Experimental pharmacokinetics of phenazepam during transdermal administration of the therapeutic phenaperkuten system

The pharmacokinetics of fenazepam upon application of the transdermal therapeutic system (TTS) fenapercuten in various forms and under different conditions was studied in rabbits. The rate of the transdermal transfer of fenazepam from TTS to blood varied from 0.76 to 2.89 mg/(ml cm2). It was found that the drug transfer rate remains constant for 2-3 days. After removal of the TTS, fenazepam is eliminated within 3 days.     

Prediction of plasma concentration of GTS-21 in hairless rats following monolithic transdermal delivery

The transdermal therapeutic systems (TTS) usually achieve constant plasma concentration for an extended period of time. This is because a sufficient drug stored in the device can keep the constant concentration on the surface of the stratum corneum during the system application. When the drug molecules are not enough to provide the constant surface concentration, the rate of drug penetration decreases with time because of decreased supply of the drug molecules from the delivery device. This paper has proposed an empirical simple approach to predict the plasma concentration for such a TTS. A novel compound, GTS-21, for Alzheimers' disease currently under development was used as a model drug. In vivo and in vitro experiments were carried out in hairless rats. The in vivo plasma concentration-time profile in hairless rats following the application of TTS well agreed with the predicted profile based on the skin pharmacokinetic model together with the model parameters determined from the in vitro experiment.     

Pharmacokinetics and pharmacodynamics of transdermally administered clonidine

Summary Clonidine was applied to the skin of healthy volunteers once weekly by means of a Transdermal Therapeutic System (TTS). The plasma concentration and renal excretion of clonidine, and its effects on mean arterial blood pressure (MAP) and heart rate (HR) were recorded for 7 days, followed by a three-day observation period when a second TTS was applied. Subjective side effects were semiquantitatively recorded. Four differents TTS formulations were tested; of which TTS-RP 600679 was the most effective. Following application of this formulation, the plasma level of the drug built-up up during the first 2 days and then remained stable for 120 h at therapeutic concentrations between 0.5 and 0.7 ng/ml; MAP was consistently reduced. During the steady state period the daily urinary clonidine excretion was in the same range as during chronic administration of Catapres tablets 0.15 mg every 12 h, or Catapres Perlongets 0.25 mg every 24 h. Transdermal clonidine applications renewed weekly provide the following therapeutic advantages: 1. patients are protected continuously throughout the entire steady state period; 2. daily fluctuations in plasma clonidine concentration are minimized, which may result in a marked reduction in side effects; and, 3. drug compliance should be improved.     

The pharmacokinetics and pharmacodynamics of tandospirone in rats exposed to conditioned fear stress.

The 5-HT1, agonist tandospirone is generally thought to have a weak anxiolytic effect with a slow onset of action. Our recent clinical study suggested that a comparatively high dose of tandospirone has excellent anxiolytic efficacy and is without significant adverse effects. The present study was designed to clarify the relationship between the anxiolytic effect of tandospirone and its plasma and brain concentrations. The anxiolytic effect was estimated by determining the conditioned fear stress-induced freezing behavior in rats after tandospirone administration. Obvious correlations between anxiolytic effect and brain concentration of tandospirone were observed 0.5 and 4 h after tandospirone administration, while the anxiolytic effect was dependent on the plasma concentration of at 0.5 h but not 4 h after tandospirone administration. The plasma concentration was significantly correlated with the brain concentration. These findings suggest that the potency of the anxiolytic effect is dependent on both the plasma and brain concentration.     

Controlled in vivo release of nicorandil from a carvone-based transdermal therapeutic system in human volunteers

The aim of our present study was to prepare and evaluate a carvone-based transdermal therapeutic system (TTS) of nicorandil to find its ability in providing the desired in vivo controlled release profile on dermal application to human volunteers. The effect of EVA 2825, and adhesive-coated EVA 2825, and adhesive-coated EVA 2825-rat skin composite on the in vitro permeation of nicorandil from a carvone-based HPMC gel drug reservoir was studied against a control (rat abdominal skin alone). The carvone-based drug reservoir system was sandwiched between adhesive-coated EVA 2825-release liner composite and a backing membrane. The resultant drug reservoir sandwich was heat-sealed to produce a circle-shaped TTS (20 cm²) that was subjected to in vivo evaluation on dermal application to human volunteers against oral administration of immediate-release tablets of nicorandil. The carvone-based TTS provided a steady-state plasma concentration of 20.5 ng/ml for ∼24 hr in human volunteers. We concluded that the carvone-based TTS of nicorandil provided the desired in vivo controlled-release profile of the drug for the predetermined period of time.     

