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Biomedical subjects

F Giordano

Publications and source records attributed to F Giordano.

At least 37 records · Page 2Linked to original sources
PubMed2001

Influence of betacyclodextrin on the release of poorly soluble drugs from inert and hydrophilic heterogeneous polymeric matrices.

The release behavior of poorly soluble drugs (naproxen and ketoprofen) from inert (acrylic resins) and hydrophilic swellable (high-viscosity hydroxypropylmethylcellulose) tableted matrices containing betacyclodextrin (betaCD) was investigated. The results demonstrated that, in both cases, betaCD can enhance the rate of drug release. Matrices obtained from formulations in which lactose replaced betaCD were also evaluated. BetaCD in inert matrices causes a dramatic increase in the rate of drug release, higher than that promoted by lactose which merely acts as a channelling agent. This result suggests that possible in situ formation of the drug-betaCD complex. which causes an improvement in apparent drug solubility, could have a greater influence on the rate of drug release than the possible increase of water uptake by a soluble filler. Indeed, if the opposite were true, lactose would be more effective in increasing the rate of drug release than betaCD, because of its greater solubility in water. On the contrary, in the case of hydrophilic matrices, lactose proves to be much more effective in promoting drug release than betaCD. It seems that, while the bulky interaction compound can freely diffuse through water-filled pores of inert systems, its diffusion through swollen macromolecular chains of hydrophilic matrices may be hindered. This hypothesis was supported by data obtained from binary (drug/polymer) and ternary (drug/polymer/betaCD) hydrophilic matrices using a betaCD-containing dissolution media.

Biocompatible Materials↗
PubMed2001

Solubility and conversion of carbamazepine polymorphs in supercritical carbon dioxide.

The aim of this work was to investigate whether mixtures of carbamazepine polymorphs could be processed in supercritical (SC) CO(2) in order to obtain the pure stable crystalline phase. To accomplish this goal the solubility of carbamazepine polymorphs I and III in supercritical CO(2) was first assessed using a low solvent flux dynamic method. Mixtures of Form I and Form III were processed in dynamic or static conditions in SC-CO(2). Differential scanning calorimetry, Fourier transformed infrared spectroscopy, and powder X-ray diffractometry were used to analyse solid samples in terms of polymorph composition. It was found that Form I and Form III of carbamazepine have different solubility in supercritical CO(2) at 55 degrees C above 300 bar. Due to the transformation of the metastable form, conversion of Form I into Form III can be carried out on a binary mixture of the two polymorphs by treating the mixture at 55 degrees C and 350 bar, under both static and dynamic conditions, via its solubilization in supercritical CO(2).

Calibration↗
PubMed2001

Renal pathological changes in Fabry disease.

Fabry disease is a rare X-linked disorder, characterized by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to systemic accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in all body tissues and organs, including the kidney. Renal manifestations are less evident in female heterozygotes than in male hemizygotes, according to the Lyon hypothesis. Accumulation of Gb3 occurs mainly in the epithelial cells of Henle's loop and distal tubule, inducing early impairment in renal concentrating ability; involvement of the proximal tubule induces Fanconi syndrome. All types of glomerular cells are involved, especially podocytes, and glomerular proteinuria may occur at a young age. The evolution of renal Fabry disease is characterized by progressive deterioration of renal function to end-stage renal failure (ESRF). Ultrastructural study of kidney biopsies reveals typical bodies in the cytoplasm of all types of renal cells, characterized by concentric lamellation of clear and dark layers with a periodicity of 35-50 A. Management of progressive renal disease requires dietetic and therapeutic strategies, usually indicated in developing chronic renal failure, with dialysis and renal transplantation required for patients with ESRF. The recent development of enzyme replacement therapy, however, should make it possible to prevent or reverse the progressive renal dysfunction associated with Fabry disease.

Disease Progression↗
PubMed2001

Extracellular matrix globules in renal oncocytoma.

