Drug loading of mesoporous silicon particles

Porous silicon (PSi) is a promising material to be utilized in drug delivery formulations. The release rate of the drug compound can be controlled by changing the pore properties and surface chemistry of PSi. The loading of a poorly soluble drug into mesoporous silicon particles enhances its dissolution in the body. The drug loading is based on adsorption. The attainable maximum loaded amount depends on the properties of the drug compound and the PSi material, and on the process conditions. The loading solvent also essentially affects the adsorption process. The loading of indomethacin into PSi particles with varying surface modification was studied. Solvent mixtures were applied in the loading, and the loaded samples were analyzed with thermal analysis methods. The best degree of loading was obtained using a mixture of dichloromethane and methanol. The drug loads varied from 7.7 w-% to 26.8 w-%. A disturbing factor in the loading experiments was the tendency of indomethacin to form solvates with the solvents applied. In addition, the physical form and stability of indomethacin loaded in PSi and silica particles were studied using Raman spectroscopy. In the case of silica, the presence of crystalline drug as well as the polymorph form can be detected, but the method proved to be not applicable for PSi particles.

IV paracetamol versus IV ibuprofen for the treatment of PDA in LBW infants: a randomized controlled trial

Patent ductus arteriosus is a prevalent problem in low birth weight infants and it has an important morbidity and mortality in this group of patients. Classical treatment options include drugs (intravenous cyclooxygenase inhibitors: indomethacin and ibuprofen) and surgical ligation, but these treatments are associated with significant adverse effects. An alternative treatment with fewer side effects is needed. The role of oral paracetamol has gained importance in recent years, this new therapeutic option is being widely studied, and there are already many studies which support oral paracetamol as first line treatment for PDA, due to its better safety profile than classical drugs. In LBW infants is difficult to administer enteral treatment, since they are often multi pathological patients with several complications that preclude oral administration and they usually receive intravenous treatments. This multicenter, prospective, single blinded, randomized, controlled, parallel-group and noninferiority trial is designed to evaluate the efficacy and safety of intravenous paracetamol versus intravenous ibuprofen in the treatment of PDA in LBW infants. Sixty eight infants with echocardiography confirmed PDA will be randomly assigned to receive either intravenous paracetamol or intravenous ibuprofen. The main endpoints will be the rate of ductal closure of each drug and adverse events in each group of treatment

Síntese e atividade antiedematogênica de derivados N-triptofil-5-benzilideno-2,4-tiazolidinadiona e N-triptofil-5-benzilideno-rodanina

Derivatives of N-tryptophyl-5-benzylidene-2,4-thiazolidinedione (7a-c) and N-tryptophyl-5-benzylidene-rhodanine (7d-f) were prepared by condensation of the intermediates 5 and 6 with different benzaldehydes, respectively. Their structural elucidation was carried through by IR, ¹H NMR and MS. The acute toxicity and antiedematogenic activity of the compounds 7b,c and 7e,f were evaluated. The data did not reveal any sign of toxicity, and no mortality was registered. As indomethacin (10 mg/kg; v.o.), the antiedematogenic activity of the compounds 7b (50 mg/kg; v.o.) and 7e, 7f (50 or 100 mg/kg; v.o.) against carrageenan-induced paw edema was verified at time intervals of 180 min.

Chemical composition and analgesic activity of the leaves and branches of Marlierea tomentosa Camb.

This paper describes the isolation of five phytoconstituents from Marlierea tomentosa. The triterpenes α-amyrin (1) and β-amyrin (2), and the flavonoids quercitrin (3) and isoquercetin (4), were isolated from the leaves. The branches afforded the triterpene arjunolic acid (5). The antinociceptive activity of crude extract, fractions and compound 5 were tested using the writhing and formalin tests in mice. The crude extract, some fractions, particularly dichloromethane and butanol (leaves), ethyl acetate (branches) and arjunolic acid (5) (81.2% inhibition) were more active against the writhing test than the two reference drugs, acetylsalicylic acid and indomethacin.

