Local Tissue Toxicity Research Articles

Toxicity of anaesthetics

Unwanted side-effects of anaesthetic drugs that occur during anaesthesia or during the post-operative recovery period are what concern anaesthesiologists and anaesthetists. Occupational risks are of concern to all health-care professionals who administer anaesthetics or who are incidentally exposed to anaesthetic gases. After regulatory requirements for marketing drugs are met, the qualitative and quantitative nature of side-effects of the drugs in the target population and the risk of incidental exposure of health-care professionals are generally well defined. However, sometimes unwanted side-effects are first detected after post-approval marketing.Numerous scientific disciplines with specialized terminology contribute to the body of knowledge about anaesthetic toxicity. Scientific inquiry spanning a range of disciplines from molecular biology to global ecology provides information essential for predicting, assessing, avoiding and treating the untoward effects of anaesthetics. Contemporary concerns with respect to side-effects of anaesthetic drugs include delayed recovery of cognitive function, addiction and tolerance, local anaesthetic cardiotoxicity and tissue toxicity, relative toxicity of enantiomeric forms of drugs, and the role of biotransformation in unwanted responses to anaesthetic drug administration.

Local tissue toxicity in response to extravascular extravasation of magnetic resonance contrast media.

The relative toxicities of the gadolinium chelates currently available in the United States were compared when extravasated in soft tissue. The increasing use of these contrast agents in higher volumes and at faster injection rates, often with a power injector, was a principal motivation for this research. Gadopentetate dimeglumine (Magnevist), gadoteridol (ProHance), gadodiamide (Omniscan), and gadoversetamide (Optimark) were evaluated at standard concentration and compared with a control (physiologic saline) and the conventional ionic radiographic contrast medium meglumine diatrizoate (Renografin 60). Each mouse received a subcutaneous injection in the hindlimb of 0.3 mL of contrast or saline. There were 6 experimental groups, with 15 animals in each group. The individual performing the injection was blinded to the identity of the contrast agent used in each mouse. After 48 hours, the mice were killed and tissue samples obtained for histopathology. A veterinary pathologist, also blinded to the agent injected, graded the degree of damage seen on microscopic examination. Of the four MR contrast agents, gadopentetate dimeglumine caused the greatest tissue damage, and gadoteridol and gadodiamide-the two lowest osmolar agents-the least. The difference was statistically significant in terms of both inflammation (P = 0.0008 for gadoteridol, and P = 0.006 for gadodiamide) and necrosis (P = 0.0067 for gadoteridol, and P = 0.031 for gadodiamide), when these agents were compared with gadopentetate dimeglumine. In regard to the control experiments, for all three variables (necrosis, edema, and inflammation), there was no statistically significant difference between the results with gadoteridol or gadodiamide and those with saline. In terms of both edema and inflammation, the effect of gadopentetate dimeglumine, although less, could not be differentiated with any statistical significance from that of meglumine diatrizoate. Gadoversetamide, which has an osmolality between the ionic agent (gadopentetate dimeglumine) and the other two nonionic agents, caused a reaction that could not be differentiated from that seen with gadopentetate dimeglumine for both necrosis and edema. Only in the scoring of inflammation was the effect less using gadoversetamide compared to gadopentetate dimeglumine with any statistical significance (P = 0.021). The risk of tissue damage due to extravasation is not widely appreciated for the gadolinium chelates. Care should be exercised during contrast injection, to avoid inadvertent extravasation and its deleterious consequences, in particular with the two higher osmolar agents (gadopentetate dimeglumine and gadoversetamide).

Intrathecal Nalbuphine After Cesarean Delivery: Are We Ready?

Intrathecal Nalbuphine After Cesarean Delivery: Are We Ready?

