The inhibitory effect of HOE 731 in isolated rabbit gastric glands

HOE 731, a substituted thienoimidazole derivative, was studied on [14C] aminopyrine uptake and oxygen consumption in isolated rabbit gastric glands. HOE 731 caused a concentration-dependent inhibition of [14C]aminopyrine uptake during histamine and dbcAMP stimulation. The inhibition during dbcAMP stimulation was in accordance with its proton-pump inhibiting properties, which has already been reported. (Herling et al., Gastroenterology 96: A206, 1989). IC50 values were during histamine stimulation 0.8 +/- 0.3 microM and during dbcAMP stimulation 1.3 +/- 0.4 microM. The inhibition was reversible after addition of dithioerythritol and was of a non-competitive type. Omeprazole caused similar inhibitory effects in the same concentration-range. During time-course studies in glands, the inhibitory effect on [14C]aminopyrine uptake of 0.1 microM HOE 731 already appeared after 10 min of incubation but decreased with increasing incubation time, while 0.1 microM omeprazole caused an unchanged inhibition which started after 30 min of incubation. The concentration of 3 microM of HOE 731 and omeprazole caused a comparable constant inhibition. After pre-incubation for 135 min under basal conditions with subsequent stimulation of the glands with dbcAMP, the inhibitory effect of 10 microM HOE 731 also decreased in contrast to omeprazole. During stimulation for 4 hr, the inhibition of both compounds remained constant. In oxygen consumption studies HOE 731, at 100 microM, caused a strong inhibition down to basal values. This inhibitory effect could be prevented totally when 10 mM imidazole was added to neutralize the acidic compartment of the parietal cell during stimulation. It is concluded that HOE 731 needs acid-activation like omeprazole to inhibit the proton pump, but probably due to its chemical differences (stability, pH for conversion of HOE 731 to its active form) it shows a different inhibitory profile (faster transformation into its active moiety with faster onset of a partially reversible inhibition) as compared to omeprazole.     

Gastric acidity and acid breakthrough with twice-daily omeprazole or lansoprazole

BACKGROUND: In patients with severe gastro-oesophageal reflux disease (GERD), proton pump inhibitors are being used increasingly in twice-daily regimens to improve control of gastric acidity. Few data exist to compare the ability of the most-often used proton pump inhibitors, omeprazole and lansoprazole, to control gastric acid at twice-daily dosage regimens. Nocturnal acid breakthrough, defined as gastric pH < 4.0 continuously for > 60 min, may compromise treatment goals in patients with GERD. AIM: To compare the effects of omeprazole 20 mg b.d. or lansoprazole 30 mg b.d. on gastric acidity and the relative ability of each dosage regimen to prevent acid breakthrough. METHODS: In a crossover pharmacodynamic study, 20 healthy volunteers (10 male, 10 female, mean age 38 years) were given omeprazole 20 mg b.d. or lansoprazole 30 mg b.d. for 7 days each, in a randomized manner. Each dosage regimen was separated by a minimum 7-day period where no medication was administered. On day 7 of each regimen, 24-h intragastric pH-metry was performed. The percentage of time for which gastric pH was below 4.0 and 3.0, the occurrence of daytime and nocturnal acid breakthrough, and the duration of action of each regimen were compared. Non-parametric statistics for paired data were used. RESULTS: The percentage time for which gastric pH was below 4.0 was significantly lower with omeprazole 20 mg b.d. (median 14.8%) than with lansoprazole 30 mg b. d. (median 24.2; P=0.0372). Fourteen subjects showed more effective acid control when taking omeprazole; these were significantly more often H. pylori-negative patients compared with those for whom acid control was better on lansoprazole (P < 0.001). Nocturnal acid breakthrough occurred in seven patients (35%) on omeprazole and in 10 (50%) on lansoprazole (N.S.). CONCLUSION: In healthy volunteers, twice-daily dosing of omeprazole 20 mg b.d. appears to be significantly more effective than lansoprazole 30 mg b.d. in controlling gastric acidity. The clinical importance of such a difference remains to be defined in GERD patients.     

