Compatibility study of paracetamol, chlorpheniramine maleate and phenylephrine hydrochloride in physical mixtures.

Paracetamol (PAR), phenylephrine hydrochloride (PHE) and chlorpheniramine maleate (CPM) are commonly used in clinical practice as antipyretic and analgesic drugs to ameliorate pain and fever in cold and flu conditions. The present work describes the use of thermal analysis for the characterization of the physicochemical compatibility between drugs and excipients during the development of solid dosage forms. Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC) were used to study the thermal stability of the drug and of the physical mixture (drug/excipients) in solid binary mixtures (1:1). DSC thermograms demonstrated reproducible melting event of the prepared physical mixture. Starch, mannitol, lactose and magnesium stearate influence thermal parameters. Information recorded from the derivative thermogravimetric (DTG) and TGA curves demonstrated the decomposition of drugs in well-defined thermal events, translating the suitability of these techniques for the characterization of the drug/excipients interactions.

Anti-inflammatory activity of Vismia guianensis (Aubl.) Pers. extracts and antifungal activity against Sporothrix schenckii.

ETHNOPHARMACOLOGICAL RELEVANCE: Vismia guianensis (Aubl.) Pers. is traditionally used in North and Northeast of Brazil for the treatment of dermatomycoses. Since the strategy associating immunomodulators with antifungal drugs seems to be promissory to improve the treatment efficacy in fungal infections, we aimed to investigate the antifungal activity of V. guianensis ethanolic extract of leaves (VGL) and bark (VGB) against Sporothrix schenckii ATCC 16345 and their antinflammatory activities. MATERIAL AND METHODS: The extracts were analyzed by HPLC-DAD-IT MS/MS for in situ identification of major compounds. Antifungal activity was evaluated in vitro (microdilution test) and in vivo using a murine model of S. schenckii infection. The production of TNF-α, IFN-γ, IL-4, IL-10 and IL-12 by measured by ELISA, as well as measured the production and inhibition of the NO after treatment with the plant extracts or itraconazole (ITR). RESULTS: Two O-glucosyl-flavonoids and 16 prenylated benzophenone derivatives already described for Vismia were detected. Both VGL and VGB showed significant antifungal activity either in in vitro assay of microdilution (MIC=3.9µg/mL) and in vivo model of infection with reduction of S. schenckii load in spleen. It was also observed a predominance of reduction in the production of NO and the proinflammatory cytokines evaluated except TNFα, but with stimulation of IL-10, as evidence of a potential anti-inflammatory effect associated. CONCLUSION: The results showed that both VGL and VGB have a significant antifungal against S. schenckii and an anti-inflammatory activity. These results can support the use of these extracts for alternative treatment of sporotrichosis.

Solid dosage forms for active antiretroviral therapy (HAART): dissolution profile study of nevirapine by experimental factorial design.

Nevirapine is the first antiretroviral member of non-nucleoside reverse transcriptase inhibitor used in active antiretroviral therapy (HAART). The aim of this work was the evaluation of the dissolution profile of nevirapine tablets by means of the Disk Intrinsic Dissolution Rate (DIDR) using a 2(3) factorial design. This study used a triplicate in central point and was based on three independent variables: the rotational speed of the apparatus, the compression force of nevirapine disk, and the distance of the tank dissolution. The dependent variable was set as intrinsic dissolution speed (IDS). IDS was strongly dependent on the rotational speed, compression force, and distance of the apparatus, analyzed by Student's t test with 95% confidence, and confirmed by ANOVA. The rotational speed of nevirapine disks was the main factor contributing to the IDS, whereas the compression force and the distance of disks on the dissolution apparatus revealed no effects.

Compatibility studies of nevirapine in physical mixtures with excipients for oral HAART.

Nevirapine is a hydrophobic non-nucleoside reverse transcriptase inhibitor, used in first line regimens of highly active antiretroviral therapy (HAART). The drug has more than one crystalline form, which may have implications for its behaviour during production and also for its in vivo performance. This study was aimed at exploring the suitability of thermoanalytical methods for the solid-state characterization of commercial crystalline forms of nevirapine. The drug powder was characterized by ultraviolet spectrophotometry, stereoscopy, scanning electron microscopy, wide-angle X-ray diffraction, measurements of density, flowability, solubility and intrinsic dissolution rate (IDR), differential scanning calorimetry, thermogravimetric analysis, and photostability measurements. The results showed that nevirapine has high stability and is not susceptible to degradation under light exposure. The drug showed compatibility with the excipients tested (lactose, microcrystalline cellulose, polyvinylpyrrolidone and polyvinyl acetate copolymer (PVP/PVA), and hydroxypropylmethylcellulose (HPMC)). Nevirapine has low solubility, an acid medium being the most appropriate medium for assessing the release of the drug from dosage forms. However, the data obtained from IDR testing indicate that dissolution is the critical factor for the bioavailability of this drug.

Effects of maximizing oxygen delivery on morbidity and mortality in high-risk surgical patients.