Micropartículas nanorrevestidas contendo um fármaco modelo hidrofóbico: preparação em etapa única e caracterização biofarmacêutica

The aim of this work was to prepare and characterize spray-dried nanocapsule-coated microparticles obtained in one step, using indomethacin as a hydrophobic drug model and poly(e-caprolactone) or Eudragit® RS100, as polymers. Nanocapsule-coated microparticles showed micrometric mean sizes (10 - 15 µm) and a reduced surface area (75 - 85 m²g-1) compared to the raw material (214 m²g-1). Microparticles coated with Eudragit® RS100-nanocapsules showed a better control of the drug release. The release profiles fit to the monoexponetial model and to the Power Law. The mechanism of the indomethacin release from the microparticles is non-Fickian and depends on the particles desagglomeration.

Pulsed corona discharge as an advanced oxidation process for degradation of organic

Advanced oxidation processes (AOPs) have been studied and developed to suffice the effective removal of refractory and toxic compounds in polluted water. The quality and cost of wastewater treatment need improvements, and electric discharge technology has a potential to make a significant difference compared to other established AOPs based on energy efficiency. The generation of active oxidant species such as ozone and hydroxyl radicals by high voltage discharge is a relatively new technology for water treatment. Gas-phase pulsed corona discharge (PCD), where a treated aqueous solution is dispersed between corona-producing electrodes free of the dielectric barriers, was developed as an alternative approach to the problem. The short living radicals and ozone formed in the gas phase and at the gas-liquid interface react with dissolved impurities. PCD equipment has a relatively simple configuration, and with the reactor in an enclosed compartment, it is insensitive towards gas humidity and does not need the gas transport. In this thesis, PCD was used to study and evaluate the energy efficiency for degrading various organic compounds, as well as the chemistry of the oxidation products formed. The experiments investigate the aqueous oxidation of phenol, humic substances, pharmaceutical compounds (paracetamol, ibuprofen, indomethacin, salicylic acids, -estradiol), as well as lignin degradation and transformation to aldehydes. The study aims to establish the influence of initial concentration of the target pollutant, the pulsed discharge parameters, gas phase composition and the pH on the oxidation kinetics and the efficiency. Analytical methods to measure the concentrations of the target compounds and their by-products include HPLC, spectrophotometry, TOC and capillary electrophoresis. The results of the research included in this summary are presented in the attached publications and manuscripts accepted for publication. Pulsed corona discharge proved to be highly effective in oxidizing each of the target compounds, surpassing the closest competitor, conventional ozonation. The increase in oxidation efficiencies for some compounds in oxygen media and at lower pulse repetition frequencies shows a significant role of ozone. The role of the ·OH radicals was established in the surface reactions. The main oxidation products, formation of nitrates, and the lignin transformation were quantified. A compound specific approach is suggested for optimization of the PCD parameters that have the most significant impact on the oxidation energy efficiency because of the different characteristics and responses of the target compound to the oxidants, as well as different admixtures that are present in the wastewater. Further studies in the method’s safety (nitration and nitrosation of organic compounds, nitrite and nitrate formation enhancement) are needed for promoting the method.

Endothelium-dependent vasodilation in response to Pseudomonas aeruginosa lipopolysaccharide: an in vitro study on canine arteries

Early systemic arterial hypotension is a common clinical feature of Pseudomonas septicemia. To determine if Pseudomonas aeruginosa endotoxin induces the release of endothelium-derived nitric oxide (EDNO), an endogenous nitrovasodilator, segments of canine femoral, renal, hepatic, superior mesenteric, and left circumflex coronary arteries were suspended in organ chambers (physiological salt solution, 95% O2/5% CO2, pH 7.4, 37oC) to measure isometric force. In arterial segments contracted with 2 µM prostaglandin F2a, Pseudomonas endotoxin (lipopolysaccharide (LPS) serotype 10(Habs) from Pseudomonas aeruginosa (0.05 to 0.50 mg/ml)) induced concentration-dependent relaxation of segments with endothelium (P<0.05) but no significant change in tension of arteries without endothelium. Endothelium-dependent relaxation in response to Pseudomonas LPS occurred in the presence of 1 µM indomethacin, but could be blocked in the coronary artery with 10 µM NG-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide synthesis from L-arginine. The inhibitory effect of L-NMMA on LPS-mediated vasorelaxation of the coronary artery could be reversed by exogenous 100 µM L-arginine but not by 100 µM D-arginine. These experiments indicate that Pseudomonas endotoxin induces synthesis of nitric oxide from L-arginine by the vascular endothelium. LPS-mediated production of EDNO by the endothelium, possibly through the action of constitutive nitric oxide synthase (NOSc), may decrease systemic vascular resistance and may be the mechanism of early hypotension characteristic of Pseudomonas septicemia.