Cladribine

Cladribine is a deaminase-resistant deoxyadenosine analogue that selectively reduces lymphocyte counts. The drug is an effective therapy for selected haematological malignancies and is being tested in patients with multiple sclerosis (MS), in whom the antilymphocytic effects of the drug may reduce the autoimmune destruction of myelin. With activity against resting and dividing cells that express high deoxycytidine kinase activity, cladribine causes prolonged, profound suppression of lymphocyte counts. Subcutaneous cladribine is 100% bioavailable and has no local tissue toxicity. Dosages used in clinical trials in patients with MS are in the range of 0.05 to 0.07 mg/kg/day subcutaneously for 5 days each month for 2 to 6 months. Temporary improvement or no change in neurological functioning and improvements in CNS lesions detected by gadolinium-enhanced magnetic resonance imaging (MRI) have been seen after cladribine use in patients with chronic progressive (CPMS) and relapsing-remitting (RRMS) forms of MS. In a randomised double-blind study of 24 pairs of patients, improvement or stabilisation of CPMS for approximately 2 years was observed in cladribine-treated patients, whereas the disease progressed in placebo recipients. Another study of 159 patients found no progression in either the treated or placebo control group. In both studies, marked improvements were seen in gadolinium-enhanced CNS lesions. Cladribine-associated improvements in neurological functioning were also seen in some patients with RRMS in one study, which also noted a reduction in the frequency and severity of relapses. In this and a separate RRMS study, cladribine resulted in the regression of CNS lesions on MRI. Bone marrow suppression is the main dose-related toxicity; in patients with MS, use of low total cladribine dosages appears to limit myelosuppression. Although thrombocytopenia is of concern with higher-dose regimens (i.e. 2.8 mg/kg total dose) in patients with MS, granulocyte counts and haemoglobin levels appear to be largely unaltered. Cladribine treatment is also associated with culture- negative fever and a risk of infections in patients with haematological malignancies. Further study of cladribine is needed to confirm present results in wider numbers of patients treated or followed up for longer durations, define optimum treatment and retreatment schedules for the drug and compare it with other agents. Nonetheless, cladribine therapy appears to have the potential to slow the progression of MS, reduce CNS lesions in patients with either the chronic progressive or relapsing-remitting forms of the disease and improve neurological functioning in some of these patients.

Site-specific delivery of colchicine in rat carotid artery model of restenosis

A periadventitial polymeric drug delivery system is one strategy for obtaining and maintaining high tissue levels of drugs at the site of vascular injury. The inhibitory effect of colchicine, an antiproliferative agent, on neointimal proliferation after vascular injury was examined in the balloon catheter carotid artery injury model in rats. Controlled-release colchicine delivery was achieved by formulating drug-containing ethylene vinylacetate copolymer matrices, and the release kinetics were determined in vitro and in vivo. Polymeric matrices containing 0.1% and 0.01% colchicine, and plain polymers were implanted perivascularly in rats following balloon catheter injury. The arterial specimens were harvested after 21 days, processed histologically and evaluated morphometrically. Site-specific delivery of colchicine from 0.1% loaded perivascular matrices, but not 0.01%, significantly inhibited neointimal proliferation after balloon injury. However, local tissue toxicity was observed in some animals. The results of this study should be reconfirmed in a larger animal model such as the porcine catheter injured artery model.

Upper Extremity Discoloration Caused by Subcutaneous Indigo Carmine Injection

Upper Extremity Discoloration Caused by Subcutaneous Indigo Carmine Injection

Sustained Release of Cisplatin in Dogs from an Injectable Implant Delivery System

Cisplatin was incorporated into an in-situ forming biodegradable implant delivery system (ATRIGELO) consisting of a biodegradable polymer dissolved in a pharmaceutically acceptable solvent. The polymer solution with the suspended cisplatin was injected subcutaneously into the flank or shoulder of six healthy beagle dogs where the water-insoluble polymer precipitated upon contact with body fluids and formed a solid implant for the controlled release of the drug. Each dog received four injections, spaced thirty days apart, of a formulation containing either poly(DL-lactide-co-caprolactone) (PLC) or pely(DL-lactide-co-glycolide) (PLGA) dissolved in dimethyl sulfoxide (DM8O) and loaded with 8% by weight cisplatin. Dosage levels of 70, 105, and 157.5 mg/m2 were used to determine dosage escalation effects. Injections of the same formulations without the drug served as controls. Samples of blood were taken at appropriate times over the four months of treatment and analyzed for platinum concentration by atomic absorption spectroscopy. Local tissue and systemic toxicities were also determined. Both formulations exhibited sustained release of cisplatin with peak serum concentrations of platinum being attained in about two days followed by gradually decreasing platinum levels to day thirty. Consistent drug release profiles were observed for each of the four thirty-day treatment periods. The dosage escalation results exhibited an approximate 50% increase in peak platinum levels and area-under-the-curve (AUC) values for each 50% increase in drug dose. Local tissue toxicity to the cisplatin-containing implants was variable and appeared to be unrelated to dose level or direction number. Tissue reaction to the implants without drug was minimal indicating a role of cisplatin in the tissue reactions. Systemic toxicity, as judged by clinical parameters and clinicopathologic evaluation, was not noted at any dose level or injection time.

