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S Martelli

Publications and source records attributed to S Martelli.

At least 19 recordsLinked to original sources
PubMed2002

Anthrapyridones, a novel group of antitumour non-cross resistant anthraquinone analogues. Synthesis and molecular basis of the cytotoxic activity towards K562/DOX cells.

1. Multidrug resistance (MDR) to antitumour agents, structurally dissimilar and having different intracellular targets, is the major problem in cancer therapy. MDR phenomenon is associated with the presence of membrane proteins which belong to the ATP-binding cassette family transporters responsible for the active drug efflux leading to the decreased intracellular accumulation. 2. The search of new compounds able to overcome MDR is of prime importance. 3. Recently we have synthesized a new family of anthrapyridone compounds. The series contained derivatives modified with appropriate hydrophobic or hydrophylic substituents at the side chain. 4. The interaction of these derivatives with erythroleukemia K562 sensitive and K562/DOX resistant (overexpressing P-glycoprotein) cell lines has been examined. The study was performed using a spectrofluorometric method which allows to continuously follow the uptake and efflux of fluorescent molecules by living cells. 5. It was demonstrated that the increase in the lipophilicity of anthrapyridones favoured the very fast cellular uptake exceeding the rate of P-gp dependent efflux out of the cell. For these derivatives, very high accumulation (the same for sensitive and resistant cells) was observed and the in vitro biological data confirmed that these compounds exhibited comparable cytotoxic activity towards sensitive and P-gp resistant cell line. In contrast, anthrapyridones modified with hydrophylic substituents exhibited relatively low kinetics of cellular uptake. 6. For these derivatives decreased accumulation in resistant cells was observed and the in vitro biological data demonstrated that they were much less active against P-gp resistant cells in comparison to sensitive cells. 7. We also studied, using confocal microscopy, the intracellular distribution of anthrapyridones in NIH-3T3 cells. Our data showed that these compounds were strongly accumulated in the nucleus and lysosomes.

3T3 Cells↗
PubMed2002

Comparison of three kinematic analyses of the knee: determination of intrinsic features and applicability to intraoperative procedures.

The evaluation of knee motion is an important step for correct diagnoses and optimal surgical reconstructions, but controversial opinions still remain about the most suitable numerical method for the elaboration of clinical kinematic tests. In this paper, we present a comparison of three methods applied to an experimental animal study (Grood and Suntay method [Grood, E.S. and Suntay, W.J. (1983) "A coordinate system for the clinical description of three-dimensional motions: application to the knee", J. Biomech. Engng, 105, pp. 136-144], Helical Axes method [Blankevoort, L., Huiskes, R. and de Lange, A. (1990). "Helical axes of passive knee joint motions", J. Biomech., 23 pp. 1219-1229] and Functional method [Martelli, S., Zaffagnini, S., Falcioni, B. and Marcacci, M. (2000). "Intraoperative kinematic protocol for knee joint evaluation", Comput. Methods Programs Biomed., 62 pp. 77-86]). The study shows the numerical differences among the three protocols and evaluates their performances and repeatability during clinical tests, i.e. laxity measurements and passive range of motion. The Functional method gives the optimal compromise among accuracy, clinical interpretability and ease of use for intraoperative kinematic evaluations.

Animals↗
PubMed2002

The shapes of the tibial and femoral articular surfaces in relation to tibiofemoral movement.