Comparison of the pharmacodynamics and pharmacokinetics of pantoprazole (40 mg) as compared to omeprazole MUPS (20 mg) after repeated oral dose administration

The effects on intragastric p11 and gastrin secretion of once daily pantoprazole (40 mg) and a new formulation omeprazole (20 mg) in a Multiple Unit Pellet System (MUPS) were investigated during two treatment periods of 7 days each in a randomized crossover study with 16 healthy Helicobacter pylori-negative male volunteers. Intragastric pH was measured using continuous 24 hour pH-metry on days 1 and 7. The results were compared to the baseline curves obtained before each treatment period. On day 1, pantoprazole raised the intragastric pH significantly higher and more quickly than omeprazole MUPS (pH median 1.9 vs. 1.6, baseline pH 1.4). After 7 days, the 24 h gastric pH medians were still in favor of pantoprazole (pH 3.0 vs. 2.8). With respect to the basal gastrin concentration, both treatments resulted in similar increases. For pantoprazole, no differences were observed in AUC and Cmax after single and repeated dosing. However, the new omeprazole MUPS formulation still showed the well-known effect of initial low bioavailability increasing after repeated dosing. Pantoprazole and omeprazole were well tolerated. There seems to be no advantage in the new omeprazole formulation compared with the conventional capsule with regard to bioavailability and increase in intragastric pH. The results of this study confirm former results in which pantoprazole (40 mg) was shown to be significantly superior to omeprazole (20 mg) in elevating intragastric pH.     

Biodegradable poly(DL-lactic-co-glycolic acid) microspheres containing tetracaine hydrochloride. In-vitro release profile

Tetracaine does not result in effective treatment of intractable pain caused by trigeminal neuralgiabecause of its short duration of effect. In asustained release system a controlled delivery of the drug at the site of administration, would avoid successive administrations. Tetracaine hydrochloride (HCl) has been encapsulated using a technique based on the evaporation of solvent from an O/O emulsion, using poly(dl-lactic-co-glycolic acid) (PLGA) 50:50. Microspheres were separated into three fractions: 106-212, 212-300 and 300-425mum. The effects of two variables of the manufacturing method (volume of the inner phase of the emulsion and volume of surfactant added to the external phase) on the drug loading into microspheres, dissolution profiles and SEM characterization of the microspheres were evaluated. Microspheres containing tetracaine hydrochloride (up to94% referred tothe theoretical) released the drug, in-vitro, over 35 days. Tetracaine HCl was delivered according to zero order kinetics from day 5 until the end of the release assay. The rate of drug release depended mainly on the viscosity of the discontinuous phase and on the size of microparticles. Microsphere size resulted more homogeneous when using the highest volume of the surfactant, being almost 80% of microparticles within the range 212-300mum.     

Gastric acid inhibitory action of a GABA-related compound, 3-amino-3-phenylpropionic acid, in the rat

The acid inhibitory properties of 3-amino-3-phenylpropionic acid, a structural GABA analogue, were studied in the perfused rat stomach preparation. 3-Amino-3-phenylpropionic acid, 10 and 30 mg/kg i.v., dose dependently suppressed the gastric acid secretion induced by baclofen (2 mg/kg s.c.). This secretagogue action had been shown to be unaffected by either GABAA or GABAB receptor antagonists. The i.v. administration of 3-amino-3-phenylpropionic acid (3 and 10 mg/kg) was also effective to abolish the acid stimulatory effects of muscimol (1 mg/kg i.v.) and 2-deoxy-D-glucose (200 mg/kg i.v.). 3-Amino-3-phenylpropionic acid, even at the high dose (30 mg/kg i.v.) had no influence on the acid output in response to histamine and bethanechol. Furthermore, 3-amino-3-phenylpropionic acid had no significant effect on the acid secretion induced by electrical vagal stimulation. These results indicate that the antisecretory effect of 3-amino-3-phenylpropionic acid is different from those of antimuscarinics, H2-receptor antagonists and vagal blockade. Together, the results suggest that 3-amino-3-phenylpropionic acid might act in the brain to inhibit central regulation mechanisms of gastric acid secretion, probably through GABA mechanisms.     