Extracellular hyaline globules resulting from abnormal accumulation of matrix components have been described in several pathological conditions, including renal tumors. We studied 16 renal oncocytomas and observed these bodies in 11 of them. In these tumors, they showed a homogeneous texture as well as roundish, smooth contours, and were easily detected in hematoxylin-eosin sections in five cases. PAS staining greatly facilitated the identification of globules in the remaining six cases, where they were fewer in number. Immunohistochemically, they appeared to be composed primarily of basement membrane material, being strongly reactive to antibodies for type IV collagen, laminin, and heparan sulphate proteoglycan. In addition, a weak immunoreactivity for type I and type III collagen, and fibronectin was observed in some cases, whereas no globule stained for tenascin. We also analyzed 89 renal cell carcinomas, and found somewhat similar bodies in 10 of them. However, they were more scanty in the latter tumors, and displayed a more irregular configuration with granular or smudged contours. We conclude that, although the mere presence of extracellular hyaline globules does not justify a distinction between renal oncocytoma and renal cell carcinoma, the detection of a large number of well-demarcated, roundish extracellular bodies with smooth contours suggests renal oncocytoma.

Adenoma, Oxyphilic↗
PubMed2001

Sudden presentation of intracranial meningioma after elective general anesthesia.

A case of "silent" intracranial meningioma unmasked by narcosis is described. The diagnosis was made because of the patient's failure to wake up after elective general anesthesia for orthopaedic surgery. Factors leading to this complication and its management are discussed. Early computed tomography scan and antiedema therapy are strongly suggested for these patients.

Anesthesia, General↗
PubMed2001

Hypocomplementemic type II membranoproliferative glomerulonephritis in a male patient with familial lecithin-cholesterol acyltransferase deficiency due to two different allelic mutations.

Patients with familial lecithin-cholesterol acyltransferase (LCAT) deficiency very often show progressive glomerulosclerosis with evolution to end-stage disease. High levels of an abnormal lipoprotein (lipoprotein X) cause glomerular capillary endothelial damage. The ultrastructural study of renal biopsy specimens shows characteristic glomerular deposits of membrane-like, cross-striated structures and vacuole structures. The gene encoding for LCAT has been mapped to chromosome 16q22.1, and several mutations of this gene cause LCAT deficiency which is inherited as an autosomal recessive trait and which is characterized by corneal opacities, normochromic normocytic anemia, and renal dysfunction. Herein we report clinical features and renal histological findings concerning a 24-year-old male patient with classical familial LCAT deficiency due to two different allelic mutations: a nonsense mutation inherited from the father and a missense mutation inherited from the mother. Moreover, the patient showed glomerular histological lesions and an immunofluorescent glomerular pattern typical of hypocomplementemic membranoproliferative type II glomerulonephritis (dense-deposit disease). The nature of electron-dense material that characterizes dense-deposit disease is still unknown, but there are suggestions that some chemical modifications might occur in the renal basement membranes. Therefore, this clinical case might induce to consider possible relations between disorders of the lipoprotein metabolism and renal dense-deposit disease.

Adult↗
PubMed2001

Effects of tri-iodothyronine on alternative splicing events in the coding region of cytochrome P450 aromatase in immature rat Sertoli cells.

Transient postnatal hypothyroidism in male rats induces a prolonged proliferation of immature Sertoli cells. This change in Sertoli cell replication at young ages is coincident with enhanced and prolonged aromatase activity that leads to a marked increase in the conversion of androgens into estrogens. Both events are drastically inhibited by tri-iodothyronine (T(3)) replacement either in vivo or in vitro. This study, after the immunolocalization of aromatase in cultured rat Sertoli cells, examined the effects elicited by T(3) on this enzyme, by simultaneously investigating three functional levels of aromatase: mRNA expression, protein content, and enzymatic activity. The immunolocalization of cytochrome P450 aromatase (P450 arom) was shown in the cytoplasm of cultured Sertoli cells from 15- and 21-day-old rats. Western blot analysis revealed an enhancement of aromatase protein content upon stimulation with N(6),2'-O-dibutyryladenosine-3':5'-cyclic monophosphate ((Bu)(2)cAMP) that was clearly down-regulated by T(3). The presence of a functional P450 arom protein in purified Sertoli cells was confirmed by the measurement of [(3)H]H(2)O released after incubation with [1 beta-(3)H]androst-4-ene-3,17-dione. With 100 nM T3, a decrease in both P450 arom mRNA levels and aromatase activity was observed. The aromatase enzymatic activity was strongly stimulated by (Bu)(2)cAMP and markedly down-regulated by T(3). In contrast, the strong increase in aromatase mRNA upon (Bu)(2)cAMP stimulation was apparently unaffected by T(3) administration. This paper shows how the identification of an altered transcript induced by T(3) coding for putative truncated and inactive aromatase protein might explain such a decrease in aromatase activity in T(3)-treated cells. On the basis of these results, it is concluded that at least two mechanisms could be involved in the down-regulatory effect of T(3) on aromatase activity in prepuberal Sertoli cells. The first mechanism is linked to a possible direct modulatory role for T(3) in the regulation of the aromatase promoter, whilst the second one is represented by the induction of altered transcripts coding for truncated and inactive aromatase proteins.

