Synthesis and analgesic properties of new 5-thioaryl pyrazole derivatives

A new series 5-thio aryl pyrazole derivatives were proposed aiming analgesic activity. In this work, 8 new compounds of this class were synthesized using usual synthetic methodology, having as key intermediate the 3-methyl-4-nitro-5-chloropyrazole-1-phenyl derivative and subsequent reaction with several nucleophiles sulfides. Pharmacological evaluation of this series showed analgesic activity in the some extent in especially for 5-(4-bromophenyl)-thio-3-methyl-4-nitro-1-phenylpyrazole which was the most potent in this series, presenting an analgesic action comparable to that show by dipyrone.     

Histomorphometric, physical, and mechanical effects of spaceflight and insulin-like growth factor-I on rat long bones

Pituitary adenylate cyclase activating peptide and vasoactive intestinal peptide belong to the same neuropeptide family. Both peptides are present in nerve fibers in the gastric wall and are thought to be involved in the regulation of inflammatory processes. Experimental ulcers were induced in the rat gastric mucosa by local application of acetic acid. During the healing process we examined the PACAP and VIP innervation by means of immunohistochemistry and in situ hybridization. The ulcer area was examined from day 1 to day 15 after ulcer induction. There was a marked depletion of PACAP in nerve fibers at the ulcer margin from day 1 and onwards. On day 10 and day 15, PACAP-immunoreactive nerve fibers could again be visualized at the ulcer margin. In contrast, VIP immunoreactive nerve fibers were present at the ulcer margin at all time points studied. From day 10 following ulcer induction PACAP- and VIP- immunoreactive nerve fibers were increased in frequency in the smooth muscle beneath the ulcer. An upregulation of VIP and PACAP mRNA was also demonstrated in the myenteric ganglia adjacent to ulcer. The present results indicate that neuronal PACAP and VIP react differently to the inflammation at the ulcer margin but similarly in the smooth muscle during the ulcer healing.     

Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer

PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine. PATIENTS AND METHODS: Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). RESULTS: At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi. CONCLUSION: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.     

Patient education for discharge after coronary bypass surgery in the 1990s: are patients adequately prepared?

Short hospitalizations for patients undergoing coronary artery bypass grafting (CABG) require continuous nursing evaluation of patients' discharge education. Six institutions collaborated in surveying 300 postoperative patients with CABG to identify learning priorities and patients' perceptions of the effectiveness of discharge education. Data analysis from the self-administered questionnaire demonstrated consistent patient priorities across institutions. Differences in teaching methods and content did not affect perceived preparedness or importance scores. Regional experience demonstrates that variable teaching efforts meet patients' priorities and provide high overall patient preparedness for discharge. Patients with the shortest hospitalizations had higher preparedness scores.     

Misleading symptoms after a minor blunt chest trauma. Thoracoscopic treatment of diaphragmatic rupture

We present a case of missed diaphragmatic rupture which was treated thoracoscopically. Rupture of the diaphragm is a serious complication of blunt trauma. The diaphragmatic injury can easily be overlooked. This report illustrates the diagnostic dilemma in a patient where the injury was missed at the time of initial presentation. The role of thoracoscopy both for diagnosis and therapy is discussed.     

Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.     

Current options in prosthetic vascular graft infection

Debate continues over which procedure is the best treatment for prosthetic graft infections. We retrospectively reviewed the medical records at our institution for all vascular graft infections that occurred from 1985 to 1995 to evaluate their occurrence, treatment, and outcome. Twenty-four patients had prosthetic graft infections. The average patient age was 62 years, and 67 per cent of the patients studied were men. The initial operation was for treatment of occlusive disease in 92 per cent of the patients, and aortofemoral bypasses were the most common procedures performed (15 of 24 patients, 63%). The average interval from graft implantation to presentation of infection was 29 months. In lower-extremity bypasses, the site of infection was most commonly in the groin (87%). Gram-positive organisms, including coagulase-negative Staphylococcus (32%) and Staphylococcus aureus (28%), were the most frequently isolated bacteria. Thirty procedures were performed for management of the graft infections. Extra-anatomic bypass was associated with no recurrent graft infections. Graft preservation was successful in two cases of early S. aureus infection (less than 1 year after original procedure), and in situ graft replacement was successful in all four cases of late-appearing coagulase-negative Staphylococcus infection (more than 1 year after original procedure). Both treatments failed in all five cases of Gram-negative infection (P = 0.008 by Fisher's exact test). The overall mortality and amputation rates were 17 per cent and 21 per cent, respectively, without significant differences between the treatment modalities. Extra-anatomic bypass remains the best treatment for prosthetic graft infection. In situ replacement and graft preservation treatments should be selective and based on presentation of the infection and the type of pathogenic organism.     