Cariporide (HOE642) limits S-100B release during cardiac surgery

Cardiac surgery with cardiopulmonary bypass (CPB) results in transient cerebral swelling in most patients. Cognitive decline occurs in 24-57% of patients and 2-5% experience stroke. Serum levels of S-100B, a potential marker of increased blood-brain barrier permeability, increase during and early after surgery. The authors studied the effects of the novel Na /H exchange inhibitor cariporide (HOE642) on postoperative serum levels of S-100B and neuron-specific enolase (NSE) in 53 patients at high risk undergoing coronary artery bypass grafting. Patients were randomly assigned to one of four groups: I, placebo; II, 20 mg cariporide; III, 80 mg cariporide; IV, 120 mg cariporide). In addition, the leukocyte activation marker myeloperoxidase (MPO) and malondialdehyde (MDA), a marker for lipid peroxidation, were evaluated by enzyme-linked immunoassay. Postoperatively, five patients experienced transient ischemic attack or stroke. S-100B levels increased from 0.43 microg/l +/- 0.33 before operation to 2.27 microg/l +/- 0.69 1 hour after surgery in the placebo group. Preoperative S-100B levels in the HOE642 groups did not differ from the placebo group whereas, 1 hour after surgery, levels were significantly lower in groups II, III, and IV (1.63 microg/l +/- 0.2, 1.27 microg/l +/- 0.27, and 0.90 microg/l +/- 0.21, respectively). NSE, MPO, and MDA serum levels did not differ among groups. These findings may stimulate larger clinical studies to examine the effects of HOE642 on cerebral swelling and neurologic/cognitive outcome of cardiac surgery with CPB.     

Gastric acid secretion in the dog: a mechanism-based pharmacodynamic model for histamine stimulation and irreversible inhibition by omeprazole

A mechanism-based pharmacodynamic model was used to describe the inhibitory effect by omeprazole on gastric acid secretion measured after histamine stimulation in the dog. The model identifies parameters that are related to the physiological system, the histamine stimulation, and the irreversible effect of omeprazole on the H⁺, K⁺-ATPase enzyme. Four different experiments with omeprazole (Exps. 1–4) and two placebo experiments were performed in each of the four Heidenhain pouch dogs used. For placebo and experiments 1–3, saline or omeprazole 0.81 mol/kg was infused during 3 hr with measurements of histamine-stimulated gastric acid secretion in two periods of 3.5–6.5 hr, one period starting just before the omeprazole infusion and a second later period up to 29 hr post infusion. In experiment 4, 0.18 mol/kg of omeprazole was infused for 22.5 min and gastric juice was collected for 5 hr post infusion. The response data was well described by the model. Similar parameter estimates were obtained by three different analysis methods; naïve pooling, two-stage method and nonlinear mixed effects modeling. The elimination rate constant for the H⁺, K⁺-ATPase enzyme, k _out, was estimated to be 0.040 hr^-1, corresponding to a half-life of about 17 hr. This rate constant determines the duration of omeprazole inhibition after long-term exposure. For short-term omeprazole exposure the duration is determined by the rate constant for transfer of enzymes from active to resting state, estimated to be 1.88 hr^-1. The second-order rate constant for histamine stimulation was estimated to be 0.064 hr^-1 per histamine concentration unit and the maximum acid secretion was estimated to be 5.0 mmol H⁺/30 min. The second-order rate constant for the irreversible binding of omeprazole to H⁺, K⁺-ATPase, k _ome, was estimated to be 2.39 L/mol hr. By modeling the histamine-induced baseline response simultaneously with active treatment, predictions of the response are possible not only following different dosing regimens of omeprazole, but also following different degrees of histamine stimulation.     

Controlled trial of nomifensin (HOE 984) and viloxazine in the treatment of depression in the elderly.

The new antidepressant nomifensin (Hoechst 36984), a drug which showed less cardiotoxicity than tricyclics, was compared in a single-blind comparative trial with viloxazine. Forty elderly depressed patients were treated during four weeks. Nomifensin, N=21, 75 mg/day; viloxazine, N=19, 150 mg/day). Antidepressant effects were assessed by the Hamilton Rating Scale (HRS) for depression, and physical disability, by the Northwestern University Disability Scales. The HRS disclosed statistically significant improvement with both treatments. However, the scores in the nomifensin group fell distinctly form the second week on (P less than 0.01). There were no side effects reported spontaneously by the patients. Sinus tachycardia was recorded in two instances (one viloxazine and one nomifensin patient).     

