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.

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.

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.

[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.

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.

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.

Preparation and evaluation of nanoparticles made of chitosan or N-trimethyl chitosan and a cisplatin-alginate complex.

In this work, nanoparticles with a negative or positive surface charge were prepared through electrostatic interaction of an anionic cisplatin-alginate complex with a cationic polyelectrolyte, namely chitosan or N-trimethyl chitosan (substitution degree of 85%). Statistical experimental design allowed the study of the influence of component amounts on the characteristics of nanoparticles. Mean particle diameter ranged from 180 nm to 350 nm. After 24 h, while the cisplatin-alginate complex released almost all the drug in saline-buffered solution at pH 7.4, approximately 40% w/w of total cisplatin was released from negative nanoparticles and roughly 50% w/w from positive ones. The same cumulative amounts of released drug were found after 48 h, with a progressive reduction to lower values up to 6 days. Drug loading of nanoparticles with a positive zeta potential (43 mV-60 mV) ranged from 13% w/w to 21% w/w and particle yield, referred to total polymers, was about 15% w/w (50% w/w if referred to cisplatin-alginate complex). Nanoparticles with a negative zeta potential (-34 mV) were obtained with a yield of 40% w/w and a drug loading of 18% w/w. These nanoparticles were the least active on all cell lines tested, while the cytotoxic activity of the positive nanoparticles was similar to or lower than that of cisplatin, probably depending on the combination of sizes and zeta potential values, on P388 murine and A2780 human cells. On A549 human cells, the nanoparticles with the smallest size and the lowest positive zeta potential were more active than cisplatin and showed a similar capability in inducing apoptosis in A2780 human cells. These results indicate that cisplatin complexes with polycarboxylate polymers can be transformed into cisplatin particulate carriers of high potential interest.

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.

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).

Embryotoxicity of cisplatin and a cisplatin-procaine complex (DPR) studied in chick embryo.

Cisplatin is widely used as an antitumor drug. To reduce its toxic side effects in patients, cisplatin has been bound with procaine in a cisplatin-procaine complex (DPR). The lethal and teratogenic effects of cisplatin alone and of complexed cisplatin were determined in the chick embryo in ovo in order to compare their influence on rapidly proliferating embryonic tissues. The embryotoxic (lethal + teratogenic) effect was examined after a single intra-amniotic injection of one of six different doses, ranging from 0.03 to 30.0 microg, on embryonic days (ED) 3, 4 or 5. The minimal embryotoxic dose was lower for cisplatin alone (0.03-0.3 microg) than for cisplatin in the DPR complex (0.3-3.0 microg), suggesting that cisplatin alone is more embryotoxic than complexed cisplatin. Both substances caused malformations in the surviving embryos evaluated on ED 9. These malformations included microphthalmia, microcephaly, hypoplasia of the upper and lower jaw, cleft beak, and haemocephaly. Moreover, heart septum defects and limb reduction deformities were found after exposure to the DPR complex. The embryotoxicity of complexed cisplatin exhibited a stage-response effect. It was highest on day 3 and gradually decreased until ED 5. Such an apparent stage-response effect was not observed for cisplatin alone. The embryotoxicity of procaine hydrochloride - a component of the complex - was also tested. Procaine hydrochloride alone did not produce any embryotoxic effect, not even after a single injection of the maximal tested dose (100.0 microg per embryo). We also examined the protective effect of procaine hydrochloride, whose separate administration at ED 4 was followed by the injection of 0.3 microg cisplatin. We did not observe any protective effect of procaine hydrochloride if injected separately.

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.

Reduction of cisplatin nephrotoxicity by procainamide: does the formation of a cisplatin-procainamide complex play a role?

Procainamide protects mice bearing P388 leukemic cells against the toxicity of cisplatin without diminishing antitumor activity. The mechanism of action of procainamide protection was investigated both in vitro and in vivo. HPLC studies showed that procainamide forms a complex with cisplatin in vitro that has a UV spectrum similar to that of DPR, a triamine platinum complex that contains procaine as ligand. We report here the effect of the reaction product of cisplatin and procainamide on both cisplatin-induced DNA interstrand cross-links (ISCLs) and on the total DNA platination of isolated DNA. Total DNA platination in vitro of isolated DNA was increased by 113% (P <.01) and 17% (P <.05) after incubation times of 1.75 and 6 h, respectively, compared with products from the reaction of cisplatin with water. Furthermore, the reaction product of cisplatin and procainamide was bound to DNA to a significantly greater extent than was cisplatin itself. ISCLs were decreased by 41% when this drug combination was incubated with DNA for 1.75 h, but no changes were observed after incubation for 6 h. We also examined the influence of the time interval between administration of cisplatin and procainamide on normal kidney injury, the renal distribution and urinary excretion of platinum, and the formation of cisplatin-DNA adducts in renal tissue of Sprague-Dawley rats after i.p. administration of 7.5 mg/kg cisplatin either with or without procainamide. The plasma concentrations of urea and creatinine and kidney histology demonstrated that procainamide provided effective protection in vivo in the rat when administered either simultaneously or at 0.5 and 1 h before or after cisplatin. The protection was accompanied by both higher renal levels of platinum and cisplatin-DNA adducts and by an increase in the formation of ISCLs. Moreover, a dose-dependent reduction of urinary excretion and concentration of platinum was also observed. We propose that procainamide, after accumulation in the kidney, may coordinate with cisplatin to form a less toxic DPR-like complex that renders rats less susceptible to cisplatin-induced toxicity.

