Revealing the Nonequilibrium Nature of a Granular Intruder: The Crucial Role of Non-Gaussian Behavior.

The characterization of the distance from equilibrium is a debated problem in particular in the treatment of experimental signals. If the signal is a one-dimensional time series, such a goal becomes challenging. A paradigmatic example is the angular diffusion of a rotator immersed in a vibro-fluidized granular gas. Here, we experimentally observe that the rotator's angular velocity exhibits significant differences with respect to an equilibrium process. Exploiting the presence of two relevant timescales and non-Gaussian velocity increments, we quantify the breakdown of time-reversal asymmetry, which would vanish in the case of a 1D Gaussian process. We deduce a new model for the massive probe, with two linearly coupled variables, incorporating both Gaussian and Poissonian noise, the latter motivated by the rarefied collisions with the granular bath particles. Our model reproduces the experiment in a range of densities, from dilute to moderately dense, with a meaningful dependence of the parameters on the density. We believe the framework proposed here opens the way to a more consistent and meaningful treatment of out-of-equilibrium and dissipative systems.

The genomics of mycobacteria.

The species Mycobacterium bovis and Mycobacterium avium subspecies paratuberculosis are the causal agents, respectively, of tuberculosis and paratuberculosis in animals. Both mycobacteria, especially M. bovis, are also important to public health because they can infect humans. In recent years, this and the impact of tuberculosis and paratuberculosis on animal production have led to significant advances in knowledge about both pathogens and their host interactions. This article describes the contribution of genomics and functional genomics to studies of the evolution, virulence, epidemiology and diagnosis of both these pathogenic mycobacteria.

Les mycobactéries Mycobacterium bovis et Mycobacterium avium subsp. paratuberculosis sont les agents étiologiques de la tuberculose et de la paratuberculose, respectivement. En outre, les deux mycobactéries (mais plus particulièrement M. bovis) peuvent infecter l'être humain et jouent donc un rôle en santé publique. En raison de cette importance et des effets de la tuberculose et de la paratuberculose sur la production animale, de grands efforts ont été déployés pour faire avancer nos connaissances sur ces deux agents pathogènes et sur leurs interactions avec leurs hôtes. Les auteurs décrivent la contribution de la génomique et de la génomique fonctionnelle dans les études sur l'évolution, la virulence, l'épidémiologie et le diagnostic de ces deux mycobactéries pathogènes.

Las especies Mycobacterium bovis y Mycobacterium avium subsp. paratuberculosis son los agentes causales de la tuberculosis y la paratuberculosis en animales, respectivamente. Además, ambas micobacterias, pero fundamentalmente M. bovis, son importantes para la salud pública, ya que pueden infectar a los humanos. Debido a esto último y al impacto de la tuberculosis y la paratuberculosis en la producción animal, en los últimos años se ha producido un avance significativo en los conocimientos de ambos agentes patógenos y de la interacción con sus hospedadores. En este artículo describiremos la contribución de la genómica y la genómica funcional a los estudios de evolución, virulencia, epidemiología y diagnóstico de ambas micobacterias patógenas.

Diffusion of individual birds in starling flocks.

Flocking is a paradigmatic example of collective animal behaviour, where global order emerges out of self-organization. Each individual has a tendency to align its flight direction with those of neighbours, and such a simple form of interaction produces a state of collective motion of the group. When compared with other cases of collective ordering, a crucial feature of animal groups is that the interaction network is not fixed in time, as each individual moves and continuously changes its neighbours. The possibility to exchange neighbours strongly enhances the stability of global ordering and the way information is propagated through the group. Here, we assess the relevance of this mechanism in large flocks of starlings (Sturnus vulgaris). We find that birds move faster than Brownian walkers both with respect to the centre of mass of the flock, and with respect to each other. Moreover, this behaviour is strongly anisotropic with respect to the direction of motion of the flock. We also measure the amount of neighbours reshuffling and find that neighbours change in time exclusively as a consequence of the random fluctuations in the individual motion, so that no specific mechanism to keep one's neighbours seems to be enforced. On the contrary, our findings suggest that a more complex dynamical process occurs at the border of the flock.

