ucb L059, a novel anti-convulsant drug: pharmacological profile in animals.

The anticonvulsant activity of ucb L059 ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide) was evaluated in a range of animal models. ucb L059 was active after oral and intraperitoneal administration in both rats and mice, with a unique profile of action incorporating features in common with several different types of antiepileptic drugs. The compound was active, with ED50 values generally within the range of 5.0-30.0 mg/kg, in inhibiting audiogenic seizures, electrically induced convulsions and convulsions induced chemically by pentylenetetrazole (PTZ), bicuculline, picrotoxin and N-methyl-D-aspartate (NMDA). ucb L059 retarded the development of PTZ-induced kindling in mice and reduced PTZ-induced EEG spike wave discharge in rats. The R enantiomer, ucb L060, had low intrinsic anticonvulsant activity, showing the stereospecificity of action of the molecule although the actual mechanism of action remains unknown. Neurotoxicity, evaluated with an Irwin-type observation test, the rotarod test and open-field exploration, was minimal, with only mild sedation being observed, even at doses 50-100 times higher than the anticonvulsant doses; at pharmacologically active doses, the animals appeared calm but slightly more active. ucb L059 thus presents as an orally active, safe, broad-spectrum anticonvulsant agent, with potential antiepileptogenic and anti-absence actions.     

ucb L059, a novel anti-convulsant drug: pharmacological profile in animals

The anticonvulsant activity of ucb L059 ((S)--ethyl-2-oxo-pyrrolidine acetamide) was evaluated in a range of animal models. ucb L059 was active after oral and intraperitoneal administration in both rats and mice, with a unique profile of action incorporating features in common with several different types of antiepileptic drugs. The compound was active, with ED₅₀ values generally within the range of 5.0–30.0 mg/kg, in inhibiting audiogenic seizures, electrically induced convulsions and convulsions induced chemically by pentylenetetrazole (PTZ), bicuculline, picrotoxin and N-methyl-D-aspartate (NMDA). ucb L059 retarded the development of PTZ-induced kindling in mice and reduced PTZ-induced EEG spike wave discharge in rats. The R enantiomer, ucb L060, had low intrinsic anticonvulsant activity, showing the stereospecificity of action of the molecule although the actual mechanism of action remains unknown. Neurotoxicity, evaluated with an Irwin-type observation test, the rotarod test and open-field exploration, was minimal, with only mild sedation being observed, even at doses 50–100 times higher than the anticonvulsant doses; at pharmacologically active doses, the animals appeared calm but slightly more active. ucb L059 thus presents as an orally active, safe, broad-spectrum anticonvulsant agent, with potential antiepileptogenic and anti-absence actions.     

Pharmacokinetic drug interactions of macrolides.

The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives. Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)     

Antibacterial and antitumor macrolides fromstreptomyces sp. Is9131

Four compounds, including two novel macrolides, were isolated from an endophyte Streptomyces sp. Is9131 of Maytenus hookeri. Spectral data indicated that these compounds were dimeric dinactin (1), dimeric nonactin (2), cyclo-homononactic acid (3), and cyclo-nonactic acid (4). Bioassay results showed that dimeric dinactin had strong antineoplastic activity and antibacterial activity.     

A pharmacological profile of piracetam (Myocalm), a drug for myoclonus

Myoclonus is defined as shock-like, brief involuntary abnormal movements in muscle jerking caused by external stimuli; and it arises from progressive myoclonus epilepsy, post-anoxic encephalopathy and Alzheimer's disease, causing disabling symptoms. It is a rare syndrome but very difficult to control. Piracetam (2-oxo-1-pyrrolidineacetamide, Myocalm) was developed more than 30 years ago as a cyclic derivative of gamma-aminobutyric acid (GABA); it has been used in European countries for the treatment of memory loss and other cognitive defects in patients. Some reports have suggested that piracetam has anti-myoclonus activities, but the mechanisms of myoclonus are not well-identified, and thus there have been few preclinical studies on piracetam for the treatment of myoclonus. We investigated the effect of piracetam and clonazepam, an anti-epileptic drug, on high dosage urea-induced myoclonus using an electromyogram in rats. The incidence of myoclonus induced by urea 4.5 g/kg (i.p.) was significantly reduced by piracetam at 300 mg/kg (i.p.) and by clonazepam at 0.3 mg/kg (p.o.). The coadministration of piracetam 100 mg/kg (i.p.) and clonazepam at 0.03-0.1 mg/kg (p.o.) significantly reduced the incidence of myoclonus, although separate administration was not effective. After oral administration of piracetam, it is rapidly and completely absorbed and excreted almost unchanged in the urine; however, it does show a little binding to human serum protein. Repeated oral administration of piracetam for 7 days in phase-I trials did not show any accumulation of the drug. In the placebo-controlled double-blind crossover trial of piracetam conducted in the UK, there was a significant improvement in cortical myoclonus. In phase-II trials, piracetam inhibited myoclonus and showed an improvement in the quality of life (QOL) of the patients. These results show that piracetam has a beneficial use in clinics for severe myoclonus patients when it is combined with anti-epileptic drugs, demonstrating an improvement in the myoclonus and QOL of patients.     

