Protective effect of amifostine during fractionated radiotherapy in patients with pelvic carcinomas: results of a randomized trial

PURPOSE: To evaluate whether pretreatment with amifostine can reduce treatment-induced toxicity in patients with pelvic malignancies undergoing radiotherapy (RT). METHODS AND MATERIALS: A total of 205 patients with pelvic malignancies (rectal, 32; bladder, 47; prostate, 40; gynecologic, 86) were randomized to receive RT (Group 1, n = 95) or RT plus amifostine (Group 2, n = 110). The patient characteristics for both treatment groups were well balanced. Amifostine was administered at 340 mg/m(2) i.v., 15 min before RT, with standard antiemetics 30 min before. All patients received conventional RT, radical (65-70 Gy) or postoperative (50 Gy), with 45 Gy given to the whole pelvis at daily fractions of 1.8-2.0 Gy, 5 d/wk. Skin, bowel, bladder, and hematologic toxicities were evaluated according to the Radiation Therapy Oncology Group/European Organization Research and Treatment of Cancer scoring system. RESULTS: A significant reduction occurred in acute Grade 2-3 bladder and lower GI tract toxicities in the amifostine group (p <0.05, Weeks 3-7). With a median follow-up of 12 months, few late Grade 2-3 effects were observed in either group. No statistically significant difference between the two groups was observed in terms of response 6 weeks after RT completion (complete response plus partial response, 96.8% in the control and 98.3% in the amifostine arm). Amifostine was well tolerated, with only moderate hypotension occurring in 2 patients and moderate nausea in 1 patient. CONCLUSIONS: The results of this randomized trial support the role of amifostine in reducing acute radiation-related toxicity of the bladder and lower GI tract in patients with pelvic malignancies, without evidence of tumor protection.     

Novel thiazolyl,thiazolinyl and benzothiazolyl Schiff bases as possible lipoxygenase's inhibitors and anti-inflammatory agents

In continuation of our previous research, several new thiazolyl/thiazolinyl/benzothiazolyl Schiff bases have been designed, synthesized and identified. The referred compounds are reported to act as lipoxygenase inhibitors affecting inflammation and/or psoriasis. The compounds were screened for their reducing activity (with the stable free radical 1,1-diphenyl-2-picryl-hydrazyl, DPPH) and for inhibition of soybean lipoxygenase (LOX). Anti-inflammatory activity was examined in vivo using the carrageenin induced mice paw edema (32.6-75%). The results are discussed in terms of structural and physicochemical characteristics of the compounds. Compound 2d possessed the highest inhibition 75%.     

Theophylline treatment may adversely affect the anoxia-induced erythropoietic response without suppressing erythropoietin production

Objective To investigate the influence of theophylline on erythropoiesis in chronic obstructive pulmonary disease (COPD) and explore the potential underlying mechanisms.Methods We evaluated the haematological parameters and erythropoietin (EPO) values in 38 COPD patients, 18 of which had been treated with theophylline (8 mg/kg daily) for at least 1 year, and the other 20 had never received this drug; 38 sex- and age-matched healthy volunteers served as controls. We further studied the development of BFU-E (bursts forming units of erythrocyte precursors) -derived colonies in semisolid methylcellulose cultures in blood samples from 7 patients randomly selected from both groups. In addition, we studied the effects of theophylline on the erythroid cell development by adding this agent to erythroid cell cultures from 6 healthy volunteers at various concentrations.Results Haemoglobin values were found to be significantly lower in COPD patients treated with theophylline than in those untreated (P<0.05). Both groups of patients exhibited significantly higher haemoglobin values than normal subjects (P<0.01 and P<0.001 for treated and untreated patients, respectively). Serum EPO levels did not differ among the three studied groups. Unlike untreated patients and controls, the serum of the theophylline-treated patients produced a significant growth inhibition of erythroid bursts (P<0.05); the in vitro use of theophylline showed a concentration-dependent inhibition (P<0.001).Conclusion Our findings confirm the decrease of red cell production, which occurs following administration of theophylline, exclude the possibility of decreased EPO synthesis and suggest a direct inhibitory action of theophylline on erythropoiesis.     

The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice

Rationale. Nicotine increases glutamate release in the ventral tegmental area and the nucleus accumbens, and thus enhances dopamine neurotransmission in the mesolimbic system that has been implicated in mediating the rewarding effects of drugs. Metabotropic glutamate receptors 5 (mGluR5) are found in the nucleus accumbens and may play a role in modulating the post-synaptic response to both glutamate and dopamine. Objectives. The present study investigated the effects of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on intravenous nicotine self-administration in Wistar rats and DBA/2J mice. Methods. Rats were allowed to self-administer nicotine (0.01, 0.03 mg/kg per infusion) or respond for food on one of two fixed-ratio 5 schedules of reinforcement. Drug-naive mice were acutely exposed, in pairs, to nicotine (0, 0.016, 0.048, 0.16, 0.48 μg per infusion) self-administration under a fixed ratio 1 schedule of reinforcement, with one subject controlling the delivery of nicotine to both subjects in each pair. Results. MPEP (1–9 mg/kg) dose-dependently reduced nicotine self-administration with no effect on food-maintained responding in the rats. Self-administration of nicotine was obtained only at the 0.048 μg per infusion dose by the mice, and administration of MPEP (5–20 mg/kg) decreased nicotine self-administration response rates in the mice. Conclusions. These results indicate that blockade of mGluR5 decreased nicotine self-administration in both rats and mice, and are consistent with findings showing a role of mGluR5 in cocaine self-administration. It is postulated that mGluR5 plays an essential role in mediating the reinforcing effects of nicotine, possibly but not exclusively, via modulation of mesolimbic dopaminergic neurotransmission. Electronic Publication     

