In vitro safety pharmacology profiling: what else beyond hERG?

One of the main reasons for drug failures in clinical development, or postmarket launch, is lacking or compromised safety margins at therapeutic doses. Organ toxicity with poorly defined mechanisms and adverse drug reactions associated with on- and off-target effects are the major contributors to safety-related shortfalls of many clinical drug candidates. Therefore, to avoid high attrition rates in clinical trials, it is imperative to test compounds for potential adverse reactions during early drug discovery.

[Risk for the transmission of Newcastle disease by contaminated poultry products].

Poultry products contaminated with pathogenic strains of Newcastle disease virus are a source of virus transmission to susceptible poultry flocks. The probability of contamination varies according to the type of product. Research conducted by various laboratories in Europe has shown that pathogenic virus can be isolated from the carcasses of chickens, whether vaccinated or not, during a brief period after experimental infection.

Repair of the in vitro HIV-1-induced immunosuppression and blockade of the generation of functional suppressive CD8 cells by anti-alpha interferon and anti-Tat antibodies.

The acute human immunodeficiency virus type 1 (HIV-1) infection of activated peripheral blood mononuclear cells (PBMCs) from normal donors results in inhibition of cell proliferation and generation of functional suppressive T cells. Cultured HIV-1 infected PBMCs but not uninfected PBMCs, following irradiation, can inhibit the proliferation of antigen-activated autologous T cells in a dose-dependent way. CD8+ cell subpopulation is responsible for this inhibition.

Evidence for an antiviral effect and interferon neutralizing capacity in human sera; variability and implications for HIV infection.

The antiviral effect (AVE) and interferon neutralizing capacity (INC) of sera originating from either seronegative or HIV-infected individuals were determined. As a rule, sera from seropositive subjects exhibited higher AVE titers than sera from seronegative individuals. Similarly, the INC of sera from HIV-infected patients, was most often stronger than that of sera from seronegative individuals.

Biological effect of active anti-IFN alpha immunization in HIV-infected patients.

Circulating interferon (IFN) was investigated in HIV-1 seropositive patients by measuring the IFN alpha antiviral effect in the serum. While serum of healthy seronegative individuals exhibits an antiviral effect, not due to IFNs, considered as background, serum of seropositive patients showed an additional antiviral effect due to the abnormal presence of IFN alpha. Increased titers of IFN alpha were found in the course of the HIV infection and seemed to correlate with the evolution of AIDS disease.

Effect of purified IgGs from HIV-1-infected and non infected individuals on immune activation.

The purification and analysis of IgGs from sera of HIV-1-infected and non infected individuals are reported. The effect of antibodies purified from sera of infected individuals on antigen-induced T cell proliferation was investigated in relation to their possible involvement in an autoimmune reaction in AIDS, in view of the previously unravelled striking peptide similarities between HIV-1 gp120 and the immunoregulatory CD4 and Fas molecules. However, our data do not allow definite conclusions to be drawn.

Pathogenic disorders involved in immunosuppression and T cell depletion characterizing AIDS.

Four cardinal immune disorders interacting with each other may promote the progressive T cell depletion and immunosuppression characterizing AIDS. Immune activation of HIV-1 infected T4 cells leads to virus release and premature cell death. Both virus release with its resulting viral load and dead cells are the source of gp120 stimulus.

Safety of infectious bursal disease vaccines: assessment of an acceptability threshold.

This study was undertaken to check the safety of commercially available infectious bursal disease (IBD) vaccines in terms of bursal damage, and their immunodepressive effects as evaluated by testing the birds after vaccination for their response to Newcastle disease vaccination. Further requirements are proposed to establish a suitable safety standard.

Mechanisms of pulmonary edema induced by an organophosphorus compound in anesthetized dogs.

To determine the mechanism governing pulmonary edema induced by an organophosphorus compound, S-(2-diisopropylaminoethyl)-O-ethylmethyl phosphonothiolate (VX), lung lymph flow and lymph-to-plasma protein concentration ratio were measured in six anesthetized, open-chest, mechanically ventilated beagle dogs before and after intravenous injection of 6 micrograms/kg of VX. Systemic and pulmonary hemodynamic data (heart rate, aortic blood flow, and left atrial, systemic arterial, pulmonary arterial, and pulmonary capillary pressures) were continuously recorded. Arterial blood gases and pH were measured every 30 min.

[Statistical analysis of the evolution of histopathological lesions during the course of experimental infection of chicken by the Marek's disease virus].

The evolution of histopathological lesions of sciatic and brachial nerves, bursa, thymus and spleen was studied during a long observation period following the challenge of chicken by the Marek's disease virus (MDV). Factorial analysis of correspondences allowed a synthetic study completed by classical statistical tests. In the nerves the sequence of type A, B and C lesions as demonstrated.

Modification of rat brain 5-hydroxytryptamine metabolism by sublethal doses of organophosphate agents.

The early and late effects of sublethal doses of two organophosphate agents (paraoxon and soman) on 5-hydroxytryptamine (5-HT) metabolism were investigated in several rat brain areas. Parallel determinations of acetylcholinesterase (AcChE) inhibition were performed. An increase in 5-HT level was observed during the first phase of soman intoxication and a rise in 5-hydroxyindol acetic acid (5-HIAA) appeared in the early and late effects of both anticholinesterase agents with a predominant action in the striatum.

Influence of intoxication by anticholinesterase agents on core temperature in rats: relationships between hypothermia and acetylcholinesterase inhibition in different brain areas.

The early and late effect of three anticholinesterase agents (physostigmine, paraoxon and soman) on core temperature and brain acetylcholinesterase (AcChE) inhibition are compared. The study was performed in adult male rats using sublethal doses of all drugs. AcChE activity was determined by hypothalamus, striatum, hippocampus, medulla oblongata-pons and rest of the brain.

Penetration of oximes across the blood-brain barrier. A histochemical study of the cerebral cholinesterases reactivation.

The comparison of the effects of 4 oximes upon the cerebral cholinesterases reactivation after intoxication with paraoxon shows that the best results are obtained with toxogonine and 1574 [(carbaldoxime-4 pyridinium)-1(methyl-1 imidazolium-3)-3 propane]. The reactivation power of this latter compound seems due to the ease with which it can pass through the blood-brain barrier.