Biomedical subjects

G De Nucci

Publications and source records attributed to G De Nucci.

At least 37 records · Page 2Linked to original sources

PubMed2001

The relaxation of isolated rabbit corpus cavernosum by the herbal medicine Catuama and its constituents.

The effects of the Brazilian herbal medicine Catuama and each of its plant constituents (Paullinia cupana, Trichilia catigua, Zingiber officinalis and Ptychopetalum olacoides) were investigated on rabbit corpus cavernosum (RbCC) using a bioassay cascade. Catuama caused short-lived and dose-dependent relaxations (11% +/- 7%, 26% +/- 5% and 82% +/- 9%, at doses of 1, 3 and 10 mg, respectively). Neither the nitric oxide synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 10 microM) nor the soluble guanylate cyclase inhibitor ODQ (10 microM) significantly affected the Catuama-induced relaxations. Similarly, the selective ATP-dependent K(+) channel (K(ATP)) blocker glibenclamide (10 microM), the muscarinic receptor antagonist atropine (1 microM) and the voltage-dependent Na(+) channel blocker tetrodotoxin (1 microM) all failed to affect significantly the Catuama-induced relaxations. These results indicate that the relaxations induced by Catuama involve neither nitric oxide release nor K(ATP) channel activation. The extracts of P. cupana, Z. officinalis and P. olacoides caused short-lived and dose-dependent RbCC relaxations, whereas T. catigua evoked long-lasting relaxations which were occasionally preceded by a brief contractile effect. The extract of P. cupana was the most active in relaxing RbCC strips. The relaxations induced by all extracts were not significantly affected by L-NAME (10 microM). The infusion of ODQ (10 microM) had no significant effect on the P. cupana- and Z. officinalis-induced relaxations but reduced by >50% (p < 0.05) those evoked by P. olacoides and T. catigua. Incubations of RbCC with Catuama(10 mg/mL for 0.25 to 5 min) caused increases of cAMP levels (143% increase at 5 min of incubation). Incubations of RbCC with P. cupana extract (1 mg/mL) increased the cAMP levels by 200% whereas higher doses (10 and 100 mg/mL) caused smaller increases in the nucleotide levels (150% and 89%, respectively). The extracts of Z. officinalis and P. olacoides (same doses) caused smaller increases of the cAMP levels compared with the P. cupana extract, whereas T. catigua (1-100 mg) did not increase the levels of this nucleotide above the basal values. Our results show that of the four extracts assayed, P. cupana was the most effective, indicating that it is the main extract responsible for the relaxing effect of Catuama on rabbit cavernosal tissue.

Animals↗

PubMed2001

The role of nitric oxide on the relaxations of rabbit corpus cavernosum induced by Androctonus australis and Buthotus judaicus scorpion venoms.

In this study, we have investigated the relaxing effects of both Androctonus australis venom (AAV) and Buthotus judaicus venom (BJV) on the rabbit corpus cavernosum (RbCC) smooth muscle strips. The RbCC strips were mounted in a cascade system and superfused with warmed and gassed Krebs solution. The nitric oxide (NO) synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 10microM), but not D-NAME (10microM), significantly inhibited the RbCC relaxations induced by acetylcholine (ACh, 0.6nmol), AAV (30microg) and BJV (30microg). Subsequent infusion of L-arginine (300microM), but not of D-arginine (300microM), partially restored the relaxations evoked by these agents. The brain NO synthase inhibitor 7-nitroindazole (7-NI, 10microM) also inhibited the relaxant responses elicited by the scorpion venoms. The guanylyl cyclase inhibitors methylene blue (MB, 30microM) and 1H-[1,2,4] oxadiazolo [4,3,-alquinoxalin-1-one] (ODQ, 10microM) virtually abolished the relaxations induced by either AAV or BJV. The infusion of muscarinic receptor antagonists such as scopolamine and atropine (1microM, each) completely abolished the ACh-induced relaxations but had no effect on those evoked by the scorpion venoms. The Na(+) channel blocker tetrodotoxin (1microM) prevented the relaxations evoked by both AAV and BJV. Thus, NO released from nitrergic nerve fibres mediates the relaxations elicited by AAV and BJV in the rabbit cavernosal tissue.

