Combined Therapy of Teicoplanin and Caffeic Acid Phenethyl Ester (CAPE) in the Treatment of Experimental Mediastinitis in the Rat

Abstract

Post-sternotomy mediastinitis affects 1-3% of patients undergoing cardiac surgery and is lethal in 10-47% of these patients.

We investigated the effect of an antioxidant/anti-inflammatory agent, caffeic acid phenethyl ester (CAPE), in the attenuation of inflammatory response induced by methicillin-resistant Staphylococcus aureus (MRSA) infection in a rat experimental mediastinitis model. Rats, divided into six equal groups, received MRSA precolonized stainless steel wire pieces implanted into their mediastinal spaces. Control group and CAPE control group received saline and CAPE 10 μmol/kg.day^?1 respectively, where Group A received a single dose of teicoplanin 24 mg/kg i.m. for the first day and then 12 mg/kg.day^?1. Group B received teicoplanin as in Group A plus CAPE 10 μmol/kg. day^?1 intra-peritoneally. Group C received teicoplanin 60 mg/kg i.m. for the first day and then 30 mg/kg.day^?1 and Group D received teicoplanin as in Group C plus CAPE 10 μmol/kg.day^?1. By the end of 14 days rats were sacrificed and serum malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), urea and creatinine levels were evaluated. Mediastinal organ tissues were collected for histopathological analysis.

Infection rates in all the drug-treated groups were lower than the control groups (P = 0.002) but statistical significance was attained only between the groups A and D (P = 0.018). In connective tissues and the peribronchial area polymorphonuclear leukocytic (PNL) infiltration in the treatment groups, although becoming very close, did not reach statistical significance (P = 0.053, P = 0.075, respectively). PNL infiltration especially in the peribronchial tissues of the Group B animals was found to be significantly less than the Control and CAPE Control groups with P values of 0.013 and 0.010, respectively. MDA and MPO levels were significantly lower in the treatment groups (P < 0.001 and P < 0.001 respectively). Levels of the degradation products of NO were lower in treatment groups compared to two control groups (P = 0.003, P = 0.005). NO levels in Group D were lowest among all treatment groups (P = 0.001).

It has been demonstrated that although bacterial colonization can be controlled in mediastinitis, the inflammatory response persists. The combination of an antioxidant / anti-inflammatory agent, CAPE, added to standard antibiotic therapy might be effective in the treatment of post-sternotomy mediastinitis due to MRSA.     

The effect of dacarbazine on wound healing

The effects of dacarbazine on wound healing were studied in an animal model. Sixty rats were divided into four groups. Each animal received a standard dorsal midline wound on day 0. Group 1 was injected with normal saline and acted as control; group 2 received 4 mg/kg of dacarbazine daily on days -3, -2, -1 (preoperative); group 3 received dacarbazine on days +1, +2, +3 (perioperatively); and group 4 received dacarbazine on days +5, +6, +7 (postoperatively). Wound bursting strength (WBS) was measured on days +7, +14, and +21. There was a significant decrease in WBS in experimental animals in groups 3 and 4 (perioperative and postoperative administration) compared to control animals, but no significant effect of preoperative dacarbazine on WBS in experimental animals (group 2). It is suggested that these effects are mediated through the late inflammatory phase of wound healing.     

Combined therapy of teicoplanin and caffeic acid phenethyl ester (CAPE) in the treatment of experimental mediastinitis in the rat