Kinetic analysis of the activation of transducin by photoexcited rhodopsin. Influence of the lateral diffusion of transducin and competition of guanosine diphosphate and guanosine triphosphate for the nucleotide site

The activation of transducin (T) by photoexcited rhodopsin (R*) is kinetically dissected within the framework of Michaelis-Menten enzymology, taking transducin as substrate of the enzyme R*. The light scattering "release" signal (Vuong, T.M., M. Chabre, and L. Stryer, 1984, Nature (Lond.). 311:659-661) was used to monitor the kinetics of transducin activation at 20 degrees C. In addition, the influence of nonuniform distributions of R* on these activation kinetics is also explored. Sinusoidal patterns of R* were created with interference fringes from two crossed laser beams. Two characteristic times were extracted from the Michaelis-Menten analysis: t(form), the diffusion-related time needed to form the enzyme-substrate R*-transducin is 0.25 +/- 0.1 ms, and T(cat), the time taken by R* to perform the chemistry of catalysis on transducin is 1.2 +/- 0.2 ms, in the absence of added guanosine diphosphate (GDP) and at saturating levels of guanosine triphosphate (GTP). With t(form) being but 20% of the total activation time t(form) + t(cat), transducin activation by R* is not limited by lateral diffusion. This is further borne out by the observation that uniform and sinusoidal patterns of R* elicited release signals of indistinguishable kinetics. When (GDP) = (GTP) = 500 microM, t(cat) is lengthened twofold. As the in vivo GDP and GTP levels are comparable, the exchange of nucleotides may well be the rate-limiting process.     

Thermal alteration of a cyclic fatty acid produced by a flaxseed extract

Methyl 8-[2-(cis-pent-2′-enyl)-3-oxo-cis-cyclopent-4-enyl] octanoate (I) is the methyl ester of a cyclic fatty acid synthesized enzymically from an incubation of linolenic acid with an extract of flaxseed (Linum usitatissimum L.). A proposed trivial name for I is methyl 12-oxo-cis-10, 15-phytodienoate (12-oxo-PDA). The evidence presented indicated that compound I has thecis configuration of the carbon chains with respect to the cyclopentenone ring. Treatment with acid, base, or heat isomerized I to a second product (II) that has thetrans configuration of the carbon chains. Prolonged heat treatment of II yielded a third cyclic product, methyl 12-oxo-9(13),cis-15-phytodienoate (III).     

Complex refractive index,single scattering albedo,and mass absorption coefficient of secondary organic aerosols generated from oxidation of biogenic and anthropogenic precursors

Refractive index and optical properties of biogenic and anthropogenic secondary organic aerosol (SOA) particles were investigated. Aerosol precursors, namely longifolene, α-pinene, 1-methylnaphthalene, phenol, and toluene were oxidized in a Teflon chamber to produce SOA particles under different initial hydrocarbon concentrations and hydroxyl radical sources, reflecting exposures to different levels of nitrogen oxides (NO_x). The real and imaginary components (n and k, respectively) of the refractive index at 375?nm and 632?nm were determined by Mie theory calculations through an iterative process, using the χ² function to evaluate the fitness of the predicted optical parameters with the measured scattering, absorption, and extinction coefficients from a Photoacoustic Extinctiometer and Cavity Attenuated Phase Shift Spectrometer. Single scattering albedo (SSA) and bulk mass absorption coefficient (MAC) at 375?nm were calculated. SSA values of SOA particles from biogenic precursors (longifolene and α-pinene) were ～0.98–0.99 (～6.3% uncertainty), reflecting purely scattering aerosols regardless of the NO_x regime. However, SOA particles from aromatic precursors were more absorbing and displayed NO_x-dependent SSA values. For 1-methylnaphthalene SOA particles, SSA values of 0.92–0.95 and ～0.75–0.90 (～6.1% uncertainty) were observed under intermediate- and high-NO_x conditions, respectively, reflecting the absorbing effects of SOA particles and NO_x chemistry for this aromatic system. In mixtures of longifolene and phenol or longifolene and toluene SOA under intermediate- and high-NO_x conditions, k values of the aromatic-related component of the SOA mixture were higher than that of 1-methylnaphthalene SOA particles. With the increase in OH exposure, k_phenol decreased from 0.10 to 0.02 and 0.22 to 0.05 for intermediate- and high-NO_x conditions, respectively. A simple relative radiative forcing calculation for urban environments at λ?=?375?nm suggests the influence of absorbing SOA particles on relative radiative forcing at this wavelength is most significant for aerosol sizes greater than 0.4?µm.

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