Acetylcholine↗

PubMed2001

Involvement of nitric oxide on the peritoneal neutrophil influx induced by staphylococcal enterotoxin B in mouse.

In this study, the role of nitric oxide (NO) on neutrophil migration induced by staphylococcal enterotoxin B (SEB) in the mouse peritoneal cavity was investigated. The NO synthase inhibitors L-NAME and aminoguanidine, as well as dexamethasone, markedly reduced SEB-induced neutrophil influx. In mice with an increased population of peritoneal macrophages, the inhibition of SEB-induced neutrophil influx by these agents was significantly lower. The in vivo treatment with aminoguanidine inhibited only the iNOS activity, whereas L-NAME inhibited both the cNOS and iNOS activities. In conclusion, NO modulates the neutrophil migration in response to SEB through the activity of an iNOS isoform.

Animals↗

PubMed2001

Nonadrenergic, noncholinergic relaxation of human isolated corpus cavernosum induced by scorpion venom.

OBJECTIVES: To examine the effects of Tityus serrulatus scorpion venom (TSV) on human corpus cavernosum (HCC) using a bioassay cascade. Priapism is occasionally observed in scorpion envenomation, mostly in children. METHODS: HCC strips were suspended in a cascade system and superfused with aerated and warmed Krebs' solution at 5 mL/min. Noradrenaline (3 micromol/L) was infused to induce a submaximal contraction of the HCC strips. The release of cyclooxygenase products was prevented by infusing indomethacin (6 micromol/L). RESULTS: N(omega)-nitro-L-arginine methyl ester (10 micromol/L; n = 10) increased the tone of the preparations and significantly reduced (P <0.01) the acetylcholine (ACh) and TSV-induced relaxations. Subsequent infusion of L-arginine (300 micromol/L) partially reversed the increased tone and significantly restored the relaxations induced by TSV and ACh (P <0.01). The soluble guanylyl cyclase inhibitor ODQ (10 micromol/L; n = 8) markedly reduced (P <0.01) the relaxations induced by TSV, ACh, glyceryl trinitrate, and bradykinin. 7-Nitroindazole (10 micromol/L; n = 8) inhibited the relaxations induced by TSV by 84% (P <0.01) and also caused small, but significant, reductions in the ACh and bradykinin-induced HCC relaxations (P <0.05). Atropine (1 micromol/L; n = 6) abolished the relaxations evoked by ACh (P <0.01), but had no effect on those elicited by TSV. Tetrodotoxin (1 micromol/L; n = 6) abolished the relaxations induced by TSV (P <0.01) and also reversed the established TSV-induced relaxation (n = 4). CONCLUSIONS: Our results indicate that TSV relaxes HCC through the release of nitric oxide from nonadrenergic, noncholinergic (NANC) nerves. The elucidation of the mechanism responsible for the TSV-induced relaxations might be useful for a better understanding of the development of priapism in cases of scorpion envenomation.

Acetylcholine↗

PubMed2001

Bioequivalence study of finasteride. Determination in human plasma by high-pressure liquid chromatography coupled to tandem mass spectrometry.

Two different finasteride (CAS 98319-26-7) tablet formulations were evaluated for their relative bioavailability (Flaxin tablets 5 mg, as the test formulation vs reference formulation, tablets 5 mg) in 23 healthy male volunteers who received a single 5 mg oral dose of each preparation. The study was open, randomized with a two-period crossover design and a 7-day washout period. Plasma samples were obtained over a 48-h interval. The finasteride concentrations were determined by high-pressure liquid chromatography (HPLC) coupled to tandem mass spectrometry (LC-MS-MS). The analytical method developed has a limit of quantitation (LOQ) of 0.50 ng/ml in plasma. For the quality control the measured concentration was 2.05 +/- 0.14 ng/ml (mean +/- SD, n = 30) with a precision of 6.9% and an accuracy of 2.55% at a concentration of the starting solution of 2.00 ng/ml, while with 20.00 ng/ml starting solution the measured concentrations were 20 +/- 0.80 ng/ml (n = 30) with a precision of 3.81% and an accuracy of 0.09%. From the plasma finasteride concentration vs time curves the following pharmacokinetics parameters were obtained: AUC0-48, AUC0-infinity, Cmax, Cmax/AUC0-48, Ke, elimination half-life and tmax. Geometric mean test/reference formulations individual percent ratio was 95.71 for AUC0-48 h and 88.70% for Cmax. The 90% confidence interval for the geometric mean of the individual ratio test/reference formulations was 95.70-120.20% for AUC0-48 h, 94.60-121.30 for AUC0-infinity and 88.70-108% for Cmax. Since for both Cmax or AUC the 90% Cl values are within the interval proposed by the Food and Drug Administration, the test formulation is bioequivalent to the reference formulation for both the rate and extent of absorption after single dose administration.

