A. for treatment of eczematous dermatoses. We investigated the effects of topical doxepin treatment on histamine-, substance P- and prostaglandin E2- (PGE2) induced responses in the skin of normal and atopic subjects. We compared the effects of topical doxepin with those of the oral antihistamine terfenadine. The weal volume and flare area responses to histamine were significantly reduced by treatment with topical doxepin or oral terfenadine in both normal and atopic subjects (P < 0.05). The mean +/- SEM percentage reduction in flare area for 10 micrograms/site of histamine in non-atopics and atopics was 48 +/- 8% and 60 +/- 17% with terfenadine, and 54 +/- 12% and 81 +/- 4% with topical doxepin, respectively. The mean percentage reduction in weal volume for the same dose of histamine in non-atopics and atopics was 70 +/- 9% and 63 +/- 16% with terfenadine, and 96 +/- 2% and 89 +/- 6% with topical doxepin, respectively. The flare but not the weal response to substance P was inhibited by both treatments in all subjects (P < 0.05). The mean +/- SEM percentage reduction in flare area for 200 pmol/site of substance P in non-atopics and atopics was 53 +/- 10% and 73 +/- 4% with terfenadine, and 74 +/- 7% and 75 +/- 4% with topical doxepin, respectively. The cutaneous responses to PGE2 were not affected by either drug. The inhibitory effects of doxepin were as great as those of terfenadine, and doxepin had a significantly greater effect than terfenadine in inhibiting the weal response to histamine and flare response to substance P in normal volunteers (P < 0.05). There was no significant difference between atopics and non-atopics in the percentage reduction of cutaneous responses by oral terfenadine or topical doxepin. Marked sedation occurred in three of the first 10 subjects treated with topical doxepin, necessitating a reduction in dosage for the remaining six subjects. In summary, topical doxepin was as effective as, and sometimes more effective than, a standard dose of oral terfenadine in the inhibition of histamine-induced and axon-reflex-mediated cutaneous responses. The marked sedative effect may limit its clinical use in some patients.     

Comparison of CYP3A activities in a subclone of Caco-2 cells (TC7) and human intestine

PURPOSE: To compare the activity of the CYP3A enzyme expressed by TC7, a cell culture model of the intestinal epithelial cell, to the activity of human intestinal CYP3A4, using terfenadine as a substrate. METHODS: The metabolism of terfenadine was investigated in intact cells and microsomal preparations from TC7, human intestine, and liver. The effect of two CYP3A inhibitors, ketoconazole and troleandomycin (TAO), on the metabolism of terfenadine was also examined. RESULTS: Only hydroxy-terfenadine was detected in TC7 microsomal incubations. In contrast, azacyclonol and hydroxy-terfenadine were detected in human intestinal and hepatic microsomal incubations. The Km values for hydroxy-terfenadine formation in TC7 cells, intestine and liver microsomes were 1.91, 2.5, and 1.8, microM respectively. The corresponding Vmax values were 2.11, 61.0, and 370 pmol/min/mg protein. Km values for azacyclonol in intestinal and hepatic samples were 1.44 and 0.82 microM and the corresponding Vmax values were 14 and 60 pmol/min/mg protein. The formation of hydroxy-terfenadine was inhibited by ketoconazole and TAO in human intestine and TC7 cell microsomes. The Km and Vmax values for terfenadine metabolism in intact TC7 cells were similar to those from TC7 cell microsomes. CONCLUSIONS: Our results indicate that TC7 cells are a potentially useful alternative model for studies of CYP3A mediated drug metabolism. The CYP3A expressed by TC7 cells is not CYP3A4, but probably CYP3A5, making this cell line suitable for studies of colonic drug transport and metabolism.     