We report a study of the shapes of the tibial and femoral articular surfaces in sagittal, frontal and coronal planes which was performed on cadaver knees using two techniques, MRI and computer interpolation of sections of the articular surfaces acquired by a three-dimensional digitiser. The findings using MRI, confirmed in a previous study by dissection, were the same as those using the digitiser. Thus both methods appear to be valid anatomical tools. The tibial and femoral articular surfaces can be divided into anterior segments, contacting from 0 degrees to 20 +/- 10 degrees of flexion, and posterior segments, contacting from 20 +/- 10 degrees to 120 degrees of flexion. The medial and lateral compartments are asymmetrical, particularly anteriorly. Posteromedially, the femur is spherical and is located in a conforming, but partly deficient, tibial socket. Posterolaterally, it is circular only in the sagittal section and the tibia is flat centrally, sloping downwards both anteriorly and posteriorly to receive the meniscal horns. Anteromedially, the femur is convex with a sagittal radius larger than that posteriorly, while the tibia is flat sloping upwards and forwards. Anterolaterally, both the femoral and tibial surfaces are largely deficient. These shapes suggest that medially the femur can rotate on the tibia through three axes intersecting in the middle of the femoral sphere, but that the sphere can only translate anteroposteriorly and even then to a limited extent. Laterally, the femur can freely translate anteroposteriorly, but can only rotate around a transverse axis for that part of the arc, i.e., near extension, during which it comes into contact with the tibia through its flattened distal/medial surface as against its spherical posterior surface.

Femur↗
PubMed2001

Synthesis, antitumor cytotoxicity, and DNA-binding of novel N-5,2-di(omega-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-5-carboxamides.

A series of DNA-binding potential antitumor agents bearing a cationic carboxamide side chain attached in position peri to an electron-withdrawing atom, N-5,2-di(omega-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-5-carboxamides, has been prepared by reaction of the appropriate 1-chloro-9-oxo-9,10-dihydro-4-acridinecarboxamides with the suitable (omega-aminoalkyl)hydrazine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potency of these derivatives toward the human colon adenocarcinoma cell line (HT29) is described and compared to that of reference drugs. Structure-activity relationships are discussed. Two highly DNA-affinic and potent cytotoxic compounds, 4m,o, have been identified as new leads in the antitumor strategies.

Acridines↗
PubMed2001

The spray drying of acetazolamide as method to modify crystal properties and to improve compression behaviour.

Acetazolamide shows a very poor compression ability and tablets must usually be produced through a wet granulation process. However, the possibility to obtain pure acetazolamide for direct compression could be interesting for industrial application. With the scope to obtain a material for direct compression, three different crystallisation methods were chosen, with respect to acetazolamide solvent solubility. (a) Acetazolamide was dissolved in an ammonia solution and then spray dried. It was possible to characterise the spherical particles as a mixture of two polymorphic forms, I and II by Powder X-ray diffraction study. (b) Pure form I was obtained by slowly cooling to room temperature a boiling water solution. (c) Pure form II, the marketed form, was obtained by neutralisation of an ammonia solution. Their compression behaviour was investigated firstly by a rotary press. Whilst pure polymorphic forms I and II could not be compressed, the spray dried particles showed very good compression properties. In fact, tablets were obtained only by spray dried particles, which show very good properties under compression and the absence of capping tendency. On the other hand, it was impossible to obtain tablets from polymorphic forms I and II, whatever compression pressures were used. In order to explain their densification mechanism, a single-punch tablet machine, equipped for the measurement of the upper punch displacement in the die, was used. From calculated Heckel's parameters, it was demonstrated that the spray dried material shows a greater particle rearrangement in the initial stage of compression due to its spherical habit and minor wrinkledness of particle surface. The crystalline structure due to the presence of polymorphic forms I and II concur to lowering the intrinsic elasticity of the material. This fact avoids the risk of the rupturing the interpaticulate bonds, which are formed during the compression, concurring to the consolidation of the tablet.

Acetazolamide↗
PubMed2001

Physical characterization of naproxen sodium hydrate and anhydrate forms.

