Organ toxicity? hepatotoxicity

After in silico and in vitro screening, short-term in vivo toleration (IVT) studies [7] are conducted to identify unexpected target organ toxicities, such as myelotoxicity and hepatotoxicity. The IVT is essentially an abbreviated version of regulatory, preclinical. 

Reactive chemicals or their reactive intermediates, such as free radicals and other electrophilic species, may form essentially irreversible covalent bonds with adjacent macromolecules, such as proteins, lipids, and DNA, resulting in the formation of adducts. Covalent adducts can disrupt the normal function of such macromolecules and result in a broad spectrum of toxic responses. These may range from localized transient skin irritation to systemic target organ toxicity (such as hepatotoxicity, neurotoxicity, and renal toxicity), genotoxicity, or carcinogenicity. 

Organ toxicity considers effects at the level of organ function (neurotoxicity, hepatotoxicity, nephrotoxicity, etc.). 

These studies use proton NMR spectroscopy to measure amino acids and other metabolites. The changes of the individual components of the NMR profile can yield information on the regional effects in the kidney (Holmes, Bonner, and Nicholson 1997 Holmes et al. 1998 Lindon, Holmes, and Nicholson 2004 Robertson et al. 2005). Several investigators have applied principal component analysis to improve the identification of affected regions of the nephron. As for other renal tests, the timing and collection procedures are critical to the application in addition, several of the measured metabolites are affected by other organ toxicities, particularly hepatotoxicity. 

The trend in liver retention (not Illustrated) does not show the pronounced uptake for trans-[Pt(NH3)2Cl2] as in the kidney. Thus, the chemlcal-blogical processes leading to tissue retention (and perhaps organ toxicity) appear quite different for the liver V8 kidney. In this context, it is worthwhile to note that while uptake of cis-[Pt(NH3)2CI2] in the kidney can lead to nephrotoxicity, reports of hepatotoxicity associated with cis-[Pt(NH3)2CI2] chemotherapy are rare. 

Side effects of streptomycin and dihydrostreptomycin treatment are mainly toxic in nature. Toxicity to the auditory vestibular organs, nephrotoxicity, hepatotoxicity, and toxicity to the bone marrow have all been observed (Rasmussen 1972 Hoigne 1975). There are also reports of peripheral neuritis and neuromuscular blockade, occurring presumably as a result of the potentiation of non-depolarizing anesthetics (Hoigne 1975). Because of its strong ototoxicity, dihydrostreptomycin is no longer in use in the Western hemisphere. 

Organ toxicants primarily affect one or more organs or body systems. For example, many chlorinated hydrocarbon compounds are hepatotoxic (i.e., Uver toxicants). Carbon tetrachloride and vinyl chloride. 

Reports of organ toxicity upon chronic exposure to styrene are rare however, since the main intermediate in styrene metabolism is an epoxide (styrene-7,8-oxide), hepatotoxicity due to covalent binding at the site of formation appears to be a possibility. Both of these substances, styrene (a Group 3 agent) and its oxide (recently upgraded to a Group 2A as probably carcinogenic to humans) have been shown to produce chromosomal aberrations under certain conditions. 

Toxicological studies with titanocene dichloride showed a different pattern of organ toxicity in comparison to organic antitumor agents and platinum cytostatic drugs. Dose-limiting toxicity was due to hepatotoxicity manifested by significant increases of the... 

A number of quinolones had to be taken off the market due to toxic effects on the liver, heart, or other organs, that became recognized only after marketing (e.g. temafloxacin, trovafloxacin, grepafloxacin). A risk for severe cardiotoxicity, hepatotoxicity, or phototoxicity is... 

Several studies have suggested that some critical adverse effects like peroxisome proliferation, hepatotoxicity, immunotoxicity, and developmental toxicity may be associated with chemical exposure to PFCs, particularly to PFOS (perfluorooctane sulfonate) and PFOA (perfluorooctanoic acid), two ubiquitous persistent organic pollutants with possible environmental and human health risks. 

In all tested organisms, PCBs — especially PCBs with 2,3,7,8-TCDD-like activity — adversely affected patterns of survival, reproduction, growth, metabolism, and accumulation. Common manifestations of PCB exposure in animals include hepatotoxicity (hepatomegaly, necrosis), immunotox-icity (atrophy of lymphoid tissues, suppressed antibody responses), neurotoxicity (impaired behavior and development, catecholamine alterations), increased abortion, low birth weight, embryolethality, teratogenicity, gastrointestinal ulceration and necrosis, bronchitis, dermal toxicity (chloracne, edema,... 

Idiosyncratic dmg reactions (IDRs) are most commonly characterized by a reaction involving fever or rash, with or without internal organ involvement. The spectrum of responses ranges from a minor rash, to potentially fatal toxic epidermal necrosis and Stevens-Johnson syndrome. Immunoglobulin E (IgE)-mediated anaphylactic shock, occasional joint pain, hepatotoxicity or nephrotoxicity are also well documented [24]. The frequency of such reactions are unknown but estimated to be between 1 1000 and 1 10000 exposures and may be enhanced on re-challenging susceptible individuals with the same dmg. 

The main target organs for compound toxicity leading to either drug withdrawal or arrest of compound development as estimated in various studies [3], are classically pointing at liver, the cardiovascular system and bone marrow (hematotoxicity). Cardiovascular and hepatotoxicity were discussed in previous chapters and this chapter focuses on hematotoxicity. 

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