The pharmacological profile and clinical use of mesalazine (5-aminosalicylic acid)

For more than 30 years mesalazine (5-aminosalicylic acid; 5-ASA) has been used for the treatment of chronic inflammatory bowel disease (IBD) especially in ulcerative colitis (UC). During this time various rectal and oral formulations have been developed. The modified drug delivery systems were designed to release sufficient 5-ASA at the sites of inflammation. Such a drug targeting strategy is needed for its topical action and especially because local concentrations in the mucosa will determine the clinical outcome. The absorbed part (20-40% of the dose) of 5-ASA is rapidly and presystemically acetylated (t1/2: 1-2.5?h; CL: 300-690?mL/min). Consequently, the systemic exposure of 5-ASA is low and adverse effects are in the range of placebo treatment. The polypotent 5-ASA has a wide spectrum of pharmacological properties and its exact mode of action is not yet clear. Recent meta-analyses of randomized placebo-controlled clinical trials provide convincing data that 5-ASA is the preferred first-line therapy for the acute treatment of mild-to-moderate UC (NNT:6) and for remission management (NNT:4). There is also some clinical benefit for patients with active Crohn's disease (NNT:7) and in the prevention of postsurgical relapse (NNT:10). There is increasing evidence that 5-ASA also has some therapeutic potential for chemoprevention of colorectal cancer, diverticular disease and irritable bowel syndrome. In all clinical studies, the side effects of 5-ASA were very low (5-10%), mild and comparable to placebo. Thus, its use is very safe and 5-ASA will remain an interesting and valuable agent. It is anticipated that more selective drug targeting, including galenic innovations and an optimized dosaging schedule, could result in some improvement of the wide use of 5-ASA.     

Analgesic profile of rimazolium as compared to different classes of pain killers

1,6-Dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazol (rimazolium, MZ-144) proved to be effective in all the analgesic assays used (independently of the nociceptive stimulus applied) (hot plate, tail flick, writhing tests, Randall-Selitto test, tail clip, surgical pain) differing in this respect from the nonsteroidal antiinflammatory analgetics. The analgesic, antiinflammatory and gastrointestinal effects of rimazolium, morphine and prostaglandin synthesis inhibitors were compared. The prostaglandin (PG) mediated pain (acetylcholine-, adenosine triphosphate- and acetic acid-induced writhing) was inhibited by all the three types of compounds, however, pain reaction where PGs are not involved (MgSO4-writhing) was inhibited only by rimazolium and morphine but not, or only slightly, by PG synthesis inhibitors. While the analgesic effect of rimazolium alone was not reversed by naloxone, the full analgesia evoked by the ineffective doses of morphine and rimazolium combinations was completely naloxone reversible (pA2 = 8.6). In addition, rimazolium produced weak analgesia by intrathecal administration, and its concomitant s.c. administration enhanced the analgesic effect of intrathecally administered morphine. Furthermore, chronic treatment with rimazolium failed to influence its analgesic activity, and no tolerance developed and no naloxone precipitated withdrawal syndrome could be seen. In addition, rimazolium did not substitute for morphine in morphine dependent rats, after morphine withdrawal, thus indicating that rimazolium lacks the capacity of producing opiate-like physiological dependence. Also rimazolium fails to show any indication of narcotic-like abuse liability by any of clinical assessments. Rimazolium, morphine and indometacin inhibited the carrageenin-induced edema formation. Gastrointestinal lesions produced by indometacin were depressed by rimazolium and enhanced by morphine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and preliminary characterization of a novel antiarrhythmic compound (KB130015) with an improved toxicity profile compared with amiodarone.

