Local tissue toxicity

Runge, V.M., Dickey, K.M., Williams, N.M., and Peng, X. (2002) Local tissue toxicity in response to extravascular extravasation of magnetic resonance contrast media. Investigative Radiology, 37, 393-398. 

Neutral synthetic sugar derivatives, for example SM-5887 (39), display good antitumor activity with reduction in local tissue toxicity and cardiotoxicity compared to, for example, adriamycin (35) [51],... 

ABSTRACT. From the gross and histological examinations, B-cyclodextrin (B-CyD) was found to reduce the muscular tissue damage produced by chlorpromazine hydrochloride (CPZ) on M. vastus lateralis in rabbits. The protective effect of B-CyD may be attributable to the decrease in affinity of CPZ to the tissue membrane through inclusion complexation. There was no appreciable difference in the pharmacokinetic and pharmacodynamic behaviors between CPZ and its B-CyD complex in rabbits. These results suggest that 3-CyD is useful to reduce the local tissue toxicity of CPZ without altering the pharmacological efficacy. 

The present data apparently indicate that 3-CyD is great utility in reducing the local tissue toxicity of CPZ without altering its pharmacological efficacy. 

Cancer. Cancer is a cellular malignancy characterized by loss of normal controls resulting in unregulated growth, lack of differentiation, and the abihty to invade local tissues and metastasize. Most cancers are potentially curable, if detected at an early enough stage. The ideal antineoplastic agent would destroy cancer cells without adverse effects or toxicities to normal cells. No such dmg exists. 

In summary, preliminary results from two animal models (rabbit and mouse) indicate that poly(N-palmitoylhydroxyproline ester) elicits a very mild, local tissue response that compares favorably with the responses observed for established biomaterials such as medical grade stainless steel or poly(lactic acid)/poly(glycolic acid) implants. At this point, additional assays need to be performed to evaluate possible allergic responses, as well as systemic toxic effects, carcinogenic, teratogenic, or mutagenic activity, and adaptive responses. 

CX is an urticant, producing instant, almost intolerable pain and local tissue destruction immediately on contact with skin and mucous membranes. It is toxic through inhalation, skin and eye exposure, and ingestion. Its rate of detoxification in the body is unknown. 

Occluded applications Composition relatively invariant in use System size (area) predetermined Specific site prescribed for application Application technique highly reproducible Delivery is sustained Generally operate at unit drug activity, at least operate at steady activity Delivery is zero-order Serum levels related to product efficacy Bioequivalency based on pharmacokinetic (blood level) endpoint Unavoidable local tissue levels consequential only to system toxicity Individual dose interruptable Whole system removed when spent... 

Specific (local tissue tolerance) toxicity studies may be necessary due to special characteristics of the product or the clinical indication. Adjuvanted vaccines are routinely evaluated for local (injection site) reactions, and cellular therapies are routinely screened for tumorigenic potential. Research is also needed to better predict the sensitizing potential of biological products and to determine the relevance of serum antibody levels following repeat dosing in animals and humans. 

For a material to be toxic (local tissue effects are largely not true toxicities by this definition), the first requirement is that it be absorbed into the organism [for which purpose being in the cavity of the gastrointestinal (GI) tract does not qualify]. Most pharmaceuticals are intended to gain such access. 

Calu-3 cells have shown the ability to perform fatty acid esterification of budes-onide [132], In pre-clinical studies, this esterification results in a prolonged local tissue binding and efficacy, which is not found when the esterification is inhibited [133]. The precise mechanism remains undefined in that the identity of specific enzyme(s) responsible for this metabolic reaction is unclear [134], Assessment of the potential toxicity and metabolism of pharmaceuticals and other xenobiotics using in vitro respiratory models is still at its infancy. The development of robust in vitro human models (i.e., cell lines from human pulmonary origin) has the potential to contribute significantly to better understanding the role of biotransformation enzymes in the bioactivation/detoxication processes in the lung. 

Toxicity appears to be negligible to the extent that both in animals ana in humans large doses for extended periods, orally and parenterally, have failed to provide evidence of abnormal function of any type [376, 377, 382]. As might be expected, large volumes of the oily ester initiated local tissue irritation. 

Side effects include unpleasant gastrointestinal symptoms, nausea, and vomiting and are very common in patients with a steady-state plasma theophylline level above 20 /xg/ml. They are not observed at plasma theophylline levels under 13 U,g/ml, regardless of the daily dose. It seems unlikely, therefore, that these troublesome toxic side effects are due to local tissue damage produced by theophylline in the gut, but rather that they are a systemic response to a high plasma theophylline level and, therefore, preventable by proper monitoring. 

We are currently on the cusp of a new era in the treatment of cancers whereby we will learn to incorporate new drugs that are likely not cytotoxic on their own but when used in combination with standard chemotherapy and radiation hold the promise of superior tumor responses that will hopefully translate into improved local control and improved survival. At the same time it is reasonable to expect an increased selectivity for malignant cells compared to normal tissues given that many of these targets are either not altered in normal cells or their expression is not usually increased in normal tissues. This leads to the anticipation of no increase in normal tissue toxicities when these novel targeted agents are used to treat patients. 

The initial combination modality clinical studies with cisplatin and fractionated radiation therapy was carried out in head and neck cancer with weekly cisplatin (120-160 mg/m2) and conventional single daily fraction radiation (95). In a follow-up intergroup study, patients were randomized to radiation therapy alone or to radiation therapy plus 20 mg/ m2/wk cisplatin (96). Both studies showed no major increase in normal tissue toxicity in the radiation field and showed an increase in response rate. There was no increase in complete response rate or in survival. Bachaud et al.(97) carried out a randomized study comparing radiation therapy alone with concurrent cisplatin (50 mg/m2) and radiation therapy in postoperative patients. This trial produced a significant reduction in local recurrence and improved disease-free survival with 59% of the patients receiving the full planned dose of cisplatin. 

Since blood levels are lowered up to 30% when vasoconstrictors are added to local anesthetics, localized neuronal uptake is enhanced because of higher local tissue concentrations in the region of drug administration, and the risks of systemic toxic effects are reduced. Furthermore, when used in spinal anesthesia, epinephrine acts directly on the cord to both enhance and prolong local anesthetic-induced spinal anesthesia by acting on a2 adrenoceptors, which inhibit release of... 

Effective DES are able to control drug elution from the polymer, Clinical experience has demonstrated that excessively rapid drug elution often fails to achieve desired clinical efficacy. Rapid drug elution can also produce vascular toxicity by exceeding the safety threshold for the drug, The ideal situation is to have a sustained release of drug for at least 30 days, as this is the critical time window for the resolution of local tissue inflammation and the suppression of neointimal proliferation. 

Local anesthetics containing an amide linkage are metabolized principally by the liver.Thus, patients with hepatic disease may be more likely to exhibit toxic effects from the injectable anesthetics. Local tissue infiltration or nerve blocks should be avoided or performed using minimally effective anesthetic doses in patients with hepatitis, cirrhosis, extrahepatic obstruction (e.g., lithiasis), or other clinically significant hepatic dysfunction. 

D- icjtiriorrij CJri Nausea and vomiting hepatic toxicity with ascites diarrhoea severe local tissue damage and necrosis on extravasation anaphylactic reaction Scomatitis oral ulceration bone marrow depression alopecia folliculitis dermatitis in previously irradiated areas... 

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