Post-sternotomy mediastinitis affects 1-3% of patients undergoing cardiac surgery and is lethal in 10-47% of these patients. We investigated the effect of an antioxidant/anti-inflammatory agent, caffeic acid phenethyl ester (CAPE), in the attenuation of inflammatory response induced by methicillin-resistant Staphylococcus aureus (MRSA) infection in a rat experimental mediastinitis model. Rats, divided into six equal groups, received MRSA precolonized stainless steel wire pieces implanted into their mediastinal spaces. Control group and CAPE control group received saline and CAPE 10 micromol/kg.day(-1 )respectively, where Group A received a single dose of teicoplanin 24 mg/kg i.m. for the first day and then 12 mg/kg.day(-1) . Group B received teicoplanin as in Group A plus CAPE 10 micromol/kg. day(-1 )intra-peritoneally. Group C received teicoplanin 60 mg/kg i.m. for the first day and then 30 mg/kg.day(-1 )and Group D received teicoplanin as in Group C plus CAPE 10 micromol/kg.day(-1) . By the end of 14 days rats were sacrificed and serum malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), urea and creatinine levels were evaluated. Mediastinal organ tissues were collected for histopathological analysis. Infection rates in all the drug-treated groups were lower than the control groups ( P=0.002) but statistical significance was attained only between the groups A and D ( P=0.018). In connective tissues and the peribronchial area polymorphonuclear leukocytic (PNL) infiltration in the treatment groups, although becoming very close, did not reach statistical significance (P =0.053, P=0.075, respectively). PNL infiltration especially in the peribronchial tissues of the Group B animals was found to be significantly less than the Control and CAPE Control groups with P values of 0.013 and 0.010, respectively. MDA and MPO levels were significantly lower in the treatment groups ( P<0.001 and P<0.001 respectively). Levels of the degradation products of NO were lower in treatment groups compared to two control groups (P=0.003, P= 0.005). NO levels in Group D were lowest among all treatment groups ( P=0.001). It has been demonstrated that although bacterial colonization can be controlled in mediastinitis, the inflammatory response persists. The combination of an antioxidant / anti-inflammatory agent, CAPE, added to standard antibiotic therapy might be effective in the treatment of post-sternotomy mediastinitis due to MRSA.     

Inhibitory Effects of Tualang Honey on Experimental Breast Cancer in Rats: A Preliminary Study

The study was conducted to determine the effect of Malaysian jungle Tualang Honey (TH) on developmentof breast cancer induced by the carcinogen 7,12-dimethylbenz(α)anthracene (DMBA) in rats. Forty nulliparousfemale Sprague-Dawley rats were given 80 mg/kg DMBA then randomly divided into four groups: Group 1served as a Control while Groups 2, 3 and 4 received 0.2, 1.0 or 2.0 g/kg bodyweight/day of TH, respectively, for150 days. Results showed that breast cancers in the TH-treated groups had slower size increment and smallermean tumor size (≤2cm3) compared to Controls (≤8cm3). The number of cancers developing in TH-treated groupswas also significantly fewer (P<0.05). Histological grading showed majority of TH–treated group cancers to beof grade 1 and 2 compared to grade 3 in controls. There was an increasing trend of apoptotic index (AI) seenin TH-treated groups with increasing dosage of Tualang Honey, however, the mean AI values of all TH-treatedgroups were not significantly different from the Control value (p>0.05). In conclusion, Tualang Honey exertedpositive modulation effects on DMBA-induced breast cancers in rats in this preliminary study.     

Effect of indomethacin on N-(4-(5-nitro-2-firyl)-2-thiazolyl)formamide-induced urinary tract carcinogenesis

The effects of indomethacin on the urinary bladder and renalpelvis in rats treated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide(FANFT) were studied. Two hundred female Sprague-Dawley ratswere divided into four groups. Group 1 received control dietwithout added chemicals. Group 2 was treated with indomethacin(1 mg/kg per day) in the drinking water throughout the experiment.Groups 3 and 4 received 0.2% FANFT in the diet for seven weeksfollowed by control diet. In addition to FANFT, Group 4 receivedindomethacin, 1 mg/kg per day, for the entire experiment. Therats were sacrificed after 92 weeks. There were no urothelialtumors in the control group, one renal pelvic tumor in the indomethacingroup, 4 tumors in the FANFT group and 10 urothelial tumorsin the FANFT ⁺ indomethacin group. The difference between Groups3 and 4 was statistically significant (P < 0.05). Moderateand severe hyperplasia of the renal pelvic and papillary epitheliumwas found in 15 of 48 rats in Group 2 (indomethacin only) ascompared with 6 of 49 control rats (P < 0.05). Moderate andsevere hyperplasia was equally frequent in Groups 3 and 4 (14and 17 animals in each group, respectively). Twenty-four ratsin Group 2 had mammary tumors as compared to 12 animals in Group1 (P < 0.01). Five of the tumors in Group 2 were adenocarcinomas.There was no difference between the number of mammary tumorsin Groups 3 and 4 (36 and 32 animals in each group, respectively).The results suggest that indomethacin enhances FANFT-inducedurinary tract carcinogenesis. Indomethacin also seems to exertsome tumorigenic activity in the mammary gland.     