Comparative electroencephalographic evaluation of anxiolytics afobazol and diazepam in MR and MNRA inbred rats with different anxiety levels

The effects of two anxiolytic drugs, diazepam (10 mg/kg, i.p.) and afobazole (20 mg/kg, i.p.) on the EEG features was studied in MR and MNRA rats with different emotionality and anxiety levels in order to reveal an EEG marker of the anxiolytic action. For this purpose, 840 EEG parameters from 24 neocortex sites were determined and analyzed. In MR (but not in MNRA) rats, both diazepam and afobazole decreased the number of EEG parameters reliably changed upon the emotional-pain stress related to the intraperitoneal injections of 0.9% NaCl. Afobazole increased the theta-rhythm power in the spectral band of 4.75-7.25 Hz in MR rats, and in the band of 4.75-5.75 Hz in MNRA rats. Diazepam did not change the theta activity in MR rats, while decreasing it in the band of 6.00-7.25 Hz for MNRA rats. In addition, diazepam increased the spectral power in a broad frequency range of alpha and beta rhythms (8.75-17.25 Hz) in the rats of both lines, while afobazole did not produce such action. Common effects include a decrease in the spectral power within a narrow frequency band (7.5-8.5 Hz) at the boundary between theta and alpha regions. It is suggested that the latter effect can be used as the EEG marker of the anxiolytic action. The biopotential coherency in this frequency band was reduced in MR and MNRA rats only under the action of afobazole. The possibility of EEG changes related to the side action of anxiolytics and expediency of using the EEG markers in rats with different emotionality levels are discussed.     

Controlled In Vivo Release of Nicorandil from a Carvone-Based Transdermal Therapeutic System in Human Volunteers

The aim of our present study was to prepare and evaluate a carvone-based transdermal therapeutic system (TTS) of nicorandil to find its ability in providing the desired in vivo controlled release profile on dermal application to human volunteers. The effect of EVA 2825, and adhesive-coated EVA 2825, and adhesive-coated EVA 2825-rat skin composite on the in vitro permeation of nicorandil from a carvone-based HPMC gel drug reservoir was studied against a control (rat abdominal skin alone). The carvone-based drug reservoir system was sandwiched between adhesive-coated EVA 2825-release liner composite and a backing membrane. The resultant drug reservoir sandwich was heat-sealed to produce a circle-shaped TTS (20 cm²) that was subjected to in vivo evaluation on dermal application to human volunteers against oral administration of immediate-release tablets of nicorandil. The carvone-based TTS provided a steady-state plasma concentration of 20.5 ng/ml for ～24 hr in human volunteers. We concluded that the carvone-based TTS of nicorandil provided the desired in vivo controlled-release profile of the drug for the predetermined period of time.     

Correlation between the pharmacokinetic indices and the pharmacological effects of fenazepam in an experiment

A good agreement was established between the anxiolytic (tranquilizing) effect of phenazepam after administration to rats per os and the rate of its supply to the systemic blood flow. The magnitude of the myorelaxant effect of phenazepam in rats after its oral and intravenous administration correlated well with the drug concentration in blood only at the late periods of time.     

Modulating effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin secretion in male rats.

1. The effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin (PRL) secretion was investigated in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Four doses of piracetam were tested (20, 100, 200 and 400 mg kg-1), being given intraperitoneally 1 h before blood sampling; control rats received saline instead. After a first blood sample, rats were subjected to immobilization stress and received morphine, 6 mg kg-1, 90 min later. 3. Piracetam had no effect on basal plasma PRL concentration. 4. While in the non-piracetam-treated rats, stress produced a significant rise in plasma PRL concentration, in the piracetam-pretreated rats PRL peaks were attenuated, especially in the group given 100 mg kg-1 piracetam, where plasma PRL concentration was not significantly different from basal values. The dose-response relationship showed a U-shaped curve; the smallest dose had a minor inhibitory effect and the highest dose had no further effect on the PRL rise. 5. In unrestrained rats, morphine led to a significant elevation of plasma PRL concentration. After the application of immobilization stress it lost its ability to raise plasma PRL concentration in the control rats, but not in the piracetam-treated rats. This tolerance was overcome by piracetam in a significant manner but with a reversed dose-response curve; i.e. the smaller the dose of piracetam, the higher the subsequent morphine-induced PRL peak. 6. There is no simple explanation for the mechanism by which piracetam induces these contradictory effects. Interference with the excitatory amino acid system, which is also involved in opiate action, is proposed speculatively as a possible mediator of the effects of piracetam.     

