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S Martelli

Publications and source records attributed to S Martelli.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1999

New controlled-release ibuprofen tablets.

Tablets containing two different doses of ibuprofen are realized. The first possesses very fast release kinetics, while the second has slow and linear release kinetics. This allows drug to produce a therapeutic effect quickly and to maintain it for a long time with only one administration unit. Such tablets are obtained by compression of a mixture of two very different kinds of granulates: an ibuprofen-starch granulate and an ibuprofen-Eudragit RS microsphere granulate. Specific proportions of mixtures of them give the described result after compression at particular tablet hardnesses.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Improved dissolution behavior of fenbufen by spherical crystallization.

Fenbufen is an analgesic, antipyretic and anti-inflammatory drug that is characterized by poor water solubility, a defect increased by very low wettability. Poor water solubility, particularly at low pH, could decrease absorption in the upper part of the gastrointestinal tract, which would be inconvenient for good bioavailability. Different spherical crystallization processes have been considered as methods to improve fenbufen dissolution behavior. A two-solvent system, in the presence of a bridging liquid, is the only method capable of producing spherical fenbufen crystals. In a first step, fenbufen solubility was considered in different solvents. The drug crystals formed were typically needle shaped. This characteristic was considered as a favorable parameter to obtain spherical crystals. After the selection of the best fenbufen solvent, several ratios of solvent (S)-nonsolvent (NS) (tetrahydrofuran [THF]-demineralized water) were studied. The addition of a bridging liquid (isopropyl acetate) improved spherical crystallization. The results from this method were reproducible batch to batch. The spherical crystals obtained showed a clear improvement in dissolution capacity, probably due to better wettability. Dissolution studies were then carried out on these spherical crystals stored for 1 month at different relative humidities (RHs). The dissolution profiles remained unchanged.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Pyrimido[4,5,6-kl]acridines. Synthesis, in vitro cytotoxicity and structure-activity relationships.

In a previous report we described the synthesis and biological properties of a group of pyrimido[4,5,6-kl]acridines 2, related to the pyrazolo[4,5,6-kl]acridines 1, promising antitumor agents possessing a broad spectrum of activity. Since the substitution of the pyrazole ring of the pyrazoloacridine chromophore with a pyrimidinone leads to derivatives that retain in vitro cytotoxic activity, we decided to further investigate the pyrimido[4,5 6-kl]acridines. Modifications at the ring system level, leading to chromophores with different characteristics, changes of substituent groups in position 6, simultaneous alteration of the chromophore and the introduction of a second cationic side chain in position 1 afforded 29 new pyrimido[4,5,6-kl]acridines, which were tested in vitro against the human colon adenocarcinoma HT29 cell line. Interesting structure-activity relationships could be drawn. Some selected derivatives were screened for their cytotoxic activity on the National Cancer Institute cell panel (60 human tumor lines).

Adenocarcinoma↗
PubMed1998

Fiber-based anterior cruciate ligament model for biomechanical simulations.

Although accurate predictions of the behavior and function of the anterior cruciate ligament would aid in diagnosis and operative treatment, no agreement exists on the best way to model the ligament with a reliable description of its mechanical and geometric features. We propose a new model of the anterior cruciate ligament based on multiple viscoelastic curvilinear fibers. This model was used for quasi-static simulations of the passive motion of eight porcine knees, after registration of the passive trajectories and digitization of the surface of the ligament in flexion. Simulations of anterior cruciate ligament deformations during passive motion predicted a fiber strain of less than 20%, low insertion forces, and isometric anterior fibers. The model explains actions of the ligament fibers, as reported in the literature, better than classic models based on linear fibers and consistent with the mechanical properties of the anterior cruciate ligament.

Animals↗
PubMed1998

Laparoscopic splenectomy. How to make it easier using an innovative atraumatic suction grasper.

BACKGROUND: With the evolution of laparoscopic surgery comes the need for specific instruments that apply traction to parenchymal tissue, like the spleen, without exposing the organ to the associated high risk of bleeding. To meet this need, we designed and developed a suction-cup grasper that allows easy grasping and manipulation of the spleen. Some of the difficulties usually encountered during laparoscopic splenectomy may be overcome by using this device. MATERIALS: The instrument consists of a cone-shaped, silicone rubber suction cup designed with an antislip internal surface. The cup is connected to a support arm with a flexible distal end that can be rotated. Traction is exerted with a commonly available suction system. The device is inserted through a 12-mm-diameter guide sheath. RESULTS: The two interventions performed with the atraumatic device were completed with laparoscopic technique. No complications arose during or after the operations. The average operating time was 110 min. The patients were discharged after 4 and 5 days postoperative, respectively. CONCLUSIONS: As a device specifically designed for grasping parenchymal organs, the atraumatic suction grasper affords the operator a faster and safer technique in laparoscopic splenectomy.

Equipment Design↗
PubMed1998

Total knee arthroplasty kinematics. Computer simulation and intraoperative evaluation.

The goal of this work was to develop computer simulations for intraoperative testing of the passive kinematics of knee prostheses. These are based on an anatomic model of the reconstructed joint, represented in the sagittal plane. A femoral component and a tibial component are linked by 3 springs that model the relevant ligaments, with the posterior cruciate providing the primary constraint. The components' behavior at each flexion angle is obtained by minimizing the total strain energy stored in the ligaments. Simulations were performed in vivo on 10 Interax implants (Howmedica International, Stain, UK) and showed good agreement with intraoperative observations, allowing monitoring of new parameters such as contact point motion, ligament strains, and the energetic state of the knee. This work contributes to the comprehension of individual knee kinematics after total knee arthroplasty, to improve long-term results and standardize the evaluation of the results of joint restoration.

