Influence of antacids on the bioavailability of glibenclamide

A single oral dose of glibenclamide (2.5 mg) was given to eight healthy volunteers in a randomized cross-over study after a standardized fasting and breakfast (374 kcal), with or without a concomitant intake of 10 ml of antacid suspension. Serum glibenclamide levels were determined by means of a specific radioimmunoassay method. The areas under the blood concentration-time curves (AUC0-infinity), with or without antacid, were 408.17 +/- 168.25 and 307.9 +/- 84.13 ng/ml (p less than 0.05), respectively. The peak concentrations of 96.88 +/- 49.9 and 66.19 +/- 32.35 ng/ml/h (p less than 0.05) with or without antacid, were reached in 4.13 and 3.81 h, respectively. Values of tmax, Vd and t1/2 were not affected by the presence of the antacid. A 33% increase in bioavailability of glibenclamide emerged, as seen from the respective AUC values, but no clinically remarkable effect was observed in the subjects.     

Cardiohemodynamic effect of FK409, a novel highly potent nitrovasodilator, in anesthetized dogs.

The cardiohemodynamic effect of (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409), a novel potent vasodilator, was studied in anesthetized open-chest dogs. FK409 (1 to 10 micrograms/kg, i.v.) decreased mean blood pressure, cardiac output and venous return (sum of the flow through the inferior and the superior vena cava). These changes accompanied decreases in left ventricular pressure, in its maximum rate of rise and in right atrial pressure. This cardiovascular profile of FK409 is very similar to those of classical nitrates.     

The effect of dosage on the bioavailability of chlorothiazide administered in solution

Chlorothiazide in solution was administered at four dose levels to three healthy male volunteers under controlled conditions. Excretion data indicated that the drug was poorly absorbed from the gastrointestinal tract. The 24 h recovery of the drug from urine fell from 33 to 6% as the dose was increased from 0·21 to 1·75 g per 70 kg of body weight. The cumulative amount of sodium excreted could be correlated with the cumulative amount of drug excreted, rather than with the dose administered. The electrolyte excretion response intensity could also be correlated with the amount of drug excreted. There was a poor linear relationship between response intensity and drug excretion rate. After higher doses the data suggested that the response was in the non-linear section of the dose response curve.     

The effect of dosage on the bioavailability of chlorothiazide administered in solution

Chlorothiazide in solution was administered at four dose levels to three healthy male volunteers under controlled conditions. Excretion data indicated that the drug was poorly absorbed from the gastrointestinal tract. The 24 h recovery of the drug from urine fell from 33 to 6% as the dose was increased from 0.21 to 1.75 g per 70 kg of body weight. The cumulative amount of sodium excreted could be correlated with the cumulative amount of drug excreted, rather than with the dose administered. The electrolyte excretion response intensity could also be correlated with the amount of drug excreted. There was a poor linear relationship between response intensity and drug excretion rate. After higher doses the data suggested that the response was in the non-linear section of the dose response curve.     

The pharmacological profile of CGP 28238, a novel highly potent anti-inflammatory compound

CGP 28238 (6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone ) exhibits very potent anti-inflammatory activity in rat adjuvant arthritis (ED40 = 0.05 mg/kg, p.o.) and pronounced analgesic and antipyretic activity in acute models in mice and rats (ED50 2-5 mg/kg, p.o.), but has clear advantages over reference NSAIDs with respect to gastro-intestinal tolerability. Threshold doses for gastro-intestinal ulcerogenicity in rats after single and repeated (10x) doses were found to be 30 mg/kg, p.o., and prostaglandin (PGE2) production in rat gastric and ileal mucosa was only marginally inhibited (ED50 greater than 30 mg/kg, p.o.). On the other hand, PGE2 production in rat inflammatory exudate and thromboxane synthesis in rat blood were inhibited with ED50 values of less than or equal to 2 mg/kg, p.o. Although CGP28238 does not inhibit cyclooxygenase in bovine seminal vesicle microsomal preparations (IC50 greater than 10(-3) mol/l), potent inhibition of prostaglandin synthesis was shown in various in vitro systems using human and animal cells with IC50 values of less than 10(-6) mol/l. IL-1-stimulated bone resorption and PGE2 production in murine calvarial cultures were inhibited with IC50 values of 3 x 10(-7) and 2 x 10(-8) mol/l, respectively. 5-Lipoxygenase (murine macrophages), phospholipase A2 (human PMN) and phospholipase C (human platelets) were not inhibited. CGP 28238 may represent a novel highly potent anti-inflammatory compound with improved gastro-intestinal safety.     

