The ß2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease.

One of the major consequences of the lack of a functional VHL protein in von Hippel-Lindau disease, a rare cancer, is the constitutive activation of the HIF pathway. This activation ends up in the generation of Central Nervous System (CNS) Hemangioblastomas among other tumours along the lifespan of the patient. Nowadays, only surgery has been proven efficient as therapy since the systemic attempts have failed. Propranolol, a non-specific ß1-and ß2-adrenergic receptor antagonist, was recently designated as the first therapeutic (orphan) drug for VHL disease. Nevertheless, its ß1 affinity provokes the decrease in blood pressure, being not recommended for low or regular blood pressure VHL patients. In order to overcome the ß1-drawback, the properties of a high specific ß2-adrenergic receptor blocker named ICI-118,551 have been studied. ICI-118,551 was able to decrease Hemangioblastomas cell viability in a specific manner, by triggering apoptosis. Moreover, ICI-118,551 also impaired the nuclear internalization of HIF-1α in Hemangioblastomas and hypoxic primary endothelial cells, reducing significantly the activation of HIF-target genes and halting the tumour-related angiogenic processes. In this work, we demonstrate the therapeutical properties of ICI-118,551 in VHL-derived CNS-Hemangioblastoma primary cultures, becoming a promising drug for VHL disease and other HIF-related diseases.

The effect of intersystem crossings in N((2)D) + H2 collisions.

The transitions between quartet and doublet states of the NH2 molecule are studied for the first time, allowing the evaluation of the N((4)S) + H2 reactive channel. High level ab initio calculations of the spin-orbit coupling are performed over the whole configurational space of the NH2 molecule and fitted to a proposed analytic form. Quasiclassical trajectories coupled with the surface hopping method are employed to calculate reaction cross section and rate constants. The reaction is largely affected by the initial rovibrational states of H2, while the formation of long-lived complexes enhances the reaction probability.

Análisis de la estabilidad de dos suspensiones orales de carbamazepina / Analysing the stability of two oral carbamazepine suspensions

Objetivo Analizar la estabilidad fisicoquímica y microbiológica de dos suspensiones orales de carbamazepina al 2,5 y al 5%.MétodoLas suspensiones orales se elaboraron a partir de carbamazepina en polvo y los vehículos comerciales Ora-sweet SF® y Ora-plus®. Se realizaron controles de calidad físicos (pH, estado de la suspensión y características organolépticas), químicos (cromatografía líquida de alta resolución [HPLC]) y microbiológicos a los 2, 4 y 6 meses de la preparación. Resultados La concentración a los 6 meses de las suspensiones de carbamazepina al 2,5% y al 5% resultó de 22,9mg/ml y de 45,9mg/ml, respectivamente, con valores de riqueza obtenidos mediante la cromatografía líquida de alta resolución se encontraron entre el 90 y el 110%, tal y como exige la Farmacopea Americana 23 NF18. Durante el período del estudio no se observó modificación de los parámetros físicos ni crecimiento en los cultivos microbiológicos realizados. Conclusiones Ambas suspensiones orales son estables física, química y microbiológicamente durante al menos 6 meses a temperatura ambiente y en frasco de vidrio topacio (AU)

Objective To assess the physical, chemical and microbiological stability of two oral suspensions of carbamazepine at concentrations of 2.5% and 5%.MethodsBoth oral suspensions were compounded from powdered carbamazepine and Ora-Sweet SF® and Ora-Plus® commercial compounding excipients. At the 2, 4 and a 6-month marks, different quality assays were performed, comprising physical (pH, state of the suspension, organoleptic properties), chemical (HPLC) and microbiological assays. Results The final concentration at 6 months for both the 2.5% and 5% carbamazapine suspensions was 22.9 and 45.9mg/ml respectively, with calculated richness values between 90 and 110% fulfilling USP23 NF18 requirements. No changes in physical properties and no culture growth were observed during the study period. Conclusion Both oral suspensions are physically, chemically and microbiologically stable for at least 6 months when preserved at room temperature in amber glass flasks(AU)

Analysing the stability of two oral carbamazepine suspensions.

