Toxic effects of 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal on the reproduction of female mice.

Cigarette smoke can affect female reproductive health by causing follicle destruction and oocyte dysfunction. Third-hand smoke has received increasing attention as a public health issue. However, the effects of third-hand smoke on the female reproductive system, particularly the ovaries, remain unclear. 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal (NNA) can be used as a biomarker of third-hand smoke. We studied the in vivo toxic effects of NNA on mice ovaries and offspring development. Three-week-old premature female mice were exposed to NNA at two different concentrations (0.075 µg/kg and 0.15 µg/kg body weight) and tap water (blank control) and diluted dimethylsulfoxide (solvent control) for 30 days. We found that oral administration of NNA (0.075 µg/kg and 0.15 µg/kg) significantly reduced ovary weight (the 0.15 µg/kg group was reduced to 18.69% ±â€¯0.89%) and ovarian follicle number (reduced by about 30%) (p < 0.05). Consumption of 0.15 µg/kg NNA reduced the survival rate of superovulated oocytes from 91.36% to 60.55% (p < 0.05). In addition, treated female mice in each group were mated with normal male mice to observe the effects of NNA on the F1 offspring, and during mating and lactation, all groups were given tap water. Two different concentrations of NNA exposure also significantly reduced body weight and impaired ear opening, tooth eruption and eye opening in F1 offspring, especially those exposed to 0.15 µg/kg NNA (p < 0.05). Our study suggested that NNA exposure had toxic effects on the reproductive health of female mice and their offspring. The results obtained may help evaluate the risks of third-hand smoke to women's reproductive health and to the health of their offspring.

Effects of octenidine mouth rinse on apoptosis and necrosis of human fibroblasts and epithelial cells - an in vitro study.

This study aimed at comparing the cytotoxicity of a new octenidine mouth rinse (MR) on gingival fibroblasts and epithelial cells using different established MRs. Octenidol (OCT), Chlorhexidine 0.2% (CHX), Meridol (MER), Oral B (OB), and control (PBS only) were used. Human primary gingival fibroblasts (HGFIBs) and human primary nasal epithelial cells (HNEPCs) were cultivated in cell-specific media (2 × 105 cells/well) and treated with a MR or PBS for 1, 5, and 15 min. All tests were performed in duplicate and repeated 12 times. The apoptosis and necrosis were determined using a Caspase-3/7 assay and LDH assay, respectively. The data were analyzed using two-way analysis of variance with subsequent Mann-Whitney U-test. No significant differences could be found between the incubation times of the MR, neither for apoptosis nor necrosis (p > 0.05). Regarding apoptosis of HGFIBs, MRs had no influence at all. In HNEPCs, OCT induced relevantly lower apoptosis than CHX (p = 0.01). Considering necrosis, MER showed the lowest numbers of necrotic HGFIBs and HNEPCs, whereas OB induced the highest number of necrotic cells. The differences between both MR were statistically relevant (p < 0.01). OCT did neither differ from the other MRs nor from the control (PBS) in induction of necrosis in both cell types. In conclusion, the slightly negative effect of OCT considering apoptosis and necrosis of HGFIBs and HNEPCs is nearly the same or even lower compared to the established MRs included in this study. The results confirm that OCT is a potential alternative to CHX.

Cytotoxic effects of octenidine mouth rinse on human fibroblasts and epithelial cells - an in vitro study.