Portal hypertensive gastropathy and colopathy

The goal of these experiments was to determine which histamine receptors are involved in the relationship between drinking and feeding in ruminants. To this end, the effects of the histamine receptor antagonists dexbrompheniramine (H1 receptor antagonist), cimetidine (H2 receptor antagonist), and terfenadine (H1 receptor antagonist) on feeding and drinking patterns of pygmy goats were investigated. Two experiments using dexbrompheniramine [1 and 2 mg/kg of body weight (BW)0.75], two experiments using cimetidine (16 and 32 mg/kg of BW0.75), and two experiments using terfenadine (5 and 11.5 mg/kg of BW0.75) were performed to assess the type and location (periphery or central nervous system) of the histamine receptors involved in the mediation of prandial drinking by pygmy goats. The H1 receptor antagonists dexbrompheniramine (2 mg/kg of BW0.75) and terfenadine (11.5 mg/kg of BW0.75) significantly reduced water intake, but cumulative feed intake did not change. Consequently, the ratio of water intake to feed intake decreased. In contrast, the H2 receptor antagonist did not affect either water or feed intake. Dexbrompheniramine at 2 mg/kg of BW0.75 and terfenadine at 11.5 mg/kg of BW0.75 also decreased draft frequency and decreased the water intake associated with meals. Results showed that blockage of peripheral H1 histamine receptors attenuates the association between water and feed intake in pygmy goats. Therefore, the stimulating effect of feed intake on water intake appears to depend on activation of peripheral H1 histamine receptors.     

Variability in PAH-DNA adduct measurements in peripheral mononuclear cells: implications for quantitative cancer risk assessment

We investigated the angiotensin II (Ang II)-generating system by analyzing the vasoconstrictor effect of Ang II, angiotensin J (Ang I), and tetradecapeptide (TDP) renin substrate in the absence and presence of inhibitors of the renin-angiotensin system in isolated rat aortic rings and mesenteric arterial beds with and without functional endothelium. Ang II, Ang I, and TDP elicited a dose-dependent vasoconstrictor effect in both vascular preparations that was completely blocked by the Ang II receptor antagonist saralasin (50 nM). The angiotensin converting enzyme (ACE) inhibitor captopril (36 microM) completely inhibited the vasoconstrictor effect elicited by Ang I and TDP in aortic rings without affecting that of Ang II. In contrast, captopril (36 microM) significantly reduced (80-90%) the response to bolus injection of Ang I, without affecting those to Ang II and TDP in mesenteric arteries. Mechanical removal of the endothelium greatly potentiated (70-95%) the vasoconstrictor response to Ang II, Ang I, and TDP in aortic rings while these responses were unaffected by the removal of the endothelium of mesenteric arteries with sodium deoxycholate infusion. In addition, endothelium disruption did not change the pattern of response elicited by these peptides in the presence of captopril. These findings indicate that the endothelium may not be essential for Ang II formation in rat mesenteric arteries and aorta, but it may modulate the response to Ang II. Although Ang II formation from Ang I is essentially dependent on ACE in both vessels, our results suggest the existence of an alternative pathway in the mesenteric arterial bed that may play an important role in Ang II generation from TDP in resistance but not in large vessels during ACE inhibition.     

Safety of antihistamines in the treatment of allergic rhinitis in elderly patients

Elderly patients may be more susceptible than younger persons to the sedating and anticholinergic effects of first-generation antihistamines. Second-generation antihistamines, such as loratadine, astemizole, and terfenadine, cause minimal sedation and little if any impairment in cognitive and psychomotor activity in healthy nonelderly patients. Although less extensively studied in elderly patients, it is probable that second-generation antihistamines are also less likely to induce the adverse central nervous system effects in older patients that are characteristic of the first-generation antihistamines. Toxic effects to the cardiovascular system, an issue of greater concern among elderly patients who may have subclinical heart disease, has not been observed with first-generation antihistamines. Among the second-generation antihistamines, however, astemizole and terfenadine, but not loratadine, can cause serious cardiovascular adverse effects, including death, when taken in high doses or coadministered with ketoconazole, itraconazole, or macrolide antibiotics.     

The effects of thiamin and its phosphate esters on dopamine release in the rat striatum

The effect of thiamin and its phosphate esters on dopamine (DA) release was examined in the rat striatum using an in vivo microdialysis. Intrastriatal administration of thiamin triphosphate (TTP) or thiamin diphosphate (TDP) induced DA release, but thiamin monophosphate (TMP) or thiamin did not show any change. In the absence of Ca2+ in the perfusate, TTP did not increase the DA release. omega-Conotoxin did not decrease the TTP-dependent DA release. These findings suggest that, in contrast to TMP and thiamin, TTP and TDP may play a specific role in DA release from nerve terminals.     

