Comparative study of the association of itraconazole with colloidal drug carriers

In the present study, the association of a new hydrophobic triazole derivative, itraconazole, with intravenously compatible drug carriers (liposomes, cholesterol complexes, nanospheres) was evaluated and the different association yields compared. We tried to elucidate the mechanism of drug-carrier association by means of dilution and zeta potential measurement in the most promising formulations. The different lipid-based drug carriers yielded low association efficiencies (< 0.6%), whereas itraconazole loading into chemically modified β-cyclodextrin nanospheres reached 6.8% (0.170 mg/mL). The longer the hydrophobic chain linked to the β-cyclodextrin, the higher the association of itraconazole within the nanospheres. The highest association yields, 4.1% (0.510 mg/mL), were obtained with nanospheres composed of the most hydrophobic polymer tested, poly-î-caprolactone, and a negatively charged steroidal surfactant, sodium deoxycholate. Itraconazole seems to be both included in the matrix (40%) and adsorbed at the surface of the nanospheres (60%). This may explain the nanosphere instability with time because of continuous itraconazole desorption from the nanospheres, although the nanosphere mean size remained unchanged. The enhanced association yields observed with sodium deoxycholate were not the result of electrostatic attraction between itraconazole (a weak base) and the negatively charged surfactant but rather to stronger hydrophobic interactions between itraconazole and sodium deoxycholate, and to increased specific area of sodium deoxycholate-coated nanospheres. This latter was due to the smaller mean diameter (80 nm) of the sodium deoxycholate-coated nanospheres compared with non ionic surfactant-coated nanospheres (130 nm). © 1996 Wiley-Liss, Inc.     

Comparative evaluation of polymeric and amphiphilic cyclodextrin nanoparticles for effective camptothecin delivery

Camptothecin (CPT) is a potent anticancer agent. The clinical application of CPT is restricted by poor water solubility and instability under physiological conditions. Solubilization and stabilization of CPT were realized through nanoparticulate systems of amphiphilic cyclodextrins, poly(lactide-co-glycolide) (PLGA) or poly-ε-caprolactone (PCL). Nanoparticles were prepared with nanoprecipitation technique, whereas cyclodextrin nanoparticles were prepared from preformed inclusion complexes of CPT with amphiphilic cyclodextrins. Polymeric nanoparticles, on the other hand, were loaded with CPT:HP-β-CD inclusion complex to solubilize and stabilize the drug. Mean particle sizes were under 275 nm, and polydispersity indices were lower than 0.2 for all formulations. Drug-loading values were significantly higher for amphiphilic cyclodextrin nanoparticles when compared with those for PLGA and PCL nanoparticles. Nanoparticle formulations showed a significant controlled release profile extended up to 12 days for amphiphilic cyclodextrin nanoparticles and 48 h for polymeric nanoparticles. Anticancer efficacy of the nanoparticles was evaluated in comparison with CPT solution in dimethyl sulfoxide (DMSO) on MCF-7 breast adenocarcinoma cells. Amphiphilic cyclodextrin nanoparticles showed higher anticancer efficacy than PLGA or PCL nanoparticles loaded with CPT and the CPT solution in DMSO. These results indicated that CPT-loaded amphiphilic cyclodextrin nanoparticles might provide a promising carrier system for the effective delivery of this anticancer drug having bioavailability problems.     

Preparation and characterization of 5‐fluorouracil‐loaded poly(ϵ‐caprolactone) microspheres for drug administration

Microspheres of 5‐fluorouracil‐loaded poly(?‐caprolactone) (PCL) were prepared by spray‐drying procedure. The degradation characteristics and 5‐fluorouracil release in vitro as well as in vivo were investigated. The average molecular weight, weight loss, crystallinity, and morphology of microspheres were determined using GPC, DSC, and SEM, at different times during the in vitro degradation process. The size distribution of the microspheres indicated that most of the particles were smaller than 3 µm. A 30% weight loss as well as an increase of crystallinity were observed on day 330 of incubation. The percentage of entrapment efficiency of 5‐FU was 49% (44 µg of drug/mg of microspheres). The in vitro total release of 5‐FU took place in 8 days. Determination of plasma 5‐FU concentration in vivo using s.c. injection of 5‐FU‐loaded microspheres in Wistar rats by HPLC with analysis of data using a non‐compartmental model showed drug in plasma 18 days after administration with a maximum drug concentration of 1.5 µg/ml at 96 h. Pharmacokineticallly, a significant increase of AUC and MRT of 5‐FU with regard to the administration of the drug in solution. Scanning electron microscopy and histological studies indicated that the microspheres were surrounded by connective tissue and inflammatory processes were not evident. As a result of these characteristics, the 5‐FU‐loaded PCL microspheres could be used for drug delivery. Drug Dev Res 63:41–53, 2004. © 2004 Wiley‐Liss, Inc.     

