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For the past few years, the world market for dietary supplements, especially supplements made from plants, has been booming, reaching $44.8 billion for 2000 in American, European, and Asian markets. However, the scientific evaluation of these products has confronted many difficulties. A new directive (Directive 2002/46/EC) on dietary supplements issued by the European commission in June 2002 includes such substances as plants extracts. Recently, the French Food Safety Agency (Agence francaise de securite sanitaire des aliments) created a team to propose a framework for the evaluation of the safety effects and the claims of foodstuffs made from plants for the human diet. This framework will contribute to the review, at the European level, initiated by the directive. WORKING STEPS AND PROPOSITIONS: The first working step included data collection and analysis for 19 plants of interest to the food industry through detailed monographs compiled in collaboration with industrial partners. The second step is based on the working group's discussion and on an expert review of scientific pharmacology, nutrition, and toxicology data. Using illustrative examples, we highlight the characteristics and the specific difficulties related to this area. Indeed, data are widely based on traditional use for a number of these plants. Traditional use is of specific interest regarding issues about plants, but limitations exist (e.g., lack of history regarding emergent risks). APPLICATION: Data on traditional use data can contribute to the assessment of risk and effect associated with the consumption of these plants in a strictly defined context, which may correspond to a clear standard of claim. However, the more the product use moves away from traditional uses, the more requirements must be increased in terms of demonstrating both safety and physiological effect and, therefore, the claim being made. This evaluation framework is now being applied to plant sources of isoflavones.

Organs-on-chip (OoC) are innovative and promising in vitro models, particularly in the process of developing new drugs, to improve predictivity of preclinical studies in humans. However, a lack of regulatory consensus on acceptance criteria and standards around these technologies currently hinders their adoption and implementation by end-users. A reflection has been conducted at the National Agency for Medicines and Health products safety (ANSM) in order to address this issue, which has gained momentum at the international level in recent years. If the subject of OoC is of international interest, France is also in the process of structuring an OoC network, in order to best support the emergence of this new technological innovation. Focusing on liver-on-a-chip, the authors drafted a first list of regulatory requirements to help standardize these devices and their use. Technological and biological relevance of liver-on-a-chip was also evaluated, in comparison with current in vitro and in vivo models, based on the available literature. The authors offer an analysis of the current scientific and regulatory situation, highlighting the key regulatory issues for the future., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sonia GOMES TEIXEIRA reports was provided by National Agency for Safety of Medicines and Health Products., (Copyright © 2023. Published by Elsevier B.V.)

The high toxicity of ricin and its ease of production have made it a major bioterrorism threat worldwide. There is however no efficient and approved treatment for poisoning by ricin inhalation, although there have been major improvements in diagnosis and therapeutic strategies. We describe the development of an anti-ricin neutralizing monoclonal antibody (IgG 43RCA-G1) and a device for its rapid and effective delivery into the lungs for an application in humans. The antibody is a full-length IgG and binds to the ricin A-chain subunit with a high affinity (KD=53pM). Local administration of the antibody into the respiratory tract of mice 6h after pulmonary ricin intoxication allowed the rescue of 100% of intoxicated animals. Specific operational constraints and aerosolization stresses, resulting in protein aggregation and loss of activity, were overcome by formulating the drug as a dry-powder that is solubilized extemporaneously in a stabilizing solution to be nebulized. Inhalation studies in mice showed that this formulation of IgG 43RCA-G1 did not induce pulmonary inflammation. A mesh nebulizer was customized to improve IgG 43RCA-G1 deposition into the alveolar region of human lungs, where ricin aerosol particles mostly accumulate. The drug delivery system also comprises a semi-automatic reconstitution system to facilitate its use and a specific holding chamber to maximize aerosol delivery deep into the lung. In vivo studies in monkeys showed that drug delivery with the device resulted in a high concentration of IgG 43RCA-G1 in the airways for at least 6h after local deposition, which is consistent with the therapeutic window and limited passage into the bloodstream., (Copyright © 2016. Published by Elsevier B.V.)