A pharmacological profile of clobazam (Mystan), a new antiepileptic drug

Clobazam (CLB) is a new antiepileptic drug that is the first 1,5-benzodiazepine (BZP) having nitrogen atoms in the 1 and 5 positions of the heterocyclic ring, whose chemical structure was designed to give it a different pharmacological profile from that of 1,4-BZPs. Although CLB has a Ki value of 2,130 nM and thus has a lower affinity for the BZP receptor than 1,4-BZPs, it had the selectivity to omega 2 receptor contributing to anticonvulsive actions compared with omega 1 receptor in relation to other CNS activities such as sedation. CLB had a wide spectrum of anticonvulsive actions against seizures in several animal models induced by chemical convulsants and maximal electroshock. CLB reduced both seizure stage and afterdischarge duration in a dose-dependent manner in amygdala or hippocampal kindled rats. Usefulness of an anticonvulsant is generally assessed by quoting the protective index (PI) in the ratio of TD50 to ED50. As the PI for CLB was greater than that for 1,4-BZPs, it suggested that CLB was superior to 1,4-BZPs in tolerability while showing anticonvulsive actions. In clinical studies, CLB was used as an adjunctive treatment in patients with refractory epilepsies. From both experimental and clinical observations, CLB was proven to possess a wide spectrum of activity, high effectiveness and good tolerability in several types of epilepsies.     

Bemiparin: pharmacological profile

Bemiparin is a low molecular weight heparin (LMWH) that has been available in Europe for 10 years and is indicated for thromboprophylaxis and the treatment of deep vein thrombosis. Bemiparin is termed a 'second-generation' LMWH, because at 3.6 kDa, it has a lower mean molecular weight than other LMWH and a narrow distribution of saccharide chain lengths, with most being less than 6 kDa. As a result of its low molecular weight, it has low anti-factor IIa (thrombin) activity and an anti-Xa?:?anti-IIa activity ratio of 8 : 1 compared with a ratio of 1 : 1 for unfractionated heparin. The anti-Xa activity of bemiparin is only partly neutralized by protamine sulphate. In addition to anti-Xa activity, bemiparin increased the release and activity of tissue factor pathway inhibitor (TFPI) from endothelial cells under both static conditions and arterial sheer stress. Bemiparin is rapidly absorbed after subcutaneous administration, attaining maximal plasma anti-Xa activity within 2-6 h. The bioavailability of bemiparin was estimated at 96% and the apparent volume of distribution was 5.1 L. Plasma anti-Xa activity was maintained for up to 12 h with single bemiparin doses of 2500 IU anti-Xa or less and for up to 20-24?h with single doses of 7500-12,500?IU. The area under the effect-time curve for bemiparin increased dose-dependently and was greater than those for slightly higher doses of enoxaparin and tinzaparin. Bemiparin has the longest half-life of all LMWH at 5.3 h compared with 0.5-1.0 h for unfractionated heparin. Elimination is linear, with a mean residence time of over 7 h and total clearance of 0.9 L/h. The peak activity for the TFPI effect was earlier than the anti-Xa effect, at 1-2 h, and lasted for 6-12 h. Bemiparin thus has good antithrombotic activity and a better pharmacological profile than unfractionated heparin.     

Levocabastine: pharmacological profile of a highly effective inhibitor of allergic reactions.

Levocabastine, selected from a series of cyclohexylpiperidine derivatives protects rats from compound 48/80-induced anaphylactic shock for at least 16 h at the oral dose of 0.0015 mg/kg. At the same dose histamine skin reactions and at slightly higher doses passive cutaneous anaphylactic reactions are inhibited. Blockade of passive cutaneous anaphylactic reactions is obtained with levocabastine, despite absence of peripheral serotonin antagonism and any other known non-specific action that may facilitate inhibition of passive anaphylaxis. In dogs allergic reactions are inhibited at oral doses 40 times lower than ketotifen. In guinea-pigs orally and topically administered levocabastine are remarkably effective against allergic conjunctivitis.     