An in vivo study of nanorod,nanosphere, and nanowire forms of titanium dioxide using Drosophila melanogaster: toxicity,cellular uptake,oxidative stress,and DNA damage

ABSTRACT

The biological impact of nanomaterials (NMs) is determined by several factors such as size and shape, which need to be taken into consideration in any type of analysis. While investigators often prefer to conduct in vitro studies for detection of any possible adverse effects of NMs, in vivo approaches yield more relevant data for risk assessment. For this reason, Drosophila melanogaster was selected as a suitable in vivo model to characterize the potential risks associated with exposure nanorods (NRs), nanospheres (NSs), nanowires (NWs) forms of titanium dioxide (TiO₂), and their microparticulated (or bulk) form, as TiO₂. Third instar larvae (72 hr old larvae) were fed with TiO₂ (NRs, NSs, or NWs) and TiO₂ at concentrations ranging from 0.01 to 10 mM. Viability (toxicity), internalization (cellular uptake), intracellular reactive oxygen species (ROS) production, and genotoxicity (Comet assay) were the end-points evaluated in hemocyte D. melanogaster larvae. Significant intracellular oxidative stress and genotoxicity were noted at the highest exposure concentration (10 mM) of TiO₂ (NRs, NSs, or NWs), as determined by the Comet assay and ROS analysis, respectively. A concentration–effect relationship was observed in hemocytes exposed to the NMs. Data demonstrated that selected forms of TiO₂.-induced genotoxicity in D. melanogaster larvae hemocytes indicating this organism is susceptible for use as a model to examine in vivo NMs-mediated effects.     

Determination of structural elements related to the biological activities of a potent decapeptide agonist of human C5a anaphylatoxin

Abstract: The structural features related to the biologic activities of a potent, response-selective decapeptide agonist of human C5a, YSFKPMPLaR (C5a_65–74, Y65, F67, P69, P71, d -Ala73), were identified by NMR analysis in H₂O, DMSO and TFE. This investigation showed that the KPM residues in H₂O and the SFKPM residues in DMSO exhibited an extended backbone conformation, whereas a twisted conformation was found in this region in TFE. In H₂O, the C-terminal region (PLaR) adopted a distorted type II β-turn or a type II/V β-turn. In the type II/V β-turn, Leu72 exhibited a conformation typical of a type II β-turn, whereas d -Ala73 exhibited a conformation characteristic of a type V β-turn. Furthermore, a γ-turn involving residues LaR overlapped with the type II/V β-turn. In DMSO, the C-terminal region had the analogous turn-like motif (type II/V β-turn overlapping with γ-turn) found in H₂O. In TFE, no β-turn motifs were formed by the PLaR residues. These turn-like motifs in the C-terminal region of the peptide in both H₂O and DMSO were in agreement with the biologically important conformations predicted earlier by a structure–function analysis of a related panel of decapeptide analogs. The motifs determined by the NMR analysis of YSFKPMPLaR in H₂O and DMSO may represent structural elements important for C5a agonist activity and thus can be used to design the next generation of C5a agonist, partial agonist and antagonist analogs.     

An autoradiographic study of dextromethorphan high-affinity binding sites in rat brain: sodium-dependency and colocalization with paroxetine

1. The distribution and some pharmacological properties of centrally located dextromethorphan high-affinity binding sites were investigated by in vitro autoradiography.
2. Sodium chloride (50 mM) induced a 7 to 12 fold increase in dextromethorphan binding to rat brain in all areas tested. The effect of sodium was concentration-dependent with a higher dose (120 mM) exerting a smaller effect on binding.
3. [³H]-dextromethorphan binding in the presence of sodium was inhibited in the presence of the anticonvulsant phenytoin at a concentration of 100 μM, while the σ ligand (+)-3-(-3-hydroxyphenyl)-N-(1-propyl)pipendine ((+)-PPP) had no effect on the binding, suggesting an interaction with the DM₂ site.
4. The distribution of the sodium-dependent binding identified in this study correlated significantly with the distribution of the selective 5-HT uptake inhibitor [³H]-paroxetine, and paroxetine and dextromethorphan mutually displaced their binding at concentrations in the low nanomolar range.
5. These data show that dextromethorphan and paroxetine share a sodium-dependent high affinity binding site in rat brain, and suggest that dextromethorphan might interact, in the presence of sodium, with the 5-HT uptake mechanism in rat brain.