The intradermal effects of the H3 receptor agonist R alpha methylhistamine in human skin

We have investigated the possible existence of the H3 histamine receptor in human skin with the highly selective ligands R alpha methylhistamine (RAMHA) (H3 agonist) and thioperamide (H3 antagonist). We compared the intradermal effects of RAMHA with histamine, and studied their potential modulation by the H1 antagonist terfenadine, and H2 antagonist cimetidine. The effects of RAMHA and thioperamide on codeine phosphate-, substance P- and histamine-induced weal and flare responses were also studied. RAMHA produced dose-related weal and flare responses that were approximately 10- and fivefold less, respectively, than responses to histamine. Flare responses to RAMHA were significantly inhibited by oral terfenadine (P < 0.05). Weal and flare responses to histamine after oral cimetidine showed much intersubject variation, and cimetidine did not significantly alter either RAMHA- or histamine-induced weal and flare responses. Codeine phosphate-, substance P- and histamine-induced responses were not significantly affected by concurrent administration of RAMHA. Thioperamide was not found to influence codeine phosphate-, substance P-, RAMHA- or histamine-induced effects. RAMHA induces vascular (weal and flare) responses in human skin, and these responses are partially inhibited by terfenadine. There is a trend for RAMHA to have an additive effect to the weal induced by substance P and histamine, although our results largely do not reach statistical significance. Thioperamide does not affect the vascular responses to RAMHA, codeine phosphate, histamine or substance P. We cannot conclude that the effects of RAMHA are induced by H3 receptors on cutaneous endothelial or mast cells.     

Characterization of antihistamines using biphasic cutaneous reaction in BALB/c mice

Effects of 11 histamine H1 receptor antagonists on IgE-mediated biphasic cutaneous reaction in mice were examined. The immediate phase reaction (IPR) assessed at 1 hour after antigen application was significantly inhibited by all antihistamines examined. The inhibition of IPR by cetirizine and mequitazine were potent, but those by cyproheptadine and diphenhydramine were weak. The later phase reaction (LPR) assessed at 24 hours after antigen application was inhibited by chlorpheniramine, oxatomide, ketotifen, mequitazine, emedastine, terfenadine and azelastine. The inhibition of LPR by emedastine was potent, but those by ketotifen and terfenadine were only partial. Emedastine inhibited both IPR and LPR comparably. Present results indicate that H1 receptor activation is involved in the IPR of the biphasic cutaneous reaction, and that the blockade of H1 receptors at IPR does not contribute to the attenuation of following LPR. Histamine H1 receptor antagonists inhibiting the LPR have a property distinct from H1 receptor antagonism, which may have an additional benefit for the treatment of allergic diseases.     

Kinetic mechanism of active site non-equivalence in transketolase

The two-step mechanism of coenzyme (TDP) binding to apotransketolase has been examined by kinetic modeling, and the rate and equilibrium constants for each binding step for two active sites have been determined. The dissociation constants for the primary fast binding step and the forward rate constants for the secondary slow binding step have been shown to be similar for two active sites. The backward rate constants for the secondary binding step are different for two active sites, providing the kinetic mechanism of their non-equivalence in TDP binding.     

Low extracellular dopamine levels are maintained in the anoxic turtle (Trachemys scripta) striatum

Amprenavir (141W94, VX-478, KVX-478) is metabolized primarily by CYP3A4 (cytochrome P450 3A4) in recombinant systems and human liver microsomes (HLM). The effects of ketoconazole, terfenadine, astemizole, rifampicin, methadone, and rifabutin upon amprenavir metabolism were examined in vitro using HLM. Ketoconazole, terfenadine, and astemizole were observed to inhibit amprenavir depletion, consistent with their known specificity for CYP3A4. The HIV protease inhibitors, indinavir, saquinavir, ritonavir, and nelfinavir, were included in incubations containing amprenavir to examine the interactions of HIV protease inhibitors in vitro. The order of amprenavir metabolism inhibition in human liver microsomes was observed to be: ritonavir > indinavir > nelfinavir > saquinavir. The Ki value for amprenavir-mediated inhibition of testosterone hydroxylation in human liver microsomes was found to be approximately 0.5 microM. Studies suggest that amprenavir inhibits CYP3A4 to a greater extent than saquinavir, and to a much lesser extent than ritonavir. Amprenavir, nelfinavir, and indinavir appear to inhibit CYP3A4 to a moderate extent, suggesting a selected number of coadministration restrictions.