OBJECTIVES: This study compared the cytotoxicity of a new octenidine mouth rinse (MR) against gingival fibroblasts and epithelial cells with different established MRs. METHODS: The following MRs were used: Octenidol (OCT), Chlorhexidine 0.2% (CHX), Listerine (LIS), Meridol (MER), Betaisodona (BET); and control (medium only). Human primary gingiva fibroblasts and human primary nasal epithelial cells were cultivated in cell-specific media (2 × 10(5) cells/ml) and treated with MR for 1, 5, and 15 min. Each test was performed 12 times. Metabolism activity was measured using a cytotoxicity assay. A cellometer analyzed cell viability, cell number, and cell diameter. The data were analyzed by two-way analysis of variance with subsequent Dunnett's test and additional t-tests. RESULTS: The cytotoxic effects of all MRs on fibroblasts and epithelial cells compared to the control depended on the contact time (p < 0.001). OCT and BET showed less influence on cell metabolism in fibroblasts than other MRs. OCT also demonstrated comparable but not significant results in epithelial cells (p > 0.005). Cell numbers of both cell types at all contact times revealed that OCT showed a less negative effect (p > 0.005), especially for epithelial cells compared to CHX after 15 min (p < 0.005). OCT and BET showed the best results for viability in fibroblasts (p > 0.005), but MER showed less influence than OCT in epithelial cells (p < 0.005). CONCLUSIONS: OCT is a potential alternative to CHX regarding cytotoxicity because of its lower cell-toxic effect against fibroblasts and epithelial cells.

Rho-kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats.

Rho-kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver-specific ROCK inhibition is required. Here, we tested vitamin A (VA)-coupled liposomes carrying the ROCK inhibitor Y-27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline-deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y-27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VA-coupled liposome accumulation in livers. Liposomal Y-27632 was 100-fold more effective in inhibiting HSC activation than free Y-27632. Liposomal Y-27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y-27632 elicited severe systemic hypotension. We conclude that VA-coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity.

Low toxicity ß-cyclodextrin-caged 4,4'-bipyridinium-bis(siloxane): synthesis and evaluation.

The toxicity of viologens can be significantly reduced by including them in tight [2]rotaxane structures alongside ß-cyclodextrin, thus turning them into candidates of pharmaceutical interest. Here, we report a synthesis pathway for a benign viologen, by capping a small ß-cyclodextrin-caged molecule, the 4,4'-bipyridine, with minimal-length presynthesized axle-stopper segments of the propyl-3-pentamethyldisiloxane type. After 90 min from the oral administration to laboratory mice, the product concentration in the bloodstream reaches a value equivalent to 0.634% of the initial dose of 800 mg·kg(-1). As compared to the nude viologen having the same structure, which proved to be lethal in doses of 40 mg·kg(-1), the product induces reversible morphological changes in the liver, kidney, lung, and cerebellum, up to a dose of 400 mg·kg(-1), with higher dosages giving rise to a chronic slow evolution.

Analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing DNA adducts in human exfoliated oral mucosa cells by liquid chromatography-electrospray ionization-tandem mass spectrometry.

Quantitation of DNA adducts could provide critical information on the relationship between exposure to tobacco smoke and cancer risk in smokers. In this study, we developed a robust and sensitive liquid chromatography-tandem mass spectrometry method for the analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing DNA adducts in human oral cells, a noninvasive source of DNA for biomarker studies. Isolated DNA undergoes acid hydrolysis, after which samples are purified by solid-phase extraction and analyzed by LC-ESI-MS/MS. The developed method was applied to the analysis of samples obtained via collection with a commercial mouthwash from 30 smokers and 15 nonsmokers. In smokers, the levels of HPB-releasing DNA adducts averaged 12.0 pmol HPB/mg DNA (detected in 20 out of 28 samples with quantifiable DNA yield), and in nonsmokers, the levels of adducts averaged 0.23 pmol/mg DNA (detected in 3 out of 15 samples). For the 30 smoking subjects, matching buccal brushings were also analyzed, and HPB-releasing DNA adducts were detected in 24 out of 27 samples with quantifiable DNA yield, averaging 44.7 pmol HPB/mg DNA. The levels of adducts in buccal brushings correlated with those in mouthwash samples of smokers (R = 0.73, p < 0.0001). Potentially, the method can be applied in studies of individual susceptibility to tobacco-induced cancers in humans.

Thermoreversible gel for delivery of activin receptor-like kinase 5 inhibitor SB-505124 for glaucoma filtration surgery.