Evidence that tolerance develops to the anxiolytic effect of diazepam in rats

The development of tolerance to the anxiolytic effect of diazepam was studied using suppression of defensive burying as an animal model of anxiolytic action. Although tolerance to the suppressive effect of diazepam was not apparent after chronic administration of diazepam when the rats were tested with a low-intensity shock, anxiolytic tolerance was detected under exactly the same drug regimen when the rats were tested with somewhat higher intensity shocks: under the latter conditions, chronically treated rats buried significantly more than acutely treated rats. Furthermore, this tolerance effect did not appear to depend upon the injection environment, the control vehicle, or the strain of rat; under each of these experimental variations rats chronically treated with diazepam buried significantly more than acutely treated rats when they had received a moderately high intensity shock. These results suggested that tolerance to the anxiolytic effects of benzodiazepines may be detectable when the stimuli eliciting anxiety are relatively intense.     

Glycerol trinitrate (nitroglycerin) plasma concentrations achieved after application of transdermal therapeutic systems to healthy volunteers

Glycerol trinitrate (nitroglycerin, in the following briefly called GTN) plasma concentrations achieved upon application of a commercial scale produced transdermal therapeutic system containing GTN (TTS-GTN, Nitroderm-TTS) were compared to those induced by 2 TTS-GTN prototypes previously used for clinical trials. Each system was applied to the chest, lateral aspect, of 14 healthy volunteers for 24 h, in a 3-period change-over study. GTN in plasma was determined by gas chromatography-mass spectrometry. The 3 systems released the drug continuously over 24 h. The mean plasma concentrations for all subjects and all sampling times (nmol/l) +/- SE were 0.92 +/- 0.18, 0.80 +/- 0.12 and 0.97 +/- 0.18 for the commercial scale TTS and the 2 other systems, respectively. No significant differences were demonstrated. The mean delivery rate of GTN calculated from the initial and residual contents of the TTS was 6.8 micrograms/min as a mean for the 3 systems. In another study, three different application sites were compared (chest, upper arm and pelvis). The results did not demonstrate significantly different GTN plasma levels. A comparison with published data after intravenous infusion showed a good availability of GTN administered transdermally by means of TTS. Its magnitude seems comparable to that of the intravenous route.     

Effect of the anxiolytic drug buspirone on prolactin and corticosterone secretion in stressed and unstressed rats

Buspirone is an atypical anxiolytic drug that exerts its action at a receptor site other than the GABA-benzodiazepine-chloride ionophore complex. The present study examined the effect of buspirone on plasma prolactin and corticosterone levels in both control and stressed rats. In unstressed rats, buspirone produced dose-dependent increases in plasma prolactin and corticosterone levels. The minimal doses of buspirone which led to significant elevations in plasma prolactin and corticosterone levels were 1.0 and 2.0 mg/kg (IP), respectively. The effect of buspirone on both hormones was maximal 30 minutes after injection. The plasma levels of prolactin and corticosterone were significantly elevated in rats that were stressed using a conditioned fear paradigm. Buspirone produced a dose-dependent attenuation of the stress-induced increase in prolactin secretion. The stress-induced increase in corticosterone secretion was inhibited by the 0.5 mg/kg (IP) dose but not by the 2.0 mg/kg (IP) dose of buspirone, which increased corticosterone secretion both in stressed and unstressed rats. These data suggest that the effect of buspirone on plasma prolactin and corticosterone levels may be mediated by two different mechanisms of action.     

Benzodiazepine effects upon Geller-Seifter conflict test in rats: analysis of individual variability

The aim of the present study was to investigate in a large group of "drug sophisticated" animals the effect of several doses of oxazepam upon conflict behavior. To this end 43 rats, trained according to the original Geller-Seifter paradigm, were tested with 5 doses (6.25, 12.5, 20.9, 25, and 50 mg/kg IP) of oxazepam. In addition the influence of prior drug experience on the effects of benzodiazepines on punished and unpunished responding was investigated comparing data from the same animals relative to a single oxazepam treatment before and after "drug sophistication." It was found that: (1) after "drug sophistication" oxazepam effect upon the unpunished schedule is decreased, while the disinhibitory action upon punished behavior is increased, unchanged or even decreased; (2) sedative and anticonflict activities of the drug cannot be explained in terms of rate dependency and are independently assessable since, even when unpunished responding is lowered by high doses, the anxiolytic effect is masked in only 27% of the cases; (3) about 20% of the animals appear to be insensitive to the anticonflict effect of oxazepam; (4) the responsiveness to the anxiolytic effect of the drug is related to the shock intensities given during training and to the animal variability under control conditions.     