The effects of doxorubicin and mitoxantrone on wound healing

Summary The goal of the present study was to determine whether mitoxantrone would impair wound healing to a similar degree as doxorubicin when given in equally cytotoxic doses. On day 0, male Fischer rats were wounded and treated with 5% dextrose (control), 6 mg/kg doxorubicin, or 1.2 or 2.4 mg/kg mitoxantrone. On day 5, WBCs for the doxorubicin group and the group that had been treated with 1.2 mg/kg mitoxantrone were 33% and 43% lower than control values, respectively. All rats that had been given 2.4 mg/kg mitoxantrone died within 1 week of being wounded due to drug toxicity. On day 21, wound-breaking strength (WBS) analysis was performed: two skin specimens were taken from each dorsal skin incision perpendicular to the scar axis and were subjected to wound disruption (grams of force) by uniaxial extension. The WBS analysis indicated significant differences between the doxorubicin treated group (1183±96 g) and the control group (2422±247 g). However, no significant difference was found between the group that had been given 1.2 mg/kg mitoxantrone (2140±191 g) and control animals. Thus, mitoxantrone seems to exert myelosuppressive effects similar to those displayed by doxorubicin, but the former drug results in significantly less impairment of wound healing in the rat model.     

The effect of <Emphasis Type="Italic">Saccharomyces boulardii</Emphasis> on reducing irinotecan-induced intestinal mucositis and diarrhea

To investigate the efficiency of Saccharomyces boulardii on irinotecan-induced mucosal damage and diarrhea in rats, fifty rats were randomized into three groups with 20 rats in two study groups and 10 rats in the control group. Control group did not receive any treatment. Irinotecan (60 mg/kg) alone was administered intravenously once a day for four consecutive days to the rats of Group A. Throughout the experiment, Group B rats were additionally given Saccharomyces boulardii (800 mg/kg) for 3 days before administration of irinotecan and 7 days throughout the experiment. Delayed diarrhea was more severe in Group A than Group B (P = 0.009). The weight loss was 34.7 ± 3.8 mg for Group A, while it was 17.4 ± 1.7 mg for Group B (P < 0.001). Findings of mucositis most clearly appeared in the jejunum. Regarding edema (P = 0.003), leukocyte migration (P = 0.038), and inflammation (P = 0.006) significant recovery was detected in the mucosa of rats receiving Saccharomyces boulardii. Villous thickness was significantly greater in Group A than Group B (P < 0.001). The results indicate that Saccharomyces boulardii provided significant improvement in irinotecan-induced diarrhea and mucositis.     