The purpose of this study is to investigate a thermoreversible gel using Pluronic F-127 to deliver an activin receptor-like kinase 5 (ALK-5) inhibitor SB-505124 in glaucoma filtration surgery (GFS). The gel was characterized for in vitro drug release and viscosity studies. Cytotoxicity of Pluronic F-127 was examined by MTT assay using cultured rabbit subconjunctival fibroblasts. In addition, Pluronic F-127 gel (18% w/v) containing 5 mg of SB-505124 was applied at the surgical site in an in vivo rabbit GFS model. In the in vitro viscosity study, the gel showed a change in viscosity (from 1000 cps to 45,000 cps) from low temperature (10°C) to body temperature (37°C). The in vitro drug release study demonstrated 100% drug release within 12 h. The gel did not show cytotoxicity to the cultured rabbit subconjunctival cells by MTT assay. In the in vivo rabbit GFS model, the drug was successfully delivered by injection and no severe post-surgical complications were observed. A thermoreversible gel system with SB-505124 was successfully prepared and delivered for the rabbit GFS model, and it may provide a novel delivery system in GFS.

[A comparative in vitro study of cell toxicity of clinically used antiseptics]. / Vergleichende In-vitro-Studie zur Zytotoxizität klinisch eingesetzter Antiseptika.

PURPOSE: Local skin antiseptics are the standard of care for chronic and non-healing wounds. However, little is known about their potential toxic properties. This study investigates the impact of three commercially available and widely used antiseptics on vitality and proliferation of human cutaneous cells. MATERIAL AND METHODS: Three antiseptics, Lavasept (PHMB), Octenisept (octenidine) and Betaisodona (PVP-iodine) were tested for their cytotoxic effects towards HaCaT cells, primary human keratinocytes and fibroblasts using MTT assay and BrDU ELISA. RESULTS: Lavasept showed only slight to moderate toxic effects on cellular vitality and proliferation. Ocentisept and Betaisodona induced severe reduction of cell vitality (p<0.05) to 0% surviving fibroblasts at 7.5% (Betaisodona) and 12.5% Octenisept, respectively. Furthermore, poliferative activity was reduced to 0% in keratinocytes at 7.5% concentration of Betaisodona and Ocentisept. CONCLUSION: This study shows that frequently used wound- and skin antiseptics show severe cytotoxic effects towards cutaneous cells. Furthermore, antimicrobial efficacy and toxic properties must be included in the clinical decision process for optimal therapy of chronic wounds. The PHMB solution Lavasept showed best results regarding toxicity in this study.

Insecticide pyriproxyfen (Dragón®) damage biotransformation, thyroid hormones, heart rate, and swimming performance of Odontophrynus americanus tadpoles.

Odontoprynus americanus tadpoles were used to determine the safety concentration of pyriproxyfen (PPF) insecticide by acute and sublethal toxicity tests (nominal range tested 0.01 to 10 [± 15%] PPF mg/L). Median lethal concentration (LC50) and no, and lowest-observed-effect concentrations (NOEC and LOEC, respectively) were calculated. We also assessed the effect on the activities of glutathione S-transferse (GST), acetylcholinesterase (AChE), and carboxylesterase (CbE) and compared to control (CO) tadpoles. Based on the 48-h NOEC value, two sublethal concentrations of PPF (0.01 and 0.1 mg/L) were assayed to detect effects on enzymes activities (GST and CbE), thyroid hormone's levels (triiodothyronine; T3 and thyroxine; T4), heart function, and tadpoles swimming behaviour. The results showed that the LC50 values of O. americanus tadpoles were 3.73 PPF mg/L and 2.51 PPF mg/L at 24-h and 48-h, respectively (NOEC = 0.1 mg/L; LOEC = 1 mg/L, for both times). PPF concentrations at 48 h, induced enzymatic activities such as GST (212.98%-242.94%), AChE (142.15%-165.08%), and CbE (141.86%-87.14%) significantly respect to COs. During the 22 days of chronic PPF exposure, GST (0.01 mg/L 88%-153% NOEC), AChE (177.82% NOEC), and T4 (70% NOEC) also significantly increased respect to COs. Similarly, heart rate (fH) and ventricular cycle length (VV interval) in CO tadpoles were significantly higher than PPF treated. Finally, at NOEC tadpoles exhibited significant effects on the behavioral endpoint (swimming distance, mean speed, and global activity; P < 0.05).