Mechanisms involved in calcium oxalate endocytosis by Madin-Darby canine kidney cells

Calcium oxalate (CaOx) crystals adhere to and are internalized by tubular renal cells and it seems that this interaction is related (positively or negatively) to the appearance of urinary calculi. The present study analyzes a series of mechanisms possibly involved in CaOx uptake by Madin-Darby canine kidney (MDCK) cells. CaOx crystals were added to MDCK cell cultures and endocytosis was evaluated by polarized light microscopy. This process was inhibited by an increase in intracellular calcium by means of ionomycin (100 nM; N = 6; 43.9% inhibition; P<0.001) or thapsigargin (1 µM; N = 6; 33.3% inhibition; P<0.005) administration, and via blockade of cytoskeleton assembly by the addition of colchicine (10 µM; N = 8; 46.1% inhibition; P<0.001) or cytochalasin B (10 µM; N = 8; 34.2% inhibition; P<0.001). Furthermore, CaOx uptake was reduced when the activity of protein kinase C was inhibited by staurosporine (10 nM; N = 6; 44% inhibition; P<0.01), or that of cyclo-oxygenase by indomethacin (3 µM; N = 12; 17.2% inhibition; P<0.05); however, the uptake was unaffected by modulation of potassium channel activity with glibenclamide (3 µM; N = 6), tetraethylammonium (1 mM; N = 6) or cromakalim (1 µM; N = 6). Taken together, these data indicate that the process of CaOx internalization by renal tubular cells is similar to the endocytosis reported for other systems. These findings may be relevant to cellular phenomena involved in early stages of the formation of renal stones.

Angiotensin-(1-7) potentiates the coronary vasodilatatory effect of bradykinin in the isolated rat heart

It has been shown that angiotensin-(1-7) (Ang-(1-7)) infusion potentiates the bradykinin (BK)-induced hypotensive response in conscious rats. The present study was conducted to identify Ang-(1-7)-BK interactions in the isolated rat heart perfused according to the Langendorff technique. Hearts were excised and perfused through the aortic stump under a constant flow with Krebs-Ringer solution and the changes in perfusion pressure and heart contractile force were recorded. Bolus injections of BK (2.5, 5, 10 and 20 ng) produced a dose-dependent hypotensive effect. Ang-(1-7) added to the perfusion solution (2 ng/ml) did not change the perfusion pressure or the contractile force but doubled the hypotensive effect of the lower doses of BK. The BK-potentiating Ang-(1-7) activity was blocked by pretreatment with indomethacin (5 mg/kg, ip) or L-NAME (30 mg/kg, ip). The Ang-(1-7) antagonist A-779 (50 ng/ml in Krebs-Ringer) completely blocked the effect of Ang-(1-7) on BK-induced vasodilation. These data suggest that the potentiation of the BK-induced vasodilation by Ang-(1-7) can be attributed to the release of nitric oxide and vasodilator prostaglandins through an Ang-(1-7) receptor-mediated mechanism.

Chronic intrathecal cannulation enhances nociceptive responses in rats

The influence of a chronically implanted spinal cannula on the nociceptive response induced by mechanical, chemical or thermal stimuli was evaluated. The hyperalgesia in response to mechanical stimulation induced by carrageenin or prostaglandin E2 (PGE2) was significantly increased in cannulated (Cn) rats, compared with naive (Nv) or sham-operated (Sh) rats. Only Cn animals presented an enhanced nociceptive response in the first phase of the formalin test when low doses were used (0.3 and 1%). The withdrawal latency to thermal stimulation of a paw inflamed by carrageenin was significantly reduced in Cn rats but not in Nv or Sh rats. In contrast to Nv and Sh rats, injection in Cn animals of a standard non-steroid anti-inflammatory drug, indomethacin, either intraperitoneally or into the spinal cord via an implanted cannula or by direct puncture of the intrathecal space significantly blocked the intensity of the hyperalgesia induced by PGE2. Cannulated animals treated with indomethacin also showed a significant inhibition of second phase formalin-induced paw flinches. Histopathological analysis of the spinal cord showed an increased frequency of mononuclear inflammatory cells in the Cn groups. Thus, the presence of a chronically implanted cannula seems to cause nociceptive spinal sensitization to mechanical, chemical and thermal stimulation, which can be blocked by indomethacin, thus suggesting that it may result from the spinal release of prostaglandins due to an ongoing mild inflammation.