     

Effects of p-chloroamphetamine and a side-chain monofluorinated analogue on levels of indoles in rat brain

Levels of tryptophan (Trp), 5-hydroxytryptamine (5-HT), and 5-hydroxyindole-3-acetic acid (5-HIAA) in rat brain were measured at 1, 2, 4, and 24 hr after intraperitoneal administration of p-chloroamphetamine (pCA) (0.03 mmol/kg) or of p-cloro-α-fluoromethylphenylethylamine (fluoro-p-chloroamphetamine; FpCA) (0.05 or 0.10 mmol/kg). FpCA is less potent than pCA at producing depletions of 5-HT and elevations of Trp, and the effects with FpCA are shorter-lasting. pCA has been reported to possess good antidepressant properties but was withdrawn from clinical studies because of reported neurotoxicity to 5-HT systems in rat brain. The less potent effects of FpCA on 5-HT and 5-HIAA reduction shown here suggest that further research on this analogue as a potential antidepressant is warranted.     

Nose-to-brain transport of melatonin from polymer gel suspensions: a microdialysis study in rats

Purpose: Exogenous melatonin (MT) has significant neuroprotective roles in Alzheimer’s and Parkinson’s diseases. This study investigates the delivery MT to brain via nasal route as a polymeric gel suspension using central brain microdialysis in anesthetized rats.

Methods: Micronized MT suspensions using polymers [carbopol, carboxymethyl cellulose (CMC)] and polyethylene glycol 400 (PEG400) were prepared and characterized for nasal administration. In vitro permeation of the formulations was measured across a three-dimensional tissue culture model EpiAirway^?. The central brain delivery into olfactory bulb of nasally administered MT gel suspensions was studied using brain microdialysis in male Wistar rats. The MT content of microdialysis samples was analyzed by high performance liquid chromatography (HPLC) using electrochemical detection. The nose-to-brain delivery of MT formulations was compared with intravenously administered MT solution.

Results: MT suspensions in carbopol and CMC vehicles have shown significantly higher permeability across Epiairway^? as compared to control, PEG400 (P?<?0.05). The brain (olfactory bulb) levels of MT after intranasal administration were 9.22, 6.77 and 4.04-fold higher for carbopol, CMC and PEG400, respectively, than that of intravenous MT in rats. In conclusion, microdialysis studies demonstrated increased brain levels of MT via nasal administration in rats.     

[Ala12]MCD peptide: a lead peptide to inhibitors of immunoglobulin E binding to mast cell receptors1

Abstract: An effort was made to discover mast cell degranulating (MCD) peptide analogs that bind with high affinity to mast cell receptors without triggering secretion of histamine or other mediators of the allergic reaction initiated by immunoglobulin E (IgE) after mast cell activation. Such compounds could serve as inhibitors of IgE binding to mast cell receptors. An alanine scan of MCD peptide reported previously showed that the analog [Ala¹²]MCD was 120‐fold less potent in histamine‐releasing activity and fivefold more potent in binding affinity to mast cell receptors than the parent MCD peptide. Because this analog showed marginal intrinsic activity and good binding affinity it was subsequently tested in the present study as an IgE inhibitor. In contrast to MCD peptide, [Ala¹²]MCD showed a 50% inhibition of IgE binding to the FcεRIα mast cell receptor by using rat basophilic leukemia (RBL‐2H3) mast cells and fluorescence polarization. Furthermore, in a β‐hexosaminidase secretory assay, the peptide also showed a 50% inhibition of the secretion of this enzyme caused by IgE. An attempt was made to relate structural changes and biologic differences between the [Ala¹²]MCD analog and the parent MCD peptide. The present results show that [Ala¹²]MCD may provide a base for designing agents to prevent IgE/FcεRIα interactions and, consequently, allergic conditions.     