Synergistic effect of non-ionic surfactants Tween 80 and PEG6000 on cytotoxicity of insecticides.

The use of surfactants in the development of a suitable formulation for insecticides should improve the solubility behavior, the permeability and the efficiency against pests meanwhile decrease the toxic risks of insecticides on human health. Cytotoxicity of insecticides including abamectin, chlorfluazuron, hexaflumuron, chlorpyrifos, and tebufenozide was assessed on human HepG2 and lepidopteran Tn5B1-4 cells utilizing insecticide alone and in combination with nontoxic concentrations of nonionic surfactants Tween 80 and PEG6000. The results showed avermection revealed high cytotoxicity, chlorfluazuron and hexaflumuron possessed median cytotoxicity, and chlorpyrifos and tebufenozide had little cytotoxicity on HepG2 and Tn5B1-4 cells. The co-incubation with Tween 80 and PEG6000 powerfully counteracted the cytotoxicity of avermectin. Tween 80 enhanced, whereas PEG6000 compressed, the cytotoxicity of chlorfluazuron on Tn5B1-4 cells, and also improved a bit of the cytotoxicity of chlorpyrifos or tebufenozide on HepG2 cells. PEG6000 was more suitable to be used as surfactant in improving insecticide solubility and reducing the cytotoxicity. The present investigation demonstrates the necessity of utilizing surfactants to weaken the cytotoxicity of insecticides.

Chimeric Nanoparticle: A Platform for Simultaneous Targeting of Phosphatidylinositol-3-Kinase Signaling and Damaging DNA in Cancer Cells.

Phosphatidylinositol-3-kinase (PI3K) signaling has been hijacked in different types of cancers. Hence, PI3K inhibitors have emerged as novel targeted therapeutics in cancer treatment as mono and combination therapy along with other DNA damaging drugs. However, targeting PI3K signaling with small molecules leads to the emergence of drug resistance and severe side effects to the cancer patients. To address these, we have developed a biocompatible, biodegradable cholesterol-based chimeric nanoparticle (CNP), which can simultaneously load PI103, doxorubicin, and cisplatin in a controlled ratiometric manner. Size, shape, and morphology of these CNPs were characterized by dynamic light scattering (DLS), field-emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), and transmission electron microscopy (TEM). Increased amounts of PI103, doxorubicin, and cisplatin were released from CNPs through controlled and continuous manner over 120 h at pH = 5.5 compared to neutral pH. The CNPs showed much enhanced in vitro cytotoxicity in HeLa, HL60, MCF7, and MDA-MB-231 cancer cells compared to a free drug cocktail at 24 and 48 h by inducing apoptosis. Confocal laser scanning microscopy (CLSM) imaging revealed that indeed these CNPs were internalized into subcellular lysosomes through endocytosis in a time dependent mode over 6 h and retained inside for 48 h in HeLa, MDA-MB-231, and MCF7 cells. These CNPs showed their efficacy by damaging DNA and inhibiting Akt as a downstream modulator of PI3K signaling in HeLa cervical cancer cells. These CNPs have the potential to open up new directions in next-generation nanomedicine by simultaneous targeting of multiple oncogenic signaling pathways and inducing DNA damage for augmented therapeutic outcome by reducing toxic side effects and overcoming drug resistance.

Impact of antiseptics on radical metabolism, antioxidant status and genotoxic stress in blood cells: povidone-iodine versus octenidine dihydrochloride.