Interaction ruling animal collective behavior depends on topological rather than metric distance: evidence from a field study.

Numerical models indicate that collective animal behavior may emerge from simple local rules of interaction among the individuals. However, very little is known about the nature of such interaction, so that models and theories mostly rely on aprioristic assumptions. By reconstructing the three-dimensional positions of individual birds in airborne flocks of a few thousand members, we show that the interaction does not depend on the metric distance, as most current models and theories assume, but rather on the topological distance. In fact, we discovered that each bird interacts on average with a fixed number of neighbors (six to seven), rather than with all neighbors within a fixed metric distance. We argue that a topological interaction is indispensable to maintain a flock's cohesion against the large density changes caused by external perturbations, typically predation. We support this hypothesis by numerical simulations, showing that a topological interaction grants significantly higher cohesion of the aggregation compared with a standard metric one.

[Pilot study to assess and compare the eating habits and nutrition knowledge in school-age Italians and Finns, using specific questionnaires]. / Studio pilota per la valutazione ed il confronto delle abitu- dini alimentari e dello stile di vita di un gruppo di ragazzi italiani ed un gruppo di ragazzi finlandesi grazie all'ausilio di specifici questionari.

In recent decades, the American diet has emerged in our country as a reference model food, particularly among young people, to the detriment of the Mediterranean diet, an healthy eating pattern rich in fruits and vegetables, olive oil, whole grains and fish. Even in Europe, North American habits are widespread at the expense of traditional northern nutritional powers, characterized by a lot of fish, wild game meat that are much thinner than from farm animals, rye, oats, cabbage, root vegetables. Given this background, in Pavia (Italy) and Tampere (Finland) we conducted a pilot study with the objective to assess and compare the eating habits and nutrition knowledge in school-age children using 2 questionnaires entitled "what do you eat?" and "what do you know about diet and health?". The results of the first questionnaire clearly shows that, among young people of both countries, there is the loss of traditional food: the Mediterranean and the Finnish diet. All the boys wear it with a low frequency fish, fruit and vegetables, and instead a high frequency of adverse health foods, such as potato chips and sweet drinks. The answers to questions which relate to nutrients and their properties, show that children of all groups have little knowledge about these topics. The use of questionnaires, such as those administered by us, can be easily performed to investigate the dietary habits and the nutritional level of culture, due to make nutrition education interventions aimed at correcting poor eating habits.

Vicsek model by time-interlaced compression: A dynamical computable information density.

Collective behavior, both in real biological systems and in theoretical models, often displays a rich combination of different kinds of order. A clear-cut and unique definition of "phase" based on the standard concept of the order parameter may therefore be complicated, and made even trickier by the lack of thermodynamic equilibrium. Compression-based entropies have been proved useful in recent years in describing the different phases of out-of-equilibrium systems. Here, we investigate the performance of a compression-based entropy, namely, the computable information density, within the Vicsek model of collective motion. Our measure is defined through a coarse graining of the particle positions, in which the key role of velocities in the model only enters indirectly through the velocity-density coupling. We discover that such entropy is a valid tool in distinguishing the various noise regimes, including the crossover between an aligned and misaligned phase of the velocities, despite the fact that velocities are not explicitly used. Furthermore, we unveil the role of the time coordinate, through an encoding recipe, where space and time localities are both preserved on the same ground, and find that it enhances the signal, which may be particularly significant when working with partial and/or corrupted data, as is often the case in real biological experiments.

A histochemical approach to the evaluation of the in vivo cytotoxicity of the nitrobutadienes (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene and methyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate in mice liver and kidney.