5-alpha Reductase Inhibitors↗

PubMed2001

Comparative bioavailability of 4 amoxicillin formulations in healthy human volunteers after a single dose administration.

OBJECTIVE: To compare the bioavailability of two amoxicillin oral suspension (250 mg/5 ml) formulations and two amoxicillin capsule (500 mg) formulations (Amoxicilina from Medley S/A Indústria Farmaceûtica, Brazil, as test formulations and Amoxil from SmithKline Beecham Laboratórios Ltda., Brazil, as reference formulations) in 48 volunteers of both sexes. MATERIAL AND METHODS: The study was conducted open with a randomized two-period crossover design and a one-week washout period. Plasma samples were obtained over a 12-hour interval. Amoxicillin concentrations were analyzed by combined reversed phase liquid chromatography and tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using the selected ion monitoring method. From the amoxicillin plasma concentration vs. time curves the following pharmacokinetic parameters were obtained: AUC(last), AUC(0-infinity) and Cmax. RESULTS: Geometric mean of Amoxicilina/Amoxil 250 mg/5 ml individual percent ratio was 103.70% for AUC(last), 103.15% for AUC(0-infinity) and 106.79% for Cmax. The 90% confidence intervals were 97.82-109.94%, 97.40 to 109.24%, and 96.38-118.33%, respectively. Geometric mean of Amoxicilina/Amoxil 500 mg capsule individual percent ratio was 93.26% for AUC(last), 93.27% for AUC(0-infinity) and 90.74% for Cmax. The 90% confidence intervals were 85.0-102.33%, 85.12-102.31%, and 80.14-102.73%, respectively. CONCLUSION: Since the 90% CI for both Cmax, AUC(last) and AUC(0-inifnity) were within the 80-125% interval proposed by the Food and Drug Administration, it was concluded that Amoxicilina 250 mg/5 ml oral suspension and Amoxicilina 500 mg capsule were bioequivalent to Amoxil 250 mg/5 ml oral suspension and to Amoxil capsule 500 mg, respectively, with regard to both the rate and extent of absorption.

Administration, Oral↗

PubMed2000

Inflammatory oedema induced by the lys-49 phospholipase A(2) homologue piratoxin-i in the rat and rabbit. Effect of polyanions and p-bromophenacyl bromide.

Piratoxin-I (PrTX-I) is a Lys-49 phospholipase (PLA(2)) homologue, isolated from Bothrops pirajai snake venom, that has no phospholipase activity. In this study, we investigated the in vivo oedematogenic activity of PrTX-I in both the rat and the rabbit as well as the ability of PrTX-I to activate rat mast cells in vitro. In the rat paw and skin, PrTX-I (3-100 microg/paw) induced a dose-dependent oedema that was associated with extensive mast cell degranulation. The involvement of mast cells in PrTX-I-mediated oedema formation in the rat was further confirmed by the findings that this protein significantly activated rat peritoneal mast cells in vitro, causing the release of [(14)C]5-hydroxytryptamine ([(14)C]5-HT; 51 +/- 1%). In the rabbit, PrTX-I (10-100 microg/site) also induced dose-dependent skin oedema formation that was not affected by either mepyramine (a histamine H(1) receptor antagonist) or cyproheptadine (1.0 microg/site), indicating that mast cells do not play a role in this animal species. The bradykinin B(2) receptor antagonist Hoe 140 (0.5 microg/site) and the platelet-activating factor (PAF) receptor antagonist WEB 2086 (200 microg/site) also failed to affect the PrTX-I-induced rabbit skin oedema, ruling out the involvement of kinins and PAF. The PLA(2) inhibitor p-bromophenacyl bromide greatly reduced the PrTX-I-induced oedema in both the rat and the rabbit, and also inhibited the rat in vitro mast cell activation induced by this PLA(2) homologue. The polyanions heparin and dermatan sulphate efficiently prevented oedema formation in both species, and heparin inhibited PrTX-I-induced rat mast cell degranulation. Our results are consistent with the suggestion that the cationic charge of PrTX-I plays a major role in the inflammatory responses induced by this PLA(2) homologue.

