Evaluation of the bioequivalence of two formulations containing the combination of 400 mg of acetaminophen (paracetamol), 4 mg of phenylephrine and 4 mg of chlorpheniramine in capsules: open-label, three-way crossover study, partially replicated in healthy volunteers of both sexes

This study was carried out in order to compare the relative bioavailability of two different formulations containing 400 mg of acetaminophen + 4 mg of phenylephrine hydrochloride + 4 mg of chlorpheniramine maleate, Test formulation (Cimegripe®) and Reference formulation (Resfenol®) in 84 healthy volunteers of both sexes under fasting conditions. The study was conducted in a single dose, randomized, open-label, crossover 3-way and partially replicated. The tolerability was evaluated by the monitoring of adverse events and vital signs, results of clinical and laboratory tests. Plasma concentrations were quantified by validated bioanalytical methods using the ultra-performance liquid chromatography coupled to tandem mass spectrometry. The Cmax, Tmax, AUC0-t, AUC0-inf, T1/2 and Kel pharmacokinetic parameters were calculated from these obtained concentrations. The 90% confidence intervals were constructed for the ratio reference/test from the geometric average of the Cmax and AUC parameters which were comprised between 80% and 125%. Only the Cmax parameter of the phenylephrine was applied the scaled average bioequivalence due to the intraindividual coefficient of variation > 30% obtained, thus extending the acceptance limits of the interval. It can be concluded that the two formulations were bioequivalent in terms of rate and absorption extent and thus interchangeable

Content of zinc, iron and their absorption inhibitors in Nicaraguan common beans (Phaseolus vulgaris L.).

Common bean (Phaseolus vulgaris L.), the staple crop of Nicaragua, provides protein and nonhaem iron, but inhibitors such as phytate may prevent absorption of iron and zinc by the consumer. Warehouses in Nicaragua do not have controlled atmospheres, so beans are exposed to high temperatures and humidities that may accelerate quality loss. To evaluate the impact of 6months of storage on quality, four national accessions of common bean were submitted to two treatments, a conventional warehouse with uncontrolled temperature and humidity, and accelerated ageing at 40°C and 75% RH. Iron content was 61-81mg/kg of which 3-4% was bioavailable, and zinc content was 21-25mg/kg, of which 10-12% was bioavailable. Bioavailability generally increased in storage, significantly so in year-old INTA Linea 628 in accelerated ageing. The concentration of phytate was 8.6-9.6mg/g and it contained 54-63% of the total phosphorus. Improvement in bioavailability of divalent cations is needed.

Effects of lipid-lowering drugs on reverse cholesterol transport gene expressions in peripheral blood mononuclear and HepG2 cells.

AIMS: The ATP-binding cassette transporters, ABCA1 and ABCG1, are LXR-target genes that play an important role in reverse cholesterol transport. We examined the effects of inhibitors of the cholesterol absorption (ezetimibe) and synthesis (statins) on expression of these transporters in HepG2 cells and peripheral blood mononuclear cells (PBMCs) of individuals with primary (and nonfamilial) hypercholesterolemia (HC). MATERIALS & METHODS: A total of 48 HC individuals were treated with atorvastatin (10 mg/day/4 weeks) and 23 were treated with ezetimibe (10 mg/day/4 weeks), followed by simvastatin (10 mg/day/8 weeks) and simvastatin plus ezetimibe (10 mg of each/day/4 weeks). Gene expression was examined in statin- or ezetimibe-treated and control HepG2 cells as well as PBMCs using real-time PCR. RESULTS: In PBMCs, statins and ezetimibe downregulated ABCA1 and ABCG1 mRNA expression but did not modulate NR1H2 (LXR-ß) and NR1H3 (LXR-α) levels. Positive correlations of ABCA1 with ABCG1 and of NR1H2 with NR1H3 expressions were found in all phases of the treatments. In HepG2 cells, ABCA1 mRNA levels remained unaltered while ABCG1 expression was increased by statin (1.0-10.0 µM) or ezetimibe (5.0 µM) treatments. Atorvastatin upregulated NR1H2 and NR1H3 only at 10.0 µM, meanwhile ezetimibe (1.0-5.0 µM) downregulated NR1H2 but did not change NR1H3 expression. CONCLUSION: Our findings reveal that lipid-lowering drugs downregulate ABCA1 and ABCG1 mRNA expression in PBMCs of HC individuals and exhibit differential effects on HepG2 cells. Moreover, they indicate that the ABCA1 and ABCG1 transcript levels were not correlated directly to LXR mRNA expression in both cell models treated with lipid-lowering drugs.