Two new molecules (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1-Naph-DNB) and (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (1-Naph-NMCB) in previous studies showed interesting antiproliferative activity in vitro. Furthermore, toxicological tests and histological analysis provided promising results, in particular for 1-Naph-NMCB that displayed lower toxic activity both in terms of lethal effect and tissue damage of the main organs. Finally, studies of the antitumour activity in vivo confirmed the efficacy of both molecules, though with some differences in tumour selectivity and levels of activity. In this investigation the activities of some specific enzymes, acid phosphatase (AcPase), alkaline phosphatase (AlkPase), catalase (Cat), succinic dehydrogenase (SDH), glucose-6-phosphatase (G6Pase) and K+ p-nitrophenyl phosphatase (K+ pNPPase) were studied in the liver and kidney as histopathological biomarkers, to assess the effects of the two compounds in organs generally involved in the metabolism and excretion of different drugs. As oxidative stress may also develop as a consequence of the toxic effect of chemicals, reactive oxygen species (ROS) production was evaluated by a histochemical method. The results indicated that some enzyme activities and ROS expression changed in a dose-related manner. Nevertheless, neither in the liver nor in the kidney were dramatic toxic effects evident. By contrast, the variations of some enzyme activities (AlkPase, AcPase, Cat, K+ pNPPase) were interpreted as possible defensive mechanisms for tolerating high dosage of the compounds.

Comparative effects of paclitaxel and docetaxel on the metabolism and pharmacokinetics of epirubicin in breast cancer patients.

PURPOSE: To investigate whether paclitaxel and docetaxel influence the pharmacokinetics and metabolism of epirubicin. PATIENTS AND METHODS: We studied the pharmacokinetics and biotransformation patterns of epirubicin in 27 cycles and 20 breast cancer patients. Four patients received epirubicin alone 90 mg/m(2) by intravenous (IV) bolus; eight patients received the same dose of epirubicin followed immediately by paclitaxel 175 mg/m(2) in a 3-hour infusion; the other eight patients received epirubicin 90 mg/m(2) followed immediately by docetaxel 70 mg/m(2) in a 1-hour infusion. Epirubicin and its metabolites, epirubicinol (EOL) and 7-deoxydoxorubicinone (7d-Aone), were identified by high-pressure liquid chromatography. RESULTS: No pharmacokinetic interaction between the parent compound epirubicin and taxanes was detected. Conversely, a significant effect on epirubicin metabolism by both paclitaxel and docetaxel was found. Epirubicin given with paclitaxel or docetaxel yielded areas under the plasma concentration-time curves (AUC) for 7d-Aone 1. 7-fold and 1.9-fold higher (P <.05), respectively, than epirubicin alone. The appearance of two polar metabolites sensitive to glucuronidase was also significantly greater in both taxane groups. Quantitatively different metabolic rates and patterns for EOL were observed in the paclitaxel and docetaxel combinations. The EOL AUC after paclitaxel treatment (1,521 +/- 150 ng/mL*h) was significantly higher (P <.01) than the corresponding values after epirubicin administered either as a single agent (692 +/- 46 ng/mL*h) or in combination with docetaxel (848 +/- 237 ng/mL*h). CONCLUSION: There is no apparent pharmacokinetic interaction between the parent compound epirubicin and paclitaxel or docetaxel. A different pattern of interaction between these taxanes and epirubicin metabolism is clearly evident.

Sequence effect of epirubicin and paclitaxel treatment on pharmacokinetics and toxicity.

PURPOSE: Sequence-dependent clinical and pharmacokinetic interactions between paclitaxel and doxorubicin have been reported. Some data have shown an influence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated whether reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics. PATIENTS AND METHODS: Patients receiving epirubicin 90 mg/m(2) by intravenous bolus followed by paclitaxel 175 mg/m(2) over 3-hour infusion or the opposite sequence every 3 weeks for four cycles were eligible. Toxicity was recorded at nadir. Pharmacokinetic data were evaluated at the first and the second cycle and were correlated with toxicity parameters. RESULTS: Thirty-nine consecutive stage II breast cancer patients were treated. Twenty-one patients received epirubicin followed by paclitaxel (ET group), and 18 received the opposite sequence (TE group). No significant difference in nonhematologic toxicity was seen. A lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery was observed in the TE group. Area under the concentration-time curve (AUC) of epirubicin was higher in the TE group (2,346 ng/mL. h v 1,717 ng/mL. h; P =.002). An inverse linear correlation between epirubicin AUC and neutrophil recovery was also observed (P =.012). No difference was detected in paclitaxel pharmacokinetics. CONCLUSION: Our results support a sequence-dependent effect of paclitaxel over epirubicin pharmacokinetics that is associated with increased myelotoxicity. Because schedule modifications of anthracyclines and paclitaxel can have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.