Recent developments in antiarrhythmic therapy have indicated that the best approach to pharmacologically controlling supraventricular arrhythmias and life-threatening ventricular tachyarrhythmias is by prolonging cardiac repolarization rather than by blocking conduction. In this context, amiodarone has emerged as the most potent compound, but its universal use has been limited by its toxicity profile. There are data to suggest that an important component of amiodarones antiarrhythmic action might be mediated via inhibition of thyroid hormone action in the heart. Therefore, a new series of carboxymethoxybenzoyl and benzyl derivatives of benzofuran has been prepared and evaluated as thyroid hormone receptor antagonists. Within this series, 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran KB130015 (7) was found to reveal the most promising in vitro data. It inhibits the binding of (125)I-T(3) to the human thyroid hormone receptors (hThR) alpha(1) and beta(1). T(3)-Antagonism was confirmed in reporter cell assays employing CHOK1 cells (Chinese hamster ovary cells) stably transfected with hThR alpha(1) or hThR beta(1) and an alkaline phosphatase reporter gene downstream a thyroid response element. The derived IC(50) values were 2.2 microM for hThR alpha(1) and 4.1 microM for hThR beta(1). Compound 7 was selected for further characterization of chronic effects on ventricular papillary muscle by transmembrane electrophysiology after daily intraperitoneal injection of the ligand (40 mg/kg body weight) in guinea pigs. Compound 7 was found to prolong the action potential duration at 90% (APD(90)) repolarization time (219 +/- 22 ms, control: 186 +/- 9 ms, p < 0.01) without exhibiting any reverse rate dependency of action in a manner similar to that of amiodarone. In general, preliminary tolerance experiments with 7 demonstrated an improved safety profile compared to that of amiodarone. In summary, 7 appears to be less toxic than amiodarone while maintaining its electrophysiologic properties consistent with antiarrhythmic activity. Its potential antiarrhythmic actions warrant further investigations.     

Acetyl-11-keto-beta-boswellic acid (AKBA): structure requirements for binding and 5-lipoxygenase inhibitory activity.

1. 5-Lipoxygenase (5-LOX) products from endogenous arachidonic acid in ionophore-stimulated peritoneal polymorphonuclear leukocytes (PMNL) and from exogenous substrate (20 microM) in 105,000 g supernatants were measured. 2. The effects of natural pentacyclic triterpenes and their derivatives on 5-LOX activity were compared with the inhibitory action of acetyl-11-keto-beta-boswellic acid (AKBA), which has been previously shown to inhibit the 5-LOX by a selective, enzyme-directed, non-redox and non-competitive mechanism. 3. The 5-LOX inhibitory potency of AKBA was only slightly diminished by deacetylation of the acetoxy group or reduction of the carboxyl function to alcohol in intact cells (IC50 = 1.5 vs. 3 and 4.5 microM, respectively) and in the cell-free system (8 vs. 20 and 45 microM). 4. beta-Boswellic acid (beta-BA), lacking the 11-keto function, inhibited 5-LOX only partially and incompletely, whereas the corresponding alcohol from beta-BA, as well as amyrin, acetyl-11-keto-amyrin, 11-keto-beta-boswellic acid methyl ester had no 5-LOX inhibitory activity up to 50 microM in either system. 5. beta-BA only partially prevented the AKBA-induced 5-LOX inhibition, whereas the non-inhibitory compounds, amyrin and acetyl-11-keto-amyrin, almost totally antagonized the AKBA effect and shifted the concentration-inhibition curve for the incomplete inhibitor beta-BA to the right. In contrast, the non-inhibitory 11-keto-beta-BA methyl ester exerted no antagonizing effect. 6. The results demonstrate that the pentacyclic triterpene ring system is crucial for binding to the highly selective effector site, whereas functional groups (especially the 11-keto function in addition to a hydrophilic group on C4 of ring A) are essential for 5-LOX inhibitory activity.     