Effect of two antacids on the bioavailability of paracetamol

Summary The effect of two antacids on the bioavailability of paracetamol has been investigated in 12 young healthy volunteers. Following a random cross over design, each subject swallowed, on three separate occasions, one weak apart, 500 mg paracetamol alone, or together with two different aluminium hydroxide, magnesium hydroxide preparations (Dimalan and Maalox). Plasma paracetamol levels were measured by HPLC. The bioavailability of paracetamol was not altered by either antacid, but they both delayed the time to peak plasma concentration (0.85 h; 1.43 h; 1.25 h, without antacid, with Dimalan and with Maalox respectively). The peak plasma concentration was not affected by concurrent antacid administration.     

Effect of antacids on aspirin dissolution and bioavailability

The in vitrodissolution profile, in vitroand in vivobuffering characteristics, and single-dose bioavailability of various buffered aspirin tablet formulations were studied. Buffering agents,such as magnesium and aluminum hydroxides (formulations B and C) or magnesium carbonate and aluminum glycinate (formulation D), significantly increased the rate of aspirin dissolution from solid dosage forms as compared to an unbuffered tablet (formulation A). The extent of aspirin absorption was equivalent with all formulations;however, the faster rate of dissolution (t₅₀ and t₉₀)with buffered formulations resulted in earlier and higher peak concentration of salicylate compared to that with unbuffered formulation, following a two-tablet dose in the fasting state. A comparison of the in vivobuffer capacity of a four-tablet dose of formulations B and D was performed in the postcibal state at the time of maximal meal-induced acid secretion, using a radiotelemetry procedure for determination of pH. Formulation B prolonged the interval of elevation of intragastric pH > 3 for 32 min as compared to 12 min for D.     

Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers

Objective To investigate the effect of concomitantly administered curcumin on the pharmacokinetics of the β1 adrenoceptor blocker talinolol. Methods The study was conducted in a self-controlled, two-period experiment with a randomized, open-labeled design, using 12 healthy volunteers and a wash out period of 1 week between the administration of a single oral dose of 50 mg talinolol and the concomitant administration of curcumin (300 mg day⁻¹ for 6 days) and a single oral dose of 50 mg talinolol on the seventh day. Concentrations of talinolol were measured in plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry. Non-compartmental analysis was used to characterize talinolol plasma concentration-time profiles, all pharmacokinetic parameters were calculated using DAS (ver. 2.0) software, and comparisons of mean values were analyzed by the Wilcoxon signed rank test. Differences were considered to be significant at p < 0.05 (two-sided test). Results The consumption of curcumin for 6 days reduced the area under the curve (AUC) from predose to infinity () of talinolol from 1860.0 ± 377.9 to 1246.0 ± 328.2 ng.h mL⁻¹, the highest observed concentration values (C_max) were significantly decreased from 147.8 ± 63.8 to 106.4 ± 39.9 ng mL⁻¹, and the CL/F was increased from 27.9 ± 5.5 to 43.1 ± 13.4 L.h⁻¹ (p < 0.05). There was no significant difference in sampling time for C_max (t_max) and elimination half-life (t_1/2) values between the two periods (p > 0.05). The interindividual variability in AUC_0–60 and C_max of talinolol was comparable in two study periods; the coefficient of variance (CV) of AUC_0–60 and C_max was 26 and 40% after curcumin versus 21 and 43% after talinolol alone, respectively. Conclusion We suggest that the reduced bioavailability of talinolol is most probably due to the low intraluminal curcumin concentration, or possibly due to the upregulation of further ATP-binding cassette transporters, such as MRP2, in different tissues.     

Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist

Herein we describe the chemical synthesis and pharmacological characterization of a novel, highly potent progesterone receptor (PR) antagonist, ZK 230211. The introduction of a 17alpha-pentafluorethyl side chain in the D-ring of the steroid skeleton allowed the combination of high antiprogestagenic activity with little or no other endocrinological effects. In contrast to many other antiprogestins, ZK 230211 did not convert to an agonist in the presence of protein kinase A (PKA) activators and showed high antiprogestagenic activity on both PR isoforms PR-A and PR-B. This high antiprogestagenic activity could also be demonstrated in several in vivo models. Furthermore, this compound displayed only marginal antiglucocorticoid effects. In tumor models ZK 230211 exhibited strong antiproliferative action. The pharmacological properties of ZK 230211 may prove useful in the treatment of endometriosis, leiomyomas, breast cancer, and in hormone replacement therapy.     

The bioavailability of rectally administered morphine

Plasma concentrations of morphine were followed for 24 hours in eight patients after intravenous and rectal administration of 10 mg morphine chloride. The plasma levels of morphine were determined by a sensitive and specific radioimmunoassay based upon an extraction procedure which separates morphine from its major polar metabolites. The bioavailability of morphine after rectal administration was found to be 53.3 +/- 17.8% (mean +/- S.D.). Peak concentrations of 16.3 +/- 8.7 ng ml-1 were reached after 59 +/- 16 min. The study indicates that first pass elimination of morphine may be partially avoided by rectal administration.     

Lornoxicam,a new potent NSAID with an improved tolerability profile

Lornoxicam is a member of the oxicam group of nonsteroidal antiinflammatory drugs (NSAIDs). Oxicams have potent antiinflammatory and analgesic effects, but their use is associated with a high risk of gastrointestinal adverse effects. Lornoxicam has been shown to be at least as effective as comparative NSAIDs and more effective than 10 mg morphine when used at doses > or = 8 mg to control pain after oral surgery. In addition, oral doses of lornoxicam of 16-24 mg daily have been more effective than tramadol 300 mg daily in pain following knee surgery. Lornoxicam combines the high therapeutic potency of oxicams with an improved gastrointestinal toxicity profile as compared to naproxen, for example. This is probably due to the short half-life of lornoxicam as compared to the other oxicams. The clinical trials published so far, mostly comparative, clearly do- cument the efficacy of lornoxicam as a potent analgesic with excellent antiinflammatory properties in a range of painful and/or inflammatory conditions, including postoperative pain and rheumatoid arthritis.     

Discovery of a novel and highly potent noncompetitive AMPA receptor antagonist

N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular modeling studies. Sound-induced seizure testing showed that this class of compounds possessed anticonvulsant properties. In particular, 10c was more potent than talampanel (2), a noncompetitive AMPA receptor antagonist currently being investigated in phase III trials as an antiepileptic agent. Furthermore, electrophysiological studies indicated that 10c was a highly effective noncompetitive-type modulator of the AMPA receptor.     

Aluminum-magnesium antacids and the bioavailability of ketoscilium in man.

The bioavailability of the gastric secretory inhibitor 3-hydroxy-8-(p-phenylphenacyl)-1 alphaH, 5 alphaH-tropanium bromide (-)-tropate (ketoscilium, Ulcesium) is not affected by a single dose of an aluminum-magnesium antacid although binding occurs in vitro.     

Adsorption of ketoprofen and bumadizone calcium on aluminium-containing antacids and its effect on ketoprofen bioavailability in man

The present study reports the adsorption of ketoprofen and bumadizone calcium, two non-steroidal anti-inflammatory drugs, on three aluminium-containing antacids. The type of aluminium antacid, the initial drug concentration and the pH of the medium were found to influence drug adsorption. At pH 3–4, binding of both drugs to aluminium hydroxide and dihydroxyaluminium sodium carbonate indicated co-operative adsorption, while adsorption profiles of bumadizone calcium on aluminium glycinate suggested a constant partitioning pattern. pH (1–8) adsorption profiles for ketoprofen and bumadizone calcium binding to aluminium hydroxide and dihydroxyaluminium sodium carbonate passed through a maximum in the pH range 3.5–4.5. Antacid dissolution during the adsorption runs was also investigated at different pH values. The effect of coadministration of ketoprofen and aluminium hydroxide on the bioavailability of ketoprofen was investigated in healthy volunteers. Urine was collected for 24 h following drug administration and samples were analyzed by HPLC for ketoprofen and its conjugates. The urinary excretion data indicated a decrease in drug bioavailability upon coadministration with aluminium hydroxide.     

