Pharmacokinetics of 4-demethoxydaunorubicin in cancer patients

Summary The clinical pharmacokinetics of 4-demethoxydaunorubicin was investigated in 28 cancer patients who received the drug orally. The majority of the patients were elderly (median age, 72 years). Nine of them also received an i. v. dose, and the bioavailability of the oral dose ranged between 9% and 39%. 4-Demethoxydaunorubicin peak levels were achieved 2–4 h after the oral dose in most patients. The drug was rapidly and extensively metabolized to 4-demethoxy-13-hydroxydaunorubicin, which is probably as active as the parent drug. The metabolite levels were much higher and longer lasting than the parent drug, suggesting that it may play an important role in the drug's pharmacological effects.     

Stabilization of rat serum proteins following oral administration of fish oil

The mechanism of action of fish oil (FO), currently used in different chronic inflammatory conditions such as rheumatoid arthritis (RA), is not completely understood, although it is thought that it could alter the metabolism of endogenous autacoids. In addition, we hypothesized that the known capability of fatty acids (FA) of stabilizing serum albumin and perhaps other proteins, may be of pharmacological relevance considering that it is shared by other anti-rheumatic agents (e.g. nonsteroidal antiinflammatory drugs). Thus, we studied the effect of oral administration of FO and corn oil (CO), a vegetable oil with a different composition, on the stability of rat serum proteins, evaluated by a classical in vitro method based on heat-induced protein denaturation. FO, and, to a lower extent, CO inhibited heat-induced denaturation of rat serum (RS): based on the inhibitory activity (EC50) of the major fatty acids against heat-induced denaturation of RS in vitro, it was possible to speculate that in vivo effects of palmitic acid (C16:0) and eicosapentaenoic acid (EPA, C20:5, n-3) may be more relevant than that of linolenic acid (C18:2). To better investigate this phenomenon, we extracted albumin from the serum of animals treated or not with FO with a one-step affinity chromatography technique, obtaining high purity rat serum albumin preparations (RSA-CTRL and RSA-FO), as judged by SDS-PAGE with Coomassie blue staining. When these RSA preparations were heated at 70 degrees C for 30 min, it was noted that RSA-FO was much more stable than RSA-CTRL, presumably due to higher number of long chain fatty acids (FA) such as palmitic acid or EPA. In conclusion, we provided evidences that oral administration of FO in the rat stabilizes serum albumin, due to an increase in the number of protein bound long chain fatty acids (e.g. palmitic acid and EPA). We speculate that the stabilization of serum albumin and perhaps other proteins could prevent changes of antigenicity due to protein denaturation and glycosylation, which may trigger pathological autoimmune responses, suggesting that this action may be involved in the mode of action of FO in RA and other chronic inflammatory diseases.     

PKC activators stimulate H+ conductance in chicken enterocytes

Chicken enterocytes present a H⁺-conducting pathway involved in the recovery of intracellular pH (pH_i) from an acid load. In the current study we have tested the effect of protein kinase C (PKC) activators on the rate of proton efflux through the H⁺-conducting pathway. The rate of proton efflux was increased by the addition of 1,2-dioctanoyl-rac-glycerol (DOG) or phorbol 12-myristate 13-acetate (PMA), but it was not affected by the addition of the inactive phorbol ester analogue, 4-phorbol 12, 13-didecanoate. DOG stimulated the process in a dose-dependent manner with a half-maximal effect at 45 M. Staurosporine and Zn²⁺ prevented the DOG-dependent increase in the rate of proton efflux. The rate of proton efflux was affected by the pH_i and DOG shifted this relationship upward and to the right. These results suggest that the proton-conducting pathway is regulated by PKC.     

How do normal subjects learn a simple adaptative task: How and why do paranoid schizophrenic patients fail?

Summary The authors studied the behavior of normal subjects and paranoid schizophrenic patients in a simple problem-solving situation. The schizophrenics were divided into two sample groups, one of individuals under treatment and the other of individuals not under treatment.The learning process involved in this problem-solving situation is very similar to an instrumental conditioning, and can be understood by means of the following assumptions: (1) the subjects use decision functions in reacting to the stimuli, although they may be not fully aware of this; (2) learning is the result of successive transformations of these decisions in the course of time; (3) the changes have specific probabilities and are related to (a) those responses which are made to the latest stimuli, and (b) a differential probability for decision functions which were effective, or only interrupted painful reinforcement, or were completely ineffective.In schizophrenics further factors of importance were (1) an inertia factor and (2) the rigidly continued use of unsuccessful or only partially successful decision criteria.The authors used a systems theory based on Galois field theory and a calculus of operators specifying three groups of subjects. A computer program based on these hypotheses was tested in a simulation experiment.The statistical evaluation of the results showed a congruence between the theoretical approach and the experimental data.This work was carried out with financial support from the Institute de Alta Cultura, Lisbon, between 1970 and 1974     