Alternative Splicing↗
PubMed2000

Stereoselectivity and chiral recognition in copper(I) olefin complexes with a chiral diamine

Trigonal copper(I) complexes of the chiral bidentate ligand (1S,2S)-N,N'-Bis-(mesitylmethyl)-1,2-diphenyl-1,2-ethanediamine ((S,S)-1) have been prepared with hydrocarbon olefins, as well as with allylic alcohols and ethers. The stereochemistry of the complexes has been investigated by 1H NMR spectroscopy and by combined quantum mechanics and molecular mechanics (QM/MM) computational methods. The coordinated chiral nitrogen atoms can display equal (R, R) or opposite (R, S) configuration, the latter being disfavored if steric hindrance is present above and below the coordination plane. Although the complexes exist as rapidly equilibrated mixtures of stereoisomers, one of these is often dominant, and prochiral olefins are coordinated with high enantioface selection. In addition, the [(S,S)-1]-Cu+ fragment selectively recognizes the R enantiomer of secondary allylic alcohols and ethers, as confirmed by the X-ray crystal structure analysis of the adduct with (R)-1-buten-3-ol. The reasons for the observed selectivities have been elucidated, and lead to some implications which are consistent with the enantioselection observed in catalytic cyclopropanation reactions promoted by copper complexes of the same ligand.

Journal Article↗
PubMed2000

Study of omeprazole-gamma-cyclodextrin complexation in the solid state.

The possibility of obtaining inclusion complexes between omeprazole (OME) and gamma-cyclodextrin (gamma-CD) by kneading, spray-drying, coprecipitation, and freeze-drying was evaluated. All these methods lead to the isolation of a true inclusion compound, as evidenced by differential scanning calorimetry (DSC), infrared spectroscopy, and X-ray diffractometry on powder (PXRD). Moreover, PXRD and scanning electron microscopy (SEM) afforded data concerning crystallinity and surface characteristics of the solid phases obtained. In all cases, a significant increase of the release rate with respect to the drug alone was found, and it was attributed to the formation of an inclusion compound. Among the solid phases obtained, the comprecipitated product presented the highest dissolution rate.

Anti-Ulcer Agents↗
PubMed2000

Isoforms of vascular endothelial growth factor act in a coordinate fashion To recruit and expand tumor vasculature.

Vascular endothelial growth factor (VEGF) is an essential regulator of vascularization. It is expressed as several splice variants; the major forms contain 120 amino acids, 164 amino acids, and 188 amino acids. We utilized transformed cells nullizygous for VEGF to specifically express each of these isoforms in isolation, in order to determine the role of each in tumorigenic neo-vascularization. We found that only the intermediate isoform, VEGF164, could fully rescue tumor growth; VEGF120 partially rescued tumor growth, and VEGF188 failed completely to rescue tumor expansion. Surprisingly, the vascular density of VEGF188 isoform-expressing tumors is significantly greater than that of wild-type VEGF cells and the other isoform-specific tumors. The failure of the hypervascular VEGF188-expressing tumors to grow may be due to inadequate perfusion of the massive number of microvessels in these tumors; three-dimensional imaging of the tumorigenic vasculature indicated little or no recruitment of the peripheral vasculature. This demonstrates that the VEGF isoforms perform unique functions which together enable tumorigenic vascularization.

Alternative Splicing↗
PubMed2000

Characterization of endothelial cells isolated by human meningiomas.