Buprenorphine: a unique drug with complex pharmacology

Buprenorphine, an opioid with mixed agonist-antagonist activity at classical opioid receptors, has been approved recently for the treatment of opioid dependency. Buprenorphine is also used as an analgesic. The buprenorphine dose-response curve is sometimes submaximal, or even bell-shaped, in nociceptive assays, depending upon the nature and intensity of the noxious stimulus. Moreover, buprenorphine, when administered with full agonists, such as morphine, antagonizes the action of these drugs. Partial agonism at the mu opioid receptor and, in some cases, antagonism at the kappa or delta opioid receptor have been considered as possible underlying mechanisms for the ceiling effect and bell-shaped dose-response curve of buprenorphine. While ceiling effects can be explained by partial agonist activity of buprenorphine, the bell-shaped dose-response curve cannot be a consequence of this property of the drug. Recently, buprenorphine has been shown to activate the opioid receptor-like (ORL-1; also known as NOP) receptor. Supraspinal activation of the ORL-1 receptor counteracts the antinociceptive and rewarding actions of morphine, raising the possibility that these actions of buprenorphine can also be altered by its ability to concomitantly activate the ORL-1 receptor. The use of molecular biological techniques has advanced our knowledge regarding the role of opioid receptors in modulation of pain and reward. In particular, generation of opioid receptor knockout mice has proven useful in this regard. Indeed, using knockout mice, we have recently shown that the antinociceptive effect of buprenorphine mediated primarily by the mu opioid receptor is attenuated by the ability of the drug to activate the ORL-1 receptor. Thus, the goal of this review is to provide evidence demonstrating that the ORL-1 receptor plays a functional role not only in the antinociceptive effect of buprenorphine but also in other actions of the drug as well.     

Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile

Background and Purpose

Glucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti-inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17α position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such molecules would retain anti-inflammatory activity.

Experimental Approach

The pharmacological properties of {"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}GW870086 were compared with fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling.

Key Results

{"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}GW870086 repressed inflammatory cytokine release from lung epithelial cells in a similar manner to FP but antagonized the effect of dexamethasone on MMTV-driven reporter gene transactivation. {"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}GW870086 had a strong effect on the expression of some glucocorticoid-regulated genes (such as PTGS2), while having minimal impact on the expression of other known target genes (such as SGK). {"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}GW870086 retained the ability to strengthen tight junctions in epithelial cell culture but, unlike FP, was unable to protect the culture from elastase-mediated damage. In murine models of irritant-induced contact dermatitis and ovalbumin-induced allergic inflammation, {"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}GW870086 showed comparable anti-inflammatory efficacy to FP.

Conclusion and Implications

{"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}GW870086 is a potent anti-inflammatory compound with a unique ability to regulate only a subset of those genes that are normally affected by classical glucocorticoids. It has the potential to become a new topical steroid with a different safety profile to existing therapies.     

Some clinical pharmacological studies with terfenadine, a new antihistamine drug.

1 A double-blind cross-over trial between placebo, chlorpheniramine, and terfenadine, a new antihistamine drug, was performed in healthy male volunteers to determine and compare their CNS and autonomic effects. 2 Terfenadine and chlorpheniramine were administered orally in therapeutic doses. 3 In objective tests of critical flicker frequency, pursuit rotor, reaction time, salivary volume and pupillary diameter, no statistically significant difference was observed between the treatments. 4 On analogue rating scales, chlorpheniramine produced a statistically significant (P less than 0.05) degree of sedation and impaired concentration as compared to placebo and terfenadine. 5 The results obtained in analogue rating scales were not normally distributed and, therefore, use of non-parametric statistical methods for analysis of such data is strongly advocated.     

An EP receptor with a novel pharmacological profile in the T-cell line Jurkat.

1. Comparison of the rank order of potency of the natural prostanoids prostaglandin E2 (PGE2), PGD2, PGF2 alpha and carbaprostacyclin in stimulating cyclic AMP in Jurkat cells is consistent with the presence of an EP receptor. 2. Lack of responsiveness to the EP1/EP3 selective agonist, sulprostone, and the EP2 agonists, butaprost and AH 13205, indicates that this receptor is not of the EP1, EP2 or EP3 subtypes. 3. Inhibition of PGE2-stimulated cyclic AMP by the EP4 antagonist, AH 23848 is non-competitive, unlike the competitive antagonism reported in the pig saphenous vein EP4 preparation. Furthermore, 16,16-dimethyl PGE2 is 100 fold less potent than PGE2 in Jurkat cells, while these agonists are equipotent in the rabbit jugular vein purported EP4 preparation. In addition, 1-OH PGE1, which also is active in the rabbit jugular vein preparation, is inactive in Jurkat cells at concentrations up to 1 x 10(-4) M. These data are not wholly consistent with any adenylate cyclase coupled EP receptor described to date. 4. It is postulated that an EP receptor, positively coupled to adenylate cyclase, with a unique pharmacological profile is present in Jurkat cells.     