OBJECTIVE: To assess the physical, chemical and microbiological stability of two oral suspensions of carbamazepine at concentrations of 2.5% and 5%. METHODS: Both oral suspensions were compounded from powdered carbamazepine and Ora-Sweet SF(®) and Ora-Plus(®) commercial compounding excipients. At the 2, 4 and a 6-month marks, different quality assays were performed, comprising physical (pH, state of the suspension, organoleptic properties), chemical (HPLC) and microbiological assays. RESULTS: The final concentration at 6 months for both the 2.5% and 5% carbamazapine suspensions was 22.9 and 45.9 mg/ml respectively, with calculated richness values between 90 and 110% fulfilling USP23 NF18 requirements. No changes in physical properties and no culture growth were observed during the study period. CONCLUSION: Both oral suspensions are physically, chemically and microbiologically stable for at least 6 months when preserved at room temperature in amber glass flasks.

Ab initio study of hydrazinyl radical: toward a DMBE potential energy surface.

A series of stationary structures of the hydrazinyl radical have been characterized by optimization at the CCSD(T)/cc-pVTZ level of theory. CCSD(T)/aug-cc-pVXZ single-point calculations have also been carried out at the optimized geometries with basis sets of different cardinal numbers (X = T, Q), which were used to obtain accurate energies via extrapolation to the complete basis set limit. A discussion on the analytical modeling of the potential energy surface of hydrazinyl is also presented.

Accurate ab initio based DMBE potential energy surface for the ground electronic state of N2H2.

A global single-sheeted double many-body expansion potential energy surface is reported for the ground electronic state of N(2)H(2). Starting from an approximate cluster expansion of the molecular potential that utilizes previously reported functions of the same family for the triatomic fragments, four-body energy terms have been calibrated from extensive accurate ab initio data so as to reproduce the main features of the title system. The switching function formalism previously suggested for three-body systems [A. J. C. Varandas and L. Poveda, Theor. Chem. Acc. 116, 404 (2006)] has been generalized to approximate the true multisheeted nature of N(2)H(2) potential energy surface, thus allowing the correct behavior at the N((2)D) + NH(2)((2)A(")) and N((4)S) + NH(2)((4)A(")) dissociation limits. The resulting fully six-dimensional potential energy function reproduces the correct symmetry under permutation of identical atoms and predicts the main stationary points of the molecule in the valence and long-range regions in good agreement with available experimental and theoretical data on the diazene molecule.

Recalibrated double many-body expansion potential energy surface and dynamics calculations for HN2.

A single-sheeted double many-body expansion potential energy surface is reported for the lowest doublet state of HN2 by fitting additional multireference configuration interaction energies in the N...NH channel. A stratified analysis of the root-mean-squared error indicates an accuracy superior to that achieved for the previously reported form. Detailed dynamical tests are also performed for the N + NH reaction using both the quasi-classical trajectory method and the capture theory, and the results are compared with available empirical data. The vibrational resonances of the HN2 metastable radical are also calculated and compared with previous theoretical predictions.

Unilateral laryngeal and hypoglossal paralysis (Tapia's syndrome) following rhinoplasty in general anaesthesia: case report and review of the literature.