BACKGROUND: Meningiomas are common neoplasms of central nervous system characterized by a prominent angiogenesis in some histological subtypes and in some phase of their progression. Angiogenesis is a required event for the progression of solid tumor. However there are increasing evidences that the biological features of endothelial cells in the tumor other than the microvessel number dictate the behavior of cancer disease. In the present study we have tested the hypothesis that in vitro endothelial cells originated by human meningiomas have a different phenotype from that of normal capillary endothelial. METHODS: To isolate endothelial cells we have used a new technical approach principally based on collagenase digestion of the tissues followed by capture of endothelial cells obtained through molecules recognizing specific endothelial markers conjugated to magnetic beads. RESULTS: By using beads conjugated with a monoclonal antibody anti CD-36 we have separated with high efficiency and purity meningioma endothelial cells and established three cell cultures. These cells uptake acetylated LDL and express CD-31, CD-36, nitric oxide synthase type III, von Willebrand factor, which are specific markers of endothelial cells. Their mitogenic and motogenic potential in resting conditions or after stimulation with vascular endothelial growth factor-A is superimposable to that of normal capillary endothelial cells. However meningioma endothelial cells produce higher amount of interleukin-6 and of monocyte chemotactic peptide-1 than control cells. CONCLUSIONS: The establishment of a new and suitable technique to isolate endothelial cells from human cancers can be useful to learn more on angiogenic mechanisms in tumor progression. Furthermore, the data shown underline the possible pathogenic role in meningioma progression of infiltrating macrophages triggered by monocyte chemotactic peptide-1 released by tumor endothelial cells.

Adrenal Glands↗
PubMed1999

Distribution of khellin in excised human skin following iontophoresis and passive dermal transport.

The aim of this work was to study in vitro khellin distribution into human skin after passive or iontophoretic transport. The experiments were performed on excised human skin, using vertical Franz-type diffusion cells. The effects of current application and reservoir pH were studied. At the end of the experiments the skin was sliced thinly and the drug was extracted and analyzed by HPLC. The results showed that khellin is able to penetrate through stratum corneum, to reach basal epidermis and upper dermis. The application time proved to be an important parameter. Current application (30 min; 0.5 mA/cm(2)), with a donor at pH 7.0, favored khellin accumulation even if the drug is not ionized. On the contrary, the use of a formulation at pH 3.2 inhibited drug accumulation. Leaving the drug reservoir in contact with the skin for 30 min after current application led to a dramatic increase of khellin concentration. A combination of dermal iontophoresis and passive diffusion is then a useful technique to govern khellin distribution in the skin.

Chromatography, High Pressure Liquid↗
PubMed1999

The role of TGFbeta1 in initiating hepatic stellate cell activation in vivo.

BACKGROUND/AIMS: The activation of hepatic stellate cells is a key initiating event in hepatic fibrogenesis. Although TGFbeta1 is a potent inducer of collagen alpha1(I) expression in vitro and elevated levels of TGFbeta1 are found in patients and experimental animals with hepatic fibrosis and cirrhosis, the role of increased TGFbeta1 in the initiation of hepatic stellate cell activation in vivo is unknown. We used two experimental approaches to study this relationship: 1) Induction of an acute liver injury with carbon tetrachloride (CCl4) in normal and TGFbeta1-knockout (ko) mice, and 2) overexpression of TGFbeta1 in the liver of wild-type mice using a recombinant replication-deficient adenovirus encoding human TGFbeta1 (Ad-TGFbeta1). METHODS: TGFbeta1-ko mice (n=6) and normal mice (n=6) were injected once intraperitoneally (i.p.) with CCl4 (1 microl/g BW) or mineral oil. Wild-type mice (n=3) were injected intravenously with Ad-TGFbeta1 (10(10) pfu) or a control virus expressing beta-galactosidase (Ad-LacZ, 10(10) pfu). Animals were sacrificed after 3 days and total liver RNA was prepared. The expression of collagen alpha1(I) mRNA normalized to GAPDH mRNA was measured by RNase protection assay, asmooth muscle actin (alpha-sma) protein expression was analyzed by Western blotting. The expression of TGFbeta1, TGFbeta2, and TGFbeta3 mRNAs were determined semi-quantitatively with RT-PCR. RESULTS: The collagen alpha1(I) mRNA was increased 10-fold in CCl4-treated wild-type mice compared to the controls. This increase was reduced about 80% in the TGFbeta1-ko mice. The TGFbeta1 mRNA levels in the wild-type mice were proportional to the collagen alpha1(I) mRNA levels. a-sma, a marker of hepatic stellate cell activation, was expressed earlier and at a higher level in wild-type mice than TGFbeta-ko mice after CCl4 treatment. The Ad-TGFbeta1 infected mice had 14-fold higher hepatic TGFbeta protein levels and 15-fold higher collagen alpha1(I) mRNA levels than the Ad-LacZ-infected control mice. Collagen alpha1(I) mRNA levels were proportional to the transgenic TGFbeta1 mRNA levels, while the endogenous TGFbeta1 was only slightly higher than in the controls. TGFbeta2 and TGFbeta3 mRNA levels were elevated in CCl4-treated wild-type and TGFbeta1-ko mice and in Ad-TGFbeta1-infected mice compared to the controls. CONCLUSIONS: Absence of TGFbeta1 inhibits hepatic collagen alpha1(I) mRNA and alpha-sma protein expression by the toxic stimulus CCl4, and targeted TGFbeta1 overexpression increases collagen alpha1(I) mRNA and alpha-sma protein levels in the liver in vivo. Other TGFbeta family members do not compensate for the TGFbeta1 deficiency. This indicates that TGFbeta1 accelerates, but is not absolutely required, for the activation of hepatic stellate cells.