Single-center,single-dose,open-label,randomized, two-period crossover study on the bioavailability of methotrexate administered using a novel prefilled,needle-free delivery system

Objective: Zeneo¹ is a needle-free injection device. We performed a pharmacokinetic study to investigate the bioequivalence of methotrexate administered subcutaneously using either the needle-free injection device or a conventional needle and syringe.

Research design and methods: This was a single-dose, open-label, laboratory-blind, randomized crossover study performed in adult healthy volunteers. Each participant received two methotrexate injections (each 25?mg), one via needle-free injection device and one via conventional injection, with a 21–28?day wash-out interval between dosing. For each participant, the administration site for both injections was either the abdomen or the thigh.

Main outcome measures: The primary pharmacokinetic outcome parameters were AUC_(0–t) and C_max. Bioequivalence was assessed by standard criteria: whether 90% confidence intervals of geometric mean ratios for the two administration methods were within 80–125%.

Results: Fifty-two individuals completed the study. Bioequivalence criteria were met for AUC_(0–t), for the overall analysis (both injection sites: 90% confidence interval: 99.4–103.1%), and for each injection site separately. Bioequivalence was similarly demonstrated with AUC_(0–∞). Bioequivalence criteria for C_max were fulfilled for abdominal administration but not for the overall analysis. Injection via the needle-free injection device was well tolerated.

Limitations: Limitations include conducting the study in healthy volunteers and the relatively small subject number (albeit satisfactory for bioequivalence).

Conclusions: This study shows that methotrexate injection via needle-free injection device is bioequivalent to a conventional needle and syringe in relation to AUC_(0–t) and AUC_(0–∞). Studies of needle-free injection device use in patients requiring methotrexate therapy are planned.     

Effect of concomitantly administered honey on the pharmacokinetics of carbamazepine in healthy volunteers

The current study was designed to investigate the effect of concomitantly administered honey on the pharmacokinetics of carbamazepine in volunteers. In a two-way cross-over design with a one-week washout period, ten healthy volunteers were randomized to receive 200 mg carbamazepine orally with 30 ml of honey or water. Blood samples were collected at 0, 0.5, 1, 2, 3, 6, 9, 12, 24, 48 and 72 h after drug administration. Carbamazepine levels were estimated by high performance liquid chromatography (HPLC). There were no statistically significant differences in the various pharmacokinetics parameters when carbamazepine was administered with honey, compared with administration with water. In conclusion, carbamazepine kinetics are not altered by honey, so epileptic patients on carbamazepine may consume honey without the risk of an interaction.     

Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist

The involvement of glutamate in the pathophysiology of depression has been suggested by a number of experiments. It was well established that compounds, which decreased glutamatergic transmission via blockade of NMDA receptor, produced antidepressant-like action in animal tests and models. The present study was carried out to investigate whether a selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) induces antidepressant-like effects after intraperitoneal injections in male Wistar rats or male C57BL/6J mice. Potential antidepressant-like activity of MTEP was evaluated using the forced swimming test (FST) in rats, the tail suspension test (TST) in mice and the olfactory bulbectomy (OB) model of depression in rats. The results of our studies showed, that MTEP (0.3-3 mg/kg) produced a significant dose-dependent decrease in the immobility time of mice in the TST, however, at doses of 1 or 10 mg/kg, it did not influence the behavior of rats in the FST in rats. Moreover, the repeated administration of MTEP (1 mg/kg) attenuated the OB-related hyperactivity of rats in the open field test, in the manner similar to that seen following chronic (but not acute) treatment with typical antidepressant drugs. These data suggest that MTEP, which is considered to be a potential therapeutic agent, may play a role in the therapy of depression.