Stimulatory effects of adenosine on prolactin secretion in the pituitary gland of the rat

We investigated the effects of adenosine on prolactin (PRL) secretion from rat anterior pituitaries incubated in vitro. The administration of 5-N-methylcarboxamidoadenosine (MECA), an analog agonist that preferentially activates A2 receptors, induced a dose-dependent (1 nM to 1 µM) increase in the levels of PRL released, an effect abolished by 1,3-dipropyl-7-methylxanthine, an antagonist of A2 adenosine receptors. In addition, the basal levels of PRL secretion were decreased by the blockade of cyclooxygenase or lipoxygenase pathways, with indomethacin and nordihydroguaiaretic acid (NDGA), respectively. The stimulatory effects of MECA on PRL secretion persisted even after the addition of indomethacin, but not of NDGA, to the medium. MECA was unable to stimulate PRL secretion in the presence of dopamine, the strongest inhibitor of PRL release that works by inducing a decrease in adenylyl cyclase activity. Furthermore, the addition of adenosine (10 nM) mimicked the effects of MECA on PRL secretion, an effect that persisted regardless of the presence of LiCl (5 mM). The basal secretion of PRL was significatively reduced by LiCl, and restored by the concomitant addition of both LiCl and myo-inositol. These results indicate that PRL secretion is under a multifactorial regulatory mechanism, with the participation of different enzymes, including adenylyl cyclase, inositol-1-phosphatase, cyclooxygenase, and lipoxygenase. However, the increase in PRL secretion observed in the lactotroph in response to A2 adenosine receptor activation probably was mediated by mechanisms involving regulation of adenylyl cyclase, independent of membrane phosphoinositide synthesis or cyclooxygenase activity and partially dependent on lipoxygenase arachidonic acid-derived substances.

Angiotensin-(1-7) improves the post-ischemic function in isolated perfused rat hearts

We evaluated the effects of angiotensin-(1-7) (Ang-(1-7)) on post-ischemic function in isolated hearts from adult male Wistar rats perfused according to the Langendorff technique. Local ischemia was induced by coronary ligation for 15 min. After ischemia, hearts were reperfused for 30 min. Addition of angiotensin II (Ang II) (0.20 nM, N = 10) or Ang-(1-7) (0.22 nM, N = 10) to the Krebs-Ringer perfusion solution (KRS) before the occlusion did not modify diastolic or systolic tension, heart rate or coronary flow (basal values for Ang-(1-7)-treated hearts: 0.72 ± 0.08 g, 10.50 ± 0.66 g, 216 ± 9 bpm, 5.78 ± 0.60 ml/min, respectively). During the period of occlusion, the coronary flow, heart rate and systolic tension decreased (values for Ang-(1-7)-treated hearts: 2.83 ± 0.24 ml/min, 186 ± 7 bpm, 6.95 ± 0.45 g, respectively). During reperfusion a further decrease in systolic tension was observed in control (4.95 ± 0.60 g) and Ang II-treated hearts (4.35 ± 0.62 g). However, in isolated hearts perfused with KRS containing Ang-(1-7) the further reduction of systolic tension during the reperfusion period was prevented (7.37 ± 0.68 g). The effect of Ang-(1-7) on the systolic tension was blocked by the selective Ang-(1-7) antagonist A-779 (2 nM, N = 9), by the bradykinin B2 antagonist HOE 140 (100 nM, N = 10), and by indomethacin pretreatment (5 mg/kg, ip, N = 8). Pretreatment with L-NAME (30 mg/kg, ip, N = 8) did not change the effect of Ang-(1-7) on systolic tension (6.85 ± 0.61 g). These results show that Ang-(1-7) at low concentration (0.22 nM) improves myocardial function (systolic tension) in ischemia/reperfusion through a receptor-mediated mechanism involving release of bradykinin and prostaglandins.

