Proinflammatory circulating markers: new players for evaluating asymptomatic acute cardiovascular toxicity in breast cancer treatment.

PURPOSE: This study aimed to evaluate markers of cardiac damage (total CK, CKMB and CRP), inflammatory markers (free iron, homocysteine and TNF-α) as well as lipidogram in breast cancer patients undergoing acute cycles of doxorubicin (DOX), paclitaxel (PTX) or trastuzumab (TZ) and to verify if there is an association between these markers and the toxicity of the chemotherapeutic treatment. Methods: Included in the study were 120 breast cancer patients and 50 healthy controls. All analyzes were performed on automated systems. For the statistical analysis, each group was compared with the controls according to their normality by Student's t-test and Mann-Whitney test. Results: Our results showed that DOX treatment led to increased hsCRP (4.80 ± 1.23 mg/dL, p = 0.0005), triglycerides (187.6 ± 25.06, p = 0.0231), TNF-α (42.31 ± 17.96 pg/mL, p = 0.01) and Fe levels (138.8 ± 18.6 µg/dL, p = 0.0193). In the meantime, PTX induced changes in CK-MB (8.78 ± 4.2 U/L, p = 0.0361), hsCRP (7.12 ± 1.87 mg/dL, p = 0.0006), cholesterol (201.7 ± 19.54, p = 0.05), triglycerides (201.7 ± 19.54, p = 0.0277), TNF-α (38.27 ± 9.12 pg/mL, p = 0.023), homocysteine (10.95 ± 0, 86 µmol/L, p = 0.005), and free iron (113 ± 18 6 µg/dL, p = 0.045) while TZ augmented CK-MB (6.9 ± 1.97 U/L, p < 0.00), hsPCR (3.12 ± 0.68 mg/dL, p = 0.095), cholesterol (218.3 ± 16.79, p = 0.0317), triglycerides (218.3 ± 16.79, p = 0.0127), TNF-α (89.6 ± 12.11, p = 0.032), homocysteine (9.95 ± 1.15 µmol/L, p = 0.0396), free iron (120.5 ± 4.64 µg/dl, p = 0.0058) as well. Conclusions: Our data demonstrated the existence of a proinflammatory net triggered by breast cancer chemotherapy that could increase cardiomyocytes permeability and allow the leakage of circulating proteins as CK-MB and induce the production of hsCRP.

The pharmacology of SDZ EAA 494, a competitive NMDA antagonist.

SDZ EAA 494 (D-CPPene) was characterized as a competitive NMDA antagonist, having a pA2 value against NMDA depolarizations in frog spinal cord and rat neocortex of 6.7-6.8 and a pKi of 7.5 in a [3H]CGP39653 binding assay, with no action on other receptors or amine reuptake. The compound was orally active in rodent maximal electroshock models with an ED50 of around 16 mg/kg, was protective in rats even 24 hours after oral application and had an oral therapeutic index of around 8. Muscle relaxation, ataxia, flattened body posture and reduced acquisition of a passive avoidance task, suggesting potential effects on memory formation, occurred at supra-anticonvulsant doses in rodents, with PCP-like stimulatory effects produced only by high i.p. doses or constant i.v. infusions. This favourable profile is discussed in relation to the negative outcome of a recent trial of the compound in patients with intractable epilepsy. The conclusion is drawn that standard models for screening new anticonvulsants are inappropriate to seeking drugs active in patients with a protracted convulsive history. The anti-ischaemic action of SDZ EAA 494 encourages further testing in brain trauma, in which the anticonvulsant action of the compound may be an added benefit.

Cholinergic effects on spatial exploration and its memory.

In their first swim in an unfamiliar circular swimming pool, control rats showed declines in average swimming speed and in the time spent in the perimeter of the pool. Both declines were antagonized by the muscarinic antagonist scopolamine, but not by methylscopolamine, a muscarinic antagonist that crosses the blood-brain barrier only poorly, indicating that these declines depend upon central cholinergic activity. In the first minute of a second swim 3 days later, control rats spent a much longer time in the central region of the pool than in the first minute of the first swim. This modification of behaviour by previous experience suggests that a long-term memory of the first swim was formed. Scopolamine, but not methylscopolamine, administered before the first swim attenuated this modification of behaviour. Pilocarpine, administered shortly after scopolamine before the first swim, significantly normalized all the scopolamine-induced changes, whereas oxotremorine and arecoline normalized only habituation of perimeter preference; agonists administered alone decreased swimming speed and perimeter preference without affecting their rates of decline. The results suggest that in this test, different cholinergic mechanisms are involved in habituation of swimming speed and habituation of perimeter preference.

Brain selective inhibition of acetylcholinesterase: a novel approach to therapy for Alzheimer's disease.