Naproxen sodium (NS) is a nonsteroidal anti-inflammatory drug used in painful and inflammatory diseases. By crystallization from water or by exposure to relative humidities over 43%, the anhydrate form can be hydrated to a dihydrate species. Different techniques have been used to characterize physically anhydrate naproxen sodium (ANS) and hydrate naproxen sodium (HNS): elemental analysis, atomic absorption, electron scanning microscopy, thermomicroscopy, differential scanning calorimetry, Karl Fisher's titrimetry, thermogravimetry, spectrophotometric analysis and X-ray diffraction study. The hydration/dehydration mechanism, at different relative humidities, was investigated to evaluate their physical stability. When stored up to 43% relative humidity, ANS shows a good stability, whereas with an increase in relative humidity it is hydrated. HNS equilibrium solubility was determined at different temperatures (21, 26, 31, and 37 degrees C). Due to the metastability and the quick phase changes in the water of ANS, its solubility was calculated from intrinsic dissolution measurements at the same temperatures, as solubility measurements of HNS. Water solubility of ANS is greater than HNS, but the solubility difference decreases when the temperature decreases. This is due to the fact that at higher temperatures the intrinsic dissolution rates (IDR) of ANS are considerably faster and decrease as the temperature falls.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Spray-drying as a method for microparticulate controlled release systems preparation: advantages and limits. I. Water-soluble drugs.

Spray-drying was used for the preparation of paracetamol/eudragit RS or RL or ethylcellulose microspheres to verify the possibility of their use in controlled-release solid-dosage forms formulation and try to determine advantages and limits of the technique of such use. Microspheres were first characterized by scanning electron microscopy, differential scanning calorimetry, x-ray diffractometry, and in vitro dissolution studies and then used for the preparation of tablets. During this step, the compressibility of the spray-dried powders was also evaluated. In vitro dissolution studies were performed also on the tablets and their release control was accessed. Although powders were unable to slow down drug release, tablets obtained from microsphere compression showed a good capability of controlling paracetamol release when eudragit RS or ethylcellulose was used, even at low polymer amounts.

Acetaminophen↗
PubMed2001

Determination of an optimal kinematic protocol for computer-assisted evaluation of anterior cruciate ligament deficiency.

The recent development of computer-assisted techniques for surgery, anterior cruciate ligament (ACL) reconstruction in particular, provides new ways of improving intraoperative kinematic evaluation and final functional outcome. In this paper we have tried to identify the optimal protocol for ACL evaluation, which can fully exploit the novel capability of electronic sensors and computer elaboration. In this work we statistically compared the main clinical tests that are used for knee evaluation and three different numerical methods for kinematic analysis. Results showed that only passive tests that investigate rotational and anteroposterior stability could discriminate ACL status and that the most effective protocol for computerized evaluation should be based on the Lachman and Drawer test, and forced internal-external rotations at full extension for pigs and 60 degrees, elaborated with the functional method (Martelli et al. Comput. Methods Programs Biomed. 62:77-86, 2000).

Algorithms↗
PubMed2000

N4-(omega-Aminoalkyl)-1-[(omega-aminoalkyl)amino]-4- acridinecarboxamides: novel, potent, cytotoxic, and DNA-binding agents.

A series of DNA-binding potential antitumor agents, (omega-aminoalkyl)-4-acridinecarboxamides, has been prepared either by reduction of the corresponding (omega-aminoalkyl)-9-oxo-9, 10-dihydro-4-acridinecarboxamides with aluminum amalgam or by aminolysis of the corresponding (omega-aminoalkyl)-1-chloro-4-acridinecarboxamides with the suitable amine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward six tumor cell lines, including human colon adenocarcinoma (HT29) and human ovarian carcinoma (A2780-sensitive, A2780cisR cisplatin-resistant, CH1-sensitive, CH1cisR cisplatin-resistant, and SKOV-3) cells, are described and compared to that of reference drugs. One highly DNA affinic analogue (3a) has been identified with a useful broad spectrum of cytotoxic activity in the 4-7 nM range (mean IC(50) of 6 nM).

Acridines↗
PubMed2000

Intraoperative kinematic protocol for knee joint evaluation.