Extracranial involvement of the recurrent laryngeal nerve and the hypoglossal nerve is known as Tapia's syndrome. Ipsilateral paralysis of the vocal cord and tongue is present. Lesion of these nerves may be a rare complication of airway management. Herein, a case of Tapia's Syndrome complicating transoral intubation during general anaesthesia in a rhinoplasty operation, together with a review of pertinent literature to evaluate the incidence and the possible pathogenic mechanism of the lesion. There are recent reports in the literature on mono or bilateral paralysis of the XII or laryngeal recurrent nerve after use of laryngeal mask with a pathogenic mechanism of compression. Furthermore, there are reports, following oro-tracheal intubation, of recurrent laryngeal paralysis, likely legacies to the compression of the anterior branch of inferior laryngeal nerve by the cuff of the oro-tracheal tube against the postero-medial part of the thyroid cartilage. Hypoglossal nerve damage could be caused by a stretching of the nerve against the greater horn of the hyoid bone by a laryngeal mask or oro-tracheal tube or compression of the posterior part of the laryngoscope or oro-tracheal tube. In our case, the lesion probably occurred as the result of a two-fold compressive mechanism: on one hand, compression by the cuff of the endo-tracheal tube due to excessive throat pack in the oro-pharynx; on the other hand a prolonged stretching mechanism of these nerves may have occurred due to excessive anterior and lateral flexion of the head. From the data reported in the literature, as in our case, complete recovery of function is generally achieved within the first six months. This progressive recovery of function suggests nerve damage of a neuro-praxic type, which is typical of compression injury. In conclusion, the response of this rare complication confirms the importance not only of the position of the head and patient on the operating table but also the meticulous and correct performance of the routine manoeuvres of airway management.

Repulsive double many-body expansion potential energy surface for the reactions N(4S)+H2<-->NH(X3Sigma-)+H from accurate ab initio calculations.

A single-sheeted DMBE potential energy surface is reported for the reactions N(4S)+H2<-->NH(X3Sigma-)+H based on a fit to accurate multireference configuration interaction energies. These have been calculated using the aug-cc-pVQZ basis set of Dunning and the full valence complete active space wave function as reference, being semi-empirically corrected by scaling the two-body and three-body dynamical correlation energies. The topographical features of the novel global potential energy surface are examined in detail, including a conical intersection involving the two first 4A'' potential energy surfaces which has been transformed into an avoided crossing in the present single-sheeted representation.

Anti-HIV activity of dibenzylbutyrolactone-type lignans from Phenax species endemic in Costa Rica.

Previously, we isolated two new dibenzylbutyrolactone-type lignans, named phenaxolactones and, from the leaves of Phenax angustifolius Wedd. (Urticaceae). In this investigation three new dibenzylbutyrolactone lignans (phenaxolactones), together with phenaxolactone, and flavones vitexin, isovitexin, were isolated from Phenax rugosus Wedd. leaves collected in Santa Ana, Costa Rica. The structures were elucidated using 1D and 2D NMR spectroscopy as well as mass spectrometry. Phenaxolactones and flavones and were evaluated for their inhibitory activity against HIV-1MN in infected C8166 cells. The most promising compound was phenaxolactone with an EC50 value of 3.0 microM, no cytotoxicity at 112 microM and a therapeutic index value of 37.3.

Efficacy of Piper (Piperaceae) extracts for control of common home and garden insect pests.

Extracts from three species of the plant family Piperaceae, Piper nigrum [L.], Piper guineense [Schum & Thonn, and Piper tuberculatum [Jacq.], were tested for efficacy against insects from five orders. All three species contain isobutyl amides, plant secondary compounds that act as neurotoxins in insects. These materials are considered safe to mammals because Piper spp. were used for centuries for spice and medicinal purposes. When 24-h P. nigrum LC50 values were compared between common insect pests from eastern Canada and the northeastern United States, the most sensitive species in order of increasing lethal concentration were eastern tent caterpillar, Malacosoma americanum (F.) < European pine sawfly larvae, Neodiprion sertifer (Geoffroy) < spindle ermine moth larvae, Yponomeuta cagnagella [Hübner] < viburnum leaf beetle larvae, Pyrrhalta viburni [Paykull] < stripped cucumber beetle adults, Acalymma vittatum (F.) < Colorado potato beetle adults, Leptinotarsa decemlineata (Say) < Japanese beetle adults, Popillia japonica [Newman] < hairy chinch bug, Blissus leucopterus hirtis [Montandon]. The life stage tested was the point at which each species causes the greatest amount of damage to the host plant and the point at which most gardeners would likely choose to treat with a conventional synthetic insecticide. Greenhouse trials revealed that the pepper formulations also had a repellent activity, thus protecting plant leaves from 1) herbivory (lily leaf beetle, Lilioceris lilii [Scopoli], adults and larvae and stripped cucumber beetle adults) and 2) oviposition [European corn borer, Ostrinia nubilalis (Hübner)]. Combinations with other botanical extracts were additive at best in toxicity and repellent trials. Nontarget toxicity to beneficial invertebrates is a possibility because the P. nigrum LC50 for beneficial ladybird beetles was 0.2%. P. nigrum extracts can provide a reasonable level of control against lepidopteran and European pine sawfly larvae and also will work as a short-term repellent and feeding deterrent. It is recommended that the use of Piper extracts be restricted to small-scale spot treatments in residential areas where insect pest outbreaks have occurred.

