The role of external defects in chemical sensing of graphene field-effect transistors.

A fundamental understanding of chemical sensing mechanisms in graphene-based chemical field-effect transistors (chemFETs) is essential for the development of next generation chemical sensors. Here we explore the hidden sensing modalities responsible for tailoring the gas detection ability of pristine graphene sensors by exposing graphene chemFETs to electron donor and acceptor trace gas vapors. We uncover that the sensitivity (in terms of modulation in electrical conductivity) of pristine graphene chemFETs is not necessarily intrinsic to graphene, but rather it is facilitated by external defects in the insulating substrate, which can modulate the electronic properties of graphene. We disclose a mixing effect caused by partial overlap of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of adsorbed gas molecules to explain graphene's ability to detect adsorbed molecules. Our results open a new design space, suggesting that control of external defects in supporting substrates can lead to tunable graphene chemical sensors, which could be developed without compromising the intrinsic electrical and structural properties of graphene.

Long hydrocarbon chain diols and diacids with central ether or ketone moieties that favorably alter lipid disorders.

Long hydrocarbon chain derivatives with bis-terminal hydroxyl or carboxyl groups and various central moieties (ketone, ether, ester, amide, carbamate, etc.) have been synthesized and evaluated for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid, glycemic and body weight variables in female obese Zucker fatty rats following one and two weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the ether or ketone central functionality from the gem dimethyl, cycloalkyl or methyl/aryl substituents. Cycloalkyl substitution alpha to the carboxyl group in keto-acids lowered the in vitro activity to micromolar values. Furthermore, in vivo biological activity was found to be greatest for cyclopropyl-substituted ketone derivatives, particularly the ketodiacid with five methylene groups on each side of the central ketone functionality, which was identified as an HDL elevator and was also found to reduce insulin and glucose.

Attempts of ranking in a series of synthetic nonpsychotropic cannabinoids.

Dexanabinol and other synthetic 6aS-trans cannabinoids are devoid of cannabimimetic activity, as they do not have affinity toward cannabinoid receptors. On the other hand, these compound bind to the NMDA receptor and possess neuroprotective properties. A ranking of 6aS-trans cannabinoids based on their NMDA receptor binding affinity and by using a variety of calculated properties included in a fully computerized expert system has been attempted. The results of the study indicate that either the present isosteric-isoelectronic-based ranking criteria is not adequate to reproduce NMDA receptor binding or that some other members of the series rather than dexanabinol are the true lead compounds of 6aS-trans cannabinoids.

Nonpsychotropic synthetic cannabinoids.

Unlike natural cannabinoids which belong to the 6aR - trans series, the synthetic dexanabinol (HU-211), a 6aS-trans enantiomer, does not have affinity toward cannabinoid receptors and is devoid of cannabimimetic activity. On the other hand, dexanabinol demonstrated significant neuroprotective properties which prompted its development as a therapeutic agent. We now present the extension of a series of 6aS-trans cannabinoids with novel derivatives, including water soluble derivatives and congeners of dexanabinol.

Water-soluble combinations of dexanabinol: prodrugs and analogs.

Design, synthesis and study of water-soluble esters of dexanabinol are described. The solubility, stability and in vitro activity of various polar or permanently charged derivatives resulting by acylation of the allylic hydroxyl or phenol functionalities was investigated. Several combination can be used as water-soluble prodrugs, and others as active congeners of dexanabinol.

Dexanabinol Pharmos.

Dexanabinol is a non-psychotropic cannabinoid NMDA receptor antagonist under development by Pharmos Corp for the potential treatment of cerebral ischemia, glaucoma, Alzheimer's disease, cardiac failure, head injury and multiple sclerosis (MS) [311522]; it is in phase III trials for traumatic brain injury (TBI) [388709]. Dexanabinol was licensed to Pharmos for development from its originator, the Hebrew University of Jerusalem [180441]. Pharmos is seeking to enter into a strategic agreement with another company to develop and commercialize dexanabinol [317369]. Unlike its enantiomer, HU-210 (Yissum Research Development Co), dexanabinol does not interact with cannabinoid receptors [223330]. It has also exhibited more effective antioxidant and anti-inflammatory properties than MK-801 (dizocilpine; Merck & Co Inc) [167980], [168212]. In addition, dexanabinol is generally well tolerated and appears toxicologically safe [170116]. Pharmos has been awarded a Small Business Innovation Research grant from the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke, Division of Stroke and Trauma. The grant covers the development of new prodrugs and novel formulations of dexanabinol and will support additional study of dexanabinol compounds for various indications. The prodrugs being studied are part of the group of compounds that include dexanabinol [247958]. A Notice of Allowance was received in March 1999 on a patent covering the use of the drug in the treatment of MS [324163]. The use of dexanabinol and its derivatives to treat MS is described in US-05932610 [358503]. An oral formulation of dexanabinol is claimed in US-05891468. Dexanabinol analogs with special utility in acute and chronic pain are claimed in US-04876276, while dexanabinol analogs for neuroprotection are claimed in US-06096740. Pharmos estimates that the worldwide market for dexanabinol in the treatment of severe head trauma may reach $1 billion per year [319244].

