Synthesis and evaluation of (18)F-labeled 4-nitrobenzyl derivatives for imaging tumor hypoxia with positron emission tomography: Comparison of 2-[(18)F]fluoroethyl carbonate and 2-[(18)F]fluoroethyl carbamate.

Two 4-nitrobenzyl derivatives, 2-fluoroethyl 4-nitrobenzyl carbonate 1 and 4-nitrobenzyl N-2-fluoroethyl carbamate 2, were radiolabeled with (18)F and evaluated for imaging tumor hypoxia with positron emission tomography. Although good tumor uptake was observed for [(18)F]1 and [(18)F]2 (>2.5%ID/g at 3-h post-injection), the tracers cleared slowly from nontarget tissues (>1.5%ID/g) and exhibited extensive defluorination in vivo (>4.0%ID/g for bone). Therefore, [(18)F]1 and [(18)F]2 are not suitable for imaging tumor hypoxia due to suboptimal tumor-to-background contrasts.

Chemical and physical properties of carbonated hydroxyapatite affect breast cancer cell behavior.

Breast microcalcifications are routinely explored for mammographic detection of breast cancer and are primarily composed of non-stoichiometric hydroxyapatite (Ca10-x(PO4)6-x(CO3)x(OH)2-x) (HA). Interestingly, HA morphology and carbonate substitution vary in malignant vs. benign lesions. However, whether or not these changes (i) are functionally linked and (ii) impact malignancy remains unclear due in part to lack of model systems that permit evaluating these possibilities. Here, we have adapted a 96 well-based mineralized culture platform to investigate breast cancer cell behavior in response to systematic changes in the chemical and physical properties of HA. By adjusting the carbonate content of the simulated body fluid (SBF) solutions used during growth, we can control the morphology and carbonate substitution of the deposited HA. Our results suggest that both the combined and individual effects of these differences alter breast cancer cell growth and secretion of tumorigenic interleukin-8 (IL-8). Consequently, changes in both HA carbonate incorporation and morphology impact the behavior of breast cancer cells. Collectively, our data underline the importance of biomineralized culture platforms to evaluate the functional contribution of HA material properties to the pathogenesis of breast cancer. STATEMENT OF SIGNIFICANCE: Breast microcalcifications are small mineral deposits primarily composed of hydroxyapatite (HA). HA physicochemical properties have been of considerable interest, as these are often altered during breast cancer progression and linked to malignancy. However, the functional relationship between these changes and malignancy remains unclear due in part to lack of model systems. Here, we have adapted a previously developed a 96 well-based culture platform to evaluate breast cancer cell behavior in response to systematic changes in HA properties. Our results demonstrate that changes in HA morphology and carbonate content influence breast cancer cell growth and interleukin-8 secretion, and suggest that characterizing the effect of HA properties on breast cancer cells may improve our understanding of breast cancer development and progression.

Siderite (FeCO3) and magnetite (Fe3O4) overload-dependent pulmonary toxicity is determined by the poorly soluble particle not the iron content.

The two poorly soluble iron containing solid aerosols of siderite (FeCO3) and magnetite (Fe3O4) were compared in a 4-week inhalation study on rats at similar particle mass concentrations of approximately 30 or 100 mg/m³. The particle size distributions were essentially identical (MMAD ≈1.4 µm). The iron-based concentrations were 12 or 38 and 22 or 66 mg Fe/m³ for FeCO3 and Fe3O4, respectively. Modeled and empirically determined iron lung burdens were compared with endpoints suggestive of pulmonary inflammation by determinations in bronchoalveolar lavage (BAL) and oxidative stress in lung tissue during a postexposure period of 3 months. The objective of study was to identify the most germane exposure metrics, that are the concentration of elemental iron (mg Fe/m³), total particle mass (mg PM/m³) or particle volume (µl PM/m³) and their associations with the effects observed. From this analysis it was apparent that the intensity of pulmonary inflammation was clearly dependent on the concentration of particle-mass or -volume and not of iron. Despite its lower iron content, the exposure to FeCO3 caused a more pronounced and sustained inflammation as compared to Fe3O4. Similarly, borderline evidence of increased oxidative stress and inflammation occurred especially following exposure to FeCO3 at moderate lung overload levels. The in situ analysis of 8-oxoguanine in epithelial cells of alveolar and bronchiolar regions supports the conclusion that both FeCO3 and Fe3O4 particles are effectively endocytosed by macrophages as opposed to epithelial cells. Evidence of intracellular or nuclear sources of redox-active iron did not exist. In summary, this mechanistic study supports previous conclusions, namely that the repeated inhalation exposure of rats to highly respirable pigment-type iron oxides cause nonspecific pulmonary inflammation which shows a clear dependence on the particle volume-dependent lung overload rather than any increased dissolution and/or bioavailability of redox-active iron.