No sufficient data are available of the of antiseptics' influence on human blood cells. Effects of two antiseptics, povidone-iodine (PVD-I) versus octenidine dihydrochloride (OD), were tested on antioxidant status, radical formation, antioxidant defence enzymes and genotoxic stress in blood cells, in vitro. Human blood was taken by venipuncture, enriched with PVD-I or OD (0.0001-20% final concentration) and incubated at 37 degrees C between 30 and 120 min. alpha-Tocopherol was assessed in erythrocytes and granulocytes. Superoxide-dismutase (SOD) and glutathione (GSH) were determined in erythrocytes, the total anti-oxidative capacity (TAC) and malondialdehyde (MDA) in their ghosts. In granulocytes status of hydrogen peroxide (H(2)O(2)), superoxide anions and MDA was observed. Genotoxic stress was determined by counting sister chromatide exchanges (SCE) in lymphocytes after enrichment within 0.05-0.4% of antiseptics. Based on all biomarker tested, concentrations up to 0.05% incubated for 30 min did not affect cell metabolism. 1% and 10% PVD-I reduced the activity of SOD (-40%), GSH (-62%) and the content of alpha-tocopherol more than OD (p<0.05). No significant differences between the antiseptics were observed for TAC and MDA. H(2)O(2) and superoxide anions were significantly reduced after the 10% addition for both substances independent on the exposure. Without having changes in lipid oxidation, the reduction of antioxidative defence mechanisms must be due to the oxidation caused by the antiseptics, mainly PVD-I. An increased SCE rate was neither observed with PVD-I nor with OD within an enrichment with 0.05-0.4%. Higher concentrations (1% and more) could not be tested on SCE formation because they caused cell bursts. The results presented indicate that concentrations up to 0.05% incubated for 30 min are safe for exposing blood cells of healthy subjects.

[Radioprotective activity and toxicity of copolymer 2-methyl-5-vinyl pyridine with 2-methyl-5-vinylpyridinium-n-oxide]. / Protivoluchevaia aktivnost' i toksichnost' sopolimera 2-metil-5-vinilpiridina s 2-metil-5-vinilpiridinii -n-oksidom.

In experiments in mice, hamsters and dogs therapeutic radioprotective efficiency and toxicity of new water-soluble copolymer were studied. It was found that at intramuscular injection of the copolymer to dogs in a dose of 5 mg/kg 24 h after irradiation with a dose of 3.30 Gy (LD85/45) it showed pronounced therapeutic effect (68.1%). In mice and hamsters, the effect was less pronounced: 42-21% after irradiation with a dose of 8.0 Gy. The copolymer is low toxic substance and according to the State standards of Russian Federation belongs to the fourth class (harmless).

Correlation of [RuCl3(dppb)(VPy)] cytotoxicity with its effects on the cell membranes: an investigation using Langmuir monolayers as membrane models.

One of the major challenges in drug design is to identify compounds with potential toxicity toward target cells, preferably with molecular-level understanding of their mode of action. In this study, the antitumor property of a ruthenium complex, mer-[RuCl3(dppb)(VPy)] (dppb = 1,4-bis(diphenylphosphine)butane and VPy = 4-vinylpyridine) (RuVPy), was analyzed. Results showed that this compound led to a mortality rate of 50% of HEp-2 cell with 120 ± 10 µmol L(-1), indicating its high toxicity. Then, to prove if its mode of action is associated with its interaction with cell membranes, Langmuir monolayers were used as a membrane model. RuVPy had a strong effect on the surface pressure isotherms, especially on the elastic properties of both the zwitterionic dipalmitoylphosphatidylcholine (DPPC) and the negatively charged dipalmitoylphosphatidylglycerol (DPPG) phospholipids. These data were confirmed by polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS). In addition, interactions between the positive group from RuVPy and the phosphate group from the phospholipids were corroborated by density functional theory (DFT) calculations, allowing the determination of the Ru complex orientation at the air-water interface. Although possible contributions from receptors or other cell components cannot be discarded, the results reported here represent evidence for significant effects on the cell membranes which are probably associated with the high toxicity of RuVPy.

Active wound dressings based on bacterial nanocellulose as drug delivery system for octenidine.

Although bacterial nanocellulose (BNC) may serve as an ideal wound dressing, it exhibits no antibacterial properties by itself. Therefore, in the present study BNC was functionalized with the antiseptic drug octenidine. Drug loading and release, mechanical characteristics, biocompatibility, and antimicrobial efficacy were investigated. Octenidine release was based on diffusion and swelling according to the Ritger-Peppas equation and characterized by a time dependent biphasic release profile, with a rapid release in the first 8h, followed by a slower release rate up to 96 h. The comparison between lab-scale and up-scale BNC identified thickness, water content, and the surface area to volume ratio as parameters which have an impact on the control of the release characteristics. Compression and tensile strength remained unchanged upon incorporation of octenidine in BNC. In biological assays, drug-loaded BNC demonstrated high biocompatibility in human keratinocytes and antimicrobial activity against Staphylococcus aureus. In a long-term storage test, the octenidine loaded in BNC was found to be stable, releasable, and biologically active over a period of 6 months without changes. In conclusion, octenidine loaded BNC presents a ready-to-use wound dressing for the treatment of infected wounds that can be stored over 6 months without losing its antibacterial activity.