Effect of HbS in the determination of HbA(2) with the TOSOH HLC-723G7 analyzer and the HELENA Beta-Thal Quik column kit

OBJECTIVES: The analytical performance of the TOSOH HLC-723G7 hemoglobin HPLC analyzer and the effect of the presence of HbS in the determination of HbA(2) using HPLC and manual column methods. DESIGN AND METHODS: The performance characteristics of the TOSOH HLC-723G7 analyzer in the determination of HbA(2) were compared to those of the HELENA Beta-Thal Quik column. The effect of HbS presence in the samples was quantified using the HELENA SAS-MX alkaline gel electrophoresis kit as the reference method. RESULTS: Within-run and between-run CVs for HbA(2) were better for the TOSOH HPLC analyzer than for the HELENA manual column method. The presence of HbS in the samples produces a strong positive bias in the %HbA(2) values when using both the HPLC and manual column methods, compared to the alkaline electrophoresis gel. CONCLUSION: Both the TOSOH HPLC and the manual column are reliable methods for %HbA(2) determination when no HbS is detectable in the samples. When HbS is present, the gel electrophoresis method gives more accurate results.     

Acute West Nile virus neuroinvasive infections: cross-reactivity with dengue virus and tick-borne encephalitis virus

Cross-reactions in serology are common among flaviviruses. During the outbreak of West Nile virus (WNV) infections in Greece in 2010, WNV IgM-positive serum and cerebrospinal fluid samples were tested for the presence of IgM and IgG antibodies against Dengue virus (DENV) and tick-borne encephalitis virus. Higher cross-reactivity was observed in IgM antibodies between WNV and DENV; however, the index of the WNV antibodies was in all cases higher than that of the DENV antibodies. There is a need for caution when evaluating serologic results of flaviviral infections, while efforts have to be focused on the development of diagnostic assays with increased specificity.     

Chronic bupropion attenuated the anhedonic component of nicotine withdrawal in rats via inhibition of dopamine reuptake in the nucleus accumbens shell

Bupropion, a dopamine reuptake inhibitor, is an effective therapy for smoking cessation, but the behavioral and neurochemical mechanisms mediating its antismoking properties are relatively unknown. To explore the hypothesis that bupropion ameliorates nicotine withdrawal partly by a dopamine-dependent mechanism, we investigated the effects of chronic bupropion on potassium-stimulated dopamine overflow in the nucleus accumbens shell in nicotine-withdrawing rats. We also assessed the effects of chronic bupropion on behavioral aspects of nicotine withdrawal measured by elevations in brain reward thresholds and somatic signs of withdrawal. Rats were treated with nicotine or saline for 7 days and then coadministration of bupropion or saline was initiated. After 14 days of coadministration of bupropion/saline and nicotine/saline, nicotine/saline administration was terminated, whereas bupropion/saline administration continued. These conditions mimic bupropion administration in human smokers. Cessation of nicotine administration in non-bupropion-treated rats elevated reward thresholds reflecting a reward deficit, increased somatic signs and diminished potassium-evoked dopamine overflow in the nucleus accumbens shell. Chronic bupropion lowered reward thresholds and increased potassium-evoked dopamine release regardless of previous nicotine exposure, possibly by inhibition of dopamine reuptake, and thus attenuated the anhedonic and neurochemical effects of nicotine withdrawal. Chronic bupropion blocked withdrawal-associated increased somatic signs. Finally, acute experimenter-administered nicotine enhanced brain reward function equally in all groups, indicating that bupropion does not alter the reward-facilitating effects of experimenter-administered nicotine. In conclusion, the bupropion-induced increase in extracellular dopamine in the nucleus accumbens shell may ameliorate the anhedonia associated with nicotine withdrawal, which in turn may facilitate smoking cessation.     

Chronic nicotine improves cognitive performance in a test of attention but does not attenuate cognitive disruption induced by repeated phencyclidine administration

Rationale

Nicotine-induced cognitive enhancement may be a factor maintaining tobacco smoking, particularly in psychiatric populations suffering from cognitive deficits. Schizophrenia patients exhibit higher smoking rates compared with the general population, suggesting that attempts to self-medicate cognitive schizophrenia deficits may underlie these high smoking levels.

Objectives

The present study explored pro-cognitive effects of nicotine in a model of schizophrenia-like cognitive dysfunction to test this self-medication hypothesis.

Materials and methods

We investigated whether chronic nicotine (3.16 mg/kg/day, base) would attenuate the performance disruption in the five-choice serial reaction time task (5-CSRTT, a task assessing various cognitive modalities, including attention) induced by repeated administration of phencyclidine (PCP), an N-methyl-d-aspartate receptor antagonist that induces cognitive deficits relevant to schizophrenia.

Results

Chronic nicotine administration shortened 5-CSRTT response latencies under baseline conditions. Nicotine-treated rats also made more correct responses and fewer omissions than vehicle-treated rats. Replicating previous studies, repeated PCP administration (2 mg/kg, 30 min before behavioral testing for two consecutive days followed 2 weeks later by five consecutive days of PCP administration) decreased accuracy and increased response latencies, premature responding, and timeout responding. Chronic nicotine did not attenuate these PCP-induced disruptions.

Conclusions

Chronic nicotine had pro-cognitive effects by itself, supporting the hypothesis that cognitive enhancement may contribute to tobacco smoking. At the doses of nicotine and PCP used, however, no support was found for the hypothesis that the beneficial effects of nicotine on cognitive deficits induced by repeated PCP administration, assessed in the 5-CSRTT, are larger than nicotine effects in the absence of PCP.