Repercussão cardiovascular, com e sem álcool, do carbonato de lodenafila, um novo inibidor da PDE5 / Repercusión cardiovascular, con y sin alcohol, del carbonato de lodenafila, un nuevo inhibidor de la PDE5 / Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption

FUNDAMENTO: A disfunção erétil afeta um grande número de homens no mundo e os inibidores de PDE 5 (iPDE5) estão entre os principais métodos de tratamento desses pacientes. O consumo social de álcool e o ato sexual apresentam uma relação considerável. Portanto, a associação entre álcool e iPDE5 pode ocorrer. O carbonato de lodenafila é um novo iPDE5 desenvolvido por uma empresa brasileira. OBJETIVO: Avaliar a repercussão cardiovascular do carbonato de lodenafila, associado ou não ao álcool, assim como as alterações na farmacocinética que esta associação possa determinar. MÉTODOS: Estudo realizado com 15 voluntários sadios que receberam em momentos diferentes o carbonato de lodenafila (CL) na dose de 160 mg em jejum, CL (160 mg) com álcool, ou somente placebo. Esses pacientes foram monitorados por 24 horas, sendo avaliado o quadro clínico, a pressão arterial (PA), a frequência cardíaca (FC), o intervalo QT e também os dados de farmacocinética. RESULTADOS: O carbonato de lodenafila, isoladamente ou associado com álcool, não determinou alterações clínicas significativas na PA ou FC, embora tenha ocorrido diminuição da PA estatisticamente significativa após 4 horas, nos voluntários que receberam medicamento e álcool, assim como um aumento da FC após 6 horas nos pacientes que receberam o CL. A análise do intervalo QT corrigido não mostrou alteração significativa. O álcool aumentou a biodisponibilidade do medicamento em 74 por cento. Houve somente 2 queixas de cefaleia leve, possivelmente associada ao medicamento. CONCLUSÃO: O carbonato de lodenafila, mesmo associado ao álcool, não determinou repercussões clínicas importantes na PA, FC, ou alterações no intervalo QTc; a ingestão com álcool, por sua vez, aumentou significativamente sua biodisponibilidade.

BACKGROUND: Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. OBJECTIVE: This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. METHODS: Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. RESULTS: Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74 percent when drug intake was associated with alcohol. CONCLUSION: These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

FUNDAMENTO: La disfunción eréctil afecta a un gran número de hombres en el mundo y los inhibidores de PDE5 (iPDE5) están entre los principales métodos de tratamiento de estos pacientes. El consumo social de alcohol y el acto sexual presentan una relación considerable. Por lo tanto, puede ocurrir una asociación entre alcohol e iPDE5. El carbonato de lodenafila es un nuevo iPDE5 desarrollado por una empresa brasileña. OBJETIVO: Evaluar la repercusión cardiovascular del carbonato de lodenafila, asociado o no al alcohol, así como las alteraciones en la farmacocinética que esta asociación pueda determinar. MÉTODOS: Estudio realizado con 15 voluntarios sanos que recibieron en momentos diferentes el carbonato de lodenafila (CL) en la dosis de 160mg en ayunas, CL (160 mg) con alcohol, o solamente placebo. Estos pacientes fueron monitoreados por 24 horas, siendo evaluado el cuadro clínico, la presión arterial (PA), la frecuencia cardíaca (FC), el intervalo QT y también los datos de farmacocinética. RESULTADOS: El carbonato de lodenafila, aisladamente o asociado con alcohol, no determinó alteraciones clínicas significativas en la PA o FC, aunque se haya registrado una disminución de la PA estadísticamente significativa después de 4 horas en los voluntarios que recibieron medicamento y alcohol, así como un aumento de la FC después de 6 horas en los pacientes que recibieron el CL. El análisis del intervalo QT corregido no mostró alteración significativa. El alcohol aumentó la biodisponibilidad del medicamento en un 74 por ciento. Se registraron sólo 2 quejas de cefalea leve, posiblemente asociada al medicamento. CONCLUSIÓN: El carbonato de lodenafila, aun asociado al alcohol, no determinó repercusiones clínicas importantes en la PA, FC, o alteraciones en el intervalo QTc; la ingestión con alcohol, a su vez, aumentó significativamente su biodisponibilidad.