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.

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.

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.

Cisplatin combined with tiopronin or sodium thiosulfate: cytotoxicity in vitro and antitumor activity in vivo.

We have previously reported that the thiol compound tiopronin protects rat kidneys in vitro against the toxic activity of cisplatin. The influence of tiopronin and sodium thiosulfate (STS) on the cytotoxicity of cisplatin has been investigated on P388 leukemic cells in vitro after 3 days. The combination has also been investigated in vivo in BDF1 mice bearing a P388 s.c. tumor. In contrast to STS, tiopronin did not significantly reduce the cytotoxic activity of cisplatin in vitro and nor did it affect the uptake of platinum (cisplatin-derived), binding to DNA or the percentage of interstrand cross-links (%ISCL) formation. The co-administration of cisplatin (4 mg/kg) and tiopronin (150 and 300 mg/kg) to BDF1 female mice bearing a s.c. P388 tumor produced a significant reduction in tumor growth similar to that of a single 6 mg/kg dose of cisplatin. Interestingly, pre-incubation in vitro of either tiopronin or STS for 2 h with the species formed from cisplatin by hydrolysis demonstrated their ability in inhibiting the cytotoxicity of these reactive platinum products. These results indicate that tiopronin does not reduce the cytotoxicity of cisplatin in vitro, as STS does. This may be, at least partly, because of a different effect of the two thiol compounds on the cellular uptake and binding of platinum to DNA. Notably, tiopronin substantially reduced tumor growth in mice treated with a non-toxic dose of cisplatin (p < or = 0.0277), suggesting some positive influence of this thiol compound on the antitumor properties of cisplatin. The ability of tiopronin to protect in vitro against the cytotoxicity of the aquation products of cisplatin may be related to its nephroprotective effect.

Tiopronin protects against the nephrotoxicity of cisplatin in the rat.

1. Tiopronin (N-(2-mercaptopropionyl)-glycine) is a drug with a free thiol (sulphydryl) group that is used clinically. We have reported previously that tiopronin protects rat kidney slices in vitro from the nephrotoxic effects of cisplatin and does not reduce the antitumour activity of cisplatin. Tiopronin has been investigated therefore for its protective effects in rats in vivo. 2. The extent of kidney damage was studied 5 days after the administration of cisplatin. A single injection (i.p.) of cisplatin (6 mg/kg; 20 micromol/kg) to female Wistar albino rats caused a sustained decrease in body weight and, after 5 days, plasma urea, creatinine and kidney weight were increased. Tiopronin (2.5 mmol/kg, p.o.) ameliorated cisplatin nephrotoxicity when given 1 h before cisplatin. Tiopronin provided marked protection against cisplatin-induced increases in urea (from 237+/-19 mg to 48+/-23 mg/100 ml; control: 17+/-1) and creatinine (from 6.5+/-0.5 to 1.7+/-0.5 mg/100 ml control: 1.0+/-0.1). Tiopronin did not, prevent the body weight loss caused by cisplatin. In addition, an intraperitoneal dose (1 mmol/kg) of tiopronin afforded similar protection to that of an oral dose. Rats that received an i.p. mixture of cisplatin (6 mg/kg) and tiopronin (65 mg/kg) displayed generally less toxicity, as indicated by a small fall in body weight and smaller increases in urea and creatinine and kidney weight. 3. The results show that tiopronin protects against cisplatin-induced nephrotoxicity. Oral administration of tiopronin may be a clinically useful way to prevent cisplatin nephrotoxicity.

Neurotoxic effect of cisplatin and the cisplatin-procaine complex DPR studied in organotypic cultures of chick embryonic dorsal root ganglia.

Neurotoxic effects of cisplatin and the cisplatin-procaine complex cis-diaminechloro-[2-(diethylamino)ethyl 4-aminobenzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR) were compared in organotypic cultures of chick embryonic dorsal root ganglia maintained in a semi-solid (soft agar) culture medium. The changes of two characteristics of the neurite outgrowth, the mean radial length of neuritic processes growing out from the ganglia and the area of neurite outgrowth around the ganglion, were used as parameters to evaluate the toxic effect of both compounds. The drugs were administered to the cultures at concentrations ranging from 13 to 120 microM. The half-maximum inhibition concentration (IC50) was determined from the concentration-response curves for both the mean radial length of neurites and the area of neurite outgrowth. An analysis of these parameters revealed that DPR was significantly less neurotoxic than cisplatin. In fact, considering the mean radial length of neurite processes, the IC50s of cisplatin were 56, 65 and 66 microM after 24, 48 and 72 h of exposure, respectively. By contrast, for DPR the IC50s were 116 microM after 24 h, and greater than 120 microM after 48 and 72 h of exposure. When we considered the area index (i.e. the area of neurite outgrowth normalized for the area of the ganglia), the IC50s for cisplatin were 41, 52 and 55 microM after 24, 48 and 72 h of exposure, respectively, whereas for DPR the IC50s were 59 microM after 24 h, and greater than 120 microM after 48 and 72 h of exposure. Our results support previous findings of lower toxicity of DPR to non-neoplastic tissues, as compared to cisplatin.