Expression of CD44v6 correlates with cell proliferation and cellular atypia in urothelial carcinoma cell lines 5637 and HT1197.

CD44 comprises a family of membrane adhesion molecules encoded by a single gene and diversified by alternative splicing and extensive posttranslational modifications. Alterations of CD44 expression patterns are linked to tumour invasion and formation of metastases. However, CD44 expression and its relation to the biological properties of tumours vary depending on the tumour type and origin. In transitional cell carcinoma of the urinary bladder, low CD44 expression is linked to enhanced tumour aggressiveness. We studied CD44 expression in two urothelial cancer cell lines, HT1197 and 5637. CD44s and a v6 variable exon-containing splice variants were detected in both cell lines by reverse transcription-PCR and by commercially available monoclonal antibodies. In both cell lines, Western blot analysis detected immunoreactive proteins with approximate sizes 70-85 kD, 95-110 kD, and 120-140 kD with CD44v6 antibody and weak bands with size 70-98 kD with CD44s antibody. At the cellular level, the pattern of CD44 immunoreactivity correlated with a lower level of cell differentiation and a higher degree of cell proliferation. In HT1197 cells, the CD44v6 was detected predominantly in small proliferating cells and in large multinuclear atypical cells. CD44s and CD44v6 displayed low immunoreactivity in HT1197 cells with a higher degree of epithelial differentiation. The 5637 cells expressed CD44v6 strongly and CD44s weakly. We conclude that CD44v6 expression correlates with a higher proliferative activity and with a stem cell-like phenotype in both cell lines and with cellular atypia in HT1197 cells.

Cisplatin combined with the new cisplatin-procaine complex DPR: in vitro and in vivo studies.

The administration of combinations of platinum compounds is considered as a useful alternative therapeutic strategy to avoid the complications of toxic events during cancer chemotherapy in order to obtain a therapeutic advantage. On the basis of previous in vitro and in vivo findings, suggesting an antitumour activity of the new cisplatin-derived compound cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR), we investigated the effectiveness of the combination of cisplatin (DDP) and DPR in vitro on murine leukaemic cells, which were either sensitive (P388) or resistant (L1210/DDP) to DDP, and on the murine M5076 reticulum cell sarcoma, and in vivo in BDF1 female mice transplanted with P388 leukaemic cells or cisplatin-resistant L1210/DDP leukaemic cells. The contemporaneous exposure in vitro to both platinum compounds gave a significantly higher cell growth inhibition than that expected on the basis of dose-response curves for single agents in all tumour models tested. In vivo, the combinations of DDP plus DPR elicited significant enhancement over the activity of the drugs alone both in the ascitic and solid P388 models. The combined treatment of 10 mg/kg DDP and 14 mg/kg DPR yielded 62.5% tumour-free mice compared with 6.2% with 10 mg/kg DDP alone, the best single agent. It is noteworthy that the combined application of DDP and DPR was also very effective in the solid cisplatin-resistant L1210/DDP model, inducing a significant reduction in the volume of tumour. A therapeutic advantage was achieved with combination treatments that had no effect on platinum-mediated body weight loss and were generally well tolerated by the mice. At equitoxic concentrations of DPR and carboplatin, the treatment with DDP plus DPR proved to have a higher efficacy against this tumour model compared to that observed after the combined treatment with DDP and carboplatin. In summary, the combination of DDP and DPR showed a therapeutic advantage over single drug treatment and has demonstrated promise at the preclinical level in its ability to circumvent acquired resistance to DDP both in vitro and in vivo.

Phenotypic and functional characterization of T cell clones following allogeneic bone marrow transplantation.