Animals↗

PubMed2000

Involvement of vanilloid receptors and purinoceptors in the Phoneutria nigriventer spider venom-induced plasma extravasation in rat skin.

Phoneutria nigriventer venom causes stimulation of capsaicin-sensitive primary afferent neurons in the rat dorsal skin, leading to neurogenic plasma protein extravasation due to the release of tachykinin NK(1) receptor agonist. In this study we further investigated the mechanisms involved in the venom-induced activation of capsaicin-sensitive primary afferent neurons. The plasma extravasation in response to venom intradermally injected was measured in Wistar rats as the local accumulation of i.v. injected 125I-labelled human serum albumin into skin sites. The tachykinin NK(1) receptor agonist, D-Ala-[L-Pro(9),Me-Leu(8)]substance P-(7-11) (GR73632; 10-100 pmol/site), induced a significant plasma leakage that was abolished by the selective tachykinin NK(1) receptor antagonist, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane chloride (SR140333; 1 nmol/site), whereas the leakage after venom (1-10 microgram/site) was significantly inhibited (but not abolished) by SR140333. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8-37), failed to further reduce the residual plasma extravasation induced by venom plus SR140333. The mu-opioid receptor agonist, [D-Ala(2), Me-Phe(4),Gly-ol(5)]enkephalin (DAMGO), and the local anaesthetic, lignocaine, had no effect on the venom-induced plasma extravasation. Similarly, the L-, N- and P/Q-type voltage-sensitive Ca(2+) channel blockers (verapamil, omega-conotoxin MVIIA and MVIIC, respectively) as well as the Na(+) channel blockers, tetrodotoxin and carbamazepine, had no effect on the venom-induced effect. Neither the systemic treatment nor the local injection of ruthenium red prevented the venom-induced plasma extravasation. However, the vanilloid receptor antagonist, N-[2-(4-chlorophenyl) ethyl]-1,3,4, 5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine; 120 micromol/kg, i.v.), reduced by 48% (P<0.05) the venom (10 microgram/site)-induced plasma extravasation. A significant inhibitory effect was also observed with the P(2) purinoceptor agonists, adenosine 5'-triphosphate (ATP; 10 and 30 nmol/site) and adenosine 5'-diphosphate (ADP; 10 nmol/site). The involvement of histamine and/or 5-hydroxytryptamine (5-HT) in the venom-induced plasma extravasation was ruled out since neither histamine and 5-HT receptor antagonists nor depletion of mast cells by compound 48/80 affected the venom response. This was further supported by the failure of venom to degranulate in vitro peritoneal mast cells. In conclusion, only vanilloid receptors and P(2) prejunctional purinoceptors had an inhibitory effect on the neurogenic plasma extravasation evoked by P. nigriventer venom in rat dorsal skin.

Animals↗

PubMed2000

Development of cardiomyocyte hypotrophy in rats under prolonged treatment with a low dose of a nitric oxide synthesis inhibitor.

Chronic administration of the nitric oxide (NO) synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats causes hypertension and morphological abnormalities in the heart, consisting mainly of ventricular hypertrophy and foci of necrosis and fibrosis. Since these phenomena have usually been described with high (or moderate) doses of L-NAME, this study was undertaken to evaluate the effects of a low dose of L-NAME on arterial blood pressure, heart weight index, left ventricular weight index, amount of ventricular fibrosis, and cardiomyocyte size. Male Wistar rats received L-NAME (7.5 mg/kg per day) in the drinking water for 2, 4, and 6 months, whereas control animals received tap water alone. At this dose, L-NAME caused 90% inhibition (P<0.001) of brain NO synthase (NOS) activity. The chronic L-NAME treatment caused an approximately 15% reduction in body weight of the animals, and no death was observed. The tail-cuff pressure was markedly (P<0.01) elevated in L-NAME-treated rats. A significant (P<0.05) reduction in both heart weight index (13-20% decrease) and left ventricular weight index (20-34% decrease) at 2, 4, and 6 months of treatment was observed in L-NAME-treated rats. The cardiomyocyte size in subendocardial, subepicardial, and midmyocardial regions of the left ventricles was time-dependently reduced, irrespective of the region studied, as measured at 2 (11% decrease), 4 (28% decrease, P<0.05), and 6 (45% decrease, P<0.05) months of chronic L-NAME treatment. The amount of fibrous tissue was unaltered at 2 and 4 months, but a small (but significant) increase in the amount of fibrous tissue was detected at 6 months (7.1+/-0.2 %, P<0.05) compared to that of control animals (5.9+/-0.2%). Our results show that chronic treatment of rats with a low dose of L-NAME for prolonged periods (up to 6 months) causes arterial hypertension accompanied by significant reductions in heart weight, left ventricular weight indexes, and cardiomyocyte size.