Radioprotective Effect of Thymoquinone in X-irradiated Rats

Background: Thymoquinone, has anti-inflammatory, anti-oxidant, and cardio protection properties. This study aimed to evaluate the radioprotective effect of thymoquinone in whole body X-irradiated rats. Methods: This study conducted on 40 male adult Wistar albino rats randomized into the following groups: Group I: Control rats did not receive thymoquinone or ionizing radiation. Group II: Whole-body irradiated rats with 6 Gy of X-ray. Group III: Rats orally intubated with thymoquinone (10 mg/kg/day) for 7 days then subjected to whole-body irradiation with 6 Gy then supplemented with thymoquinone for another 7 days. Group IV: Rats orally intubated with thymoquinone (20 mg/kg/day) for 7 days then subjected to whole-body irradiation with 6 Gy then supplemented with thymoquinone (20 mg/kg/day) for another 7 days. LDH, CK-MB, ALT, AST, MDA, TAC, Catalase activity, GPX, GSR and GSH were measured. Results: Lipid peroxidation biomarker in the blood of X-irradiated rats significantly increased and accompanied by decrease in the levels of GSH, GSR, GPX, catalase as well as TAC. Moreover, exposure to IR significantly increases cardiac and liver enzymes. However, administration of TQ to X-irradiated rats with either 10 mg/kg or 20 mg/kg have the same reform effects and significantly protects rats against adverse effects of IR. Conclusion: Exposure to X-ray leads to significant changes in cellular biochemical and morphological conditions. Administration of TQ before radiation treatment significantly decreases the adverse effects of IR. TQ can improve cardiac function, decrease myocardial enzyme levels and inhibit oxidative stress.     

Long-term administration of a small molecular weight catalytic metalloporphyrin antioxidant, AEOL 10150, protects lungs from radiation-induced injury

PURPOSE: To determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL 10150, with superoxide dismutase (SOD) mimetic properties, reduces the severity of radiation-induced injury to the lung from single-dose irradiation (RT) of 28 Gy. METHODS AND MATERIALS: Rats were randomly divided into four different dose groups (0, 1, 10, and 30 mg/kg/day of AEOL 10150), receiving either short-term (1 week) or long-term (10 weeks) drug administration via osmotic pumps. Rats received single-dose irradiation (RT) of 28 Gy to the right hemithorax. Breathing rates, body weights, blood samples, histopathology, and immunohistochemistry were used to assess lung damage. RESULTS: There was no significant difference in any of the study endpoints between the irradiated controls and the three groups receiving RT and short-term administration of AEOL 10150. For the long-term administration, functional determinants of lung damage 20 weeks postradiation were significantly worse for RT + phosphate-buffered saline (PBS) and RT + 1 mg/kg/day of AEOL 10150 as compared with the irradiated groups treated with higher doses of AEOL 10150 (10 or 30 mg/kg/day). Lung histology at 20 weeks revealed a significant decrease in structural damage and collagen deposition in rats receiving 10 or 30 mg/kg/day after radiation in comparison to the RT + PBS and 1 mg/kg/day groups. Immunohistochemistry demonstrated a significant reduction in macrophage accumulation, oxidative stress, and hypoxia in rats receiving AEOL 10150 (10 or 30 mg/kg/day) after lung irradiation compared with the RT + PBS and 1 mg/kg/day groups. CONCLUSIONS: The chronic administration of a novel catalytic antioxidant, AEOL 10150, demonstrates a significant protective effect from radiation-induced lung injury. AEOL 10150 has its primary impact on the cascade of events after irradiation, and adding the drug before irradiation and its short-term administration have no significant additional benefits.     

Hepatotoxicity associated with lapatinib in an experimental rat model

BackgroundThe current study is the first to evaluate the biochemical and histopathological features of hepatic toxicity of lapatinib.MethodsTwenty Wistar albino rats were allocated into three groups: experimental toxicity was induced with lapatinib (10 mg/kg) administered for 28 days (Group 1), 42 days (Group 2) orally in a single dose by gavage. Control group received only sterile water. Rats in Group 1 and Group 2 were sacrificed after the collection of blood and tissue samples on the 28th and 42nd days, respectively.ResultsSubjects in Group 1 and Group 2 had significantly higher levels of alanin aminotransferase (ALT), albumin, triglyceride and very low density lipoprotein (VLDL) when compared with the control group. None of the subjects in the two experimental groups showed normal histology. There were parenchymal acinar transformation zones, sinusoidal dilatation, hydropic degeneration of hepatocytes, vacuolisation of hepatocytes around the portal areas, and mild inflammation with dominance of mononuclear cells besides neutrophil and eosinophil leucocytes in portal areas, especially pronounced in Group 2.ConclusionThis study demonstrated that lapatinib brings about deterioration of lipid profile and triggers hepatic toxicity mainly as sinusoidal injury with elevation in transaminase levels, especially ALT.     