T cell clones (n = 456) were derived from 9 patients following allogeneic bone marrow transplantation (BMT) with or without acute graft versus host disease (aGVHD) and from 4 healthy donors. The cloning efficiency was 63.2% in controls, 13.2% and 12.1% in patients with or without aGVHD. Once established, T cell clones were typed for surface markers (CD3, CD4, CD8) and tested for production of IL-2 and expression of cytolytic activities in a lectin-dependent cellular cytotoxicity assay (LDCC) and against the K562 target cell line to detect natural killer activity. We found the expected imbalance of CD4/CD8 clones in BMT patients, as compared to controls. A higher proportion of IL-2-producing clones was observed in patients with aGVHD (83.5%; P less than 0.02) as compared to patients without aGVHD (64.8%) and controls (68.5%). No major differences were found in terms of LDCC, whereas an increased percentage of clones with NK-like activity was found in patients with aGVHD (34.7%, P less than 0.05) as compared to patients without aGVHD (29.5%) and controls (21.3%). The clones were also tested for inhibition of IL-2 production mediated by cyclosporine. Such inhibition could be obtained in virtually all clones both in patients with or without aGVHD, suggesting that the latter is probably not due to the emergence of CsA-resistant clones. In conclusion, this study demonstrates a low cloning efficiency in BMT patients associated with the well-known CD4/CD8 imbalance. A higher production of IL-2, an increased NK activity, but not the presence of CsA-resistant clones appear to differentiate patients with from patients without aGVHD.

Modifications of cell-cycle induced by dpr, a new platinum-triamine complex containing procaine.

cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR) is a new platinum-triamine complex containing as ligand the local anesthetic procaine. In this study DPR was compared to the parent compound cisplatin (cis-DDP) in order to study the influence of both molecules on the cell cycle phases, and particularly on the induction of apoptosis. P388 murine leukemic cells were used as cellular model, and were exposed in vitro to either compound, continuously for 24 hours. At the end of the incubation, the thymidine uptake, the trypan blue dye exclusion assay, and the flow cytometry were assessed. Both the cytotoxic activity and the inhibition of DNA synthesis evaluated after 24 h incubation with DPR or cis-DDP were comparable. Moreover, cell cycle was modified in a comparable manner by both molecules. In particular the induction of the apoptotic effect was similarly induced by the same concentrations of the compounds and time exposure. In conclusion, DPR and cis-DDP seem to have a similar effect on the cell cycle of P388 leukemic cells and particularly on the induction of the programmed cell death.

TCR gamma/delta positive lymphocytes after allogeneic bone marrow transplantation.

Peripheral gamma/delta+ T cells were studied in patients following allogeneic bone marrow transplantation (BMT) by indirect immunofluorescence utilizing two monoclonal antibodies (G1 and A13) able to recognize the two major subpopulations (V delta 2+ and V delta 1+, respectively) of these cells. We found that the relative percentage of 'total' (gamma/delta+ T lymphocytes) (V delta 2 + V delta 1 positive cells), and particularly of G1+ (V delta 2+) cells, in CD3+ lymphocytes was higher in transplanted patients, and especially in those presenting with acute graft-versus-host disease (aGVHD), than in normal controls. This finding was confirmed by the analysis of the V delta 2+/V delta 1+ cell ratio which was again significantly higher in patients with aGVHD as compared to controls. Similarly, the absolute number of 'total' gamma/delta+ and V delta 2+ cells was also significantly increased in patients with aGVHD. TCR gamma/delta+ T cells increased as a function of time after BMT reaching a plateau value at about day 60 post-BMT. When patients were stratified for the presence or absence of aGVHD this correlation was maintained only for patients with aGVHD. Finally, most V delta 2+ cells expressed surface T cell activation markers such as CD25 (IL-2 receptor) and DR (MHC class II) antigens. Our results suggest a possible involvement of gamma/delta+ T cells and particularly of V delta 2+ cells in the clinical and immunological events (aGVHD) occurring after allogeneic BMT.

Cytotoxicity and cellular accumulation of a new cis-diammineplatinum (II) complex containing procaine in murine L1210 cells sensitive and resistant to cis-diamminedichloroplatinum (II).