Carbamazepine can induce kidney water absorption by increasing aquaporin 2 expression.

BACKGROUND: Carbamazepine (Carba) is an anticonvulsant and psychotropic drug used widely for the treatment of intellectual disability and severe pains, but the incidence of hyponatremia is a common related occurrence. This hyponatremia is frequently attributed to a SIADH induced by this drug. It is also known that Carba is used to decrease the urinary volume in Diabetes Insipidus (DI) because it has an antidiuretic effect. Lithium (Li) is one of the most important drugs used to treat bipolar mood disorders. However Li has the undesirable capacity to induce DI. Nowadays, the association of these drugs is used in the treatment of patients with psychiatric and neurological problems. METHODS: In vivo and in vitro (microperfusion) experiments were developed to investigate the effect of Carba in the rat Inner Medullary Collecting Duct (IMCD). RESULTS: The results revealed that Carba was able to stimulate the V2 vasopressin receptor-Protein G complex increasing the (Pf) and water absorption. In vivo studies showed that in rats with lithium-induced DI, Carba decreased the urinary volume and increased the urinary osmolality. AQP2 expression was increased both in normal IMCD incubated with Carba and in IMCD from lithium-induced DI after Carba addition to the diet, when compared with the control. CONCLUSION: These results showed that the hyponatremia observed in patients using this anticonvulsant drug, at least in part, is due to the Carba capacity to increase IMCD's Pf and that the Lithium-Carbamazepine association is beneficial to the patient.

Photopolymerizable and injectable polyurethanes for biomedical applications: synthesis and biocompatibility.

Two types of photopolymerizable and injectable polyurethane acrylates (PUAs), based on poly(propylene glycol) or poly(caprolactone diol) and hydroxyethyl methacrylate, were synthesized and characterized in order to obtain information regarding their use as an injectable material for biomedical applications. Structural characteristics of the biomaterials, including the degree of phase separation, were evaluated by Fourier transform infrared spectroscopy. The viscosities of the obtained biomaterials make them suitable for injection, molding and photopolymerization using visible light, as demonstrated by the injection test. The cured polymers had mechanical properties comparable to those of certain soft tissues, such as skin. An in vitro cell-polyurethane cytotoxicity study was carried out with mesenchymal stem cells from rat tibias and femurs. The proliferation/viability of the cells in the presence of the synthesized material was assessed by the MTT assay, collagen synthesis analysis and the expression of alkaline phosphatase. The results that were obtained through the in vitro tests indicated that PUAs are cytocompatible. The in vivo experiments were correlated with the in vitro tests and showed low levels of toxicity for the obtained biomaterials. Histology cross-sections showed that the biomaterials induced no significant inflammatory reaction. Our study demonstrates the potential for using synthesized photocurable polyurethanes in biomedical applications. Furthermore, the obtained injectable polymer systems employ minimally invasive procedures and can be molded in situ before photopolymerization with visible light.

Fluoxetine effect on kidney water reabsorption.