Dose-Dependency of Hepatocellular Necrosis in a Canine Model of Chemoembolization

The degree of local tissue toxicity from hepatic arterial chemoembolization relative to the dose of anticancer drugs was evaluated in 13 dogs. Animals were divided into four groups. Group 1 was the control group in which embolization was performed with gelatin sponge particles only (n = 4); group 2 animals underwent embolization with 0.4 mg/kg of Adriamycin (ADR) and 0.2 mg/kg of mitomycin C (MMC) (n = 4); group 3, with 0.8 mg/kg of ADR and 0.4 mg/kg of MMC (n = 2); and group 4, with 1.6 mg/kg of ADR and 0.8 mg/kg of MMC (n = 3). Animals were killed 1 week after embolization, and histopathologic evaluation was performed. The average percentage liver necrosis in the embolized lobe was 0% in group 1, 1% in group 2, 85% in group 3, and 92% in group 4. Hepatic arterial chemoembolization with high doses of anticancer drugs causes severe liver damage, but 0.4 mg/kg of ADR and 0.2 mg/kg of MMC is relatively safe, causing only minimal changes in this canine model.

Local Soft Tissue Toxicity Following Cisplatin Extravasation

Local Soft Tissue Toxicity Following Cisplatin Extravasation

Pharmacokinetics of subcutaneous azidothymidine in rhesus monkeys.

The pharmacokinetics of subcutaneous bolus and continuous infusion azidothymidine (AZT) was studied in rhesus monkeys. Three animals received 100 mg/m2 as a bolus injection both intravenously and subcutaneously, with the order of administration randomly determined. Two animals received a continuous subcutaneous infusion of 25 mg/m2 per h for 12 or 24 h. AZT was measured in plasma by a reverse-phase high-pressure liquid chromatographic assay. Following intravenous bolus administration, AZT elimination was rapid, with a mean half-life of 1.2 h and a mean clearance of 318 ml/min per m2 (range, 200 to 441 ml/min per m2). The bolus subcutaneous dose was rapidly (time to peak concentration, 15 to 30 min) and nearly completely (fraction absorbed, 92%) absorbed without evidence of local tissue toxicity. With continuous subcutaneous infusion of AZT, the steady state was attained within 4 h and steady-state concentrations in plasma in the two animals exceeded 3.0 mumol/liter. No local tissue toxicity was observed at the infusion site. The subcutaneous route may be a practical alternative to intravenous administration of AZT and deserves further clinical study.

Resident essay award: Matching intraoperative electron-beam fields: Dosimetric and clinical considerations

In the setting of a large or irregularly shaped tumor, adjacent or intentionally overlapped intraoperative electron fields may be required to give adequate coverage of the intraoperative target volume. The matching of such intraoperative electron fields present special dosimetric problems because of the divergence of electron isodose curves with depth. In the intraoperative setting, where large, single-fraction doses are delivered, the low- and high dose areas which result from gaps or overlaps between the diverging isodose curves of electron fields matched at depth or the surface may translate into decreased local tumor control or excessive normal tissue toxicity. This study examines the dosimetry of gapped, adjacent, and overlapped 8 × 9 cm 2 rectangular intraoperative fields, for 9 to 18 MeV electrons, using film densitometry. “Ideal” methods of matching rectangluar intraoperative electron fields are presented, and include: 1) a 2-mm gap plus surface bolus for adjacent fields, and 2) placing a tenth-value layer shaped lead cutout in the overlap region for intentionally overlapped fields.

Reduction in the local tissue toxicity of chlorpromazine by beta-cyclodextrin complexation.

Effect of beta-cyclodextrin (beta-CyD) on the local tissue toxicity of chlorpromazine (CPZ) was investigated following the intramuscular injection to rabbits. From the gross and histological examinations, beta-CyD was found to alleviate the muscular tissue damage produced by CPZ on M. vastus lateralis in rabbits. The protective effect of beta-CyD may be ascribed to the decrease in affinity of CPZ to the tissue membrane through inclusion complexation. The present data suggest that beta-CyD complexation is particularly useful to reduce the local toxicity of phenothiazine neuroleptics without altering the pharmacological efficacy.

Histopathological evaluation of cocaine-induced skin lesions in the rat.