Although knee kinematics has been investigated widely, no standard, objective evaluation of the kinematics behaviour of the joint is used at present during surgical treatment. We propose a kinematic protocol for a manual intraoperative evaluation of the knee behaviour, with which the range of motion, the 'screw-home' mechanism and knee instabilities could be quantified. The method does not require anatomical landmarks, because it is computed from standard tests used in clinical practice and gives a decomposition of the knee movement comparable to the well known Grood and Suntay analysis [E.S. Grood, W.J. Suntay, A joint coordinate system for the clinical description of three-dimensional motions: application to the knee, J. Biomech. Eng. 105 (1983) 136-144]. We describe the protocol, report the evaluation of its numerical features and provide a comparison with Grood and Suntay method on ten porcine knees.

Animals↗
PubMed2000

Emulsion/solvent evaporation as an alternative technique in pellet preparation.

Paracetamol/Eudragit RS, paracetamol/ethylcellulose, and paracetamol/cellulose acetate pellets of different drug/polymer ratios (w/w) were prepared by the dissolution/solvent evaporation technique. These pellets were then characterized by particle size distribution analysis, ultraviolet (UV) spectroscopy, differential thermal analysis, and scanning electron microscopy (SEM). Hard gelatin capsules were filled with each particle size fraction of these pellets, and in vitro dissolution studies were performed to verify the capability of each series of pellets to control drug release. Pellets were spherical, presented a polynucleated microcapsule structure, and under certain experimental conditions, the yield of the preparation process reached very high values. The dissolution studies pointed out the slow paracetamol release from these pellets.

Acetaminophen↗
PubMed2000

Polymers with pH-dependent solubility: possibility of use in the formulation of gastroresistant and controlled-release matrix tablets.

Polymers usually utilized for gastroresistant film coating of tablets or pellets such as cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), and Eudragit L and S were used in the preparation of drug/polymer matrix tablets. These tablets were prepared either by direct compression of both powders or by the formulation of microspheres that were then compressed. The microspheres were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffractometry analyses. Dissolution studies were finally carried out to verify if the tablets possessed gastroresistant or controlled-release characteristics. Except for Eudragit L, the polymers can be used under certain conditions in the formulation of modified-release tablets.

Acetaminophen↗
PubMed2000

Molecular mobility of the paracetamol amorphous form.

The purpose of this paper is to study the molecular mobility of paracetamol molecules in their amorphous state below the glass transition temperature (Tg) in order to evaluate the thermodynamic driving force which allows the amorphous form to recrystallize under different polymorphic modifications. Samples were aged at temperatures of -15, 0, 6, and 12 degrees C for periods of time from 1 h to a maximum of 360 h. The extent of physical aging was measured by a DSC study of enthalpy recovery in the glass transition region. The onset temperature of glass transition was also determined (Tg). Enthalpy recovery (deltaH) and change in heat capacity (deltaCp) were used to calculate the mean molecular relaxation time constant (tau) using the empirical Kohlausch-Williams-Watts (KWW) equation. Enthalpy recovery and onset glass transition temperature increased gradually with aging and aging temperatures. Structural equilibrium was reached experimentally only at an aging temperature of 12 degrees C (Tg-10 degrees C), according to the deltaH(infinity) results. The experimental model used is appropriate only at lower aging temperatures, while at higher ones the complexity of the system increases and molecular polymorphic arrangement could be involved. When structural equilibrium is experimentally reached, molecules can be arranged in their lowest energy state, and the polymorphic form I formation is the one preferred.

Acetaminophen↗
PubMed2000

The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations.

Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor compounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficient condition for antitumor activity of these compounds. Rational design of new compounds of this chemotype requires knowledge about the structure of the intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) may provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and position of side chains. Each of the compounds was simulated in two systems: i) in water, and ii) in the intercalation complex with the dodecamer duplex d(GCGCGCGCGCGC)2. The orientation of the side chain in relation to the ring system is determined by the position of its attachment. Orientation of the ring system inside the intercalation cavity depends on the number and position of side chain(s). The conformations of the side chain(s) of all PATs studied in the intercalation complex were found to be very similar to those observed in water.