Actins↗
PubMed1999

Pathological relevance of epithelial and mesenchymal phenotype plasticity.

Epithelium and mesenchyme, two tissue types virtually found in every organ, are endowed with fundamentally different functional properties. Active motility, a capability that is limited to the mesenchymal repertoire, is the principal characteristic that distinguishes them. During embryonic development, conversions from epithelium to mesenchyme and from mesenchyme to epithelium normally occur, allowing morphogenetic processes and tissue remodelling to take place. However, there is now increasing evidence that the modulation between the epithelial and the mesenchymal phenotypes is not limited to embryonic life. Indeed, the pathogenesis of some adult diseases seems to implicate an inappropriate activation of this change. On the other hand, failure of normally occurring embryonic epithelial-mesenchymal interconversions could result in the development of some pathologies. It is now possible to study some molecular events underlying these phenotype transitions, since several biological agents implicated in the epithelial-mesenchymal interconversion, such as growth factors, extracellular matrix components and their receptors, transcription factors and oncogenes have been identified. The malignant potential of some oncogenes seems to express itself through the disruption of the mechanisms involved in the maintenance of the epithelial phenotype while, on the other hand, some observations suggest the existence of regulatory genes able to counteract the action of oncogenes by restoring epithelial characteristics. Therefore, the manipulation of the tissue phenotype could represent a novel strategy for the prevention and treatment of diseases in the future.

Bone Neoplasms↗
PubMed1999

Physical properties of parabens and their mixtures: solubility in water, thermal behavior, and crystal structures.

The peculiar solubility behavior of propylparaben (propyl ester of 4-hydroxybenzoic acid) in aqueous solution, when tested separately and together with methyl-, ethyl-, and butyl-parabens, has been investigated in detail. The results clearly indicate that the decrease in solubility (approximately 50% compared to the solubility value of propylparaben alone) is typical of those mixtures containing also ethylparaben, as demonstrated by solubility experiments on binary, ternary, and quaternary mixtures of the parabens. Phase diagrams of all the six binaries show that propylparaben and ethylparaben are the only pair that form almost ideal solid solutions near the melting temperatures. Moreover, phase-solubility analysis shows that propylparaben and ethylparaben, at room temperature, can also form solid solutions whose solubility is related to the composition of the solid phase at equilibrium. To achieve an independent confirmation of the possible solid solution formation that supports the above interpretation of the solubility behavior, the crystal structures of the four parabens have been examined and isostructurality has been found to exist only between ethylparaben and propylparaben. Powder X-ray diffraction has also been performed on ethylparaben, propylparaben, and their solid solutions obtained by recrystallization from water. The progressive shift of distinctive diffraction peaks with phase composition clearly indicates that propylparaben and ethylparaben form substitutional solid solutions. The small value (<1) of the disruption index provides thermodynamic support for substitutional solid solutions based on isostructural crystals.

Calorimetry, Differential Scanning↗