Synthesis and in vitro transdermal penetration of methoxypoly(ethylene glycol) carbonate derivatives of stavudine.

The objective of this study was to synthesize derivatives of the anti-HIV drug stavudine (d4T) with more favourable physicochemical properties for transdermal delivery in an effort to increase transdermal penetration of stavudine and thus reduce the severe side effects associated with the dose-dependent oral therapy. The synthesis, hydrolytic stability, and in vitro human skin permeation flux of a series of novel methoxypoly(ethylene glycol) (MPEG) carbonates of stavudine are reported. The carbonates were synthesized in a two-step process by coupling the MPEG promoiety of various chain lengths to C-5' of d4T. In kinetic studies the carbonates proved to be markedly stable in weakly acidic phosphate medium (pH 5.0) with half-lives ranging from 16 to 58 days. The aqueous solubility increased as the ethylene oxide chain lengthened. However, there was no significant increase in the estimated solubility in octanol. In vitro in the phosphate buffer (200 mM; pH 5.0) almost all carbonates permeate the human skin. However, the most effective penetrant, the derivative with 3 ethylene oxide units in the side chain, exhibited a flux of 26.1 nmol/cm(2)/h as compared to 59.15 nmol/cm(2)/h of the parent drug stavudine. Thus, no permeation enhancement was observed during this study.

Macromolecule oxidation and DNA repair in mussel (Mytilus edulis L.) gill following exposure to Cd and Cr(VI).

The oxidation of DNA and lipid was analysed in the marine mussel (Mytilus edulis) in response to exposure (10microg/l and 200microg/l) to cadmium (Cd) and chromium [Cr(VI)]. Concentration dependent uptake of both metals into mussel tissues was established and levels of gill ATP were not depleted at these exposure levels. DNA strand breakage in gill cells (analysed by the comet assay) was elevated by both metals, however, DNA oxidation [measured by DNA strand breakage induced by the DNA repair enzyme formamidopyrimidine glycosylase (FPG)] was not elevated. This was despite a statistically significant increase in both malondialdehyde and 4-hydroxynonenal - indicative of lipid peroxidation - following treatment with Cd. In contrast, both frank DNA stand breaks and FPG-induced DNA strand breaks (indicative of DNA oxidation) were increased following injection of mussels with sodium dichromate (10.4microgCr(VI)/mussel). The metals also showed differential inhibitory potential towards DNA repair enzyme activity with Cd exhibiting inhibition of DNA cutting activity towards an oligonucleotide containing 8-oxo-7,8-dihydro-2'-deoxyguanosine and Cr(VI) showing inhibition of such activity towards an oligonucleotide containing ethenoadenosine, both at 200microg/l. The metals thus show DNA damage activity in mussel gill with distinct mechanisms involving both direct and indirect (oxidative) DNA damage, as well as impairing different DNA repair capacities. A combination of these activities can contribute to adverse effects in these organisms.

Chemical and biological characterization of new Re(CO)3/[99mTc](CO)3 bombesin analogues.

INTRODUCTION: Bombesin, a neuropeptide with potential for breast and prostate tumor targeting, is rapidly metabolized in vivo, and as a result, uptake in tumor xenografts in mice is poor. An improvement can be expected from the introduction of nonnatural amino acids and spacers. Leu13 was replaced by cyclohexylalanine and Met14 by norleucine. Two spacers, -betaAla-betaAla- and 3,6-dioxa-8-aminooctanoic acid, were inserted between the receptor-binding amino acid sequence (7-14) of bombesin (BBS) and the retroN(alpha)-carboxymethyl histidine chelator used for labeling with the [99mTc](CO)3 core and the rhenium (Re) congener. METHODS: The biological characterization of the new compounds was performed both in vitro on prostate carcinoma PC-3 cells (binding affinity, internalization/externalization) and in vivo (biodistribution in nude mice with tumor xenografts). The stability was also investigated in human plasma. The Re analogues were prepared for chemical characterization. RESULTS: The nonnatural amino acids led to markedly slower degradation in human plasma and PC-3 cell cultures. The receptor affinity of the new technetium 99m ([99mTc])-labeled BBS analogues was similar to the unmodified compound with Kd<1 nM. Uptake in the pancreas and in PC-3 tumor xenografts in nude mice was blocked by unlabeled BBS. The best target-to-nontarget uptake ratio was clearly due to the presence of the more polar spacer, -betaAla-betaAla-. CONCLUSIONS: The different spacers did not have a significant effect on stability or receptor affinity but had a clear influence on the uptake in healthy organs and tumors. Uptake in the kidneys was lower than in the liver, which is likely to be due to the lipophilicity of the compounds. A specific, high uptake was also observed in the gastrin-releasing peptide receptor-rich pancreas. Thus, with the introduction of spacers the in vivo properties of the compounds can be improved while leaving the affinity unaffected.