The emergence of drug resistance during tumor chemotherapy is one of the main problems associated with cancer treatment, particularly with cisplatin (cis-DDP). In the hope of overcoming this problem, various cis-DDP-derived compounds have been synthesized, and their pharmacological activity was compared with that of cis-DDP. In this paper we report on studies on the cytotoxic activity induced by cis-diamminechloro-[2-(diethylamino)ethyl-4-aminobenzoate, N4]- chlorideplatinum(II) monohydrochloride monohydrate (DPR), a new complex of platinum containing procaine. All experiments were carried out on murine leukemic cells, which were either sensitive (L1210) or resistant (L1210/DDP) to cis-DDP. A tetrazolium dye (MTT) assay conducted 5 days after a 2-h exposure of cells to both drugs was utilized to determine the resistance factor (RF) of L1210/DDP cells as compared with the sensitive wild-type cells. Drug accumulation and efflux, together with the amount of platinum bound to DNA, were also investigated. The activity of DPR on sensitive cells was not significantly different from that of cis-DDP. Conversely, DPR was 4.3 times more effective than cis-DDP on resistant cells. A decreased drug accumulation is one of the mechanisms of resistance to cis-DDP of L1210/DDP cells. However, DPR accumulation was not significantly different in sensitive and resistant L1210 cells. Under culture conditions that yielded similar intracellular platinum concentrations, treatment with DPR produced significantly greater DNA platination than did treatment with cis-DDP in both cell lines. No difference in efflux was observed between L1210 and L1210/DDP cells exposed to either cis-DDP or DPR. Our results show that in parental cells, DPR is as potent as cis-DDP on a molar basis, and it is also minimally cross-resistant with cis-DDP in L1210/DDP cells. A direct implication of our results is that DPR could be useful in those human tumors showing a mechanism of resistance similar to that of L1210/DDP cells.

Intraperitoneal mitoxantrone: a feasibility and pharmacokinetic study.

Fractionated doses have been advocated to prevent chemoperitonitis after intraperitoneal infusion of mitoxantrone. Patients with peritoneal carcinomatosis of various origin underwent surgery, including intestinal resections, with minimal residual disease. Peritoneal mitoxantrone in 1000 ml/m(2) saline was planned on the first post-operative day in groups of four patients (5 mg/m(2) for 3 and 5 days, 7.5 mg/m(2) for 3 and 4 days, 10 mg/m(2) for 2-4 days, if possible). Due to dose-limiting myelosuppression, only one and three patients received the 7.5-mg 4-day and 10-mg 3-day regimens, respectively. A total of 20 patients were consequently treated. Neither major complications nor severe pain were observed. Pharmacokinetics were completed on the 1st day in five 5-mg and five 10-mg patients, on the 5th day in three 5-mg patients, and on the 3rd day in one 10-mg patient. On the 1st day, mean peritoneal peak concentrations of mitoxantrone resulted 1.45 +/-0.56 (range 0.48-1.9) and 1.9+/-0.85 (range 1.27-3.13) microg/ml in the 5-mg and 10-mg patients, respectively. Mean dialysate/plasma exposure (AUC) ratio was 115. Even in patients with sutures, early post-operative fractionated intraperitoneal mitoxantrone appears feasible and safe, with a high local advantage, for up to 5 days of treatment and a maximum tolerated total dose of 20-25 mg/m(2).

Chemical and biological properties of a new cis-diammineplatinum (II) complex containing para-aminobenzoic acid as amino ligand.

In this paper we report on the synthesis, characterization and preliminary pharmacological evaluation of a new platinum (II) complex obtained by reaction of cis-diamminedichloroplatinum(II) (DDP) with para-aminobenzoic acid (PABA). The structure of this platinum compound was defined by UV, IR, 1H-NMR and elemental analysis. DPAB tested in vitro and in vivo against P388 leukemic cells displayed good antiproliferative (IC50 values after 48 h exposure of cells = 3 micrograms/ml) and antitumor activity (T/C% = 150). This compound also possesses desirable physical properties, such as a good solubility and stability in aqueous media, and a low toxicity (LD50 > 1200 mg/kg body weight) combined with a moderate nephrotoxic activity [plasma urea nitrogen (PUN) level: 36 +/- 8(SD) mg/100 ml]. DPAB was cleared from plasma ultrafiltrate (UF-plasma) very rapidly [clearance (CL), 55.3 ml x min-1 x kg-1], showing a half-life of 13.6 min. Platinum exposure (AUC) in the kidney was 2.6 times greater than that found in UF-plasma. AUCS for liver, stomach and UF-plasma were similar, while the AUC value for the spleen was 1.7 times lower than that of UF-plasma. These preliminary results seem to hold interest for further preclinical evaluation of the biological activity of this new platinum compound.