OBJECTIVE: To evaluate the effects of maximizing the oxygen delivery on morbidity and mortality in patients >60 yrs of age and/or with chronic diseases of vital organs who underwent major elective surgery. DESIGN: Prospective, randomized, controlled trial. SETTING: A 24-bed general intensive care unit of a teaching hospital. PATIENTS: Thirty-seven high-risk patients who underwent major surgery. INTERVENTIONS: The hemodynamic and oxygen transport variables and outcomes in 18 patients (control group) treated to maintain normal values of oxygen delivery were compared with 19 patients (protocol group) treated to maintain "supranormal" values. Therapy in both groups consisted of volume expansion and, when necessary, dobutamine to reach target values, during the surgery and 24 hrs postoperatively. MEASUREMENTS AND MAIN RESULTS: We interrupted the study because of a significant difference in the 60-day mortality rate. The mortality rate in the control group was significantly higher when compared with the protocol group (9/18 [50%] vs. 3/19 [15.7%], p < .05). The prevalence of clinical and infectious complications was higher in the control group than in the protocol group (67% and 31% respectively; relative risk, 0.47; 95% confidence interval, 0.226-0.991; p < .05) and there was a trend toward more severe organ dysfunction in nonachievers patients (17/24 [71%] vs. 6/13 [46%], relative risk, 0.65; 95% confidence interval, 0.343-1.237; NS). CONCLUSION: Older patients with existing cardiorespiratory illness undergoing major surgery have a reduced morbidity and mortality when dobutamine is used to maximize oxygen transport.

Adult respiratory distress syndrome (ARDS): the pathophysiologic role of catecholamine-kinin interactions.

The pathophysiology of the adult respiratory distress syndrome (ARDS) seems to be based on a cybernetic imbalance of the central nervous system (CNS), with activation of secondary peripheral effectors (PE). Lung vascular hyperpermeability is a crucial feature of PE actions in ARDS. Kinins (Bk), as PE, are important vascular hyperpermeability-inducing factors, with potential participation in ARDS induction. To test this hypothesis, we produced experimental ARDS in male Wistar rats using the anterior hypothalamic nuclei lesion model. Adrenalectomy, adrenal demedullation and denervation, alpha-adrenergic blockade, and catecholamine (CA) depletion reduced ARDS severity whereas beta-adrenergic blocking and CA uptake I inhibition resulted in a potentiated aspect. The Bk depletion or inhibition of the generation of these peptides resulted in attenuation of the pathologic features of ARDS. Bk half-life prolongation produced intense potentiation of the respiratory syndrome. This work suggests that Bk and CA systems are interactive and interdependent in their pathogenic actions on lungs in ARDS, involving, probably, a reciprocally-activating mechanism.

Role of the central nervous system in the adult respiratory distress syndrome.

The CNS might play an important pathophysiologic role in the induction of the adult respiratory distress syndrome (ARDS). Post-traumatic development of cerebral microthromboses seems to be a major feature. To test this hypothesis, we subjected Wistar rats with postburn ARDS to the following microneurosurgical procedures in an attempt to morphologically detect modifications in the evolving pattern: a) anterior (AH) or posterior (PH) hypothalamus nuclei stereotaxic electrolytic lesion; b) intracerebroventricular microinjections of phenoxybenzamine (PB)-50, micrograms propranolol-0.5 micrograms, cocaine-5 micrograms, epinephrine-0.5 micrograms, carbachol(CA)-5 micrograms, pirilamine-20 micrograms, cimetidine-30 micrograms, lidocaine-20 micrograms, atropine (AT)-40 micrograms; c) intra-AH microinjections of CA-10 micrograms, AT-20 micrograms; and d) intra-PH microinjections of PB-10 micrograms, norepinephrine-0.05 microgram. The results showed that the alpha-adrenergic components of PH induce a potentiation in ARDS whereas the cholinergic components of AH seem to attenuate this syndrome. This work suggests that a damaged CNS may suffer cybernetic derangements as to induce it to generate inappropriate adaptative responses that can result in the development of ARDS.

Acute respiratory distress syndrome (ARDS): the prophylactic effect of neurodepressant agents.

It has been suggested that acute respiratory distress syndrome (ARDS) is induced by a cybernetic imbalance of the central nervous system secondary to alarm reaction-provoked intravascular coagulation into cerebral microvessels. The brain metabolic and electrical resting state through the use of neurodepressant drugs might theoretically reduce the intensity and duration of the alarm reaction, thus diminishing the possibility of self-induced secondary brain lesions. In this work, Wistar rats were submitted to central (anterior hypothalamic electrolytic lesion) and peripheral (scald burn) trauma as effective models of reproducing an ARDS-like syndrome. Pretreatment of these animals with the following neurodepressant drugs: morphine, pentobarbital sodium, haloperidol, diazepam, chlorpromazine, and urethane, resulted in significant attenuation of the evolution of the ARDS-like syndrome, reinforcing the suggestion of a centrally-based origin of such pathologic manifestations.

Psychopharmacological effects of the essential oil fraction and of the hydrolate obtained from the seeds of Licaria puchury-major.

An essential oil fraction obtained from powdered seeds of Licaria puchury-major contained 51.3% of safrol, 3.3% of eugenol and 2.9% of methyleugenol, among other substances. Fifty to 800 mg/kg of this fraction reduced motor activity and anesthetized mice; it also protected the animals against transcorneal electroshock. A hydrolate obtained from the powder, contained 0.2 mg of essential oil fraction per ml: 0.1 and 0.2 ml/10 g of this hydrolate reduced motor activity and potentiated barbiturate sleeping time of mice; 2.5-10 ml/kg given to rats produced a drop in body temperature. The hydrolate, however, did not anesthetize and did not protect mice against convulsions induced by electrical shock. These amounts of the hydrolate corresponded to dosing the animals with 2-4 mg/kg of the essential oil (or 1-2 mg/kg of safrol), doses which were inactive per se. This suggested that the pharmacological activity of the hydrolate was not due to its essential oil content. Corroborating this possibility the hydrosoluble portion of the hydrolate mimicked all of its effects: reduced motor activity, potentiated barbiturate sleeping time of mice and decreased body temperature of rats. The hydrosoluble material, as the hydrolate, was also incapable of anesthetizing and protecting mice against electroshock induced convulsions.