Integrin α5β1: a new purification strategy based on immobilized peptides

Abstract: Novel efficient and robust affinity chromatography material: There are several strategies known for the purification of integrins by affinity chromatography, but the disadvantages of common strategies like insufficient selectivity or compelling conditions for the elution still require alternatives. A new strategy, based on the immobilized C‐terminally modified peptide Ac‐Gly‐Ala‐c‐(Cys^SS‐Arg‐Arg‐Glu‐Thr‐Ala‐Trp‐Ala‐Cys^SS)‐Gly‐Ala‐O(CH₂CH₂O)₂CH₂CH₂‐NH₂ allows for the affinity purification of the integrin α₅β₁. While RGD peptides have been proven in the past to be inappropriate for selective purification of integrins by affinity chromatography, the new peptide can be efficiently used for selective enrichment of the integrin α₅β₁. It is a specific ligand of the target protein, but does not contain an RGD sequence. The application of well‐characterized affinity chromatography material with a site‐specifically immobilized peptide allows to obtain integrin α₅β₁ in a single chromatography step without contamination by other integrins. This process combines the advantages of a selective and monospecific protein‐ligand recognition with mild elution conditions and a low sensitivity of the immobilized ligand with respect to column regeneration.     

Effect of penbutolol on neuroendocrine responses to buspirone and mood in SSRI‐refractory patients: a preliminary study

The β‐adrenoceptor antagonist, penbutolol, is an effective serotonin_1A (5‐HT_1A) receptor antagonist in the rat and through this action enhances the ability of selective serotonin re‐uptake inhibitors (SSRIs) to increase levels of serotonin in terminal fields. In healthy volunteers, penbutolol (40 mg orally), produced a modest attenuation of the prolactin response to the 5‐HT_1A receptor antagonist, buspirone (30 mg orally), but did not antagonise the hypothermic response. Furthermore, penbutolol addition (40 mg daily for 3 weeks) failed to improve the symptomatology of 10 depressed patients who had shown an inadequate clinical response to serotonergic antidepressants. These preliminary data suggest that at the typical dose used to treat hypertension, penbutolol does not antagonise 5‐HT_1A autoreceptors in humans and does not augment the effect of serotonergic antidepressants in treatment non‐responders. Copyright © 1999 John Wiley & Sons, Ltd.     

Enhancement of gene transfection into human dendritic cells using cationic PLGA nanospheres with a synthesized nuclear localization signal

Effective delivery of DNA encoding antigen into the dendritic cells (DCs), which are non-dividing cells, is very important for the development of DNA vaccines. In a previous study, we developed the PLGA nanospheres that contained a cationic nanomaterial and showed high transfection efficiency in COS7 cells, which divide. In the present study, to produce an effective vector for the DNA vaccines, the gene expression and intracellular trafficking of pDNA complexed with PLGA/PEI nanospheres, in combination with an NF-κB analog as a nuclear localization signal (NLS) and electroporation were evaluated in human monocyte-derived DCs (hMoDCs). Cellular uptake of pDNA both in COS7 cells and hMoDCs was enhanced using the PLGA/PEI nanospheres. On the other hand, the PLGA/PEI nanospheres significantly promoted the transfection in COS7 cells, but had almost no effect on transfection in hMoDCs. The intranuclear transport of pDNA by PLGA/PEI nanospheres in COS7 cells was significantly higher than that in hMoDCs. These results indicate that pDNA complexed with PLGA/PEI nanospheres cannot enter into the nuclei of non-dividing cells. However, PLGA/PEI nanospheres combinated with NLS and electroporation (experimental permeation enhancer) greatly elevated the transfection efficiency by improvement of not only intracellular uptake but also intranuclear transport of pDNA in the hMoDCs. Thus, this delivery system using nanospheres combined with synthesized NLS might be applicable to DC-based gene vaccines when much non-invasive application such as needle-free injector should be required.     

Hypoxic augmentation: The tale of a strange contraction

Almost fifty years ago, experiments on isolated veins showed that acute hypoxia augments venoconstrictor responses in vitro and that such facilitation relied on anaerobic glycolysis. Over the years, this phenomenon was extended to a number of arterial preparations of different species and revisited, from a mechanistic point of view, with the successive demonstration that it depends on calcium handling in the vascular smooth muscle cells, is endothelium‐dependent and requires the production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) and the activation of soluble guanylyl cyclase (sGC). However, rather than the vasodilator cyclic nucleotide 3′,5′‐cyclic guanosine monophosphate (cGMP), its canonical product, the latter enzyme produces 3′,5′‐cyclic inosine monophosphate (cIMP) instead during acute hypoxia; this non‐canonical cyclic nucleotide facilitates the contractile process in the vascular smooth muscle cells. This ‘biased’ activity of soluble guanylyl cyclase appears to involve stimulation of NAD(P)H:quinone oxidoreductase 1 (NQO‐1). The exact interactions between hypoxia, anaerobic metabolism and NQO‐1 leading to biased activity of soluble guanylyl cyclase remain to be established.     