Arthroplasty, Replacement, Knee↗
PubMed1998

Evaluation of the mixing effectiveness of a new powder mixer.

The effectiveness of the new powder mixer Canguro J tumbler was evaluated using lactose, microcrystalline cellulose, and salicylic acid as chemical indicator with the ratio 88:10:2 (w/w). The mixing time, the speed of the tumbler (rpm), its inclination, and filling percentage were varied in order to assess the limits of the mixer and the best parameters to use for obtaining a mixture as uniform as possible. The same experiments were then repeated after addition of 1% (w/w) magnesium stearate to the mixture of powders. The efficiency in the distribution of this lubricant was estimated by the progressive hardness reduction of the tablets derived from the compression of the powders, at a constant applied force. Finally, a comparison between Canguro J and a very efficient V-shaped mixer of the same capacity was performed. The results show that all investigated parameters influenced the mixing capability of Canguro J. The best effectiveness of the mixer occurred at the filling rate of 50% and a rotation speed of 20 rpm; in this case, Canguro J is even a little more effective than the V-shaped mixer. However, even at the filling rate of 70%, the same distribution uniformity of the powders can be obtained after a mixing time protraction of a few minutes.

Cellulose↗
PubMed1998

Interactions between lonidamine and beta- or hydroxypropyl-beta-cyclodextrin.

The possibility of obtaining inclusion complexes between lonidamine and beta- or hydroxypropyl-beta-cyclodextrin have been evaluated by phase solubility diagram, differential scanning calorimetry (DSC), and x-ray diffractometry. The applied complexation methods were spray-drying, kneading, and solid dispersion. DSC and x-ray analyses of the powders revealed an external interaction between lonidamine and cyclodextrins. Dissolution profiles of the obtained powders were also studied to define the most appropriate preparation method and molar ratio to use in attempts to increase lonidamine water solubility.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1998

The role of structural factors of anthraquinone compounds and their quinone-modified analogues in NADH dehydrogenase-catalysed oxygen radical formation.

Anthraquinone compounds belong to the most important class of clinical antitumour agents. However, their use is limited by their peroxidating activity, being the consequence of free radical formation initiated by three oxyreductases. This activity is considered to be the main cause of cardiotoxic effects. The affinity of anthraquinone compounds to these enzymes is an essential factor governing the rate of one-electron transfer and the generation of oxygen radicals. A series of novel derivatives and analogues of natural and synthetic anthraquinones has been examined with the aim of identifying the structural factors essential for the ability to stimulate oxygen radical formation catalysed by NADH dehydrogenase. Functional groups and moieties favouring or disfavouring the interaction of the compounds with the enzyme have been determined. The quinonoid moiety as well as at least two phenolic groups in peri positions favoured the affinity of these compounds for NADH dehydrogenase. The modification of the quinonoid structure to iminoquinonoid or carboquinonoid forms dramatically decreased interaction with the enzyme. The O'-substitution by a bulky group in the sugar moiety of daunorubicin decreased the ability of the derivatives to stimulate oxygen radical formation. It has also been shown that the presence of an ionizable amino group on the sugar moiety of daunorubicin favours interaction with the NADH dehydrogenase. However, its location is not essential for this effect.

Anthraquinones↗
PubMed1998

The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: molecular dynamics simulations.

Intercalative binding of the antitumor drugs ametantrone and mitoxantrone to the dodecamer duplex d(CGCGAGCTCGCG)2 was studied by applying molecular dynamics in water with the GROMOS 87 force field. A number of reasonable binding orientations were tested by short pre-simulations. It was shown that in energetically favourable orientation the anthraquinone chromophore is perpendicular to the direction of inter-base hydrogen bonds. Helically shaped side-chains of the drugs fit to the minor groove. The best orientation obtained in pre-simulations was applied in the main simulations. Small but significant differences were found between structures of intercalation complexes of the two drugs with the dodecamer duplex, the mitoxantrone complex possessing more favourable energy. The molecular nature of interactions responsible for those differences has been discussed.

Antineoplastic Agents↗
PubMed1997

1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines as intercalating cytotoxic agents: synthesis, DNA binding, and biological evaluation.

A series of DNA-intercalating potential antitumor agents, 1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines, has been prepared by aminolysis of the corresponding 4-[N-(omega-aminoalkyl)carbamoyl]-1-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these bis-functionalized compounds have been examined using a combination of fluorometric and thermal denaturation techniques and are compared with the behaviors for established DNA intercalants and cationic minor groove ligands. The results indicate that (i) the agents are considerably more DNA-affinic than less functionalized acridinones, with 'apparent' binding constants of (0.1-2.1) x 10(7) and (0.3-7.5) x 10(7) M-1 at pH 5 and 7, respectively, (ii) overall affinity is sensitive to both the length of the flexible side chain and the complexity of the attached amine substituents, and (iii) the pendant side chains effect a switch to moderate AT-preferential binding. In vitro cytotoxic potencies toward six tumor cell lines broadly parallel the observed DNA affinities, although poor correlation is evident for certain compounds. The octanol/water partition coefficients have been also calculated, but there is no correlation with cytotoxicity values. Two highly DNA-affinic analogs, 10 and 13, have been identified with a useful broad spectrum of cytotoxic activity.

Acridines↗