Comparative nephrotoxicity of carboplatin and cisplatin in combination with tobramycin

Summary The nephrotoxic potentials of cisplatin and carboplatin, alone and in combination with the aminoglycoside antibiotic tobramycin, were compared in male rats. Sixty (60) male Sprague-Dawley rats were divided into six groups of ten rats each and received the following treatments: Group I, saline; group II, cisplatin (5 mg/kg); group III, cisplatin (5 mg/kg)+tobramycin (50 mg/kg); group IV, carboplatin alone (50 mg/kg); group V, carboplatin (50 mg/kg)+tobramycin (50 mg/kg); and group VI, tobramycin alone (50 mg/kg). Carboplatin and cisplatin were each administered as a single i. v. injection on day l. Tobramycin was administered i.-m. once daily on days 1–5. All rats were euthanatized on day 6. Smaller body weight gains occurred in groups II–V than in saline controls. Serum urea nitrogen (BUN) levels recorded on day 6 were elevated in group III. BUN values of all other groups were normal. Histopathologic examination of kidneys revealed acute tubular injury in rats treated with cisplatin, whether acute tubular injury in rats treated with cisplatin, whether alone or in combination with tobramycin, and in carboplatin/tobramycin-treated rats. Carboplatin and tobramycin, when administered separately, were not nephrotoxic. The combination of cisplatin and tobramycin proved to be the most nephrotoxic treatment.     

Influence of perinatal genistein exposure on the development of MNU-induced mammary carcinoma in female Sprague-Dawley rats

Genistein, a phytoestrogen, was subcutaneously (s.c.) injected to pregnant Sprague-Dawley CD rats on gestational days 16-20 at either 25 mg (Group 1) or 5 mg/day (Group 2). Female offspring of mothers not exposed to genistein during pregnancy received 12.5 mg genistein s.c. at neonatal days 15 and 18 (Group 3), or received vehicle only (Group 4). At 35 days of age, 4-9 female offspring from each group were autopsied to observe the influence of genistein, and remainder of female offspring received 50 mg/kg N-methyl-N-nitrosourea (MNU) intraperitoneally and were sacrificed when mammary tumors were larger than 1 cm in size or when they reached 35 weeks of age. Genistein treatment during the perinatal period resulted in lower body weight and lower relative uterine-ovarian weight at 35 days, and a prolonged estrus cycle with a long estrus phase at 12-16 weeks. However, at 35 days (time at MNU administration), mammary gland development, cell proliferation rate (PCNA labeling index), and the number of estrogen receptor (ER)- and progesterone receptor (PgR)-positive cells were similar between genistein-treated and untreated rats. Twenty-five or 5 mg genistein/day in utero (between days 16 and 20 of gestation) or 12.5 mg genistein/day on neonatal days 15 and 18 did not affect the incidence of mammary tumors > 1 cm or the latency but did increase the number of mammary cancer lesions when MNU was administered at the time when the mammary gland growth in genistein-treated and untreated rats was similar. Thus, perinatal genistein is an endocrine disrupter and increases the multiplicity of MNU-induced mammary carcinoma in rats.     

The modulation of irinotecan-induced diarrhoea and pharmacokinetics by three different classes of pharmacologic agents