Evaluation of the antiedematogenic activity of artemetin isolated from Cordia curassavica DC

The species Cordia curassavica (Boraginaceae), known popularly as "erva baleeira", is used in folk medicine for the treatment of several inflammatory processes and as a healing agent. The objective of the present study was to evaluate the antiedematogenic activity of crude dichloromethane extracts of Cordia curassavica and of the artemetin-enriched fraction. The crude extract and artemetin fraction were tested in the model of carrageenin-induced paw edema in male Swiss mice (25-30 g). The crude dichloromethane extract (300 and 1000 mg/kg, po, N = 6) showed significant antiedematogenic activity, reducing the edema by 42, 57 and 45% and 46, 62 and 69%, 3, 4 and 5 h after carrageenin administration, respectively. Indomethacin (10 mg/kg, po, N = 6) reduced the edema by 45 and 48%, after 4 and 5 h, but the artemetin-enriched fraction (30, 100 and 300 mg/kg, po, N = 6) had no activity. The dichloromethane extract (300 and 1000 mg/kg, po, N = 6) also showed antinociceptive activity by reducing acetic acid-induced writhing in mice from 37.1 ± 2.28 (control) to 17.3 ± 1.34 and 13.2 ± 1.44, respectively, but had no activity in the hot-plate test.

Antinociceptive properties of the essential oil of Ocimum gratissimum L. (Labiatae) in mice

We have investigated the antinociceptive effects of the essential oil of Ocimum gratissimum L. (Labiatae) (EOOG) in two classical models of pain in male Swiss mice (25-35 g), the writhing test and the formalin test. At doses of 30, 100 and 300 mg/kg (po), EOOG produced a dose-dependent inhibition (from 58.3 ± 4.4 to 40.7 ± 6.3, 36.4 ± 3.6 and 24.6 ± 3.6, respectively; N = 8-10, P<0.05) of acetic acid-induced writhing, causing up to a ~60% inhibition at the highest dose used, comparable to that obtained with indomethacin (10 mg/kg, po). At the same doses, EOOG predominantly inhibited the late (inflammatory) phase of the formalin-induced pain response (from 59.3 ± 8.3 to 40.4 ± 4.8, 23.2 ± 2.8 and 25.3 ± 5.5, respectively; N = 6, P<0.05), with a maximal reduction of ~60% of the control, although a significant reduction of the initial (neurogenic) phase was also observed at 300 mg/kg (from 62.5 ± 6.07 to 37 ± 5.9; P<0.05). On the basis of these data, we conclude that EOOG possesses interesting antinociceptive properties in the writhing and formalin tests. Due to the relatively low toxicity of EOOG, further detailed examination is strongly indicated for a better characterization of its pharmacological properties and its potential therapeutic value.

Do endogenous opioids and nitric oxide participate in the anticonvulsant action of dipyrone?

It was previously reported that systemic administration of dipyrone inhibited the tonic component of generalized tonic-clonic seizures in both the electroshock and the audiogenic seizure models. The aim of the present study was to investigate the mechanisms involved in the anticonvulsant action of dipyrone by assessing the role of nitric oxide and opioids in the electroshock (female 60- to 90-day-old Wistar rats, N = 5-11) and audiogenic seizure (female 60- to 90-day-old Wistar audiogenic rats, N = 5-11) models of epilepsy. Naloxone (5 mg/kg, sc) significantly reversed the anticonvulsant effect of dipyrone in rats submitted to the induction of audiogenic seizures (ANOVA/Bonferroni's test), suggesting the involvement of opioid peptides in this action. In the electroshock model no reversal of the anticonvulsant effect of dipyrone by naloxone (5 mg/kg, sc) was demonstrable. The acute (120 mg/kg, ip) and chronic (25 mg/kg, ip, twice a day/4 days) administration of L-NOARG did not reverse the anticonvulsant action of dipyrone in the audiogenic seizure model, suggesting that the nitric oxide pathway does not participate in such effect. Indomethacin (10, 20 and 30 mg/kg, ip) used for comparison had no anticonvulsant effect in the audiogenic seizure model. In conclusion, opioid peptides but not nitric oxide seem to be involved in the anticonvulsant action of dipyrone in audiogenic seizures.