Polymer-free cerivastatin-eluting stent shows superior neointimal inhibition with preserved vasomotor function compared to polymer-based paclitaxel-eluting stent in rabbit iliac arteries.

AIMS: The present study was designed to evaluate vasomotor function and vascular biological responses following a novel non-polymeric cerivastatin-eluting stent (CES) versus polymer-based paclitaxel-eluting stent (PES) in a rabbit iliac artery model. Optimisation of DES components and non-polymeric stents may contribute to vascular healing and beneficial to vasomotor function. METHODS AND RESULTS: In vitro human aortic and coronary smooth muscle cells (hASMC & hCSMC), as well as endothelial cells (hAEC & hCEC) were cultured. IC50 curves were determined for cerivastatin (CER). In vivo PES (n=6) and CES (n=12) stents were implanted in nine rabbits. Vasomotor function was investigated at 28 days by acetylcholine (ACh) followed by histopathological and histomorphometric analyses. CER was cytotoxic to hASMC and hCSMC (IC50s of 10-6 M and 10-5 M, respectively), although such cytotoxic effects were not observed for hAEC and hCEC at maximal study dose. PES-associated vasodilation response to endothelial-dependent ACh was significantly suppressed at both proximal and distal adjacent arterial segments, as compared to CES. Furthermore, microscopically, neointimal inhibition quantified by the neointimal cross-sectional area (IA) was superior with CES (0.60 + or - 0.27 mm(2)) compared to PES (1.35 + or - 0.16 mm(2); P <0.05). Medial area was smaller for PES (0.3 + or - 0.04 mm(2)) than CES (0.5 + or - 0.03 mm(2), p <0.001). Additionally, significant inflammation and fibrin deposition was clearly evidenced in PES compared to CES (p <0.05). CONCLUSIONS: CER elicits a differential effect on hSMC compared to hEC in vitro. In contrast to PES, a novel bioabsorbable sol-gel coated CES demonstrated effective neointimal inhibition with less vessel wall toxicity accompanied by preservation of vasomotor function in the rabbit iliac model.

Phase I study of oxaliplatin in combination with capecitabine and radiotherapy as postoperative treatment for stage II and III rectal cancer.

PURPOSE: A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicity (DLT) of oxaliplatin (OXA) combined with capecitabine and radiotherapy as adjuvant treatment in patients with operable rectal cancer. PATIENTS AND METHODS: A total of 21 patients with Stage II or III rectal adenocarcinoma after curative surgery were treated with radiotherapy to a total dose of 50 Gy in 5 weeks. OXA was administered at a dosage of 40 (n = 6), 50 (n = 3),60 (n = 3), 70 (n = 3), or 80 mg/m(2) (n = 6) once a week for 2 weeks (first cycle) followed by a second cycle after a 7-day break. Capecitabine at a fixed dose of 1,300 mg/m(2)/d was administered orally at the same schedule as for OXA. DLT was defined as Grade 3 or 4 hematologic and nonhematologic toxicity. RESULTS: Grade 1-3 leukopenia, diarrhea, and nausea/vomiting were the most common toxic side effects, and most were Grade 1-2. A DLT was first observed in 1 of 3 patients at 40 mg/m(2) (Grade 3 diarrhea) but was not observed in the next 3 patients at the same level or in patients who received a dose level of 50-70 mg/m(2). At 80 mg/m(2), DLT occurred in 3 of 6 patients (1 Grade 4 leukopenia and 2 Grade 3 diarrhea). CONCLUSIONS: OXA combined with a fixed dose of capecitabine at 625 mg/m(2) twice daily by mouth plus radiotherapy in the adjuvant setting was tolerable and clinically feasible. The maximal tolerated dose of OXA in this setting was 80 mg/m(2), comparable to the maximal tolerated dose of OXA in the neoadjuvant setting.

