Search

In an attempt to gain insight in the mode of inclusion of sulfonylurea hypoglycemic drugs into β-cyclodextrin (βCD), the molecular structures of the inclusion complexes of three such drugs, tolbutamide (TBM), tolazamide (TLZ) and glimepiride (GLP), have been determined for the first time by X-ray crystallography. The drugs share a common moiety, a H-bond forming sulfonylurea group in the middle, flanked by a tolyl-group at one end and an additional hydrophobic group (different in the three drugs) at the other end, GLP being further elongated by a 2-pyrrolidinone moiety at the tolyl end. The structures of the inclusion complexes comprise βCD dimers aligned in channels. The hydrophobic groups enter the cavities of two adjacent βCD dimers from the primary sides, whereas the hydrophilic sulfonylurea moiety is located in-between, forming H-bonds with the hosts without disturbing the dimers. In the GLP/βCD complex, the pyrrolidinone extension threads the βCD cavity and emerges from the secondary side. These results are supported by NMR 2D ROESY spectra in aqueous solutions. The extended length of GLP imposes a change in the crystal packing placing the βCD dimers further apart. However, the overall inclusion mode of the three drugs is the same, thus a common inclusion and crystallization process is proposed for sulfonylurea drugs. The structures of the complexes explain the effects of complexation on dissolution, bioavailability and hypoglycemic activity. [ABSTRACT FROM AUTHOR]

The inclusion of the long conjugated 4-pyridinealdazine molecule in β-cyclodextrin results in a novel trimer association of β-cyclodextrin macrocycles observed for the first time and an unusual face-to-face assembly of hydrated guest dimers inside the cavity. [ABSTRACT FROM AUTHOR]

β-Cyclodextrin forms a 1:1 host:guest inclusion complex ([2]pseudorotaxane) with 4-[2-(4-aminophenyl)ethyl]-benzenamine ( 1) in water as determined by 1D and 2D NMR experiments. In the crystalline state, the structure of the complex has revealed a 2:2 stoichiometry, with two βCD molecules forming head-to-head dimers by H-bonds between the secondary O3 hydroxyl groups and enclosing two molecules of the guest. The packing mode of the present complex is encountered for the first time, since it does not belong to any of the four known packing types of the dimeric βCD inclusion complexes. On the other hand, N1, N4-bis(4-aminophenyl)-1,4-benzenedimethanamine 2), which is longer than 1 by a phenylene diamine unit, has not afforded any crystals, at present, however it threads into βCD in aqueous solution forming most probably [2]- and [3]pseudorotaxanes. The solution structures and the equilibria in this system are investigated. [ABSTRACT FROM AUTHOR]

A geometrical method for assessing stochastic processes in plasma turbulence is investigated in this study. The thermodynamic length methodology allows using a Riemannian metric on the phase space; thus, distances between thermodynamic states can be computed. It constitutes a geometric methodology to understand stochastic processes involved in, e.g., order-disorder transitions, where a sudden increase in distance is expected. We consider gyrokinetic simulations of ion-temperature-gradient (ITG)-mode-driven turbulence in the core region of the stellarator W7-X with realistic quasi-isodynamic topologies. In gyrokinetic plasma turbulence simulations, avalanches, e.g., of heat and particles, are often found, and in this work, a novel method for detection is investigated. This new method combines the singular spectrum analysis algorithm with a hierarchical clustering method such that the time series is decomposed into two parts: useful physical information and noise. The informative component of the time series is used for the calculation of the Hurst exponent, the information length, and the dynamic time. Based on these measures, the physical properties of the time series are revealed.

Stroke is a frequent occurrence among patients suffering from systemic lupus erythematosus (SLE), but it rarely occurs as the initial manifestation of the disease. We here present the case of a 37 year-old patient who developed an acute cerebellar ischemic stroke as initial event of SLE: elevated partial thromboplastin time and ESR, thrombocytopenia, anti-ds-DNA, anti-SSA, anti-JO-1, and the lupus anticoagulant were detected, and the diagnosis of SLE was established. In addition, we reviewed the literature in order to clarify the demographic, clinical, imaging and outcome characteristics of such a presentation, and found 10 similar cases. Most patients were young (age 31.7 ± 8.5 years) and women (8/11, 72.7%). Stroke most often affected the vertebrobasilar territory (7/11, 63.6%). The stroke mechanism was not clearly defined in these cases. Treatment with immunosuppression and anticoagulation was considered to be a reasonable choice for early secondary stroke prevention. The occurrence of ischemic stroke, primarily in the vertebrobasilar system among young patients, especially women, should always raise suspicion for underlying SLE, and prompt diagnostic investigations to confirm or exclude its presence.

