Effects of cetirizine on the delayed K+ currents in cardiac cells: comparison with terfenadine.

Effects of cetirizine on the delayed K+ currents in cardiac cells: comparison with terfenadine. 1. The aim of the present experiments was to analyse the effect of the H1-histamine antagonist, cetirizine, on the delayed K+ currents in cardiac cells and to compare its effects with another H1-histamine antagonist terfenadine, known to possess proarrhythmic effects. 2. Whole cell currents were measured by use of the single electrode patch-clamp technique in rabbit and guinea-pig myocytes. 3. The activation relationship for the IKr current in rabbit ventricular myocytes was depressed and its voltage-dependence shifted in the negative direction with a V1/2 value -13.4+/-2.4 mV under control conditions which changed to -19.1+/-1.9 mV (n=4) in the presence of 0.1 mM cetirizine. 4 In rabbit ventricular myocytes the IC50 for block of IKr was 108+/-8 microM (n=5); in guinea-pig ventricular myocytes this concentration of cetirizine reduced the rapidly activating component IKr to 49+/-4.5% (n=5), while the slowly activating IKs was less affected and only inhibited to 79+/-2.3% (n=5). 5 The block of IKr did not show use-dependence and the time course of the tail current was not changed, suggesting rested-state block or fast activated-state block and no rapid recovery on deactivation. No important difference was found in the activity of the two enantiomers of cetirizine. 6 Terfenadine in comparison was more potent in blocking IKr, the IC50 being 96+/-15 nM (n=6). 7 Based on the present results and information in the literature on binding, it was concluded that cetirizine is a relatively selective H1-histamine receptor antagonist, with minor effects on K+ currents. The IC50 concentration for IKr block in heart cells was 1.000 times higher than the concentrations needed to block H1 histamine receptors. The occurrence of cardiac arrhythmias due to K+ current blockade is therefore unlikely with this drug. Journal ISSN: 0007-1188 Issue: 124-4 (1998) Pages: 663-8

Store-operated calcium influx in human gastric cells: role of endogenous prostaglandins.
Store-operated calcium influx in human gastric cells: role of endogenous prostaglandins. BACKGROUND: Store-operated calcium influx (SOCI) appears to be a key component in regulating processes such as gene expression and cellular metabolism in nonexcitable cells. Our objective was to determine what effect, if any, prostaglandin inhibition had on SOCI in human gastric cells. METHODS: SOCI was induced in human gastric cells (AGS) with thapsigargin, a microsomal Ca++ adenosine triphosphatase inhibitor. Quantitation of SOCI was achieved by two different methods: sustained intracellular calcium elevation and manganese (Mn++) uptake. Endogenous prostaglandin E2 (PGE2) synthesis was measured by enzyme immunoassay. Three different nonsteroidal anti-inflammatory drugs (NSAIDs; indomethacin, ibuprofen, and aspirin) were used to minimize the nonspecific actions of any individual agent. RESULTS: SOCI in AGS cells was inhibited by the store-operated Ca+2 channel blocker lanthanum (La+3) but not the voltage-operated Ca+2 channel antagonists verapamil or nifedipine. Each of the three NSAIDs equally inhibited SOCI. The inhibition of SOCI induced by indomethacin was partially reversed by the addition of exogenous PGE2. Finally, AGS cells exposed to thapsigargin demonstrated significantly increased endogenous PGE2 release. CONCLUSIONS: These data suggest that NSAIDs inhibit (or endogenous prostaglandins modulate) SOCI in human gastric cells, at least in part. Because SOCI appears to be a critical mechanism involved in cell proliferation, this may provide one explanation of how NSAIDs inhibit (and endogenous prostaglandins enhance) gastric epithelial renewal and repair. Journal ISSN: 0039-6060 Issue: 124-2 (1998) Pages: 429-37