Anti-inflammatory and antinociceptive activities of Loasa speciosa in rats and mice.

In the range of doses of 250-500 mg/kg (given i.p.) the aqueous extract of Loasa speciosa leaves showed an inhibitory effect on leukocyte migration, and a reduction on the pleural exudate, as well as dose-dependent anti-inflammatory and peripheral antinociceptive activities.

Traditionally-used antimalarials from the Meliaceae.

A quantitative ethnobotanical approach to antimalarial drug discovery led to the identification of Lansium domesticum Corr. Ser. (Meliaceae) as an important antimalarial used by Kenyah Dyak healers in Indonesian Borneo. Triterpenoid lansiolides with antimalarial activity were isolated from the bark and shown to have activity in both in vitro bioassays with Plasmodium falciparum, and in mice infected with P. berghei. A survey of African and tropical American Meliaceae led to further development of the limonoid gedunin from the traditionally used medicinal plants, tropical cedar, Cedrela odorata L., and neem, Azadirachta indica A. Juss. Gedunin has significant in vitro activity but initially showed poor in vivo activity. In vivo activity was improved by (1) incorporation into an easy to absorb suspension, (2) preparation of a more stable compound, 7-methoxygedunin; and (3) synergism with dillapiol, a cytochrome P450 3A4 inhibitor. The results show the potential for both antimalarial drug and phytomedicine development from traditionally used plants.

A theoretical approach to the influence of the macrocycle conformation on the molecular electronic structure in Mg-porphyrins.

Nonplanar saddled (sad) ruffled (ruf) and domed (dom) conformations of the Mg-porphyrin (MgP) macrocycle in several degrees of deformation have been computed. These symmetrical distortion modes were induced in unsubstituted macrocycle using molecular definitions for calculations which permits us to achieve a systematical variation of the nonplanarity varying only a convenient geometrical parameter of the molecule. Series of nonplanar macrocycles like those synthesized in previous works employing peripheral substitutions are obtained. The procedure here used to induce deformations gives the possibility of investigating the modulator role of the out-of-plane distortions on the geometry and electronic properties of the porphyrin avoiding additional influences due to the substituents or the surrounding protein scaffolding.

Mortality supposedly due to intoxication by pyrrolizidine alkaloids from Heliotropium indicum in a horse population in Costa Rica: a case report.

This article describes a case of massive mortality among horses which was probably due to intoxication by pyrrolizidine alkaloids from Heliotropium indicum. Over 4 years more than 75% of a population of about 110 horses on a farm in Costa Rica died after showing nervous neurological symptoms. Two clinical manifestations were encountered, an acute and a chronic one, both with a fatal outcome. Pathological findings in 2 horses coincided with those reported in the literature for intoxication by pyrrolizidine alkaloids and were not specific for VEE. However Venezuelan equine encephalitis (VEE) was the main differential diagnosis and could not completely be excluded because this disease was endemic in the region and VEE titres were found to be high. Taxonomic and toxicological investigations implicated Heliotropium indicum as the most probable principal cause of the intoxication.

Essential oil of Lepechinia schiedeana (Lamiaceae) from Costa Rica.