Diarrhoea is the major dose-limiting toxicity of irinotecan hydrochloride (CPT-11) in the clinical setting. This study was designed to evaluate the effects of different pharmacological agents in the modulation of CPT-11 induced diarrhoea in Sprague-Dawley rats. We studied the effects of intravenous valproic acid (VPA), ceftriaxone (CTX) and oral charcoal in the modulation of CPT-11 induced diarrhoea. Male Sprague-Dawley rats (n=7 per group) were given CPT-11 60 mg/kg as intravenous injection from day 1 to 5 (total dose 300 mg/kg) in all treatment groups. Group 1 (G1) rats only received CPT-11, group 2 to 6 (G2 to G6) rats received in addition to IV CPT-11 60 mg/kg, IV valproic acid (VPA) 200 mg/kg (G2), IV VPA 200 mg/kg + IV ceftriaxone (CTX) 100 mg/kg (G3), IV VPA 200 mg/kg + oral activated charcoal 250 mg administered twice daily (G4), IV CTX 100 mg/kg (G5) and oral charcoal 250 mg every 12 hourly (G6). We compared the pharmacokinetics of total CPT-11 and its metabolites and the frequency and grade of diarrhoea in each group of rats. There were no significant differences in the pharmacokinetic parameters of total CPT-11 between treatment groups (p>0.05). Cotreatment with CTX and charcoal resulted in a lower total SN-38G AUC0- infinity (p<0.05 and p<0.01, respectively). Cotreatment with CTX also resulted in a lower Cmax for total SN-38G compared to other groups (p<0.01). A higher frequency of grade 3 diarrhoea was observed in G1 rats compared to other groups. Co-treatment with VPA (log OR: -1.13; 95% CI: -1.85, -0.41) or CTX (log OR: -1.66; 95% CI: -2.43, -0.88) were found to be associated with a lower odds of grade 3 diarrhoea compared to control or charcoal treated groups. Our findings indicate that CPT-11 treated rats given VPA and CTX, either alone or in combination has similar effects in preventing high grade diarrhoea. Activated charcoal was not found to be effective in the prevention of high grade diarrhoea.     

Antioxidant Role of Selenium in Rats with Experimental Acute Otitis Media

The aim of this prospective experimental animal study was to determine whether selenium had a protective effect on oxidative stress in rats with acute otitis media, by measuring the alterations of antioxidant parameters and lipid peroxidation on days 4 and 10 after inoculation into the middle ear. Streptococcus pneumoniae was inoculated into the middle ear cavities of 32 rats in animal laboratory of a tertiary medical center. Group 1 served as the control group and the animals were administered 1.5 ml/day saline. Group 2 received 0.2 mg/kg/day oral selenium for 10 days. The blood samples of each group were obtained on post-inoculation days 4 and 10. The levels of thiobarbituric acid reactive substances, albumin, total sulphydryl, superoxide dismutase and glutathione peroxidase were investigated. Day 10 level of thiobarbituric acid reactive substance in group 2 was lower than the day 4 level of the same substance in the control group. Although glutathione peroxidase and superoxide dismutase levels significantly decreased starting from 4th day until 10th day in group 1, their levels increased in group 2. Day 10 levels of albumin and total sulphydryl in group 1 were significantly higher than day 4 levels in group 2. We found that selenium supplementation for 10 days decreased thiobarbituric acid reactive substances and increased glutathione peroxidase and superoxide dismutase levels when compared to the control group. We believe that selenium supplementation may be beneficial to prevent the clinical sequelae and recurrence of otitis media.     

A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma therapy

Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received two courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab‐related targeted toxicity (grade 4 hypertension, proteinuria or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2–4 major wound complications). Thirty‐one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4‐year event‐free survival (EFS) rate and overall survival rate were 57.5 ± 10.0% and 83.4 ± 7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (<5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.     