Background: Aerosol therapy is an expanding technique allowing administration of drugs acting locally in the bronchial tree and lungs or acting systemically after absorption through the respiratory tract. However, the choice of solvents and adjuvants is a critical step in the formulation process of new drugs. Pulmonary tolerance of ethanol, propylene glycol and sorbitan ester was evaluated in a rat model of intratracheal administration using a Microsprayer in a 4-day toxicity study., Methods: Four groups of Sprague-Dawley rats (11 rats per group, n = 44) have received, on 4 consecutive days 150 microL of solutions containing the solvents, by intratracheal route using a IA-1B-2 inches-Microsprayer (PennCentury, Philadelphia, PA). Once a day, the rats received deionized water (control) or ethanol 10% or propylene glycol 30% or sorbitan monooleate 10%. All rats were sacrificed 24 h after the fourth administration. Biochemical analysis on bronchoalveolar lavage (BAL) fluid was performed on seven rats per group. The respiratory tract of the remaining four rats/group was examined histologically., Results: Biochemistry and histopathology findings demonstrated that under the conditions tested, deionized water, 10% ethanol, and 30% propylene glycol were tolerated in a qualitatively similar way presenting limited cellular reaction. In contrast, 10% sorbitan monooleate produced an accumulation of foamy macrophages in the lungs and a higher degree of inflammation. In addition, animals in this group showed higher polymorphonuclear neutrophil recruitment and total proteins levels in BAL fluid., Conclusion: The overall results recommended ranking the vehicles according to the degree of inflammation which was induced: deionized water <10% ethanol < or =30% propylene glycol <10% Tween 80.

The effects of 50 microM LCB29 (idrocilamide) were tested on depolarization-induced and caffeine contractures of rat soleus muscle fibers. When applied intracellularly by free diffusion in cut-end voltage-clamped fibers, LCB29 decreased tension amplitude by about 25%. The same amount of inhibition by LCB29 was observed on contractures induced by 6 mM caffeine. The drug did not affect the repriming of caffeine contractures, indicating that internal recycling of calcium was not affected. The voltage-dependent inactivation of tension was facilitated by external application of LCB29. This effect was calcium dependent, so that the greater the external calcium concentration, the greater the drug effectiveness. The spontaneous relaxation of K+ contractures was also accelerated by LCB29. It is concluded that LCB29 acts intracellularly by decreasing sarcoplasmic reticulum calcium release and externally by facilitating the voltage-dependent inactivation of the voltage sensor for excitation-contraction coupling.

Trabecular bone loss in estrogen deficiency is associated with enhanced bone resorption with a smaller increase in bone formation. We previously reported that low doses of strontium can increase trabecular bone volume in rodents by affecting bone resorption and formation. In this study we determined the effect of a new divalent strontium salt (S12911) on bone loss induced by E2 deficiency. Sprague-Dawley female rats (230 g, n = 15-25 per group) were sham operated or ovariectomized (OVX) and treated with 17 beta-estradiol (E2, 10 micrograms/kg/day, sc) or S12911 by gavage at the dose of 77, 154, or 308 mg/kg/day or the vehicle. Treatment for 60 days with S12911 resulted in a dose-dependent increase in plasma, urine, and bone strontium concentrations without any deleterious effect on total or skeletal growth. OVX rats were osteopenic compared to sham rats as shown by decreased femoral dry bone weight and mineral content measured on bone ash and by DXA. Treatment of OVX rats with S12911 prevented bone loss as bone ash and bone mineral content were restored to the values in sham rats. Trabecular bone volume measured by histomorphometry on the tibial metaphysis was decreased by 46% in OVX rats and was corrected by E2. Treatment of OVX rats with S12911 increased the trabecular bone volume by 30-36%. Histomorphometric indices of bone resorption (osteoclast surface and number) were increased in OVX rats and were reduced by S12911 to the levels in sham rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of LCB29 was tested on twitch characteristics, tetanic tension, and K+ and voltage-clamp contractures of rat soleus muscle fibers. In concentrations ranging from 10(-6) to 5 x 10(-4) M, LCB29 simultaneously inhibited the twitch amplitude, the maximum rate of tension development, and the maximum rate of relaxation. In concentrations ranging from 10(-5) to 10(-4) M, tetanic tension (100 Hz, 1 s) was inhibited by the same amount. The effect of 5 x 10(-5) M LCB29 was studied on K+ contractures and contractures induced, under voltage-clamp conditions, by long-lasting depolarizations. Its effect was significantly stronger than those on twitch and tetanic tension. In addition, LCB29 had a dual effect on strength--duration curves for mechanical threshold. It increased both the rheobasic potential and the steepness of the curve. It is concluded that LCB29 exerts a direct myorelaxant effect on rat soleus muscle; two sites of action are probably involved.