Paraneoplastic cerebellar degeneration is a rare neurological disorder that frequently precedes the detection of malignancy. Here, we report the case of a 60 year-old woman with locally advanced squamous cell carcinoma of the tongue who developed a subacute cerebellar syndrome associated with the presence of anti-CV2/CRMP5 antibodies in the cerebrospinal fluid, after achieving complete remission of the primary tumor and the involved cervical lymph nodes by chemoradiation. The patient's symptoms on presentation were dizziness and gait unsteadiness. On examination she showed dysarthria, nystagmus and limb and gait ataxia. The diagnosis of paraneoplastic cerebellar syndrome was made on the basis of the clinical findings and immunological testing that revealed the presence of anti-CV2/CRMP5 antibodies in the patient's cerebrospinal fluid. This syndrome, which is very rare in association with head and neck cancer, commonly precedes the detection of malignancy by a year or more and has been documented in only a few cases after completion of anticancer treatment.

Neostriatal GABAergic neurons projecting to the globus pallidus synthesize the opioid peptide enkephalin, while those innervating the substantia nigra pars reticulata and the entopeduncular nucleus synthesize dynorphin. The differential control exerted by dopamine on the activity of these two efferent projections concerns also the biosynthesis of these opioid peptides. Using in situ hybridization histochemistry, we investigated the role of opioid co-transmission in the regulation of neostriatal and pallidal activity. The expression of the messenger RNAs encoding glutamate decarboxylase-the biosynthetic enzyme of GABA-and the precursor peptides of enkephalin (preproenkephalin) and dynorphin (preprodynorphin) were measured in rats after a sustained blockade of opioid receptors by naloxone (s.c. implanted osmotic minipump, eight days, 3 mg/kg per h), and/or a subchronic blockade of D2 dopamine receptors by haloperidol (one week, 1.25 mg/kg s.c. twice a day). The density of mu opioid receptors in the neostriatum and globus pallidus was determined by autoradiography. Naloxone treatment resulted in a strong up-regulation of neostriatal and pallidal mu opioid receptors that was not affected by the concurrent administration of haloperidol. Haloperidol alone produced a moderate down-regulation of neostriatal and pallidal micro opioid receptors. Haloperidol strongly stimulated the expression of neostriatal preproenkephalin and preprodynorphin messenger RNAs. This effect was partially attenuated by naloxone, which alone produced moderate increases in preproenkephalin and preprodynorphin messenger RNA levels. In the neostriatum, naloxone did not affect either basal or haloperidol-stimulated glutamate decarboxylase messenger RNA expression. A strong reduction of glutamate decarboxylase messenger RNA expression was detected over pallidal neurons following either naloxone or haloperidol treatment, but concurrent administration of the two antagonists did not result in a further decrease. The amplitude of the variations of mu opioid receptor density and of preproenkephalin and preprodynorphin messenger RNA levels suggests that the regulation of neostriatal and pallidal micro opioid receptors is more susceptible to a direct opioid antagonism, while the biosynthesis of opioid peptides in the neostriatum is more dependent on the dopaminergic transmission. The down-regulation of mu opioid receptors following haloperidol represents probably an adaptive change to increased enkephalin biosynthesis and release. The haloperidol-induced increase in neostriatal preprodynorphin messenger RNA expression might result from an indirect, intermittent stimulation of neostriatal D1 receptors. The haloperidol-induced decrease of pallidal glutamate decarboxylase messenger RNA expression suggests, in keeping with the current functional model of the basal ganglia, that the activation of the striatopallidal projection produced by the interruption of neostriatal dopaminergic transmission reduces the GABAergic output of the globus pallidus. The reduction of pallidal glutamate decarboxylase messenger RNA expression following opioid receptor blockade indicates an indirect, excitatory influence of enkephalin upon globus pallidus neurons and, consequently, a functional antagonism between the two neuroactive substances (GABA and enkephalin) of the striatopallidal projection in the control of globus pallidus output. Through this antagonism enkephalin could partly attenuate the GABA-mediated effects of a dopaminergic denervation on pallidal neuronal activity.

