Pharmacokinetics of diclofenac sodium and papaverine hydrochloride after oral administration of tablets to rabbits

Non-compartmental pharmacokinetic analysis of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) after oral administration of composed tablets to rabbits was developed. HPLC method for determination of DIC and PAP in rabbit plasma was developed and validated. Chromatographic separation of DIC, PAP and the IS was achieved on a Zorbax SB C18 5-μm column (150 mm ◊ 4.6 mm) using methanolwater (55 : 45, v/v) as mobile phase at a flow rate of 0.8 mL/min. Pharmacokinetic analysis showed that oral administration of a tablet composed of DIC and PAP do not change the pharmacokinetic parameters such as MRT, MAT, Cl and bioavailability of the active substances compared with single administration of DIC and PAP after single dose

Involvement of NMDA receptor complex in the anxiolytic-like effects of chlordiazepoxide in mice

In the present study, we demonstrated that low, ineffective doses of N-methyl-d-aspartic acid (NMDA) receptor antagonists [competitive NMDA antagonist, CGP 37849, at 0.312 mg/kg intraperitoneally (i.p.), antagonist of the glycineB sites, L-701,324, at 2 mg/kg i.p., partial agonist of glycineB sites, d-cycloserine, at 2.5 mg/kg i.p.] administered jointly with an ineffective dose of the benzodiazepine, chlordiazepoxide (CDP, 2.5 mg/kg i.p.), significantly increased the percentage of time spent in the open arms of the elevated plus-maze (index of anxiolytic effect). Furthermore, CDP-induced anxiolytic-like activity (5 mg/kg i.p.) was antagonized by NMDA (75 mg/kg i.p.) and by an agonist of glycineB sites of the NMDA receptor complex, d-serine [100 nmol/mouse intracerebroventricularly (i.c.v.)]. The present study showed a positive interaction between γ-aminobutyric acid (GABA) and glutamate neurotransmission in the anxiolytic-like activity in the elevated plus-maze test in mice and this activity seems to particularly involve the NMDA receptors

A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice

Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and d-cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or d-cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and d-cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by d-serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway

Effect of hydrophilic substances on liberation of quinidine from starch—methylcellulose spheres

The spheres were prepared by the desolvation technique combined with gravitational sedimentation of droplets of methylcellulose gel suspensions with the addition of 25% quinidine adsorbate on the potato starch and 5% hydrophilic agents such as Span 80, Tween 60, glyceryl monostearate or PEG 2000 instilled into a desolvation liquid (saturated sodium acetate:paraffin liquid:heptane 1:1:1, v/v/v) through a standardized capillary.As follows from the physicochemical studies the sphericity (Sp) changed within the range 1.020–1.314, the porosity (P) was 19.1–66.5% and the loading efficiency was 35.10–67.07%. The release studies show that the dissolution efficiency after 60 min (DE60) in acidic medium was 78.6% for quinidine and 52.6–63.4% for the spheres; in phosphate buffer pH 6.8 DE60 was 32.4% for quinidine, but ranged within 16.3–26.0% for the spheres. The release of the drug from the spheres was fast and it was slightly difference (the loaded drug was released within 60 min) in acidic medium, while differentation of release in the phosphate buffer made it possible to evaluate the effect of hydrophilic additives on the dissolution rate.The general process of release can be described by the modified Higuchi equation Mt*=K0·(t−TD) , which facilitates the analysis of the theoretical amount of the released substance Mt* depending on the zero-order dissolution rate constant K0 and the dissolution lag time (TD). Accordingly, spheres with sustained release can be most effectively produced by addition of PEG 2000. These spheres are characterized by Sp = 1.035, P = 60.2% and a loading efficiency of quinidine 67.07%. The release in acidic medium proceeds with K0 = 3.857 mg·min−0.5 and TD = 6.21 min, in phosphate buffer K0 was 1.293 rng·min−0.5 and TD = 7.14 min. These parameters were of less importance for the other formulations. The modified Higuchi equation gives information about the parameters of drug released

Release Kinetics of Papaverine Hydrochloride from Tablets with Different Excipients

The influence of excipients on the disintegration times of tablets and the release of papaverine hydrochloride (PAP) from tablets were studied. Ten different formulations of tablets with PAP were prepared by direct powder compression. Different binders, disintegrants, fillers, and lubricants were used as excipients. The release of PAP was carried out in the paddle apparatus using 0.1 N HCl as a dissolution medium. The results of the disintegration times of tablets showed that six formulations can be classified as fast dissolving tablets (FDT). FDT formulations contained Avicel PH 101, Avicel PH 102, mannitol, β-lactose, PVP K 10, gelatinized starch (CPharmGel), Prosolv Easy Tab, Prosolv SMCC 90, magnesium stearate, and the addition of disintegrants such as AcDiSol and Kollidon CL. Drug release kinetics were estimated by the zero- and first-order, Higuchi release rate, and Korsmeyer-Peppas models. Two formulations of the tablets containing PVP (K10) (10%), CPharmGel (10% and 25%), and Prosolv Easy Tab (44% and 60%) without the addition of a disintegrant were well-fitted to the kinetics models such as the Higuchi and zero-order, which are suitable for controlled- or sustained-release

Comparative dissolution studies on granules with acetaminophen and caffeine using the basket and paddle methods with simultaneous spectrophotometric determination of active substances

Acetaminophen and caffeine, popular therapeutic substances used to relieve pain or alleviate the symptoms of cold. The aims of the study were the comparison of granules, in terms of dissolution rate and moreover the development of spectrophotometric method to the simultaneous determination of both active pharmaceutical ingredients (APIs) in granules. The granules were tested by two pharmacopoeial methods of dissolution for solid dosage forms, and the dissolution profiles for each formulation were compared. A method of simultaneous determination of two medicinal substances by the double calibration method using derivative spectrophotometry was used. Considering the dissolution process carried out in the paddle apparatus, it was shown that more than 80% of acetaminophen and caffeine were released from each of the preparations in a clearly shorter time than 10 minutes. Carrying out the basket test, substances dissolved gradually, much slower than in the paddle method. The time required to release 80% of both active substances from majority of tested preparations was from 30 to 45 minutes. Application of the first derivative spectrophotometric method allows simultaneous determination of acetaminophen and caffeine in the mixture, without the need to separate them first