Modification and uptake of a cisplatin carbonato complex by Jurkat cells.

The interactions of Jurkat cells with cisplatin, cis-[Pt(15NH3)2Cl2]1, are studied using 1H-15N heteronuclear single quantum coherence (HSQC) NMR and inductively coupled plasma mass spectrometry. We show that Jurkat cells in culture rapidly modify the monocarbonato complex cis-[Pt(15NH3)2(CO3)Cl]- (4), a cisplatin species that forms in culture media and probably also in blood. Analysis of the HSQC NMR peak intensity for 4 in the presence of different numbers of Jurkat cells reveals that each cell is capable of modifying 0.0028 pmol of 4 within approximately 0.6 h. The amounts of platinum taken up by the cell, weakly bound to the cell surface, remaining in the culture medium, and bound to genomic DNA were measured as functions of time of exposure to different concentrations of drug. The results show that most of the 4 that has been modified by the cells remains in the culture medium as a substance of molecular mass <3 kDa, which is HSQC NMR silent, and is not taken up by the cell. These results are consistent with a hitherto undocumented extracellular detoxification mechanism in which the cells rapidly modify 4, which is present in the culture medium, so it cannot bind to the cell. Because there is only a slow decrease in the amount of unmodified 4 remaining in the culture medium after 1 h, -1.1 +/- 0.4 microM h(-1), the cells subsequently lose their ability to modify 4. These observations have important implications for the mechanism of action of cisplatin.

Sorption of cobalt and nickel on anaerobic granular sludges: isotherms and sequential extraction.

The objective of this study was to investigate the sorption capacity and the fractionation of sorbed nickel and cobalt onto anaerobic granular sludges. Two different anaerobic granular sludges (non-fed, pH=7) were loaded with nickel and cobalt in adsorption experiments (monometal and competitive conditions). The combination of sequential extraction with the sorption isotherm analysis allowed the assessment of the sorption capacity of individual fractions present in the anaerobic granular sludges. The operational fractionation of the sorbed heavy metals was determined using a modified Tessier sequential extraction procedure. The sorption characteristics of each extracted fraction (exchangeable, carbonates, organic matter/sulfides and residual fractions) fitted well to the Langmuir model. The organic matter/sulfides fraction showed the highest affinity for cobalt and nickel in both sludges investigated compared to the other operationally defined fractions. The presence of iron negatively affected cobalt and nickel accumulation in this organic matter/sulfides fraction. The trace metals-iron sulfide interactions are likely to be the key process in controlling the distribution of cobalt and nickel during sorption onto non-fed methanogenic granules due to the high affinity of iron sulfides towards the metals studied.

Synthesis and biological evaluation of bis and monocarbonate prodrugs of 10-hydroxycamptothecins.

In an effort to improve the stability of labile lactone ring of camptothecins, the bis and mono-alkyl carbonate prodrugs of 10-hydroxycamptothecins were synthesized and their chemical and enzymatical stability as well as antitumor activity were studied. The in vitro evaluation of the stability of these carbonates indicates that the 10,20-biscarbonates are firstly hydrolyzed to afford the stable 20-monocarbonates. And the 10-carbonates are not stable in human plasma, mouse plasma and pH7.4 phosphate buffer, while the 20-carbonates are relatively stable in the three media and can be readily cleaved by porcine liver esterase. The overall toxicity of the tested carbonate against mice bearing S180 sarcoma is much lower when compared with the parent compound, and the antitumor activity is maintained.

Biodistribution of cyclic carbonate of ioxilan: a radiopaque particulate macrophage imaging agent.