Predicting vegetative bud break in two arctic deciduous shrub species, Salix pulchra and Betula nana.

The factors controlling bud break in two arctic deciduous shrub species, Salix pulchra and Betula nana, were investigated using field observations and growth-chamber studies. A bud-break model was calibrated using a subset of the experimental observations and was used to predict bud break under current and potential future climate regimes. The two species responded similarly in terms of bud break timing and response to air temperature in both field and controlled environments. In the field, the timing of bud break was strongly influenced by air temperatures once snowmelt had occurred. Growth chamber studies showed that a period of chilling is required before buds break in response to warming. Model simulations indicate that under current conditions, the chilling requirement is easily met during winter and that even with substantial winter warming, chilling will be sufficient. In contrast, warm spring temperatures determine the timing of bud break. This limitation by spring temperatures means that in a warmer climate bud break will occur earlier than under current temperature regimes. Such changes in bud break timing of the deciduous shrubs will likely have important consequences for the relative abundance of shrubs in future communities and consequently ecosystem processes.

In vitro and in vivo study of water-soluble prodrugs of dexanabinol.

Trialkylammonium acetoxymethyl esters of dexanabinol were synthesized and evaluated as water-soluble prodrugs. Syntheses were performed by conventional methods; solubility in water and stability in buffers and human plasma were determined by HPLC, and in vivo tissue distribution studies were performed in a rat model. Most of the new derivatives were soluble in water (approximately 50 mg/mL). They were relatively stable in water, while rapidly hydrolyzed in human plasma. Distribution studies indicated that peak concentrations of drug both in blood (30 microg/mL) and brain (2 microg/mL) were rapidly (5 min) achieved after iv administration of a selected prodrug to rats. The blood concentration decreased faster than brain levels which were detectable even after 24 h. Some of the examined esters could be further developed as water soluble prodrugs of dexanabinol.

Cannabinoids, endogenous ligands and synthetic analogs.

The investigation of natural and synthetic cannabinoid ligands, including (-)-Delta(9)-tetrahydrocannabinol, cannabinol, cannabidiol, HU-210, HU-211, CT3, CP 55, 940, WIN 55, 212-2, SR 14, 1716A, anandamide, 2-arachidonoylglycerol, and numerous novel analogs, has led to important findings that have contributed to a better understanding of the role of these compounds in physiological processes. Their potential use for medicinal purposes is also better understood as a result.

Chemistry of loteprednol etabonate and related steroids. II. Reactions at ring C and NMR structural studies of the resulting compounds.

Several derivatives of lotoprednol etabonate (1), a soft corticosteroid antiinflammatory drug, are formed during the synthesis and sterilization process. Some of these contaminants of 1 result from side reactions taking place on the steroid ring C including oxidation, dehydration, chlorination and chlorohydroxylation. The products have been identified, synthesized, and fully characterized by 1H and 13C NMR spectroscopy.

Clinical pharmacokinetics of escalating i.v. doses of dexanabinol (HU-211), a neuroprotectant agent, in normal volunteers.

The pharmacokinetics of dexanabinol (HU-211), a synthetic, nonpsychotropic cannabinoid with neuroprotectant action, was evaluated in a phase I clinical trial. The compound was administered at doses of 48 mg, 100 mg, and 200 mg as short i.v. infusions in a Cremophor-ethanol vehicle diluted with saline. All administrations were well-tolerated and no compound-related side-effects were observed. Plasma concentrations of dexanabinol were quantitated using a GC/MS/MS technique which provided a limit of quantitation of 100 pg/ml. The elimination of dexanabinol was best fitted to a 3-compartment model with a rapid distribution half-life (< 5 min), an intermediate phase half-life of approximately 90 min, and a slow terminal elimination half-life (approximately 9 h). The pharmacokinetics were linear over the evaluated dose range. The plasma clearance of the drug was high (1,700 ml/min) and the volume of distribution approximately 15 l/kg. These data are similar to those reported for naturally occurring cannabinoids such as delta 9-tetrahydrocannabinol and cannabidiol.