Acridines↗
PubMed1999

8,11-dihydroxy-6-[(aminoalkyl)amino]-7H-benzo[e]perimidin-7-ones with activity in multidrug-resistant cell lines: synthesis and antitumor evaluation.

The synthesis of dihydroxybenzoperimidine derivatives, which are chromophore-modified dihydroxyanthracenediones with an additional pyrimidine ring incorporated into the chromophore, is reported. These derivatives are structurally related to the antitumor agent mitoxantrone. Their synthesis was carried out by the reaction of 6-amino-8,11-dihydroxy-7H-benzo[e]perimidin-7-one (5) or 6,8, 11-trihydroxy-7H-benzo[e]perimidin-7-one (10) with a number of respective (alkylamino)alkylamines. The dihydroxybenzoperimidine derivatives exhibited in vitro cytotoxic activity against murine leukemia L1210 and human leukemia HL60 cell lines comparable to that of mitoxantrone. These compounds also exhibited a range of in vitro activity against the human MDR-type resistant leukemia K562R cell line with the MDR phenotype. The most active compound of this series, namely 6a, exhibited potent in vitro cytotoxic activity against a panel of human cell lines. Furthermore, in contrast to both mitoxantrone and doxorubicin, it displayed little cross-resistance in cell lines characterized by a MDR phenotype. Cell cycle analysis in the sensitive HT-29 and mitoxantrone-resistant HT-29/Mx (not identified resistance mechanism) cell lines has revealed that both mitoxantrone and 6a induce a G2/M block. However, while the proportion of apoptotic cells after mitoxantrone treatment is similar for both sensitive and resistant cell lines, it is much lower for 6a. Compound 6a tested against P388 murine leukemia in vivo displayed a significant antitumor effect (%T/C 196 at an optimal dose of 10 mg/kg). The property of overcoming the cross-resistance was maintained also in in vivo efficacy studies, where no difference was observed in the antitumor activity of compound 6a against the A2780 human tumor xenograft and its MDR A2780/Dx subline. We conclude that benzoperimidines, if properly substituted, constitute a novel class of compounds that can overcome multidrug resistance.

Animals↗
PubMed1999

2,3-Dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione derivatives, a class of cytotoxic agents active on multidrug-resistant cell lines: synthesis, biological evaluation, and structure-activity relationships.

A series of DNA-intercalating potential antitumor agents, (amino)alkyl-substituted 2,3-dihydro-1H,7H-pyrimido[5,6, 1-de]acridine-1,3,7-triones, has been prepared by aminolysis of the corresponding 6-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward eight tumor cell lines, including human colon adenocarcinoma (HT29, LoVo sensitive and LoVo/Dx (doxorubicin-resistant)) and human ovarian carcinoma (A2780 sensitive, A2780cisR (cisplatin-resistant), CH1, CH1cisR (cisplatin-resistant), and SKOV-3) cells, are described and compared to that of reference drugs. The cytotoxic activity often parallels the observed DNA affinities, for almost all the target compounds. Interesting structure-activity relationships have been found. The octanol/water partition coefficients have also been calculated, but there was no correlation either with cytotoxicity values or with resistance index. Three highly DNA-affinic analogues, 9 and 15f,15h, have been identified with a useful broad spectrum of cytotoxic activity.

Acridines↗
PubMed1999

Methoxybutropate microencapsulation by gelatin-acacia complex coacervation.

Microcapsules of methoxybutropate solid particles or of an oily saturated solution of the same drug were prepared by complex coacervation between gelatin and acacia and dried with three different methods: isopropanol addition, spray-drying, and freeze-drying. Successively, microparticles were analyzed by infrared thermobalance, ultraviolet (UV) spectroscopy, optical and scanning electron microscopy, and sieves to find out parameters such as yield, moisture content, encapsulation percentage, morphology of solid particles, and particle size. Results highlighted that the most appropriate drying method for industrial purposes was spray-drying, particularly for oil-containing microcapsule formulations.

2-Propanol↗