Chlorpyrifos-induced delayed polyneuropathy

Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60–90 mg/kg p.o., corresponding to 4–6 times the estimated LD₅₀. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (>70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5–6 days. High AChE inhibition (>90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10–20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A-esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.Part of this work was presented at the 25th Annual Meeting of the Society of Toxicology held in New Orleans, LA, USA, March 1986, at the International Symposium on Biochemical and Cellular Indices of Toxicity in Occupational and Environmental Medicine held in Milan, Italy, June 1986, and at the 9th Meeting of the Peripheral Nerve Study Group, Praglia (PD), Italy, August – September, 1989     

Shortlasting, Unilateral, Neuralgiform Headache Attacks With Conjunctival Injection, Tearing, and Subclinical Forehead Sweating ("Sunct" Syndrome): II. Changes in Heart Rate and Arterial Blood Pressure During Pain Paroxysms.

The recently described "Sunct" syndrome is a rare picture of unilateral, shortlasting headache attacks accompanied by autonomic phenomena (conjunctival injection, tearing, etc.) on the symptomatic side. Heart rate and blood pressure were monitored in two elderly "Sunct" patients during and outside headache attacks. An ultrasound Doppler servo method was used for the non-invasive, continuous, beat-to-beat determination of instantaneous arterial blood pressure. In a third patient, systolic and diastolic blood pressure, both outside and during pain paroxysms, were assessed using the standard Korotkoff method. Heart rate was found to be significantly decreased during pain paroxysms. Systolic blood pressure was observed to be significantly increased during attacks, when compared with the inter-attack period, while a less consistent pattern was observed for diastolic blood pressure. Some of the changes in the cardiovascular system seemed to start prior to pain onset. Therefore, it seems unlikely that these changes were caused by pain activation of the sympathetic nervous system or the oculocardiac reflex.     

Spatial and Temporal Patterns of Neurogenesis in the Chick Retina

Chick embryo retinas were labelled in ovo by single injections of [3H]thymidine at selected times between days 2 and 12 of incubation. Embryos were later removed, at different stages of development, and the retinas processed for autoradiography of either serial sections or dissociated cell preparations. Analysis of unlabelled cells shows that neurogenesis starts, on day 2 of incubation, in a dorsotemporal area of the central retina, close to the posterior pole and to the optic nerve head. A gradient of neurogenesis spreads from this central area to the periphery, where neurogenesis ends, shortly after day 12, when the last few bipolar cells withdraw from the cell cycle. Additional dorsal-to-ventral and temporal-to-nasal gradients can be discerned in our autoradiographs. In all retinal sectors, ganglion cells start first to withdraw from the cell cycle, followed, with substantial overlapping, by amacrine, horizontal, photoreceptor plus Müller, and bipolar neuroblasts. Ganglion cells are also the first to reach the 50% level of unlabelled cells, followed this time by horizontal, photoreceptor, amacrine, Müller and bipolar cells. Finally, 100% levels of unlabelled cell populations are attained simultaneously by ganglion, horizontal and photoreceptor cells, followed by amacrine, then by Müller, and last by bipolar cells. Although all classes of neurons, in varying proportions, are being produced most of the time, our results also demonstrate that, in any given retinal area, the first cells leaving the cycle are determined to become ganglion cells, and the last ones bipolar cells, and not other types.     

Molecular mechanisms of tolerance to and withdrawal of GABAA receptor modulators

Here, we summarize recent data pertaining to the effects of GABA_A receptor modulators on the receptor gene expression in order to elucidate the molecular mechanisms behind tolerance and dependence induced by these drugs. Drug selectivity and intrinsic activity seems to be important to evidence at the molecular level the GABA_A receptor tolerance. On the contrary, we suggested that all drug tested are equally potentially prone to induce dependence. Our results demonstrate that long-lasting exposure of GABA_A receptors to endogenous steroids, benzodiazepines and ethanol, as well as their withdrawal, induce marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and these drugs in modulating the functional activity of specific neuronal populations. We report here that endogenous steroids may play a crucial role in the action of ethanol on dopaminergic neurons.