Urinary polyamine excretion as related to cell death and cell proliferation induced by carbon tetrachloride intoxication

This study addresses the question whether urinary polyamine excretion is related to cell death or cell proliferation. CCl₄ intoxication of the rat was used as the experimental model. Treatment with CCl₄, a hepatotoxic haloalkane, produces an initial phase of liver cell death succeeded by a regenerative phase of growth, during which the liver is restored. The highest rate of putrescine (and spermidine) excretion occurred during the first 24 hr of CCl₄ intoxication and coincided with the period of maximum liver damage. During subsequent liver regeneration the rate of excretion of both polyamines decreased.     

Blood flow in liver tumors--effects of vasoactive drugs estimated with xenon (133Xe) clearance

BACKGROUND/AIMS: The aim of the present study was to identify in a standardized experimental rat liver tumor system the drugs which are most appropriate in influencing the relationship between liver tumor and normal liver parenchyma blood flow as estimated with 133Xe washout clearance method, and thereby positively influencing the kinetics of chemotherapeutic drugs. A battery of vasoactive drugs, which according to a literature review were considered to be active, were tested. METHODOLOGY: Twelve drugs were administered intravenously on 113 Wistar-Fu rats with an experimental adenocarcinoma in the liver (weight 0.62 g). 133Xe was applied in the tumor and in normal parenchyma with and without administration of a vasoactive drug. The pulses were registered with a NaI (Tl)-scintillation detector connected to a multichannel analyzer. The disappearance rate of the isotope was calculated according to a single compartment model. Four recordings were performed in each rat randomly in tumor and liver parenchyma with and without a drug (series A) and one series twice in tumor and twice in parenchyma with a drug (series B). RESULTS: In unaffected animals the tumor to liver quotient was 0.57+/-0.35. This quotient was higher in tumors less than 0.53 g. Angiotensin-II 8 mg i.v. increased the quotient to 0.95+/-0.20. No other drug significantly influenced the quotient. CONCLUSIONS: In an experimental adenocarcinoma in the liver this study has investigated the possibility of increasing the tumor to normal liver parenchyma blood flow quotient by a variety of vasoactive substances for the beneficial modification of tumor blood flow. Angiotensin II 8 mg i.v. was the only drug, which increased the quotient. None of the other tested drugs were supporting previous presented results on influencing tumor blood flow.     

133Xe clearance estimates the effect of vasopressin on peritoneal blood flow in rats

BACKGROUND/AIMS: When assessing the peritoneal microcirculation with invasive methods, interference with the mechanisms of vaso-regulation may occur. The 133Xe clearance technique renders the possibility, by minimal invasiveness, to estimate the influence of a vasoactive agent on the peritoneal microcirculation. METHODOLOGY: Ten to 15MBq of 133Xe were injected in the abdominal cavity in thirty-eight Wistar-FU (W-FU) rats and 35 Lister-Hooded (LH) rats. A NaI (Tl)-scintillation detector registered activity before and during vasopressin infusion. Gamma camera imaging confirmed the washout from the abdominal cavity. The laser Doppler flowmetry technique was used as a comparison. RESULTS: Vasopressin at 0.07 IU/kg/min IV significantly reduced 133Xe-clearance by 37% (p = 0.029) and 52% (p=0.036) and laser Doppler flowmetry by 69% (p=0.0019) and 44% (p=0.0039) in W-FU and LH rats, respectively. A linear correlation between dose of vasopressin and relative decrease in 133Xe clearance was demonstrated in the W-FU rat model (r2=0.98, p=0.023). The 133Xe clearance from the abdominal cavity in rat using a single-compartment model or the slow compartment in a double-compartment model gave reproducible information. CONCLUSIONS: The usefulness of this mini-invasive technique for sequential measurements before and during intervention will render the 133Xe clearance suitable for assessment of blood flow changes in the abdominal cavity.     