Intravenous and oral pharmacokinetic evaluation of a 2-hydroxypropyl-beta-cyclodextrin-based formulation of carbamazepine in the dog: comparison with commercially available tablets and suspensions.

Complexation of carbamazepine with 2-hydroxypropyl-beta-cyclodextrin was performed to provide improved formulations of this widely used antiepileptic drug. Based on this approach, liquid dosage forms were configured for both parenteral and oral use. Intravenous administration of an aqueous carbamazepine x 2-hydroxypropyl-beta-cyclodextrin (CBZ x HPbetaCD) complex at a CBZ dose of 20 mg/kg was well tolerated and generated high initial drug levels that fell monoexponentially as a function of time, yielding a plasma elimination half-life of 38 min. Oral studies were completed with three preparations: a commercially available tablet and suspension, as well as a CBZ x HPbetaCD oral solution. Oral administration of tablets gave erratic and slow absorption, leading to maximum CBZ concentrations (C(max)) of <2 microg/mL, which were manifested only at 2.5 h after drug dosing. The absolute bioavailability of CBZ from the tablets was approximately 25%. Both the suspension and CBZ x HPbetaCD solution gave a significantly improved profile. Thus, the liquid oral dosage forms approximately doubled the oral bioavailability of CBZ compared with the tablets.

Effect of sustained estradiol release in the intact male rat: correlation of estradiol serum levels with actions on body weight, serum testosterone, and peripheral androgen-dependent tissues.

The differential effect of increasing serum estradiol on various parameters in the intact male rat was assessed through the use of subcutaneously implanted, hormone-laden pellets. The delivery systems were designed to release drug through bioerosion at a zero-order rate over a 12-day time-course. Male Sprague-Dawley rats (190 to 220 g) were given estrogen pellets at increasing labeled strenghts (0, 0.001, 0.01, 0.1, 1.0, 10, 50, and 100 mg). Animals were weighed at various intervals before and after implantation. At Day 6, 12, and 26 after drug administration, rats were examined for 4 additional parameters, including serum estradiol and testoterone concentrations and accessory organ weights (i.e., ventral prostate and seminal vesicles). Serum estradiol levels were consistent with pellet potency and lifetime. Increases in body weight were suppressed 50% by circulating estradiol levels of approximately 200 pg/mL at Day 6,250 pg/mL at Day 12, and 285 pg/mL at Day 26. On the other hand, suppression of serum testosterone was more sensitive and was decreased 50% by peripheral estrogen levels of 36, 43, and 51 pg/mL at Days 6, 12, and 26, respectively. Accessory organ weights essentially reflected serum testosterone levels as indicated by their similar ED50 values: 50.5, 50.5, and 44.3 pg/mL for the ventral prostate at Day 6, 12, and 26, respectively, and 48, 56, and 51.5 pg/mL for the seminal vesicle regression at Day 6, 12, and 26, respectively. The data indicate the pellet used provided sustained plasma levels of hormone and these constant peripheral levels exerted potent pharmacological action. Initial body weight changes seemed to be less sensitive to the action of estradiol than serum testosterone or derivative properties, such as accessory organ weight.

Evaluation of a brain-targeting zidovudine chemical delivery system in dogs.

AIDS encephalopathy is an insidious complication of human immunodeficiency virus infection which is difficult to treat because of the poor uptake of many potentially useful antiretroviral drugs through the blood-brain barrier. A chemical delivery system (CDS) for zidovudine (AZT) based on redox trapping within the brain has been prepared and tested in several animal models to circumvent this limitation. The behavior of the AZT-CDS in the dog was considered. Parenteral administration of AZT resulted in rapid systemic elimination and poor uptake by the central nervous system. Ratios of the area under the concentration-time curve of AZT for cerebrospinal fluid to that for blood were 0.32, and ratios of the area under the concentration-time curve of AZT for brain to that for blood were approximately 0.25. Administration of an aqueous formulation of the AZT-CDS resulted in rapid tissue uptake and conversion of the CDS to the corresponding quaternary salt with the subsequent production of AZT. Delivered in this way, the levels of AZT in brain were 1.75- to 3.3-fold higher than those associated with conventional AZT administration. In addition, the levels of AZT in blood were 46% lower than those associated with AZT administration. The higher concentrations in brain and lower concentration in blood combined to significantly increase the ratio of the concentration of AZT in the brain to that in blood after AZT-CDS administration compared to that after AZT dosing.