The aim of the present work was to study the activity of a new antihypertensive drug, a synthetic furopyridine, cicletanine, upon hypertensive morphological lesions of the retina. The stroke-prone spontaneously hypertensive rat strain (SHR-SP), known to develop hypertensive retinopathy, was a particularly suitable material in this view. The experiment was carried out in 39 rats (SHR-SP/A3N Iffa Credo), initially at the age of 11 weeks, divided into 3 groups: one as control group, the other two treated orally with 100 and 150 mg/kg cicletanine, respectively. All rats had free access to tap water containing 1% NaCl. For 46 days, blood pressure, body weight and death rate were recorded, then the rats were sacrificed. The eyes were removed, the posterior pole collected and fixed with Trump's liquid for transmission electron microscopy. In the control group, the capillaries showed marked hypertensive lesions. Multivesicular bodies were found in the different layers, particularly in the innermost layers; photoreceptor impairments could also be observed. In contrast to this group, both cicletanine-treated groups showed only rare and minimal lesions.

Toxicity for albino rats is very low. In mice an anxiolytic effect is exhibited and the pentobarbital evokated sleeping time is increased in animals given essential oil, but this effect disappears if they are administrated during five days.

If circadian variations in tolerance to drugs have been often demonstrated, such observations about heavy metals are still very scarce. The present study proposes to determine if circadian variations occur in the tolerance of Mice to single lethal dose of cadmium sulphate. 400 female mice, kept in cages on a 8.00-20.00 L/D cycle, received IP a single cadmium sulphate injection at different doses (2.5, 3, 3.5 and 4 mg/kg) at different hours in the day (8.00, 14.00, 20.00 and 2.00 hrs.). Death number was determined each day during 10 consecutive days. The mortality percentage is a function of the time of the cadmium administration, varying between 3.3 and 21.7% for 2.5 mg/kg, between 16.7 and 43.3% for 3 mg/kg, between 33.3 and 71.7% for 3.5 mg/kg and between 73.3 and 96.7% for 4 mg/kg. The metal is the most toxic at 20.00 hr (mean: 58.3%) and the least at 2.00 hr. (mean: 33.7%). A circadian susceptibility to cadmium sulphate in Mice thus clearly appears, as has been recently described with mercury and platinum.

All studies carried out on stroke-prone spontaneously hypertensive rats (SHR-SP) have clearly demonstrated that cicletanine protects tissues and vessels. This effect has also been observed with captopril. However, the effectiveness of captopril seemed to be dependent on its blood pressure lowering effect, and this was not found with cicletanine in previous experimental studies on SHR-SP. In view of the difference in effectiveness between captopril and cicletanine as regards blood pressure, it was considered important to compare the two compounds in a similar blood pressure complex. In this study, the effects of cicletanine at two dosage levels (3.33 and 10 mg/kg/day) on the tissue and vascular lesions of SHR-SP were compared with those of captopril in doses of 1 mg/kg/day. Iffa Credo SHR-SP rats aged 7 weeks were divided into four groups of 12 animals each: 2 groups received cicletanine 3.33 and 10 mg/kg/day respectively, 1 group received captopril 1 mg/kg/day and 1 group served as control. Blood pressure was recorded once a week. After 44 days of treatment, all animals were killed and autopsied. A significant antihypertensive effect was observed with both captopril (p less than 0.001) and cicletanine 10 mg/kg (p less than 0.05). In doses of 3.33 mg/kg cicletanine induced only a very slight fall in blood pressure, not significantly different from controls. On the other hand, histological and ultrastructural examinations showed better preservation of tissues and, chiefly, vessels with cicletanine at the two dosage levels than with captopril 1 mg/kg.

Mice Swiss are orally given essential oil of lavander diluted at 1/60 in olive oil. Sedative effects are observed with some tests (hole board test, four plates test, plus-maze test, potentiation of barbiturate sleeping time). A significant interaction exists with pentobarbital: the sleeping time is increased and the asleeping time shortened.

Aging laboratory animals constantly present with chronic progressive nephrosis. The purpose of this study was to investigate the protective effect of a chronic treatment with cicletanine in aging rats, notably as regards kidneys. Sixteen Wistar rats aged 26 months were divided into two groups: one group served as control, while the other received oral cicletanine 30 mg/kg/day. Blood pressure, weight and death rate were recorded. No rise of arterial pressure was observed in either group. The rats were killed on day 151, i.e. aged 31 months, after 5 months of treatment. All were autopsied and their kidneys, heart, lungs, liver, brain and eyes were removed for examination. Light microscopy of the renal tissue showed the lesions described in the chronic progressive nephrosis of the aging rat. These lesions were diffuse and pronounced in the control group and minimal in treated rats. The difference was confirmed by electron microscopy. The basal membrane of renal tubules was slightly thickened in the treated rats and two or three times thicker in control rats. Mitochondrial alterations were observed in the proximal tubules of controls but not in those of rats treated with cicletanine. Thus, after a 5-months treatment with cicletanine aging Wistar rats well known for their renal pathology were protected against kidney lesions in contrast with untreated rats.