Animals↗

PubMed2000

Comparative bioavailability of two cefadroxil formulations in healthy human volunteers after a single-dose administration.

OBJECTIVE: To compare the bioavailability of two cefadroxil capsule (500 mg) formulations (Cefadroxila from Eurofarma Laboratórios Ltd, Brazil, as test formulation and Cefamox from Bristol-Myers Squibb, Brazil S.A. as reference formulation) in 24 volunteers of both sexes. MATERIAL AND METHODS: The study was conducted open with randomized two-period crossover design and a 1-week washout period. Plasma samples were obtained over a 12-h interval. Cefadroxil concentrations were analysed by combined reversed-phase liquid chromatography and tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using a selected ion monitoring method. From the cefadroxil plasma concentration versus time curves the following pharmacokinetic parameters were obtained: AUC(last), AUC(0-infinity) and C(max). RESULTS: Geometric mean of Cefadroxila/Cefamox 500 mg individual percent ratio was 103.97% for AUC(last), 104.08% for AUC(0-infinity) and 95.23% for C(max). The 90% confidence intervals (CI) were 98.14-110.16%, 98.37-110.12%, and 85.59-105.96%, respectively. CONCLUSION: Since the 90% CI for C(max), AUC(last) and AUC(0-infinity) were within the 80-125% interval proposed by the Food and Drug Administration, it was concluded that the Cefadroxila 500 mg capsule was bioequivalent to the Cefamox 500 mg capsule, according to both the rate and extent of absorption.

Adolescent↗

PubMed2000

Role of kinins and nitric oxide on the rabbit arthritis induced by Bothrops jararaca venom.

The effects of the nitric oxide synthase inhibitor N(omega)Nitro-L-arginine-methyl ester (L-NAME) and of the bradykinin B(2) receptor antagonist HOE 140 were evaluated in the inflammatory reaction induced by Bothrops jararaca venom (BjV) in New Zealand White rabbits. Arthritis was induced by injecting 0.5 ml of a sterile solution of BjV (1-64 microg/ml) into the knee intraarticular cavity. The contralateral joint was injected with bovine serum albumin (BSA) diluted in sterile saline. At selected times thereafter (4, 24 and 48 h), the vascular permeability and the leukocyte influx in both the synovial fluid and synovium were evaluated. BjV caused a dose-dependent increase in both leukocyte influx and protein extravasation which reached a maximal response at 16 microg. Bothrops jararaca venom also induced the increase in the leukocyte accumulation in the synovium and in the concentration of both NO(2)/NO(3) in the synovial fluid. Chronic administration of L-NAME (20 mg/kg/day in the drinking water for 2 weeks) markedly reduced the leukocyte accumulation (90%), protein leakage (44%), and NO(2)/NO(3) (50%) levels in the synovial fluid, measured at the 4th h. Hoe 140, given i.v. (0.3 mg/kg, 30 min before) also reduced leukocyte accumulation (75%), protein leakage (48%), and NO(2)/NO(3) (79%) levels in the synovial fluid, measured at the 4th h. Similar results were obtained with acute administration of L-NAME (30 mg/kg, i.v., 30 min before). These results indicate that arthritis induced by BjV is triggered by kinin formation and that the increase in both vascular permeability and leukocyte accumulation is modulated by NO release.

Animals↗

PubMed2000

Leucocyte recruitment induced by type II phospholipases A(2) into the rat pleural cavity.