BACKGROUND: The pathogenesis of hyponatraemia caused by fluoxetine(Fx) use in the treatment of depression is not well understood. It has been attributed to a SIADH, although ADH-enhanced plasma level has not yet been demonstrated in all the cases reported in humans. This experiment aimed at investigating the effect of fluoxetine on the kidney and more specifically in the inner medullary collecting duct (IMCD). METHODS: (1) In vivo study: (a) 10 rats were injected daily i.p. with 10 mg/kg fluoxetine doses. After 10 days, rats were sacrificed and blood and kidneys were collected. (b) Immunoblotting studies for AQP2 protein expression in the IMCD from injected rats and in IMCD tubules suspension from 10 normal rats incubated with 10(-7) M fluoxetine. (2) In vitro microperfusion study: The osmotic water permeability (P(f), mum/s) was determined in normal rats IMCD (n = 6), isolated and perfused by the standard methods. RESULTS: In vivo study: (a) Injected rats with fluoxetine lost about 12% body weight; Na(+) plasma level decreased from 139.3 +/- 0.78 mEq/l to 134.9 +/- 0.5 mEq/l (p < 0.01) and K(+) and ADH plasma levels remained unchanged. (b) Immunoblotting densitometric analysis of the assays showed an increase in AQP2 protein abundance of about 40%, both in IMCDs from injected rats [control period (cont) 99.6 +/- 5.2 versus Fx 145.6 +/- 16.9, p < 0.05] and in tubule suspension incubated with fluoxetine (cont 100.0 +/- 3.5 versus 143.0 +/- 2.0, p < 0.01). In vitro microperfusion study fluoxetine increased P(f) in the IMCD in the absence of ADH from the cont 7.24 +/- 2.07 to Fx 15.77 +/- 3.25 (p < 0.01). CONCLUSION: After fluoxetine use, the weight and plasma Na(+) level decreased, and the K(+) and ADH plasma levels remained unchanged, whereas the AQP2 protein abundance and water absorption in the IMCD increased, leading us to conclude that the direct effect of fluoxetine in the IMCD could explain at least in part, the hyponatraemia found sometime after this drug use in humans.

Effect of the diuretic furosemide on urinary essential nutrient loss and on body stores in growing rats.

Studies using a model of non-infectious diarrhea, have shown that increasing fecal mass by using laxatives resulted in greater fecal losses of nutrients and lower intestinal absorption. In the present study we used a diuretic to determine if increasing urine volume could result in greater urinary losses of essential nutrients. This is a relevant question because diuretics are widely and successfully used in the treatment of diseases associated with water retention and hypertension. They are known to increase potassium losses. However, there is less information on the effect of diuretics on the urinary losses of essential nutrients. Accordingly, urinary nitrogen, phosphorous, sodium, potassium, magnesium, zinc and retinol were measured in young rats consuming increasing concentrations of furosemide (0, 0.5, 1.0, 1.5 mg/g diet) in the diet over 15 days. The results showed that dietary furosemide caused a dose-dependent polyuria. In addition it reduced food intake and feed efficiency and leaded to poor growth and greater urinary losses of all the measured nutrients and electrolytes. These losses were proportional to urine volume and represented an important fraction of the rats daily intake. The losses were negatively associated with the body and liver content of the same electrolytes and nutrients. In general, this study showed that the diuretic furosemide caused malnutrition in a short period of time by reducing food intake as well as the capacity of retaining macro and micronutrients including the liposoluble vitamin A in a relatively short period of time. This study, together with our previous studies on diarrhea, indicate that proper nutrient utilization requires both an adequate intestinal and renal function.

Influence of the dielectric medium on the carbonyl infrared absorption peak of acetylferrocene.

The solvent effect on the position of the carbonyl vibrational stretching of acetylferrocene in aprotic media was studied in this work. The solvent-induced shifts in this organometallic compound were interpreted in terms of the alternative reaction field model(SCRF-MO) proposed by Kolling. In contrast to the established trends for carbonyl groups in organic systems, the results suggest that the continuum models for the reaction field are not adequate and that the influence of dipolarity-polarizability described by an inhomogeneous coupling function theta(epsilon )L(n(2)) that assumes optical dielectric saturation is responsible for the carbonyl band shift and, there is empirical evidence that the effect of field-induced intermolecular interaction on band shift, interpreted in terms of the van der Waals forces from the solvent, have a important contribution to this phenomena.

Antinutritional properties of plant lectins.