In-vitro distribution of terbinafine in rat and human blood

The association of drugs with plasma lipoproteins has the potential to influence drug action and disposition. In this study, the uptake and distribution of the lipophilic antifungal drug, terbinafine, was investigated in rat and human blood and plasma. Fresh plasma was incubated with terbinafine (200-1000 ng mL(-1)), then subjected to vertical spin density gradient ultracentrifugation to separate protein fractions. The concentrations of terbinafine in each fraction was determined using a validated reversed-phase HPLC method. The association of terbinafine with very-low-density lipoproteins (15.5 +/- 7.1% of total concentration) in human plasma was significantly lower than that associated with fractions containing soluble proteins (28.0 +/- 6.2%), high- (26.8 +/- 7.7%) and low-density lipoproteins (31.6 +/- 4.6%). In rats terbinafine was found to be distributed evenly through plasma protein fractions. The association of terbinafine in lipoproteins was independent of concentration (over the range 200-1,000 ng mL(-1)) and species. The distribution of terbinafine was examined in human and rat blood and the blood-to-plasma ratio of terbinafine was 0.70+0.09 and 1.01 +/- 0.20, respectively, indicating higher association of terbinafine with plasma components than erythrocytes in humans. This study suggests that in humans and rats, terbinafine associates with a number of plasma proteins independently of terbinafine concentration. Alteration in plasma lipoprotein concentrations are therefore likely to influence terbinafine binding in blood and distribution in the body.     

The effects of diazepam on brain 5-HT and 5-HIAA in stressed and unstressed rats

Diazepam, administered to rats at a high dose (25 mg/kg PO) has been shown to have no effect on the plasma corticosterone response to the stress of an elevated open platform. It did however, reduce the plasma corticosterone in rats repeatedly exposed to the apparatus. Diazepam-withdrawal from stress-habituated rats increased plasma corticosterone (p less than 0.01) whereas withdrawal of diazepam from unstressed rats had no effect on plasma corticosterone. It is concluded that this effect of diazepam-withdrawal may reflect the development of dependence upon the drug. Significant effects were not observed following the administration of a lower non-selective dose (5 mg/kg PO) of diazepam and, therefore, it is not clear whether dependence to its sedative, rather than the anxiolytic properties have been measured. Acute diazepam (25 mg/kg) increased (p less than 0.05) hippocampal 5-hydroxyindoleacetic acid; its withdrawal from unstressed rats after 40 days reduced (p less than 0.01) hypothalamic 5-hydroxytryptamine. There was no evidence that the effects of diazepam or its withdrawal on plasma corticosterone in stressed rats were associated directly with changes in brain 5-hydroxyindoles.     

Transdermal Scopolamine in Motion Sickness

Motion sickness is a common clinical malady. Until recently, the use of scopolamine, the drug of choice for the treatment of motion-induced nausea and vomiting, has been sometimes associated with a variety of unacceptable side effects. These side effects could result from the unpredictable blood levels attained with oral dosage (pulse delivery). A new system of drug delivery, the transdermal therapeutic system (TTS) — Transderm®-V — has been developed. The TTS delivers scopolamine across the skin at a constant rate. This permits a drug with a very short half life to be administered over prolonged periods, thereby maintaining blood concentrations at the defined therapeutic level. This precludes the necessity for frequent dosing and increases patient acceptability and compliance while minimizing the untoward effects associated with conventional dosage forms of the drug.     

Studies on the transdermal delivery of nimodipine from a menthol-based TTS in human volunteers