Bothropstoxin-I (BthTX-I) and bothropstoxin-II (BthTX-II) are Lys-49 and Asp-49 phospholipases A(2) (PLA(2)s), respectively, isolated from Bothrops jararacussu venom. Piratoxin-I (PrTX-I) is a Lys-49 PLA(2) isolated from Bothrops pirajai venom. In this study, the ability of BthTX-I, BthTX-II and PrTX-I to recruit leucocytes into the rat pleural cavity and potential mechanisms underlying this effect were investigated. Intrapleural injection of either BthTX-I or PrTX-I (10-100 microg/cavity each) caused a significant leucocyte infiltration at 12 h after injection. The maximal cell migration was observed with the dose of 30 microg/cavity (14.9+/-15.5 and 17.6+/-1. 6x10(6) cells/cavity, respectively). Leucocyte counts consisted mainly of mononuclear cells, but significant amounts of neutrophils and eosinophils were also observed. Intrapleural injection of BthTX-II (10-100 microg/cavity) caused a marked leucocyte infiltration at 6 and 12 h after injection. The maximal response was observed with the dose of 100 microg/cavity (57.3+/-3.4x10(6) cells/cavity, 6 h). The leucocyte counts were mainly composed of neutrophils and mononuclear cells. The treatment of either BthTX-I (30 microg/cavity, 12 h) or BthTX-II (30 microg/cavity, 6 h) with the PLA(2) inhibitor p-bromophenacyl bromide (p-BPB) had no effect on the total and differential leucocyte counts induced by these proteins. The same treatment partially reduced the PrTX-I-induced pleural leucocyte infiltration. In rats depleted of the histamine and 5-hydroxytryptamine (5-HT) stores by chronic treatment with compound 48/80, the total leucocyte counts in response to BthTX-I, BthTX-II and PrTX-I was not significantly affected compared to control animals. In addition, BthTX-I, BthTX-II and PrTX-I (100 microg/ml each) significantly degranulated pleural mast cells in vitro leading to the release of [(14)C]5-hydroxytryptamine ([(14)C]5-HT). p-BPB and heparin (50 IU/ml) significantly reduced the [(14)C]5-HT release induced by these PLA(2)s. Our results demonstrate that BthTX-I, BthTX-II and PrTX-I recruit leucocyte into the pleural cavity of the rat by mechanisms unrelated to enzymatic activity and pleural mast cell degranulation.

Acetophenones↗

PubMed2000

Investigation of the haemodynamic effects of Phoneutria nigriventer venom in anaesthetised rabbits.

The haemodynamic alterations induced by the central and peripheral administration of the armed spider (Phoneutria nigriventer) venom (PNV) were investigated in anaesthetised rabbits. The intracerebroventricular injection of increasing doses of PNV (30 and 100 microg/kg) elicited a biphasic cardiovascular response characterised by a brief hypotension (1-3 min) followed by a marked and sustained (more than 30 min) increase in mean arterial pressure (61 +/- 5 and 61 +/- 10%, respectively) and in systemic vascular resistance (135 +/- 21 and 161 +/- 37%) accompanied by mild increases in cardiac contractility. Systemic alterations such as salivation and muscular fasciculation were also observed. At the opposite, the dose of 100 microg/kg of PNV injected intravenously produced only a hypotensive effect (29 +/- 4% decrease in mean arterial pressure) and a decrease in vascular resistance (38 +/- 5%). Nevertheless, a much higher dose of PNV (1 mg/kg) injected intravenously produced a hypertensive response analogous to the one observed upon central administration. The central hypertensive response induced by PNV was not affected by preteating the animals with selective antagonists of receptors of different neurotransmitters or endogenous mediators such as: acethylcoline muscarinic, bradykinin B2, angiotensin II AT1 receptors and also antagonists of the excitatory amino acid receptors of the central nervous system. Nevertheless, the intravenous pretreatment with the selective alpha1-adrenergic receptor antagonist prazosin significantly blunted the excitatory cardiovascular response evoked by the central injection of PNV. It is concluded that PNV can induce central as well as peripheral haemodynamic effects. The central component seems to be mediated by the activation of cardiovascular centres which in turn lead to an increase in the sympathetic outflow to the periphery, whereas the peripheral component can be accounted for either by direct activation of the vascular alpha1-adrenergic receptors or by catecholamine release from the sympathetic nerve endings.

