Oral high-dose ankaferd administration effects on gastrointestinal system.

BACKGROUND AND AIMS: Ankaferd Blood Stopper (ABS) is a herbal extract obtained from five different plants. It has a therapeutic potential for the management of external hemorrhage and controlling gastrointestinal bleeding. However, ABS's effects are not unknown on gastrointestinal systems. The aim of this study was to assess the effect of short- and long-term systemic exposure and gastrointestinal safety following the oral administration of high-dose ABS in rats. METHODS: Eighteen healthy adult male rats were included into the study. The rats were divided into 4 groups: group A was fed with high dose ABS (2ml/Kg) for one week, group B for one month, group C for three months and group D's diet did not contain any ABS. On termination of the ABS treatment, the gastrointestinal system from the esophagus to the anus and the liver were surgically removed and histological investigated. RESULTS: During the study period, there was no mortality; signs of intoxication in any of the studied groups. No gastrointestinal tissue fibrosis, dysplasia, or metaplasia was detectable in any of the groups. The stomach had a normal morphology in all groups. However, the other gastrointestinal tract sections showed mucosal inflammation, goblet cell decrements, and intra-epithelial lymphocyte infiltration. The most common changes were mucosal inflammation in all rats in group B and C. Frequency of inflammation was greater in groups B and C in comparison to group A (P= 0.001). Loss of goblet cell and intra-epithelial lymphocyte infiltration were not significantly different between groups A and B (P=0.308 and P=0.189, respectively). However, there was significantly higher intra-epithelial lymphocyte infiltration in group C than in group A (P=0.04). Histopathological examination of the liver showed no inflammation, fibrosis, bile duct destruction or proliferation in any of the groups. However, each groups revealed vascular dilatation and erythrocyte accumulation at the sinusoidal structures of the liver. CONCLUSIONS: ABS seems to be a safe agent and it can be used for hemorrhage originated from gastric lesions. Further work needs to be done to establish whether ABS leads to be used to stop gastrointestinal bleeding.

Feasibility of mFOLFOX6 as the adjuvant treatment after curative resection of metastases from colorectal cancer in Japanese patients.

BACKGROUND: An oxaliplatin-based regimen as the adjuvant treatment for stage III colon cancer demonstrated a survival advantage over fluorouracil (FU) and leucovorin (LV) in the MOSAIC and NSABP C-07 trials. For adjuvant treatment after the resection of metastases from colorectal cancer), active chemotherapy regimens such as FOLFOX are recommended. However, the safety data of FOLFOX are insufficient for its use after metastasectomy of colorectal cancer in Japanese patients. The aim of this study was to evaluate the safety of mFOLFOX6 for adjuvant treatment after the resection of metastases from colorectal cancer. METHODS: Among 67 consecutive patients who received mFOLFOX6 as the adjuvant treatment after resection of metastases from colorectal cancer between September 2002 and March 2009 in our institution, 51 patients who had not received preoperative chemotherapy were reviewed. The mFOLFOX6 treatment comprised oxaliplatin 85 mg/m(2) and l-leucovorin 200 mg/m(2) given intravenously over a 2-h period on day 1, followed by a 5-FU bolus of 400 mg/m(2) and a 46-h infusion of 5-FU 2400 mg/m(2), every 2 weeks for up to 12 cycles. RESULTS: National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI-CTC) grade 3-4 toxicities per patient were: peripheral neuropathy 8%, allergic reaction 4%, aspartate transaminase (AST) 4%, febrile neutropenia 4%, nausea 2%, anorexia 2%, fatigue 2%, alanine transaminase (ALT) 2%, bilirubin 2%, neutrophils 49%, leukocytes 6%, and hemoglobin 2%; 71% of the patients completed the scheduled 12 cycles. CONCLUSION: Adjuvant therapy with mFOLFOX6 after resection of metastases from colorectal cancer is feasible for Japanese patients.

Treatment and complications in elderly stage III colon cancer patients in the Netherlands.

BACKGROUND: We evaluated which patient factors were associated with treatment tolerance and outcome in elderly colon cancer patients. DESIGN: Population-based data from five regions included in the Netherlands Cancer Registry were used. Patients with resected stage III colon cancer aged ≥75 years diagnosed in 1997-2004 who received adjuvant chemotherapy (N = 216) were included as well as a random sample (N = 341) of patients who only underwent surgery. RESULTS: The most common motives for withholding adjuvant chemotherapy were a combination of high age, co-morbidity and poor performance status (PS, 43%) or refusal by the patient or family (17%). In 57% of patients receiving chemotherapy, adaptations were made in treatment regimens. Patients who received adjuvant chemotherapy developed more complications (52%) than those with surgery alone (41%). For the selection of patients who had survived the first year after surgery, receiving adjuvant chemotherapy resulted in better 5-year overall survival (52% versus 34%), even after adjustment for differences in age, co-morbidity and PS. CONCLUSION: Despite high toxicity rates and adjustments in treatment regimens, elderly patients who received chemotherapy seemed to have a better survival. Prospective studies are needed for evaluating which patient characteristics predict the risks and benefits of adjuvant chemotherapy in elderly colon cancer patients.