Lectins are carbohydrate binding (glyco)proteins which are ubiquitous in nature. In plants, they are distributed in various families and hence ingested daily in appreciable amounts by both humans and animals. One of the most nutritionally important features of plant lectins is their ability to survive digestion by the gastrointestinal tract of consumers. This allows the lectins to bind to membrane glycosyl groups of the cells lining the digestive tract. As a result of this interaction a series of harmful local and systemic reactions are triggered placing this class of molecules as antinutritive and/or toxic substances. Locally, they can affect the turnover and loss of gut epithelial cells, damage the luminal membranes of the epithelium, interfere with nutrient digestion and absorption, stimulate shifts in the bacterial flora and modulate the immune state of the digestive tract. Systemically, they can disrupt lipid, carbohydrate and protein metabolism, promote enlargement and/or atrophy of key internal organs and tissues and alter the hormonal and immunological status. At high intakes, lectins can seriously threaten the growth and health of consuming animals. They are also detrimental to numerous insect pests of crop plants although less is presently known about their insecticidal mechanisms of action. This current review surveys the recent knowledge on the antinutritional/toxic effects of plant lectins on higher animals and insects.

Thiazide induces water absorption in the inner medullary collecting duct of normal and Brattleboro rats.

The reduction of urinary volume after the use of thiazide in the treatment of diabetes insipidus (DI) is known as the "paradoxical effect." Since enhanced proximal solute and water reabsorption only partially account for the reduction in urinary volume, an additional diuretic effect on nephron terminal segments was postulated. Thus the aim of our work was to investigate the effect of hydrochlorothiazide (HCTZ) on water transport in the inner medullary collecting duct (IMCD) of normal and Brattleboro rats. Osmotic water permeability (P(f)) and diffusional water permeability (P(dw)) were studied at 37 degrees C and pH 7.4 by the in vitro microperfusion technique. In the absence of antidiuretic hormone (ADH), HCTZ (10(-6) M) added to the perfused fluid enhanced P(f) from 6.36 +/- 0. 56 to 19.08 +/- 1.70 micro(m)/s (P < 0.01) and P(dw) from 38.01 +/- 4.52 to 52.26 +/- 4.38 x10(-5) cm/s (P < 0.01) in normal rats and also stimulated P(f) in Brattleboro rats from 3.53 +/- 1.41 to 11.16 +/- 1.13 micro(m)/s (P < 0.01). Prostaglandin E(2) (PGE(2)) (10(-5) M) added to the bath fluid inhibited HCTZ-stimulated P(f) (in micro(m)/s) as follows: control, 16.93 +/- 2.64; HCTZ, 29.65 +/- 5.67; HCTZ+PGE(2), 10.46 +/- 1.84 (P < 0.01); recovery, 16.77 +/- 4.07. These data indicate that thiazides enhance water absorption in IMCD from normal rats (in the absence of ADH) and from Brattleboro rats and that the HCTZ-stimulated P(f) was partially blocked by PGE(2). Thus we may conclude that the effect of thiazide in the treatment of DI occurs not only in the Na(+)-Cl(-) cotransport in the distal tubule but also in the IMCD.

Vitamin A and beta-carotene can improve nonheme iron absorption from rice, wheat and corn by humans.

After the rapid decrease in the prevalence of iron deficiency and iron-deficiency anemia in the Venezuelan population when a national program for fortification of flours with iron and vitamins was instituted, we studied micronutrient interactions in Venezuelan diets. One hundred human adults were fed three cereal-based diets, labelled with either 59Fe or 55Fe in six studies. Each diet contained different concentrations of vitamin A (from 0.37 to 2.78 micromol/100 g cereal) or beta-carotene (from 0.58 to 2.06 micromol/100 g cereal). The presence of vitamin A increased iron absorption up to twofold for rice, 0.8-fold for wheat and 1.4-fold for corn. beta-carotene increased absorption more than threefold for rice and 1.8-fold for wheat and corn, suggesting that both compounds prevented the inhibitory effect of phytates on iron absorption. Increasing the doses of vitamin A or beta-carotene did not further significantly increase iron absorption. We measured the iron remaining in solution performing in vitro studies in which the pH of solutions was adjusted from 2 to 6 in the presence of vitamin A or beta-carotene. All of the iron from ferrous fumarate was soluble after changing the pH of the solution containing 3.4 micromol of beta-carotene to 6.0. Vitamin A was less effective. However, 78 +/- 18% of iron was soluble in the presence of 3.3 micromol of vitamin A, whereas with no vitamin addition, only 26 +/- 13% of iron was soluble (<0.05). Vitamin A and beta-carotene may form a complex with iron, keeping it soluble in the intestinal lumen and preventing the inhibitory effect of phytates and polyphenols on iron absorption.