RATIONALE AND OBJECTIVES: A biodegradable radiopaque particulate contrast agent formulated from cyclic carbonate of ioxilan (IXC), which is a prodrug of nonionic water-solubel contrast ioxilan, recently has been developed. This contrast agent enhances liver attenuation and is cleared from the body as ioxilan. In the current study, we tested whether the biodistribution of IXC particles would be affected by the characteristics of particles. METHODS: IXC nanoparticles (average diameter = 290 nm) and IXC microparticles (average diameter = 1.7 mm) were prepared, characterized, and injected intravenously (i.v.; 50 mg I/kg body weight) into rats. Two sensitive, reproducible analytic methods--inductively coupled plasma-mass spectrometry (ICP-MS) and high-performance liquid chromatography (HPLC)- were used to quantify tissue iodine and ioxilan concentrations. RESULTS: Both IXC nanoparticles and microparticles were taken up in the liver and spleen. The IXC nanoparticles remained in the liver at high concentrations for 6 hr and were slowly cleared. They also gave a high blood iodine concentration in the first 5 min after i.v. injection, suggesting their potential use as a blood-pool imaging agent. Unlike the nanoparticles, the microparticles had a significantly lower uptake by the kidney. CONCLUSION: Because of reduced renal uptake, microparticles are a preferred macrophage imaging agent. Biodegradable radiopaque particles may be used either as blood-pool imaging agents or as macrophage imaging agents depending on their size and distribution characteristics. The ICP-MS and HPLC methods are useful for biodistribution studies of iodinated contrast agents.

Preclinical evaluation of manganese carbonate particles for magnetic resonance imaging of the liver.

RATIONALE AND OBJECTIVES: We characterized the physical, biological, and imaging properties of a manganese (Mn) carbonate particle suspension, a contrast agent for hepatic magnetic resonance (MR) imaging. METHODS: Mn carbonate suspensions were produced by controlled precipitation and characterized using light microscopy, transmission electron microscopy, and in vitro relaxivity studies. Efficacy of the agent was studied in normal and tumor-bearing rats using T1-weighted MR imaging. RESULTS: Following intravenous injection of Mn carbonate particles at doses ranging from 10 to 100 mumol Mn/kg, peak hepatic contrast enhancement of approximately 35% occurred from about 125 min until the termination of the MR imaging studies that varied from 125 to 305 min. Lesion conspicuity was increased because of relative intensity differences between normal liver and tumor. Data also showed that Mn carbonate particles dissolved on delivery to the liver, allowing Mn to interact with intrahepatic macromolecular complexes to provide positive contrast enhancement. CONCLUSION: Mn carbonate particles produce significant and sustained hepatic enhancement and should improve detection of small or isointense liver lesions.

Preparation, characterization, and evaluation of ioxilan carbonate particles for computed tomography contrast enhancement of liver.

RATIONALE AND OBJECTIVES: To prepare and characterize a new particulate contrast medium, cyclic carbonate of ioxilan (IX-C) particles, as a macrophage imaging agent for computed tomography (CT) enhancement of the liver. METHODS: Cyclic carbonate of ioxilan was synthesized from ioxilan, a nonionic water-soluble contrast agent. The IX-C particles prepared by a solvent extraction-evaporation method were characterized by size distribution, degradability, suspension stability, and median lethal dose. Pharmacokinetics of IX-C particles and their effectiveness in enhancing liver attenuation and in detecting hepatic tumors were evaluated using normal and VX2-tumor-bearing rabbits. RESULTS: The IX-C particles were biodegradable, with ioxilan and carbon dioxide as the degradation products. The particles had an average size of 1 to 2 microns and were stable in saline suspension. The median lethal dose determined for IX-C particles was 2.6 and 3.1 g/kg body weight for female and male rabbits, respectively. A dose of 200 mg iodine/kg body weight caused an increase of 38 Hounsfield units in liver attenuation. In rabbit, hepatic clearance of the contrast medium occurred in 2 days. A tumor barely visible in precontrast scans could be detected after contrast injection. CONCLUSIONS: Development of particulate contrast medium from nonionic contrast agents represents a new approach. Ioxilan carbonate particles have suitable physicochemical properties that warrant further studies before clinical evaluation.

Effect of copper and iron on neutrophil function and humoral immunity of gestating beef cattle.