CHF2819: pharmacological profile of a novel acetylcholinesterase inhibitor

CHF2819 is a novel orally active acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD). CHF2819 is a selective inhibitor of AChE, it is 115 times more potent against this enzyme than against butyrylcholinesterase (BuChE). Moreover, CHF2819 is more selective for inhibition of central (brain) AChE than peripheral (heart) AChE. In vivo CHF2819, 0.5, 1.5, and 4.5 mg/kg p.o., significantly and in dose-dependent manner increased acetylcholine (ACh) levels in hippocampus of young adult rats. Moreover, aging animals, with lower basal ACh levels than young adult rats, also exhibit a marked increase in hippocampal levels of this neurotransmitter after administration of CHF2819. At 1.5 mg/kg p.o. CHF2819 attenuated scopolamine-induced amnesia in a passive avoidance task. Furthermore, it decreased dopamine (DA) levels and increased extracellular levels of 5-hydroxytryptamine (5-HT) in the hippocampus, without modifying norepinephrine (NE) levels. By oral administration to young adult rats CHF2819 did not affect extracellular hippocampal levels of glutamate (Glu), aspartate (Asp), gamma-aminobutyric acid (GABA), taurine (Tau), arginine (Arg) or citrulline (Cit). Functional observational battery (FOB) screening demonstrated that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological endpoints (body weight and temperature). CHF2819 induced, however, involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner. The neurochemical and behavioral profiles of CHF2819 suggest that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer-type dementia associated with multiple neurotransmitter abnormalities in the brain. In particular, CHF2819 might be a useful therapeutic drug for AD patients with cognitive impairment accompanied by depression.     

Urocontrin, a novel UT receptor ligand with a unique pharmacological profile

In recent years, several studies have demonstrated that urotensin II (UII) and urotensin II-related peptide (URP) can exhibit differential biological activity. So far, known antagonists of the urotensin II receptor (UT) are of limited usefulness for investigating the specific pathophysiological role of UII or URP. Therefore, identification of new compounds able to discriminate UII- and URP-associated biological activities is crucially needed. In the present study, we report preliminary data regarding the pharmacological properties of a novel UT ligand termed urocontrin, i.e. [Bip(4)]URP, that is able to reduce the ex vivo efficacy of hUII- but not URP-induced vasoconstriction in rat aortic rings. In vivo studies support the pharmacological profile described above. Although urocontrin exert some residual agonist activity, this compound should be useful for the rational design of potent molecules that would allow discriminating specific biological action mediated by UII or URP.     

Memantine hydrochloride: pharmacological and clinical profile

Memantine (Axura, Merz Pharmaceuticals GmbH; Ebixa, H. Lundbeck A/S, Namenda, Forest Laboratories, Inc.) is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with low to moderate affinity for the (+)MK-801 binding site. It is characterized as a voltage-sensitive open-channel NMDA receptor blocker that antagonizes NMDA receptor-mediated inward currents in vitro with an IC50 of 1-3 microM. In animal models, memantine displays both neuroprotective (antiexcitotoxic) and cognition-enhancing properties at therapeutically relevant concentrations. The strong voltage dependency and rapid blocking/unblocking kinetics of memantine are thought to be the basis for its excellent clinical tolerability. Recently completed clinical studies demonstrate positive effects of memantine in Alzheimer's disease both as a monotherapy and in patients receiving continuous donepezil treatment. Memantine treatment also has demonstrated significant improvement of cognitive performance in patients suffering from vascular dementia. Furthermore, the safety and tolerability of memantine in clinical trials has been excellent, with the incidence of premature withdrawals due to adverse events no greater than placebo and overall low frequencies of total adverse events. In 2002, memantine was approved by the European Medicines Agency (EMEA) for the treatment of moderately severe to severe Alzheimer's disease. More recently, memantine was approved in the US for the treatment of moderate to severe Alzheimer's disease (October 2003). Here, we review the most recent pharmacological and clinical data in dementia patients that has emerged from the systematic evaluation of memantine.