Short-term sucralfate administration alters potassium diclofenac absorption in healthy male volunteers.

AIMS: Since patients who regularly take NSAIDS may use sucralfate because of its cytoprotective properties, we examined the influence of this compound on the pharmacokinetics of diclofenac. METHODS: Potassium diclofenac (105 mg) was administered orally to eighteen healthy male volunteers with or without a 5-day pre-treatment with sucralfate (2000 mg twice daily). Blood samples were collected at intervals post-dose and serum concentrations of diclofenac were determined by reverse-phase h.p.l.c. RESULTS: Pre-treatment with sucralfate significantly decreased both the AUC(0,8 h) [2265 ng h ml-1 (geometric mean) (range 1815-2827) vs 1821 ng h ml-1 (1295-2562)] and the Cmax [1135 ng ml-1 (geometric mean) (range 898-1436) 701 ng ml-1 (501-981)] with no significant delay in absorption [tmax 1.0 h (median) (range 0.5-2.0) vs 1.0 h (0.5-4.0)]. CONCLUSIONS: The short-term treatment of healthy male volunteers with sucralfate decreases potassium diclofenac bioavailability. These findings suggest that either an appropriate increase in the diclofenac intake or the use of another gastric mucosa protector must be adopted.

Influence of spontaneous contractions of the lymphatic vessels on the lymphatic absorption rate of the peritoneal cavity in CAPD.

The lymphatic vessels have sympathetic innervation. Noradrenaline increases the number of spontaneous contractions of the lymphatic vessels, whereas isoprenaline slows these contractions. The purpose of this study was to analyze the influence of the blockade of spontaneous contractions of the lymphatic vessels on the lymphatic absorption rate (LAR) in 6 patients on continuous ambulatory peritoneal dialysis (CAPD) by using 0.12 mg of isoprenaline added to 2 L of 2.5% dextrose dialysis solution. This dose of isoprenaline has been shown to inhibit bovine mesenteric lymphatic contractions. The LAR was measured by the quantification of the intraperitoneal disappearance of dextran 70 added to this same dialysis solution during a 4-hour dwell. All patients were submitted to a control test without isoprenaline. The LAR was 0.57 +/- 0.19 and 0.65 +/- 0.38 mL/minute (p > 0.05), with and without isoprenaline, respectively. We conclude that spontaneous contractions of the lymphatic vessels do not play an important role in the lymphatic drainage mechanism of the peritoneal cavity. The diaphragmatic contractions seem to be more important, since drugs that interfere with such diaphragmatic mechanisms alter the LAR.

Penetration of antibiotics through omiderm in vitro and on split-thickness skin grafts in burn patients.

Penetration of antibiotic preparations (gentamicin, neomycin, silver sulfadiazine, mupirocin) through Omiderm, a synthetic wound covering, was tested in vitro and in 5 patients with full-thickness burns who had undergone tangential excision and split-thickness skin grafting. All antibiotic preparations tested penetrated both meshed and unmeshed Omiderm. Omiderm did not affect the zones of inhibition of antimicrobial activity as compared with controls.

Effect of propranolol and nifedipine on in vitro fluid absorption by the isolated perfused proximal convoluted tubule of the rabbit.

The inhibition of fluid absorption (Jv) by the antiarrhythmic and antihypertensive drugs propranolol and nifedipine, which increase cytosolic Ca2+ concentration, was studied using the isolated rabbit proximal convoluted tubule perfused in vitro. Proximal convoluted tubules were perfused and bathed with a modified Krebs-Henseleit solution containing bovine serum albumin. Jv was measured after a 30-min control period, after 40 min with either 0.1 mM propranolol or 1.0 mM nifedipine on the peritubular side and after a 40-min recovery period. Both drugs inhibited Jv (58% propranolol, and 21% nifedipine). The 40-min recovery period was sufficient to reverse the effect of nifedipine, but propranolol-treated tubules (N = 6) only reached 78% of the control Jv value. These results demonstrate that antiarrhythmic and antihypertensive drugs are powerful inhibitors of net fluid absorption by exerting a direct effect on proximal or distal tubule cells, thus acting like "local diuretics".