Changes in bowel mucosal permeability and wound healing after neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NAC) with 5-fluorouracil (5-FU) and cisplatin (CDDP) is a promising approach for locally advanced gastric cancer. We investigated the influence of NAC with 5-FU/CDDP on the permeability of intestinal mucosa and wound healing. Male Sprague Dawley rats were divided into four groups (n=6). Group 1 received saline (control group) and Groups 2-4 were administered preoperative 5-FU/CDDP (NAC groups). The NAC consisted of daily intraperitoneal administration of 5-FU from day 1 to 5 and from day 8 to 12 and intravenous administration of CDDP on days 2 and 9. The rats underwent gastrotomy (1.0 cm) with a laparotomy of 3 cm in length, under general anesthesia. Seven days after surgery, the rats were orally administered with phenolsulfonphthalein (PSP), and the 24-h urinary excretion of PSP was quantified. On postoperative day 8, the bursting pressure (BP) of the gastric suture line and the tensile strength of the abdominal wound were measured. The hydroxyproline (HP) content in the tissue of the abdominal suture line was then measured, and the number of fibroblast cells in the tissue of the gastric suture line was calculated by histopathological examination. The PSP urinary excretion rate was significantly higher in Group 2 in comparison with the other groups (P<0.05), while the BP of a selected gastrorrhaphy region was significantly lower in Group 2 (P<0.05). No significant differences were noted in the HP content. NAC with 5-FU/CDDP disturbs the healing of intestinal anastomoses when the interval between chemotherapy and surgery is insufficient. Neither HP content nor fibroblast counts were correlated with BP. Consequently, NAC appeared to affect the remodeling of collagen fiber. Thus, the integrity of the intestine may play a role in intestinal wound healing.     

Effect of Ginkgo biloba extract (EGb 761) on rats in an experimental model of acute encephalopathy after total body irradiation]

PURPOSE: To define the therapeutic effect of Ginkgo biloba extract (EGb 761) in an experimental model of acute encephalopathy following total body irradiation in rats. MATERIAL AND METHODS: Ninety four-month-old rats received 4.5 Gy total body irradiation (TBI) at day 1 while 15 rats received sham irradiation. A behavioural study based on a conditioning test of negative reinforcement, the one-way avoidance test, was performed test, was performed after irradiation. Orally treatment was started one day (study A) or twenty two days (study B) after irradiation and repeated daily for twelve days. In the irradiated group, three subgroups were defined according to the treatment received: EGb 761 (50 mg/kg), EGb 761 (100 mg/kg), water. RESULTS: This work comprised two consecutive studies. In study A (45 rats) the one-way avoidance test was administered daily from day 7 to day 14. In study B (45 rats) the behavioural test was performed from day 28 to day 35. Study A (three groups of 15 rats): following TBI, irradiated rats treated with water demonstrated a significant delay in a learning the one-way avoidance test in comparison with sham-irradiated rats (P < 0.0002) or irradiated rats treated with EGb 761 (50 mg/kg; P < 0.0017) or EGb 761 (100 mg/kg; P < 0.0002). The irradiated rats, treated with EGb 761 (50 or 100 mg/kg) did not differ from the sham-irradiated controls. Study B (three groups of 15 rats): the irradiated rats, treated with water or EGb 761 (50 or 100 mg/kg) did not differ from the sham-irradiated controls. CONCLUSION: This study indicates that a relatively low dose of total body irradiation induces a substantial acute learning dysfunction in the rat, which persists fourteen days after TBI. This effect is prevented by the administration of EGb 761 (50 or 100 mg/kg) started twenty-four hours after irradiation.     

NTP Toxicity Studies of Dimethylaminopropyl Chloride, Hydrochloride (CAS No. 5407-04-5) Administered by Gavage to F344/N Rats and B6C3F1 Mice