Adrenergic alpha-Antagonists↗

PubMed2000

Clarithromycin bioequivalence study of two oral formulations in healthy human volunteers.

OBJECTIVE: To assess the bioequivalence of two tablet formulations of clarithromycin (Clamicin 500 mg from Medley Indlistria Farmaceutica, Brazil, as the test formulation, and Biaxin 500 mg from Abbott Industries, USA, as the reference formulation). METHODS: A single 500 mg oral dose of each formulation was administrated in 24 healthy volunteers of both sexes (12 males and 12 females). The study was conducted open, randomized, two-period crossover design with a 7-day interval between doses. The plasma concentrations of clarithromycin were quantified by reversed phase liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM) method. 14-hydroxyclarithromycin concentration was estimated semiquantitatively as equivalent of clarithromycin/ml. The precision of the method was evaluated using calibration curves and plasma quality control samples. The pharmacokinetic parameters calculated for both compounds included: AUC(0 - 48h), AUC(0 - infinity), Cmax, Cmax/AUC(0 - 48h), Tmax, T1/2 and Ke. RESULTS: Standard curves of clarithromycin in plasma were linear in the range of 0.05 microg x ml(-1) to 10 microg x ml(-1) (r > 0.999). The limit of quantification was 5 ng/ml. Within- and between-run plasma quality control CV were 5.8% and 15.7%, respectively. Inaccuracy within- and between-runs were 14% and 17%, respectively. 90% CI for clarithromycin geometric mean AUC(0 - 48h), AUC(0 - infinity) and Cmax ratios (test/reference) were: 8.7% - 103.1%, 89.4% - 103.7% and 85.4% - 99.6%, respectively, and for hydroxyclarithomycin were 80.3% - 108.6%, 80.1% - 110.1% and 85.4% - 112.6%, respectively. CONCLUSION: The method described for the quantification of charithomycin and its main metabolite is accurate and sensitive. Clamicin was considered bio-equivalent to Biaxin based on the rate and extent of absorption. Since these were no significant differences in the bioequivalence determined using the pharmacokinetic parameters of either clarithromycin or 14-hydroxyclarithromycin, we suggest that future bioequivalence trials of this drug may be performed by quantifying clarithromycin only.

Adult↗

PubMed1999

Plasma hydroxy-metronidazole/metronidazole ratio can detect early changes in hepatic function in ethanol-induced liver injury.

AIMS: To evaluate the usefulness of plasma hydroxy-metronidazole/metronidazole (OH-MET/MET) ratios as a dynamic liver function test in ethanol abusers with or without liver cirrhosis. METHODS: Metronidazole was administered intravenously for 20 min to healthy volunteers, and to patients with alcohol-induced, non-cirrhotic hepatopathy and liver cirrhosis. Plasma concentrations of metronidazole and hydroxy-metronidazole were measured by high performance liquid chromatography in samples collected 5, 10, 20 and 30 min after the metronidazole infusion. RESULTS: Patients with non-cirrhotic alcoholic hepatopathy had significantly elevated aminotransferase levels compared to healthy volunteers and Child A patients. Child-Pugh C patients had significantly prolonged prothrombin times when compared to healthy volunteers and patients with non-cirrhotic hepatopathy. Metronidazole metabolism, as measured by the OH-MET/MET ratio following the intravenous administration of 500 mg of the drug, was significantly impaired in all ethanol-abusing individuals, including patients with non-cirrhotic alcoholic hepatopathy. CONCLUSIONS: Metronidazole metabolism was impaired in ethanol abusers, even in the absence of liver cirrhosis, indicating that ethanol was capable of affecting liver function in the early stages of alcohol-induced liver disease.

Adolescent↗

PubMed1999

The role of heart rate in the modulation of the decreased cardiac output induced by acute nitric oxide synthesis inhibition in anaesthetized dogs.