The purpose of the present study was to design a membrane-moderated transdermal therapeutic system (TTS) of nimodipine using 2%w/w hydroxypropyl methylcellulose (HPMC) gel as a reservoir system containing menthol as penetration enhancer and 60%v/v ethanol-water as solvent system. The flux of nimodipine was markedly increased from 35.51 microg/cm2/h to 167.53+/-3.69 microg/cm2/h with the addition of 8%w/w menthol to HPMC drug reservoir. There was an increase in the flux of nimodipine through ethylene vinyl acetate (EVA) copolymer membrane with an increase in vinyl acetate content (9 to 28%w/w) of the copolymer. The permeability flux of nimodipine from the chosen EVA 2825 (with 28%w/w vinyl acetate content) was 152.05+/-2.68 microg/cm2/h, and this flux decreased to 132.69+/-1.45 microg/cm2/h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat. However, the transdermal flux of nimodipine across EVA 2825 membrane coated with TACKWHITE A 4MED/ rat skin composite was found to be 116.05+/-2.39 microg/cm2/h, which is about 1.4 times greater than the required flux. Thus a new transdermal therapeutic system for nimodipine was designed using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED, and 2%w/w HPMC gel as reservoir containing 8%w/w of menthol as a penetration enhancer. The in vivo evaluation of nimodipine TTS patch was carried out to find the ability of the fabricated menthol-based TTS patch in providing the predetermined plasma concentration of the drug in human volunteers. The results showed that the menthol-based TTS patch of nimodipine provided steady plasma concentration of the drug with minimal fluctuations with improved bioavailability in comparison with the immediate release tablet dosage form.     

Housing conditions and the anxiolytic efficacy of buspirone: the relationship between main and side effects

Serotonergic anxiolytics yield contradictory results both in the laboratory and clinically. In an attempt to investigate the cause of discrepancies, the anxiolytic effect of buspirone (0, 3 or 10 mg/kg, single treatment) was tested 1 h and 4 h after injection in rats in different housing conditions. At 1 h after drug administration, buspirone increased corticosterone production and decreased locomotor behaviour in both the elevated plus-maze and the social interaction tests. No anxiolytic-like effect was produced in either test. At 4 h after drug injection, no corticosterone or locomotor effects of buspirone were observed. In contrast, anxiolytic effects emerged in this phase. Open arm exploration and social investigation were increased in the plus-maze and social interaction test, respectively. In the plus-maze, the anxiolytic effect was significant in isolated animals only. In the social interaction test, the anxiolytic effect was stronger in isolated than in group-housed animals. When corticosterone secretion was inhibited by adrenalectomy, a full anxiolytic effect of buspirone was observed 1 h after drug administration. It appears that the side effects of buspirone have a shorter duration than the main anxiolytic effect. The buspirone-induced increase in corticosterone may have abolished the anxiolytic effects of the drug shortly after injection. Individual housing enhanced the anxiolytic efficacy of buspirone 4 h after administration.     

General pharmacology of the novel centrally acting antihypertensive agent moxonidine

Moxonidine (4-chloro-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine, BDF 5895) reduces blood pressure and heart rate in rats with genetic hypertension (SHR/Okamoto) and in rats with renovascular hypertension (Goldblatt 1 k/1 c). The hypotensive action was also confirmed in renal-hypertensive dogs. The hypotensive action is preceded by a reduction in plasma noradrenaline concentration, thus reflecting a reduction in sympathetic activity. In anesthetized cats, administration of moxonidine into the vertebral artery induces a greater hypotensive effect than i.v. injection of same doses, indicating the central nervous system as the site of hypotensive action. Similar to clonidine, the hypotensive action of moxonidine is abolished by pretreatment of the animals with a selective alpha 2-antagonist. Direct application of moxonidine into the cisterna magna of anesthetized rabbits revealed a 10-fold greater hypotensive potency than clonidine, in contrast to i.v. application where moxonidine was 10-fold less potent than clonidine. At least 10-fold higher doses of moxonidine were needed to cause side effects (sedation, inhibition of gastric secretion), when compared with clonidine. Interruption of presynaptic noradrenergic pathways completely abolished the hypotensive action of moxonidine. Thus moxonidine is endowed with a specific central site of action, presumably by stimulating central presynaptic alpha 2-adrenoceptors. This specific central hypotensive action enables a greater dissociation between the antihypertensive effect on the one hand, and the side effects on the other.     

Effect of typical and atypical anxiolytics on the behavior and electrophysiological parameters of rats with model cerebrovascular pathology

The influence a series of anxiolytics (tranquilizers) on behavioral disturbances was studied in outbread white male rats with cerebrovascular pathology modeled by ligation of common carotid arteries. All studied anxiolytics (diazepam, buspirone, mexidol) exhibited more of less pronounced protective action with respect to the pathology studied. The most significant protective effect was produced by the atypical anxiolytic mexidol. Special features of the effect of mexidol are probably explained by combination of several effects (anxiolytic, nootrope, antioxidant, and antihypoxant). in the pharmacological activity spectrum of this drug.