In vivo pharmacokinetics and toxicity of a novel hydrophilic oral formulation of the potent non-nucleoside reverse transcriptase inhibitor compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443).

The thiophene ethyl thiourea (TET) compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443) is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI). The pharmacokinetics of 17 different novel oral formulations of HI-443 were compared in an attempt to identify the most suitable dosage form for clinical use in HIV-infected persons. Plasma concentrations of HI-443 were monitored in mice after administration of the drug using these 17 different formulations at three time points. Two-way ANOVA showed highly significant formulation (p < 0.0001), time (p < 0.0001) and formulation*time interaction effects (p = 0.0003). Planned linear contrasts were performed to identify which formulations showed the highest bioavailability at 10, 30, 60 min and at all time points relative to DMSO alone. A significant positive regression was observed comparing bioavailibility of HI-443 at 10 min and hydrophilic-lipophilic balance (HLB) values of the formulations (R2 = 26%, p < 0.0001). The results showed that formulations that were hydrophilic, containing PEG400 and propylene glycol, gave the highest overall drug concentrations over the 60-min time period. The lead oral formulation of HI-443 exhibited a very favorable toxicity profile in BALB/c mice.

Comparative study of in vitro cytotoxicity of povidone-iodine in solution, in ointment or in a liposomal formulation (Repithel) and selected antiseptics.

The cytotoxicity of povidone-iodine in Repithel, Betaisodona ointment and Betaisodona solution was investigated using CHO-K1 cells. To estimate the vitality of test cells after 30 min contact time using vital dye neutral red, the following IC(50) were determined: 16-18% Repithel, 8-9% Betaisodona ointment and 1.8-2% Betaisodona solution; using MTT for detecting vitality, the IC(50) were: 5-10% Repithel, 1.3-2.5% Betaisodona ointment and 0.6-1.3% Betaisodona solution. Therefore, the first attack of the antiseptic agent iodine to mammalian cells is carried out on enzymes, perhaps by oxidation, followed by membrane attack. Murine fibroblasts were used to compare the cytotoxic impact of povidone-iodine with those of chlorhexidine digluconate (CHex), octenidine dihydrochloride (Oct) and polyhexamethylene biguanide (PHMB). On the base of molecular concentration, povidone-iodine is more than 20 times better tolerated by L929 cells than CHex, Oct or PHMB. Moreover, after 30 min contact of L929 cells with povidone-iodine, there is a temporarily cytotoxic reaction, which leads after 24 h culture to an unexpected revitalisation of murine fibroblasts. This phenomenon was not detected using CHex, Oct or PHMB. Povidone-iodine seems to be the most tolerated antiseptic in comparison with CHex, Oct or PHMB.

Acute and subacute toxicity in Sherman strain rats exposed to 4,4'- and 2,2'-dipyridyl.

Acute and subacute toxicity was studied in adult Sherman strain rats exposed to 4,4'-and 2,2'-dipyridyl. The single oral LD50 for 4,4'-dipyridyl was 175 mg/kg in male and 172 mg/kg in female rats; for 2,2'-dipyridyl it was 100 and 107 mg/kg, respectively. Symptoms of toxicity for 4,4'-dipyridyl included subdued behavior, red stains around mouth and eyes, lacrimation, swelling around the eyes, and occasional convulsions. Rats receiving 2,2'-dipyridyl had subdued behavior, loss of muscle coordination, red urine, tremors, and convulsions. Onset of symptoms was rapid, and most rats died from internal hemorrhage within 2 d after dosing. Rats given lower single oral doses of 90 mg/kg 2,2'-dipyridyl and 155 mg/kg 4,4'-dipyridyl had no symptoms and no organic pathology 2 wk after dosing. Rats given doses of 5.1 and 25.5 mg/kg 4,4'-dipyridyl and 7.13 and 35.6 mg/kg 2,2'-dipyridyl in their drinking water for 3 mo showed no significant effects that could be related to the consumption of dipyridyl.