Pharmacogenetics of drug-induced arrhythmias: a feasibility study using spontaneous adverse drug reactions reporting data

PURPOSE: The bottleneck in pharmacogenetic research on rare adverse drug reactions (ADR) is retrieval of patients. Spontaneous reports of ADRs may form a useful source of patients. We investigated the feasibility of a pharmacogenetic study, in which cases were selected from the database of a spontaneous reporting system for ADRs, using drug-induced arrhythmias as an example. METHODS: Reports of drug-induced arrhythmias to proarrhythmic drugs were selected from the database of the Netherlands Pharmacovigilance Centre (1996-2003). Information on the patient's general practitioner (GP) was obtained from the original report, or from another health care provider who reported the event. GPs were contacted and asked to recruit the patient as well as two age, gender and drug matched controls. Patients were asked to fill a questionnaire and provide a buccal swab DNA sample through the mail. DNA samples were screened for 10 missense mutations in 5 genes associated with the congenital long-QT (LQT) syndrome (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2). RESULTS: We identified 45 eligible cases, 29 GPs could be contacted of which seven were willing to participate. Four cases and five matched controls could be included in the study, giving an overall participation rate of 9% (4/45). The main reason for GPs not being willing to participate was lack of time. Variants were identified in KCNH2, SCN5A and KCNE1. CONCLUSIONS: Spontaneous reporting systems for ADRs may be used for pharmacogenetic research. The methods described, however, need to be improved to increase participation and international collaboration may be required.     

Anti-inflammatory activity of telmisartan in rat models of experimentally-induced chronic inflammation: Comparative study with dexamethasone

Recently, significant progress has been made through the application of peroxisome proliferator activated receptor-γ (PPAR-γ) agonists as anti-inflammatory drugs that are efficacious, relatively free of side effects, and can be used effectively for a long time. The present study was designed to evaluate the dose–response relationship of the anti-inflammatory activity of telmisartan in rat models of chronic inflammation. The study protocol includes four stages: First stage: 48 rats were allocated into eight groups, each containing six rats, for the study of the anti-inflammatory activity of different doses of telmisartan in rat model of formaldehyde-induced chronic inflammation. Second stage: six rats were used to study the anti-inflammatory activity of telmisartan (1.5 mg/kg) in combination with dexamethasone (0.5 mg/kg) in the same model. Third stage: 48 rats were allocated into eight groups, each containing six rats, for the study of the anti-inflammatory activity of telmisartan in rat model of cotton pellet-induced granuloma. Fourth stage: six rats were used to study the anti-inflammatory activity of telmisartan (1.5 mg/kg) when used as adjuvant with dexamethasone (0.5 mg/kg) in the same model. Telmisartan in a dose-dependent pattern (0.1, 0.2. 0.4, 0.6, 1.5, 3 mg/kg) significantly suppressed inflammation in rat models of formaldehyde-induced chronic inflammation and cotton pellet-induced granuloma. When combined with dexamethasone, telmisartan (1.5 mg/kg body weight) significantly suppressed inflammation in both models, which is significantly higher than all of the effects produced by other approaches of treatment when telmisartan used alone. In conclusion, telmisartan decreased formaldehyde-induced chronic inflammation and cotton-pellet induced granuloma in rats in a dose-dependent pattern. Therefore, it may be considered as a potential treatment for chronic inflammatory conditions in human.     

Clinical determinants of calcineurin inhibitor disposition: a mechanistic review

The calcineurin inhibitors (CNIs) tacrolimus and cyclosporine are widely used immunosuppressive drugs characterized by high pharmacokinetic and pharmacodynamic variability, both between and within patients. CNIs are highly lipophilic, poorly soluble, undergo extensive first-pass metabolism and are cleared by the liver. In both gut and liver, CNIs are substrates for the cytochrome P450 (CYP) enzymes 3A4 and 3A5 as well as the P-glycoprotein (P-gp) transporter, whose functions are determined by a complex interplay between genetic polymorphisms, the inductive or inhibitory effects of many drugs, herbs, food constituents and endogenous substances such as uremic toxins in case of end-stage renal disease. The current literature is reviewed for all common clinical determinants of variability in CNI disposition such as food intake, diarrhea and other intestinal pathology, anemia, hypoalbuminemia, hyperlipidemia, liver and kidney disease, aging, ethnicity, formulation and time post-transplant, focusing on the underlying mechanisms. Drugs and herb- and food constituents mainly interact with CNIs at the gut level by affecting bioavailability, with interactions generally being much more pronounced in case of oral compared with intravenous co-administration. Cyclosporine disposition is less susceptible to these interactions compared with tacrolimus, possibly because cyclosporine is itself a moderately strong CYP3A4- and strong P-gp inhibitor, blunting the effect of additional inhibitors. P-gp also has a major role in limiting distribution of CNI to tissues such as the brain, placenta, lymphocytes and kidney. Inactivating polymorphisms and inhibition of P-gp have the potential to significantly increase CNI exposure in these tissues with possible implications for toxicity and efficacy.     