1. The role of the heart rate modulating the decrease in cardiac output induced by the nitric oxide synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) was investigated in anaesthetized dogs. This was achieved in dogs in which a positive pacemaker (PM) cable was located at the right ventricle. 2. The haemodynamic events were evaluated: mean arterial blood pressure (MABP), systemic vascular resistance index (SVRI), stroke volume index (SVI), heart rate (HR) and cardiac index (CI). 3. The infusion of L-NAME (0.01-10 mg kg(-1)) in the animals with the PM off caused a dose-dependent rise in MABP and SVRI, accompanied by significant decreases of HR and SVI. A resulting decrease in CI was observed at all doses of L-NAME used. 4. In the animals with the PM on, HR was maintained stable. Under this condition, the increase in MABP and SVRI as well as the decrease in SVI induced by the L-NAME infusion did not significantly differ from the PM-off animals. However, the resulting decreased CI was markedly attenuated compared to PM-off animals but significant decreases in CI were still observed at higher doses of L-NAME. 5. The results suggest that HR plays an important role in the L-NAME-mediated decreased cardiac output but other factors might also be involved.

Analysis of Variance↗

PubMed1999

Comparative bioavailability of two different diclofenac formulations in healthy volunteers.

The aim of the study was to assess the bioequivalence of two different diclofenac (CAS 15307-86-5) formulations (diclofenac free acid suspension as test formulation and diclofenac resinate suspension, Cataflam, as reference formulation) in 24 healthy volunteers. After an overnight fast, the volunteers received a single oral dose (50 mg) of each formulation, following an open, randomized, two-period crossover design, with a fourteen-day washout interval between doses. Serum samples were obtained over a 24-h interval post-dosing, and were analysed for their diclofenac content by HPLC-UV. No adverse effect was reported for any of the formulations administered. Geometric mean test/reference individual ratios were: 92.8% for AUC(0-24 h), 93.2% for AUC(0-infinity), 117.2% for Cmax, 131.0% for Ke and 76.2% for T1/2. The variability of Cmax parameter expressed as CV was greater than 25%. Since the 90% CI for AUC(0-24 h) mean ratio were within the 80-125% interval proposed by the Food and Drug Administration, it can be concluded that diclofenac free acid formulation is bioequivalent to diclofenac resinate formulation for the extent of absorption. Since the European Community Agency accepts a 90% CI for Cmax of 70-143%, it can be concluded that diclofenac free acid formulation is bioequivalent to diclofenac resinate formulation for both the rate and the extent of absorption after single dose administration.

Administration, Oral↗

PubMed1999

Fluconazole bioequivalence study: quantification by tandem mass spectrometry.

To develop a new method for quantifying fluoconazole in human plasma and to compare the bioavailability of two fluconazole capsule formulations, an open, randomized, two-period crossover study with a one-week washout interval was conducted in 24 healthy volunteers. Plasma samples were obtained up to 168 hours after drug administration and the serum fluconazole concentrations were analyzed using electrospray tandem mass spectrometry coupled to liquid chromatography using multiple reaction monitoring mode. The pharmacokinetic parameters obtained for fluconazole after the administration of each formulation included the Area under the curve (AUC)(0-168h), AUC(0-infinity), Cmax, Cmax/AUC(0-168h), Tmax, elimination rate constant (Ke), and half-life (T1/2). Within- and between-run imprecision was less than 2.3% and 8.2%, respectively. Inaccuracy within and between runs was -1.5% and -9.7%, respectively. The pharmacokinetic parameters for bioequivalence showed a normal distribution, and the variance of AUC(0-168h), AUC(0-infinity), and Cmax were homoscedastic. The geometric mean for the Fluconal/Zoltec (Fluconal; Libbs Farmacêutica Ltda, São Paulo, Brazil; Zoltec; Laboratórios Pfizer Ltda., São Paulo, Brazil) individual percent ratio was 94.9% for AUC(0-168h), 94.7% for AUC(0-infinity), 80.1% for Cmax, 102.6% for Ke, 97.5% for T1/2, and 0.93 for Tmax (arithmetic mean of individual differences). We have developed a method in which liquid chromatography is coupled with electrospray tandem mass spectrometry to improve the pharmacokinetic analysis of fluconazole. Because the 90% CI AUC is within the interval proposed for the Food and Drug Administration, we concluded that Fluconal is bioequivalent to Zoltec in terms of absorption. The CV was 27.5% for the Cmax parameter, indicating that fluconazole's absorption rate is highly variable. The European Union Regulatory Agency accepts an interval of 70-143%, and because the 90% CI for Cmax is within the interval proposed for the European Union agency, we conclude that Fluconal is bioequivalent to Zoltec for the rate of absorption.

Administration, Oral↗