Treatment of erectile dysfunction.
Treatment of erectile dysfunction. Erectile dysfunction (ED) is an inability to attain or maintain an erection sufficient for satisfactory sexual intercourse. It is an undertreated and underdiagnosed condition that can be due to vasculogenic, neurogenic, hormonal and psychogenic factors. Effective treatment of ED should restore quality of life and allow patients to return to the sex life they had before. Current therapeutic options include non-pharmacological treatments, locally administered drugs and oral therapies. The oral phosphodiesterase-5 (PDE5) inhibitors are considered first-line treatments of ED and have revolutionized ED management in the last five years. Three PDE5 inhibitors are currently available, sildenafil, vardenafil and tadalafil. They are all effective with similar efficacy and good safety profiles. However, tadalafil has the added benefit of a broad window opportunity offering patients more freedom to choose when to initiate sexual activity. Journal ISSN: 0956-4624 Issue: 15-4 (2004) Pages: 215-21

Emerging oral drugs for erectile dysfunction.
Emerging oral drugs for erectile dysfunction. Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. Many drugs are now available for the treatment of ED, with oral pharmacotherapy representing the first-line option for most patients. Sildenafil citrate, an inhibitor of the enzyme phosphodiesterase type 5 (PDE5), is the most widely prescribed oral agent and has a very satisfactory efficacy-safety profile in all patient categories. Tadalafil (Cialis; Eli Lilly & Co., ICOS) and vardenafil (Levitra; Bayer Pharmaceuticals, GlaxoSmithKline) are new PDE5 inhibitors that have recently been approved worldwide. Both have been associated with significant positive efficacy-safety profiles. Apomorphine sublingual is a dopamine D1 and D2 receptor agonist, which has been approved for marketing in Europe. It is best selected for treating patients with mild-to-moderate ED, but it is seldom used in clinical practice due to its limited efficacy and side effects, particularly nausea. Patients who do not respond to oral pharmacotherapy or who are unable to use it are appropriate candidates for intracavernosal and intraurethral therapy. The efficacy of second-line treatment is high, but the attrition rate remains significant. For the purpose of this review, clinical and pharmacological analysis focuses on the recent advances in the field of oral therapy, including PDE5 inhibitors and sublingual apomorphine. Journal ISSN: 1744-7623 Issue: 9-1 (2004) Pages: 179-89

High-performance liquid chromatography with a column-switching system and capillary electrophoresis for the determination of ibuprofen in plasma.
High-performance liquid chromatography with a column-switching system and capillary electrophoresis for the determination of ibuprofen in plasma. Quantitative aspects of high-performance liquid chromatography with a column-switching system (CSS-HPLC) and capillary electrophoresis (CE) were investigated for the determination of ibuprofen in plasma. For CSS-HPLC, 100 microl of plasma was directly injected onto the column system for the three separation steps: (1) deproteinization and fractionation of plasma samples with a polymer-coated mixed-function phase column, (2) concentration with an intermediate column and (3) final separation with a main column. For CE, a mixture of 50 microl of plasma and 1 ml of acetonitrile was centrifuged and the supernatant was introduced onto the capillary (66 cmX50 microm I.D.; 62 cm to detector) at 20 degrees C. Run buffer was 250 mM sodium borate buffer (pH 8.5) and applied electric field was 379 V cm(-1). Linear dynamic ranges were 0.1-250 microg ml(-1) in CSS-HPLC and 1-1000 microg ml(-1) in CE. Intra-day and inter-day coefficients of variation were less than 5.6% and 6.5% for CSS-HPLC, 6.3% and 6.5% for CE, respectively. The limits of detection (S/N=3) for CSS-HPLC and CE were 25 ng ml(-1) and 300 ng ml(-1), respectively. CSS-HPLC was superior in simplicity and sensitivity, while CE was better in efficiency, rapidity, and cost. Journal ISSN: 1387-2273 Issue: 712-1-2 (1998) Pages: 153-60

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