Platelet-activating factor (PAF) inhibitory profile of KO-286011 on blood platelets in vitro and in vivo

Summary A newly synthesised structural analogue of PAF, coded KO-286011 (1-O-hexadecyl-2-O-ethyl-racglycero-3-phosphoric acid 4-(N,N-dimethylamino)pyridinium butylester), was proved for its ability to inhibit PAF-mediated platelet responses in vitro and in vivo. The compound inhibited effectively the PAF-induced aggregation and secretion of human and rabbit platelets. In contrast, there was little influence on ADP-, collagen-, and arachidonic acid-triggered platelet responses. Schild-analysis of aggregation data ascertained in human platelet-rich plasma was consistent with a simple competitive antagonism and yielded a pA₂, of 6.44. Pro-aggregatory activity of KO-286011 was excluded turbidimetrically as well as by means of a single cell counting technique. [³H]PAF binding studies provided evidence that KO-286011 exerts its inhibitory action at the PAF-receptor level. A significant inhibition of the ex vivo PAF-induced platelet aggregation was found after i.v. administration of 0.5 mg/kg KO-286011 to rabbits. The effect was most pronounced 5 min after dosing the inhibitor and detectable over a period of 30 min. Intravenous administration of 10 and 25 μg/kg KO-286011 to guinea pigs prevented dose-dependently the PAF-induced formation of thromboxane A₂. The PAF-inhibitory action of KO-286011 was more potent than that of the ginkgolide BN 52021. Send offprint requests to G. Ostermann at the above address     

Pharmacokinetic comparison of omeprazole capsules and a simplified omeprazole suspension.

The pharmacokinetics of omeprazole delayed-release capsules and a simplified omeprazole suspension (SOS) were studied. Seven healthy volunteers randomly received either one 20-mg omeprazole delayed-release capsule or SOS (omeprazole 20 mg in 10 mL) for seven days before being crossed over to the opposite treatment for seven more days after a two-week washout period. On days 1 and 7, blood samples were drawn at intervals up to 360 minutes after drug administration. Plasma omeprazole concentrations were determined by a validated high-performance liquid chromatographic method, and pharmacokinetic values were determined. Area under the concentration-versus-time curve (AUC) from zero to six hours, AUC from time zero to infinity (AUC0-infinity), and maximum plasma concentration (Cmax) increased by 102%, 113%, and 85%, respectively, after seven days of treatment with the capsule. AUC0-infinity for SOS on day 1 was 58% of that for the capsule (p = 0.0141), and on day 7 it was 49% of that for the capsule (p = 0.0044). AUC0-infinity for SOS increased by 85% from day 1 to 7, but the difference was not significant. Cmax for SOS on day 1 was twice that for the capsule (p = 0.0014), but by day 7 the difference between the two formulations was negligible. Time to Cmax (tmax) for SOS on days 1 and 7 was shorter than for the capsule by 82% (p < 0.0001) and 70% (p < 0.0006), respectively. After one week of therapy, omeprazole absorption was faster and tmax was 70% shorter for SOS than for the capsule formulation, but AUC0-infinity was 49% lower for SOS.     

Gastric antisecretory activity of lansoprazole in different experimental models: comparison with omeprazole

• 1.1. The activity of the novel proton pump inhibitor lansoprazole was examined in different gastric secretion models in vitro and in vivo, in comparison with omeprazole.
• 2.2. In the conscious cat with gastric fistula lansoprazole (0.25-2 μmol/kg i.v.) caused a dose-dependent reduction of the acid secretion induced by dimaprit, pentagastrin, 2-deoxy-d-glucose and bombesin, being approximately as potent as omeprazole (0.25–1.5 μmol/kg i.v.). Similar to omeprazole, lansoprazole was also more effective when administered in hyperacidic states.
• 3.3. In the anaesthetized rat with lumen perfused stomach lansoprazole (0.03–1 μmol/kg i.v.) was approximately 3 times more potent than omeprazole (0.1–3 μmol/kg i.v.) in inhibiting the acid secretion induced by histamine, 2-deoxy-d-glucose and forskolin.
• 4.4. In the isolated gastric fundus from the immature rat lansoprazole (1–30 μM) reduced basal acid secretion and the acid response to histamine and forskolin, with a potency not significantly different from that of omeprazole.
• 5.5. No significant differences were found in the different species between lansoprazole and omeprazole as for the duration of action.
• 6.6. In conclusion, lansoprazole exerts a marked antisecretory effect in a variety of gastric secretion models from different species. However, it did not significantly differ from omeprazole when considering either the potency or the duration of action.