Isolation of subunits, α, β and γ of the complex taipoxin from the venom of Australian taipan snake (Oxyuranus s. scutellatus): characterization of β taipoxin as a potent mitogen

The venom of Australian taipan snake (Oxyuranus s. scutellatus) is extremely potent due to the presence of taipoxin. The intact complex molecule of taipoxin having molecular weight 45.6 kDa is composed of α, β and γ subunits. This report describes the high pressure liquid chromatography (HPLC) separation of α, β (β-1 and β-2) and γ subunits from taipan crude venom. The fractions containing the taipoxin subunits were further purified to obtain homogeneous proteins. The toxicity in mice showed the α subunit as most toxic, the γ subunit as moderately toxic and the β-1 and β-2 subunits were nontoxic. The proteins β-1 and β-2 were found to be mitogenic having neurotrophic activity on PC12 cells in culture similar to nerve growth factor. Immunologically, α, β-1, β-2 and γ subunits were found to be different, showing cross reactivity, and β-1 and β-2 were found to be identical for biological properties and molecular weight. Further characterization of unexpected mitogenic activity of β subunits is underway.     

In vivo pharmacology of irindalone,a 5-HT2 receptor antagonist with predominant peripheral effects

The in vivo effects of irindalone, a newly developed serotonin₂ (5-HT₂) antagonist, have been investigated in comparison with a series of reference compounds. Irindalone potently antagonizes the pressor response induced by 5-HT in pithed rats, but has a 173 times weaker effect against the α₁-adrenoceptor agonist phenylephrine. Irindalone is relatively weak in rat models detecting central 5-HT₂ antagonism, that is, inhibition of quipazine- or I-5-HTP plus citalopram-induced head twitches, inhibition of I-5-HTP plus citalopram-induced increases of flexor reflexes, and inhibition of the discriminative stimulus properties induced by d-LSD. Furthermore, it displaces in vivo ³H-ketanserin binding in frontal cortex. Irindalone weakly antagonizes the flexor reflex stimulated by the α₁-adrenoceptor agonist St 587. No dopamine receptor inhibition is detected in the methylphenidate gnawing test in mice. High bioavailability is indicated by the identical ED₅₀ values obtained in the head twitch model after s.c. and p.o. administration. The activity profile of irindalone resembles that of ketanserin except in two characteristics: ketanserin has greater potency than irindalone as an antagonist in the 5-HTP-induced flexor reflex, but has a shorter duration of action. The effect of irindalone is stereoselective, since its opposite enantiomer Lu 21-099 is almost inactive in the models for central and peripheral 5-HT₂ receptor antagonism. Finally, the effect of repeated treatment with irindalone (18 μmol/kg, p.o., twice daily for 2 weeks) on inhibition of quipazine-induced head twitches was studied. Two days after the last dose, the potency for inhibiting quipazine was unchanged, indicating that no tolerance to 5-HT₂ receptor antagonism develops using this dose regimen. It is concluded that irindalone is a potent 5-HT₂ antagonist with preferential effects at peripheral sites.     

A crystal-state,solution and theoretical study of the preferred conformation of linear Cα,α-diphenylglycine derivatives and dipeptides with potential anticonvulsant activity

Several linear molecules containing the C^α,α-diphenylglycine residue were prepared as potential anticonvulsants. The conformational preferences of the C^α,α-diphenylglycine residue were assessed in these synthetic derivatives and dipeptides by X-ray diffraction, FTIR absorption and ¹H NMR techniques, and by conformational energy computations. Five (out of six) derivatives adopt the fully extended C₅ conformation in the crystal state. This intramolecularly H-bonded form is largely populated in chloroform solution in all the derivatives investigated. Conformational energy computations in vacuo support the view that the intramolecularly H-bonded C₇-ring form is the most stable structure for these compounds. Only one linear derivative exhibits a (modest) anticonvulsant activity.