It could be argued that clinical experience with cholinergic drugs in the therapy of AD has not yet shown relevant symptomatic improvements. The main reasons for this might be attributed to peripheral cholinergic effects and the liver toxicity of some of these drugs, which limit their use and prevent confirmation of the cholinergic hypothesis (Gray et al., 1989). The main disadvantages of the cholinesterase inhibitors used in clinical trials are the short duration of action in the case of physostigmine and the potential for liver toxicity seen with the aminoacridine derivatives. The results presented with SDZ ENA 713 indicate that the disadvantages of AChE inhibitors might be overcome by improving CNS selectivity and thereby decreasing the peripheral cholinergic effects and toxicity. Clinico-pharmacological studies with SDZ ENA 713 have been performed in healthy volunteers; while central activity was clearly demonstrated in an EEG-sleep study (Holsboer et al., 1992), no prohibitive peripheral side effects were seen, confirming in humans the results obtained in experimental animals (Enz et al., 1991). A multicentre clinical investigation in AD patients has been performed in Europe and is currently being evaluated.

The pharmacological assessment of RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide). A potent, specific muscarinic acetylcholine receptor agonist.

The effects of the compound RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide) in a number of in vitro and in vivo test systems for muscarinic cholinergic activity were analyzed and compared to those of classical muscarinic receptor agonists. In radioligand binding assays RS 86 presented high nanomolar apparent affinity only for sites labeled by 3H-muscarinic receptor agonists while its apparent affinity for sites labeled by 3H-muscarinic receptor antagonists including [3H]QNB, [3H]NMS and [3H]pirenzepine was in the micromolar range. RS 86 had no or only low affinity (IC50 greater than 10 microM) for other neurotransmitter or drug receptor sites. The compound induced scopolamine-sensitive contractions of the isolated guinea-pig ileum showing a pD2 of 6 in this model. In the isolated rat superior cervical ganglion RS 86 was also an agonist with a pD2 of 6.7. When given to mice or rats by different routes RS 86 induced central and peripheral effects typical of a muscarinic receptor agonist, such as hypothermia, tremor, mydriasis, salivation, lacrimation, diarrhoea and modification of behavior as observed in an open field. In several of these tests RS 86 was about 10 times less potent than oxotremorine but more potent than arecoline, pilocarpine, aceclidine or the compound (cis) AF-30. The ED50 values for some central effects, including the induction of hypothermia and alert non-mobile behavior were lower than those for tremor and peripheral effects. Some of the effects lasted for up to 6 h, depending on the dose. Finally, RS 86 administration resulted in modifications of brain acetylcholine turnover and high affinity choline uptake typical of a central muscarinic receptor agonist. Taken together these results demonstrate clearly that RS 86 is a potent, centrally acting, selective muscarinic receptor agonist. RS 86 appears to be an adequate tool for the clinical examination of the cholinergic hypothesis of Alzheimer's disease.

Burnout and self-actualization in public school teachers.

Public school teachers (N = 211) in six northwestern Ohio school districts completed the Maslach Burnout Inventory (MBI), Shostrom's Personal Orientation Inventory (POI), and a brief, biographic questionnaire. The responses to the MBI produced the three factors previously named by Maslach as Emotional Exhaustion, Depersonalization, and Personal Accomplishment. Each of the three scales correlated with the summed POI score (r = -.28, -.22, and .35, respectively) and produced high to moderate levels of internal consistency (alphas of .92, .85, and .88, respectively). Teachers with more students tended to produce higher scores on the Depersonalization scale.

[Bovine tuberculosis control in Lódz Province and its results]. / Analiza akcji zwalczania gruzlicy bydla i jej wyników w województwie lodzkim.

In the years 1964--1969 the Lódz Voivodeship has been involved in the fight against the cattle tuberculosis in result of which all socialized farms have been liberated from this disease. Also, a percentage of cattle specific tuberculin reactions in individual farms has been diminished to 0.20% and the cases of tuberculosis after slaughter to 0.83%. The action had also some influence on the increase of the cattle stock. The loss has been diminished because of the sequesters of internal organs and the loss of the meat value of the animals submitted to slaughter. The fight against the tuberculosis had also an influence on the diminution of the number of the pigs and sheep infected with this disease. The course of the fight against the cattle tuberculosis conducted on the territory of the Lódz Voivodeship was dependent in some degree on its geographical place. In the administrative districts adjacent to the areas on which a great percentage of the tuberculosis was stated the course of the liquidation of this disease was slower than on the remaining terrains. Also, the action ran slower in the regions characterized by the majority of the ploughland in relation to the meadows and pastures and there where an intensive cow-shed rearing was carried out. The Lódz Voivodeship rivers, being many a time sewer ditches, did not cause the increase of the cattle morbidity. It was stated, that in the administrative districts, where the average of the animals condensation was small, the percentage of the infections with the tuberculosis at the beginning of the fighting against it was also low, however at a greater condensation of cow-shed rooms the number of infected head increased respectively. A considerable expansion of tuberculosis over the hens and also a frequent amounting to about 71% use of the cow-sheds as common rooms for the cattle, pigs and poultry caused the occurrence of cattle unspecific tuberculin reactions and led to the infections of the pigs with this disease.