S 16924 antagonized locomotion provoked by dizocilpine and cocaine, reduced conditioned avoidance responses and blocked climbing elicited by apomorphine, models predictive of control of the positive symptoms of schizophrenia: its median inhibitory dose (ID)50 was 0.96 mg/kg, s.c. vs. 1.91 for clozapine and 0.05 for haloperidol. Rotation elicited in unilateral, substantia nigra-lesioned rats by the D1 agonist, SKF 38393, and by the D2 agonist, quinpirole, was blocked equipotently by S 16924 (0.8 and 1. 7) and clozapine (0.6 and 2.0), whereas haloperidol preferentially blocked quinpirole (0.02) vs. SKF 38393 (1.8). S 16924 more potently inhibited the head-twitches elicited by 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the locomotion provoked by phencyclidine than it inhibited the locomotion elicited by amphetamine (ID50s = 0.15 and 0.02 vs. 2.4). Clozapine showed a similar preference (0.04 and 0.07 vs. 8.6), but not haloperidol (0. 07 and 0.08 vs. 0.04). The discriminative stimulus (DS) properties of DOI were also blocked by S 16924 (ID50 = 0.17) and clozapine (0. 05) but not by haloperidol (>0.16). S 16924 fully (100%) generalized [effective dose (ED)50 = 0.7] to a clozapine DS and clozapine (0.23) fully generalized to a S 16924 DS whereas haloperidol (>/=0.08) only partially generalized (/=80.0) or clozapine (>/=80.0). Further, S 16924 (ID50 = 3.2) and clozapine (5.5) inhibited induction of catalepsy by haloperidol. This action of S 16924 was abolished by the 5-HT1A receptor antagonist, WAY 100,635 (0.16), which less markedly attenuated the anticataleptic action of clozapine. Further, although gnawing elicited by methylphenidate was inhibited by S 16924 (ID50 = 8.4), clozapine (19.6) and haloperidol (0.04), only the action of S 16924 was blocked by WAY 100,635 (0.16). Haloperidol potently (0.01-0.16, approximately 24-fold) increased prolactin levels whereas they were less markedly affected by S 16924 (2.5-40.0, 4-fold) and clozapine (10.0-40.0, 3-fold). Clozapine displayed high affinity at cloned, human, muscarinic (M1) and native, histamine (H1) receptors (Kis = 4.6 and 5.4 nM, respectively), whereas S 16924 (>1000 and 158) and haloperidol (>1000 and 453) displayed low affinity. In conclusion, S 16924 displays a profile of activity in diverse models of potential antipsychotic and extrapyramidal properties similar to that of clozapine and different to that of haloperidol. In particular, reflecting its partial agonist actions at 5-HT1A receptors, S 16924 inhibits rather than induces catalepsy in rats. However, in contrast to clozapine, S 16924 displays only low affinity for muscarinic and histaminic receptors.

The normal values of latency, amplitude and conduction velocity of the sensory nerve action potentials of a group of infrequently or even rarely examined nerves, are reported. A number of preliminary testings was made in order to establish the most appropriate and practical stimulation and recording procedures for the study of the axillary, lateral antebrachial cutaneous, medial antebrachial cutaneous, lateral femoral cutaneous, saphenous, superficial peroneal and medial plantar nerves. The examination techniques and the normal data obtained from their application on 30 healthy subjects, 20 to 36 years of age, at constant skin temperature, are discussed and compared to those already existing in the available literature.

In rats sustaining unilateral 6-hydroxy-dopamine lesions of the substantia nigra (SN), the indirect dopaminergic agonist, (+)-amphetamine (AMPH), dose-dependently induced robust, ipsilateral rotation: this could be dose-dependently abolished by the dopamine (D2/D1) antagonist, haloperidol. The selective alpha 1 antagonist, prazosin, dose-dependently attenuated the action of AMPH though rotation was not completely abolished. In the presence of a constant dose of prazosin, the dose-response curve for induction of rotation by AMPH was shifted to the right. The action of prazosin was mimicked by a further alpha 1 antagonist, corynanthine. In contrast, the selective alpha 1 agonist, ST 587, potentiated the rotation evoked by AMPH. The selective alpha 2 antagonist, idazoxan, dose-dependently potentiated the action of AMPH and, in the presence of a constant dose of idazoxan, the dose-response curve for AMPH was shifted to the left. This effect of idazoxan was mimicked by a further alpha 2 antagonist, yohimbine. In distinction, the selective alpha 2 agonist, UK 14,304, dose-dependently attenuated the action of AMPH, an action mimicked by the alpha 2 partial agonist, clonidine. Upon administration alone, the above mentioned drugs did not induce rotation. The data indicate that activation and antagonism of alpha 1 receptors enhance and inhibit rotation, respectively, whereas activation and antagonism of alpha 2 receptors inhibit and enhance rotation, respectively. These findings demonstrate an opposite alpha 1 and alpha 2 receptor-mediated control of rotation in this model. They suggest that an increase and decrease in noradrenergic tone, respectively, facilitate and inhibit locomotor activity controlled via the nigro-striatal dopaminergic pathway. The possible relevance of these findings to Parkinson's disease is discussed.