Cardiorespiratory effects of nicotine exposure during development

Exposure to tobacco smoke is a major risk factor for the sudden infant death syndrome. Nicotine is thought to be the ingredient in tobacco smoke that is responsible for a multitude of cardiorespiratory effects during development, and pre- rather than postnatal exposure is considered to be most detrimental. Nicotine interacts with endogenous acetylcholine receptors in the brain and lung, and developmental exposure produces structural changes as well as alterations in neuroregulation. Abnormalities have been described in sympathicovagal balance, arousal threshold and latency, breathing pattern at rest and apnea frequency, ventilatory response to hyperoxia or hypoxia, heart rate regulation and ability to autoresuscitate during severe hypoxia. This review discusses studies performed on infants of smoking mothers and nicotine-exposed animals yielding varying and sometimes inconsistent results that may be due to differences in experimental design, species and the dose of exposure. Taken together however, developmental nicotine exposure appears to induce vulnerability during hypoxia and a potential inability to survive severe asphyxia.     

Effects of auranofin on leukotriene production and leukotriene stimulated neutrophil function

Arachidonic acid is metabolized in neutrophils by lipoxygenase to leukotrienes, which are suggested to play a central role in inflammation. The antirheumatic drug auranofin (4 g/ml) was found not to inhibit neutrophil production of the lipoxygenase products 5-HETE, 15-HETE and LTB₄,in vitro when stimulated with the calcium ionophore A23187. Auranofin, however, modulated neutrophil aggregation, enzyme release and chemotaxis induced by LTB₄. The results suggest that auranofin may exert some of its antirheumatic effects through affecting neutrophil responses to leukotrienes.Supported by grants from: Swedish National association against Rheumatism, King Gustav V 80 years Fund, Tore Nilssons Fund, P and A Hedlunds Fund, Swedish Society for Medical Research, Förenade Liv Mutual Group Life Insurance Company, Stockholm, Sweden.     

Non-nutritive sucking by infants exposed to pethidine in utero

Obstetric analgesia in the form of pethidine (meperidine) to mothers during delivery has adverse effects on some aspects of the behaviour of their newborn infants. The non-nutritive sucking (NNS) pattern of nine healthy full-term infants exposed to pethidine in utero was compared to that of a control group of infants. The pattern was analysed and quantified using an automatic computer-based method. The results are discussed in the context of endogenous and exogenous opiates and their effect on brain-stem rhythm generators. Conclusions: The typical NNS pattern with alternating sucking activity (bursts) and pauses is preserved in the exposed infants. There is a significantly lower sucking frequency (md 1.74 vs 1.90 Hz, p = 0.030*) and a tendency to a less stable rhythm in pethidine-exposed infants.     

Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer

Background Hepatocellular cancer (HCC), as well as cholangiocellular cancer (CCC), has an extremely poor prognosis due to the extent of tumor at diagnosis and the underlying liver disease. Sirolimus is used in the transplantation setting as an immunosuppressive agent, but it also possesses antiproliferative and antiangiogenic properties. The objective of the study was to evaluate the effect of sirolimus on HCC and CCC. Methods In a prospective single-arm protocol, the tumor response to sirolimus as the primary endpoint was studied in 21 patients with advanced HCC and nine with CCC. Sirolimus was administered once daily by mouth, with the dose adjusted to a serum trough level between 4 and 15 μg/ml. Tumor response was evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), according to the Response Evaluation Criteria in Solid Tumors (RECIST), every third month. Secondary measures were overall survival, time to tumor progression, tumor markers, and side effects. Results Of the patients with HCC, one had partial remission (PR) and fi ve patients had stable disease (SD) at 3 months. Of the patients with CCC, three had SD. The median survival for patients with HCC was 6.5 months (range, 0.2–36 months) and that for patients with CCC was 7 months (range, 2.6–35 months). Conclusion Treatment of HCC and CCC with sirolimus can induce temporary PD or SD. This pilot study indicates that sirolimus might be a promising drug for this treatment, but further clinical studies elucidating the biological effects are advocated. All authors contributed to the conception of the study, analysis of data, and writing of the communication