Time-dependent influence of procaine hydrochloride on cisplatin antitumor activity in P388 tumor bearing mice.

In previous papers (1,2) we demonstrated that procaine hydrochloride may increase the therapeutic index of cisplatin by an improvement of its antitumor activity and a reduction of its nephrotoxicity. In the present study we investigated the relationship between the antitumor activity obtained by cisplatin associated with procaine hydrochloride and the relative time of administration of these two agents. When procaine hydrochloride (40 mg/Kg body wt) was administered 30 or 120 minutes before cisplatin (16 mg/kg) diluted in normal saline (i.e. clinical condition) it increased, although not significantly, its percent increase in life span (%ILS) and cure rate (%ILS: +292 and +217 vs +150; cure rate: 46.2% and 42.3% vs 23%, respectively), compared to cisplatin alone treatment. These results became statistically significant when procaine hydrochloride was given either simultaneously with cisplatin or 30 and 120 minutes thereafter (%ILS: > 400 vs +150; cure rate: 65.4%, 73.1% and 68% vs 23%, respectively). In conclusion procaine hydrochloride increased the antitumor activity of cisplatin independently from its timing of administration, although it seemed to be a better potentiating agent when administered after cisplatin.

Effect of para-aminobenzoic acid on the pharmacokinetics and urinary excretion of cis-diamminedichloroplatinum(II) in rats.

Para-aminobenzoic acid (PABA) has been previously reported as being an inhibitor of DDP toxicity, and its use did not result in any observable loss in antitumor activity of DDP. The following studies investigated the effect of PABA on the pharmacokinetics and urinary excretion of cis-diamminedichloroplatinum(II) (DDP) in male Sprague-Dawley rats. DDP was injected i.p. at the dose of 7.5 mg/kg in normal saline alone and with a concurrent i.p. injection of PABA (100 mg/kg). The combined treatment with PABA produced a significant increase in the plasma concentrations of total platinum, without affecting the levels of platinum species in the plasma ultrafiltrate. Similar results were also obtained in additional studies in rats receiving the same dose of DDP plus PABA through different routes of administration (i.e. DDP i.v. and PABA i.p.). Both the area under the total platinum plasma concentration-time curve (AUC) up to 60 min and AUC0-120 min were increased by PABA by an average of 113% and 66% respectively. The administration of PABA in rats was followed by a substantial reduction in total urinary excretion of platinum (P < 0.05) and by a significant (P < 0.01) lower concentration of DDP derived platinum in the urine collected during the first 4 h after treatment. The renal clearance of filterable platinum was reduced by PABA by an average of 67.5% from 1.11 to 0.36 ml/min/100 g body wt. Total 24-h urinary excretion of platinum was also decreased, although not significantly, by PABA. Urine volumes from rats treated with DDP+PABA were similar to those from animals receiving DDP alone. HPLC studies indicate that PABA reacts readily with the species generated from DDP in vitro, while the agent is essentially unreactive toward the parent DDP and does not influence its decomposition rate. The overall data of this study suggest that the protective effect exerted by PABA on DDP toxicity may be at least partially due to its ability to interact with aquated DDP as well as to alter the renal excretion of platinum.

Cytotoxicity in vitro and preliminary antitumor activity in vivo of a novel organotin compound.

The cytotoxic effect and antitumor activity induced by the novel organotin compound triethyltin(IV)lupinyisulfide hydrochloride, have been investigated. Different patterns of antiproliferative effects have been observed in a panel of human tumor cell lines in vitro. Toxicity studies in mice reported acute toxicity at the doses of 21 and 17.5 mg/kg which progressively disappeared at lower concentrations. On this basis, the doses of 3.5, 7 and 14 mg/kg were selected to assess the antitumor activity in vivo against the P388 leukemic cells xenografted in mice. This compound was able to induce a dose-dependent significant reduction of tumor volume, up to 46%, at the highest concentration (p = 0.0062) without important toxicity, as also confirmed by histological analysis of the main organ tissues. This preliminary study seems to hold interest for further investigations in different tumor models as well as for the evaluation of optimal drug route and schedule.