A series of experiments was performed to characterize the nature of local tissue reactions to cocaine. The time‐course of tissue injury was assessed over a 21‐day period by gross and microscopic examination of the skin of rats administered 0.1–2.0% cocaine hydrochloride by i.e. or s.c. injection. Pronounced blanching, progressively severe hemorrhage, delayed extravasation of Evans blue dye, and eventual scar formation were seen grossly at injection sites. Marked engorgement of blood vessels, small hemorrhagic foci, and hyalinization of scattered muscle bundles of the pannieulus carnosus were apparent microscopically at 15 min post‐injection. Subsequent changes during (he next 3 h included progressively severe hemorrhage and loss of muscle bundles, degeneration of hair follicles and necrosis of the vascular endothelium and epidermis. Healing of cocaine‐induced lesions, as monitored for 21 days, was relatively rapid and complete. A hyperplastic epidermis covered formerly ulcerated areas by 6 days. Destroyed cellular structures in the derm is were replaced by collagen. Since cocaine's local tissue toxicity has been ascribed to vasoconstriction, the toxic potential of cocaine was contrasted with that of a potent vasoconstrictor, epinephrine (EPI). Although 0.1% EPI produced greater vasoconstriction than did cocaine, s.c. injection of EPI did not result in skin damage. The slight acidity of cocaine hydrochloride solutions appeared to be of little consequence, since s.c. injection of pH 5 and 6 saline had little effect on tissues. Our results suggest that cocaine is directly cytotoxic, though ischemia resulting from vascular injury and vasoconstriction may contribute to the local tissue injury caused by the drug.

A rapidly polymerizing polyurethane for transcatheter embolization.

A polyurethane prepolymer was evaluated as a transcatheter embolizing agent. Low viscosity permits injection through small catheters. Polymerization is initated on contact with blood and completed within 10 seconds. Downstream propagation is better then that of cyanoacrylate and comparable to that of silicone rubber. No systemic toxicity was observed in acute animal experiments. However, dissolution of arterial walls and extravasation out of the vascular bed of chronically embolized organs suggest significant local tissue toxicity and make further evaluation necessary before clinical testing.

Observations on the use of the trypan blue and skin-twitch tests for measuring local tissue toxicity

An objective and reasonably quantitative test method for estimating sting reaction following intradermal injection of a chemical irritant in the dog by means of the skin-twitch reponse was described. The end point, designated as the threshold twitch concentration (TTC), was defined as that concentration, expressed in per cent, which produced no more than a mild skin-twitch response. The results obtained were compared with local tissue irritancy data as measured by the trypan blue test in the rabbit (TIC). The local tissue response to hypo- and hypertonicity and to change in the pH of normal saline was essentially the same by both test methods. Of the fourteen compounds studied, sting appeared to be closely associated with irritancy in nine. Among the remaining five compounds, the TIC was found to be from 5 to 2560 times as great as the TTC. The ratio TIC: TTC, for each of these compounds was as follows: meperidine HCl, 5; tyloxapol, 7.8; polyethylene glycol 600 monooleate, 7.8; théraleptique, 500; and histamine, 2560; this indicates that it is possible to separate a sting reaction from mild reversible tissue injury. A negative sting reaction to normal saline and strongly positive sting reactions to distilled water and isotonic solutions of Théraleptique were observed following intradermal injection in man. The local tissue response to quinine HCl, as measured by the trypan blue test, was found to be the same in the rabbit and the dog.

Long-lasting local anesthetic agents in ophthalmic surgery.

THIS PAPER presents certain experimental and clinical observations on the ophthalmologic use of two new long-lasting anesthetic agents, efocaine and U-0045.* The duration of anesthesia and local tissue toxicity produced by these new agents were compared with those produced by such widely used local anesthetics as procaine, tetracaine (Pontocaine), and lidocaine (Xylocaine). Conclusions based on the use of U-0045 to obtain retrobulbar anesthesia in more than 550 operations upon the eyeball or extraocular muscles are presented. The advantages which would accrue from local anesthesia of sufficient duration to avoid postoperative pain are obvious. Nearly all patients have some discomfort, often severe, after intraocular surgery. Pain may cause patients to become apprehensive and restless. They may squeeze their eyelids forcibly together beneath the dressings and thus interfere with re-formation of the anterior chamber. Iris prolapse may result. Nausea and vomiting may be precipitated by ocular pain through the vagus reflex. The