Toxicity, Pharmacokinetics, And Antitumor Activity Study of a Novel Long-Acting Paclitaxel Nanodrug Delivery System Constructed On a Curcumin Derivative Carrier

Purpose/Background: Paclitaxel (PTX) has been widely used in the clinic to treat breast cancer. However, its poor water solubility and intolerable toxicity greatly reduce the efficacy and medication safety. In this paper, a curcumin derivative (CUD) synthesized by the research group was used as a carrier to prepare a new type of PTX nanodrug delivery system (CUD-PTX-LN), thereby improving the safety of PTX medication and enhancing the anti-tumor effect.Methods: CUD-PTX-LN was prepared by solid dispersion technology and the dialysis method was adopted to investigate the release behavior of CUD-PTX-LN in vitro. Meanwhile, the dynamic process of nanoparticles in vivo was analyzed by pharmacokinetic experiments. Hemolysis experiment, acute toxicity and cumulative toxicity were conducted in mice to evaluate the safety of CUD-PTX-LN. Subsequently, the anti-tumor activity of CUD-PTX-LN was investigated using in vitro and in vivo breast cancer cell models.Results: The average particle size, PDI, and Zeta potential of CUD-PTX-LN were 238.5 ± 4.79 nm, 0.225 ± 0.011 and -33.8 ± 1.26 mV, respectively. CUD-PTX-LN had an encapsulation efficiency (%EE) of 94.20 ± 0.49% and an achievable drug loading (%DL) of 10.98 ± 0.31%. This nanoparticle was stable for up to half a year when the lyophilized powder was stored at room temperature. Cytotoxicity test on MCF-7 cells demonstrated the stronger cytotoxic activity of nanoparticles in comparison to free PTX. CUD-PTX-LN significantly prolonged the half-life and retention time of PTX. The area under the curve (AUC) of CUD-PTX-LN was 14.72 mg/L × h, which was 6 times that of the free PTX group (2.38 mg/L × h). In anti-tumor experiments in vivo, CUD-PTX-LN possessed the advantages of improving the antitumor efficacy and reducing the toxic side effects of drugs. Importantly, CUD-PTX-LN is safer than free PTX in terms of assessing hemolytic, acute and cumulative toxicity.Conclusion: A novel PTX nanodrug delivery system constructed based on CUD as a carrier holds great potential in improving breast cancer treatment.

CONCEPT OF DUSHI VISHA (CUMULATIVE TOXICITY) IN MODERN ERA: A CRITICAL REVIEW

In present era, thousands of harmful toxins are accumulated in environment are taken by human beings in different forms. These harmful toxins cause cumulative toxicity in human being which results in symptoms that can be seen slowly after their long- term use. These harmful toxins may be of Sthavara Visha/plant origin (e.g. Fruits and vegetables contaminated with pesticides, ripening agents, infections, heavy metal toxicity in plants, Maida, Pollen grains, dust, Latex from plants) Jangama Visha/ animal origin (e.g. Animal dander, adulteration in milk and milk products, Sea food containing heavy metals such as Hg, PCBs) Kritrim Visha (e.g. Toxic ingredients in cosmetics, Food preservatives, Food Flavouring agents, Synthetic Colour Additives, Environmental Pollution, Agricultural poisons, Medications like aspirin etc.). This Cumulative toxicity is similar to Dushi Visha as described in Ayurveda. A poison, which is having fewer properties, which means less than ten classical properties that a poison should contain, or either the poison which is having lesser potency of all the ten properties, attains a latent stage in the body is called as Dushi Visha (latent poison). The aim and objectives of this study is to study the concept of Dushi Visha in modern era and its toxic effects on human body.

“AYURVEDIC MANAGEMENT OF CUMULATIVE TOXICITY (DUSHI VISHA)”: A REVIEW

Dushi Visha is cumulative poisons which retains and accumulate within the tissues of human beings due to exposure seems prolonged period persistently. It may be originated from inanimate, animate or artificial source of poisons. The clinical manifestation, Complication & Management of Dushi Visha has been found in various Samhitas, but matter is scattered. This study has been taken a serious effort to present a management of cumulative Toxicity with special reference to Dushi Visha with scientific justification.

Time-Cumulative Toxicity of Neonicotinoids: Experimental Evidence and Implications for Environmental Risk Assessments

Our mechanistic understanding of the toxicity of chemicals that target biochemical and/or physiological pathways, such as pesticides and medical drugs is that they do so by binding to specific molecules. The nature of the latter molecules (e.g., enzymes, receptors, DNA, proteins, etc.) and the strength of the binding to such chemicals elicit a toxic effect in organisms, which magnitude depends on the doses exposed to within a given timeframe. While dose and time of exposure are critical factors determining the toxicity of pesticides, different types of chemicals behave differently. Experimental evidence demonstrates that the toxicity of neonicotinoids increases with exposure time as much as with the dose, and therefore it has been described as time-cumulative toxicity. Examples for aquatic and terrestrial organisms are shown here. This pattern of toxicity, also found among carcinogenic compounds and other toxicants, has been ignored in ecotoxicology and risk assessments for a long time. The implications of the time-cumulative toxicity of neonicotinoids on non-target organisms of aquatic and terrestrial environments are far reaching. Firstly, neonicotinoids are incompatible with integrated pest management (IPM) approaches and secondly regulatory assessments for this class of compounds cannot be based solely on exposure doses but need also to take into consideration the time factor.

Isavuconazole in the Treatment of Coccidioidal Meningitis

ABSTRACT Patients with coccidioidal meningitis require lifelong antifungal therapy. Cumulative toxicity and lack of antifungal efficacy require salvage therapy in the treatment of some patients. In a retrospective review of nine patients with coccidioidal meningitis treated with isavuconazole, successful therapy was seen in three patients and stable disease was confirmed in six patients. Isavuconazole may be a useful addition to the therapeutic choices currently available for coccidioidal meningitis.

THE VISHAGHNA PROPERTIES OF MANJISHTHA (Rubia cordifolia) IN AYURVEDIC AND CONTEMPORARY SCIENCE: AN OVERVIEW

The present concept is given to help for to establish as bridge between Ayurveda and contemporary science. The Concept of Ayurvedic vishaghna properties is near about detoxifying action (Antidote action) in modern era. It is may be beneficial integrated concept for metabolic toxicity, substance acquired acute and chronic toxicity, biological toxicity, cumulative toxicity etc. and it also help to understand the detoxifying phenomenon. The single and multiple preparations of manjistha are available which indicates its utility in many poisoning. All aspects of manjishtha are studied in detail especially in field of detoxification. Selection of all logical references are done and collection, correlation and explanation as per requirement. According to indication and detoxifying therapeutic use of manjishtha are highlights, which described especially in Ayurvedic and modern text. All ayurvedic and contemporary references regarding vishaghna are collected from Ayurvedic fundamental books and various textbooks, research article, international journals. Theoretically, it will breakdown the pathogenesis of toxicity and progress forward to denaturized any poison. It can be useful for disease which comes under area of any field of toxicity. We can prevent and treat much toxicological disorder. On the basis of concept of vishaghana properties of manjishtha, it can be broadly used in today’s era for preventive as well as curative disease free life from toxicological agent. Keywords; manjishtha, vishaghana properties, detoxifying uses