A permanently charged tamoxifen derivative displays anticancer activity and improved tissue selectivity in rodents.

A quaternized form of tamoxifen (TAM), tamoxifen methiodide (TMI), was shown to demonstrate very low brain uptake compared to TAM and, unexpectedly, was considerably less estrogenic than TAM in the uterus. The agonist activity of TMI in the bone was similar to that of TAM. TMI manifested significant dose-dependent tumoricidal activity with a rapid onset of action against MCF-7 human breast cancer implants in nude mice and a mean reduction in tumor size of 60% over six weeks.

Structural studies of loteprednol etabonate and other analogs of prednisolone using NMR techniques.

Several structural analogs of prednisolone, prepared by esterification of the carboxylic and/or the C(17)-hydroxy group of 11 beta, 17 alpha-dihydroxy-3-oxo-androsta-1,4-diene-17 beta-carboxylic acid, were investigated by NMR. Step-by-step analysis of the 1H and 13C NMR spectra of these steroids, including proton-proton selective decoupling, nuclear Overhauser effect difference spectra, attached proton test, proton-carbon correlation (HETCOR), proton-proton correlation (COSY), and long-range proton-carbon decoupling (INAPT) techniques, led to unequivocal assignments of all their proton and carbon resonances. The stereochemical structure of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene-17 beta-carboxylate, 1), a soft corticosteroid antiinflammatory drug, was proved to be analogous to prednisolone.

Derivatives of dexanabinol. II. Salts of amino acid esters containing tertiary and quaternary heterocyclic nitrogen with increased water-solubility.

PURPOSE: Amino acid esters containing tertiary or quaternary nitrogen heterocycles were synthesized for dexanabinol (1) and evaluated as water-soluble prodrugs or congeners. METHODS: Syntheses were performed by conventional methods; stability studies in water, blood (rat, dog, human) and assay-media were performed by HPLC; NMDA receptor binding was determined by [3H] MK-801 displacement; neuroprotection and neurotoxicity studies were performed in cortical cell cultures. RESULTS: 7-morpholino and N-methylpiperazino acetates and butyrates and the respective N-methylmorpholinium and piperazinium iodides as well as a 3'-N-methyl morpholino butyrate and the corresponding N-methyl quaternary type derivative were synthesized. All compounds were relatively soluble in water or 10% aqueous ethanol. The examined derivatives were stable in water and generally less stable in blood and assay media. Quaternary derivatives of dexanabinol were found to hydrolyze faster. All examined compounds inhibited NMDA receptor and protected neurons against NMDA induced toxicity. Neuroprotection (with one exception) is however attributed to the parent 1 released by hydrolysis during the assay. CONCLUSIONS: Some of the examined derivatives could be further evaluated as prodrugs on congeners of 1.

Derivatives of Dexanabinol. I. Water-soluble salts of glycinate esters.

PURPOSE: Glycinate ester-type water soluble derivatives of dexanabinol (HU-211) (1) a non-psychotropic cannabinoid with potential use in the treatment of brain damage were synthesized and evaluated as prodrugs or congeners. METHODS: Conventional procedures were used for the synthesis of the novel derivatives. Stability studies in water and blood (rat, dog, human) were performed by HPLC; NMDA receptor binding was determined by radio ligand [3H] MK-801-displacement; the neuroprotection and neurotoxicity studies were performed in cortical cell cultures. RESULTS: Glycinate (3), dimethyl- and diethylamine (5, 6), trimethyl- and triethyl- ammonium (7, 8) acetates of 1 were synthesized. All compounds were relatively soluble and stable in water. The quaternary ammonium salt-type derivatives rapidly hydrolyzed to the parent drug in various types of blood including human. In vitro activity studies indicated that the novel derivatives possess NMDA receptor binding properties. The neuroprotecting properties manifested by some of the new derivatives were associated with very low neuronal cell toxicity and are credited to parent compound released by hydrolysis during the experiments rather than to intrinsic activity. CONCLUSIONS: Compounds 7 and 8 are promising water-soluble pro-drug candidates for 1; the glycinate ester 3 might be used as an active analog.