The composition of the essential oil isolated by steam distillation from aerial parts of the Costa Rican herb Lepechinia schiedeana (Schlecht) Vatke (Lamiaceae) collected in El Empalme, Costa Rica, was determined by capillary gas chromatography (GC) and coupled gas chromatography-mass spectrometry (GC-MS) analyses. Fifty-one components were identified corresponding ca. 93% of the oil. The major components were beta-pinene (26.6%), cis-pinocamphone (25.1%), delta-3-carene (6.1%), trans-pinocamphone (4.0%), camphor (3.8%) and beta-caryophyllene (3.7%).

Anti-inflammatory activity of aqueous extracts of five Costa Rican medicinal plants in Sprague-Dawley rats.

The anti-inflammatory properties of Loasa speciosa and Loasa triphylla (Loasaceae), Urtica leptuphylla and Urera baccifera (Urticaceae), and Chaptalia nutans (Asteracene) were studied using the carregeenan induced rat paw edema model. Aqueous extracts of each plant were made according to the ethnobotanical use. The hippocratic assay was made with female rats; the dose used was 500 mg/kg i.p. and the control group received 0.5 ml of n.s.s.. All the animals treated showed hypothermia, and those treated with the extracts of Chaptalia nutans, Urera baccifera and Urtica leptuphylla showed an increased colinergic activity. Acute toxicities of the aqueous extracts were studied in mice an the mean lethal doses ranged between 1.0226 and 1.2022 g/kg. The extracts of Urera baccifera, Chaptalia nutans, Loasa speciosa and Loasa triphylla (500 mg/kg i.p.) showed an anti-inflammatory activity comparable with that of indomethacin. The extracts of U. baccifera and C. nutans, which showed the greatest anti-inflammatory activity, did not show it when used orally (500 mg/kg p.o.).

Volatile constituents of Cunila polyantha (Lamiaceae) from Costa Rica. A rich source of menthone.

The constituents of the volatile oil of Cunila polyantha from Dota, Costa Rica, were investigated using coupled gas chromatography-mass spectrometry (GC-MS) analyses. Menthone (63%), pulegone (14%), beta-caryophyllene (4.5%) and 3-octanyl acetate (3%) were found to be the major constituents of the volatile oil.

Antimalarial activity of tropical Meliaceae extracts and gedunin derivatives.

Extracts of 22 species of Meliaceae were examined for antimalarial activity using in vitro tests with two clones of Plasmodium falciparum, one sensitive to chloroquine (W2) and one chloroquine-resistant (D6). Twelve extracts were found to have activity, including extracts of Cedrela odorata wood and Azadirachta indica leaves, which contained the limonoid gedunin. These extracts were more effective against the W2 clone than the D6 clone, suggesting there is no cross-resistance to chloroquine. Gedunin was extracted in quantity, and nine derivatives prepared for a structure-activity study, which revealed essential functionalities for activity. The study also included four other limonoids derived from related Meliaceae. Only gedunin had better activity than chloroquine against the W2 clone. This active principle could be used to standardize a popular crude drug based on traditional use of A. indica in West Africa.

Methyl 4-hydroxy-3-(3'-methyl-2'-butenyl)benzoate, major insecticidal principle from Piper guanacastensis.

The CHCl3-soluble extract of Piper guanacastensis (Piperaceae) was found to have noteworthy insecticidal activity to Aedes atropalpus mosquito larvae (LC50 80.5 micrograms/mL). Bioassay-guided fractionation afforded methyl 4-hydroxy-3-(3'-methyl-2'-butenyl)benzoate (1) as the major bioactive constituent (LC50 20.5 micrograms/mL). The separation of compound 1 from its transesterification artifact (2), ethyl 4-hydroxy-3-(3'-methyl-2'-butenyl)benzoate, was achieved by recycling reversed-phase HPLC. The flavonoids acacetin, chrysin, and pinostrobin were also isolated from the active fraction but did not display insecticidal properties.