Dimethylaminopropyl chloride, hydrochloride is used primarily as an industrial and research organic chemical intermediate acting as an alkylating reagent in Grignard and other types of reactions. It is also used as a pharmaceutical intermediate for the synthesis of many types of drugs, as an agricultural chemical intermediate, as a photographic chemical intermediate, and as a biochemical reagent for enzyme and other studies. Human occupational or other accidental exposure can occur by inhalation, ingestion, or skin absorption. Male and female F344/N rats and B6C3F1 mice received dimethylaminopropyl chloride, hydrochloride (greater than 99% pure) in water by gavage for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. In the 2-week toxicity studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg dimethylaminopropyl chloride, hydrochloride/kg body weight in deionized water by gavage, 5 days per week for 16 days. All dosed male and female rats and mice survived until the end of the 2-week study; one vehicle control female mouse died early. Mean body weights of all dosed groups of rats and mice were similar to those of the vehicle control groups. No gross or microscopic lesions were considered related to dimethylaminopropyl chloride, hydrochloride administration. In the 3-month toxicity studies, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg/kg in deionized water by gavage, 5 days per week for 3 months. One male rat in the 50 mg/kg group died during week 12 of the study, and one female mouse in the 100 mg/kg group died during week 9 and another during week 13. The final mean body weights of 50 mg/kg male rats and 50 mg/kg female mice were significantly less than those of the vehicle controls. Possible chemical-related clinical findings in rats included lethargy in one 50 mg/kg male and one 100 mg/kg male, tremors in one 100 mg/kg male, and ataxia in one 50 mg/kg male and two 100 mg/kg males. Absolute lung weights in the 25, 50, and 100 mg/kg groups of female mice were significantly less than those of the vehicle controls. Total serum bile acid concentrations were increased in 50 mg/kg male rats and 100 mg/kg male and female rats. The incidence of goblet cell hypertrophy of the nose was significantly increased in 100 mg/kg male rats compared to the vehicle controls. There were no significant histopathologic findings in mice. Dimethylaminopropyl chloride, hydrochloride was mutagenic in the Salmonella typhimurium base substitution strains TA100 and TA1535, with and without hamster or rat liver S9 activation enzymes; no mutagenic activity was seen in TA97 or TA98. No increase in the frequency of micronucleated erythrocytes was seen in peripheral blood of male or female mice administered dimethylaminopropyl chloride, hydrochloride for 3 months by gavage. In summary, dimethylaminopropyl chloride, hydrochloride caused increased incidences of goblet cell hypertrophy in the nose of male rats and increased serum bile acid concentrations in male and female rats. In mice, dimethylaminopropyl chloride, hydrochloride caused deaths in females administered 100 mg/kg. The estimated no-observed-effect levels were 50 mg/kg per day for male rats and female mice, 100 to 200 mg/kg per day for female rats, and greater than 100 mg/kg per day for male mice. Synonyms: 3-Chloropropyldimethyl-ammonium chloride; (3-chloropropyl)dimethylamine, hydrochloride; N-(3-chloropropyl)-N,N-dimethylammonium chloride; 3-dimethylamino-1-propyl chloride hydrochloride; 3-dimethylaminopropyl chloride hydrochloride; DMPC; 1-propylamine, 3-chloro-N,N-dimethyl-, hydrochloride.     

Effects of prochlorperazine on experimental nephrotoxicity

Summary In early studies of the antitumor drug 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1nitrosourea (methyl-CCNU), animal models consistently predicted that the compound would be nephrotoxic in humans. Nephrotoxicity in cancer patients who had received methyl-CCNU was not confirmed until about 6 years after clinical trials began. We have investigated the possibility that prochlorperazine, a commonly used antiemetic, might affect the development of neprhotoxicity. Prochlorperazine (1, 2, 5, and 8 mg/kg IP on days 1–3) produced a dose-related reduction in the concentrations of plasma urea nitrogen in mice that received nephrotoxic doses of methyl-CCNU (42, 52, or 63 mg/kg IP on day 1). The frequency and severity of renal lesions evaluated histopathologically were reduced significantly as the prochlorperazine dose increased. To study further this apparent protective activity of prochlorperazine, we chose a second nephrotoxin, mercuric chloride (HgCl₂, 1 mg/kg IP on day 1) and a rodent species used more commonly as a model for nephrotoxicity, the rat. Prochlorperazine (2.5 or 10 mg/kg IP on days 1–5) inhibited HgCl₂-induced urinary excretion of N-acetylglucosaminidase and leucine aminopeptidase. Urinary excretion of these enzymes on day 1 reflected proximal tubular epithelial degeneration and necrosis in rats that received HgCl₂ alone. The severity of HgCl₂-induced renal lesions evaluated histopathologically on day 16 was significantly reduced by combination treatment with prochlorperazine. Phenothiazines have numerous pharmacologic properties that might account for this observation, and additional studies will be required to establish the mechanism of this protective effect of prochlorperazine against acute nephrotoxicity in rodents.