Eighty gestating beef cattle were used to determine the effect of trace mineral salt mixtures containing copper (Cu) and iron (Fe) on selected immune functions and factors affecting copper bioavailability. Pastured cattle were randomly assigned to receive one of the following combinations of Cu and Fe in the free-choice trace mineral salt: (1) 0 mg of Cu/0 mg of Fe/kg of trace mineral salt, (2) 1,600 mg of Cu (CuSO4)/3,000 mg of Fe/kg of trace mineral salt, (3) 1,600 mg of Cu (CuSO4)/0 mg of Fe/kg of trace mineral salt, and (4) 1,600 mg of Cu (CuCO3)/3,000 mg of Fe/kg of trace mineral salt. Total Cu/Fe consumption (from trace mineral salt) was 2/678, 193/1,050, 162/553, and 202/1,140 mg/head/d, respectively, for the 4 groups. After a 1-month period of acclimation and also on day 28 of the 36-day study, copper concentrations in serum were significantly (P < 0.05) lower in group 1 than in groups 3 and 4. Serum copper concentrations did not increase with time for any group, whereas hepatic copper concentrations increased significantly (P < 0.05) with time for all groups except group 1. Hepatic iron concentrations were similar among groups at the time of the initial and final hepatic biopsies on days 0 and 28, respectively. Hepatic iron concentrations increased significantly (P < 0.05) with time in groups 3 and 4. Humoral response to chicken gamma-globulin was high but did not differ among groups on any of the days analyzed.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrogenic anion absorption in rabbit distal colon.

The mechanisms of anion transport in the rabbit distal colon were investigated in vitro under short-circuit conditions by examining the effects of transport inhibitors (the stilbene derivatives SITS and DIDS) under a variety of conditions. These agents consistently inhibited Jm-sCl: SITS (10(-3) M) reduced both unidirectional chloride fluxes to the same degree and did not alter JnetCl. In contrast, 10(-4) M DIDS had no effect on Js-mCl and had a significant chloride antiabsorptive effect. DIDS had no effect on either tissue cyclic AMP levels or on basal flux of potassium. The effects of SITS and the cyclic AMP-related secretagogue theophylline on Isc were independent. Additionally, there was no significant alteration of intracellular potential difference or apical membrane fractional resistance elicited by SITS during microelectrode impalement of colonic surface epithelial cells. These results suggest a complex mechanism of anion transport in the distal colon, with a component of electrogenic anion absorption inhibited by the stilbenes. The subsequent changes in current, conductance, and chloride fluxes are dependent upon additional, independent anion transport processes. These pharmacologic agents exhibit an antiabsorptive effect, rather than a stimulation of electrogenic chloride secretion.

A preliminary study of the bioavailability of iron- and zinc-glycine chelates.

Groups of rats were fed diets containing marginal levels of Fe and Zn as glycine chelates (tradename 'Chelazome', Albion Laboratories, Verona, New Jersey, USA), or the same level of mineral as ferrous sulphate or zinc carbonate. The Fe diets were fed to weanling rats for 4 weeks and the Zn diets to young adult rats for 5 weeks. Blood Hb concentrations were significantly higher in the group fed Fe-chelazome than ferrous sulphate, 149 and 128 g/l respectively (P less than 0.001), but PCV and liver Fe concentrations were similar between the two groups. No difference in plasma Zn, pancreas, testes or femur Zn concentrations were observed between the two Zn groups, indicating that Zn-chelazome has no advantage over zinc carbonate. The results of this preliminary study indicate that Fe-chelazome has a higher bioavailability than ferrous sulphate and merits further study.

Comprimidos de carbonato de lítio: influência da técnica de obtençäo na velocidade de liberaçäo do princípio ativo / Lithium carbonate tablets: preparation techniques influence over active ingredient liberation

Comprimidos de carbonato de lítio, obtidos através dos processos que aplicam a granulaçäo por via úmida e por via seca, foram avaliados in vitro quanto à velocidade de dissoluçäo do princípio ativo. Empregaram-se, no estudo, formulaçöes padronizadas e estruturadas com excipientes tradicionais (lactose e amido). Paralelamente ao estudo de dissoluçäo, analisou-se a influência do processo de obtençäo sobre algumas características físicas dos comprimidos (dureza, friabilidade e tempo de desagregaçäo). Embora observando-se melhor performance de liberaçäo para os comprimidos obtidos por via seca, concluiu-se que o processo por via úmida é o mais adequado para a preparaçäo de comprimidos com o fármaco em questäo

Use of 111In-labeled alginate to study the pH dependence of alginic acid anti-esophageal reflux barrier.

Mixtures of alginic acid and antacid, when given orally, react with gastric acid to form a viscous barrier (raft) which floats on the surface of the gastric contents. 111In was used to label magnesium alginate in order to study the effect of gastric acidity on the extent of formation of the raft. In vitro, acid concentrations less than 0.05 N diminished raft formation. In vivo, raft formation was significantly better in normal subjects who ingested dilute acid with the labeled alginate/antacid than in subjects who ingested the labeled alginate/antacid with plain water. Gastric emptying of the labeled alginate was also slowed by the presence of acidified gastric contents. These results suggest that the formation of an effective alginic acid antireflux barrier requires acidic gastric contents.