Initial report of KSCC0803: feasibility study of capecitabine as adjuvant chemotherapy for stage III colon cancer in Japanese patients.

BACKGROUND: A prospective feasibility study was planned to clarify the proportion of compliance and adverse events in the administration of capecitabine as adjuvant chemotherapy for colon cancer in Japanese patients. METHODS: We aimed initially to register 92 cases of R0 stage III colon cancer. Capecitabine (2,500 mg/m(2)/day) was given orally on days 1-14 every 3 weeks for 8 cycles. The proportion of treatments completed as planned was selected as the primary endpoint. RESULTS: Ninety-seven cases were registered and treated between September 2008 and August 2009. The proportion of treatments completed in the full analysis set was 64/97 [66.0%; 95% confidence interval (CI), 55.7-75.3%] and in the per protocol set was 64/91 (70.3%; 95% CI, 59.8-79.5%). Adverse events which led to treatment discontinuation included hand-foot syndrome (HFS) (7), haematotoxicity (5) and increased hepatic damage (4). The proportions of patients with major grade 3/4 adverse events were HFS 22.7%, neutropenia 7.2%, diarrhoea 2.1%, and increased bilirubin 0.0%. CONCLUSIONS: This collaborative multi-facility study, the first of its kind in Japan, presented results of a safety confirmation experiment on capecitabine as adjuvant chemotherapy for stage III colon cancer. The results suggest that capecitabine may be administered safely to Japanese patients.

Third-line sunitinib following sequential use of cytokine therapy and sorafenib in Japanese patients with metastatic renal cell carcinoma.

BACKGROUND: The aim of this study was to evaluate the use of sunitinib as third-line therapy for metastatic renal cell carcinoma (mRCC). METHODS: This study included a total of 35 consecutive Japanese patients with mRCC who were treated with third-line sunitinib after sequential use of cytokine therapy (interferon-α and/or interleukin-2) and sorafenib between September 2008 and December 2010. The clinical outcomes of third-line sunitinib in these patients were retrospectively reviewed. RESULTS: Of the 35 patients, 3 (8.6%), 28 (80.0%) and 4 (11.4%) were judged to have a partial response, stable disease and progressive disease, respectively, as the best response to sunitinib. The median progression-free survival (PFS) and overall survival (OS) of these patients following the introduction of sunitinib were 10.9 and 14.2 months, respectively. Of several factors examined, response to sorafenib and performance status appeared to be independently associated with PFS and OS, respectively, on multivariate analyses. The common grade 3-4 adverse events related to third-line sunitinib were thrombocytopenia (51.4%), neutropenia (42.9%) and hypertension (14.3%). CONCLUSION: Despite the low response rate, third-line sunitinib is well tolerated and could provide comparatively favorable prognostic outcomes in Japanese patients with mRCC after first-line cytokine therapy and second-line sorafenib; therefore, treatment with sunitinib could be one on the therapeutic options for patients with mRCC even after the failure of sequentially performed systemic therapies, such as cytokine therapy and sorafenib.

Safety monitoring of herb-drug interactions: a component of pharmacovigilance.

Adverse drug reactions, including those resulting from interactions between herbal medicines and conventional drugs, are a public health problem worldwide. The need for pharmacovigilance for herb-drug interactions (HDIs) is essential for the identification and assessment of risks of using herbal products (questionable safety, efficacy and quality), which are not always tested with rigor, or often not subject to approval by regulatory agencies. Spontaneous and active surveillance conducted by national pharmacovigilance centres permits a rapid detection of potentially harmful combinations of products. The incidence and prevalence of HDIs are difficult to predict because of the underreporting of adverse effects. It is important for health professionals, consumers, regulatory authorities and suppliers of herbal medicines to be aware of the possible adverse effects and drug interactions caused when herbal medicines are co-administered with conventional drugs. National pharmacovigilance centres continue to play a significant role in increasing awareness of drug safety, in this case with HDIs. The authors' objective for this paper is to provide awareness among policy makers responsible for the design of appropriate pharmacovigilance practices and therefore to highlight the importance of pharmacovigilance in the safety monitoring of HDIs.

[Anaesthesia and breast-feeding: should breast-feeding be discouraged?]. / Leser fragen - Experten antworten - Stillen nach Narkosen: Ist eine Stillpause obligat?

Until a few years ago an interruption of breast-feeding for 12 or even 24 hours was recommended for breast-feeding mothers after anaesthesia, this is no longer valid. If it is the mother's wish, if she is sufficiently awake and physically able, there is no reason not to start breast-feeding a mature and healthy baby immediately after recovery from a general or regional anaesthesia. Even breast-feeding after a Caesarean delivery with administration of the common anaesthetics in the usual (single) doses is no longer considered to be a problem since the amount of the substance taken up from colostrum is vanishingly small in comparison to the amount that is transferred by transplacental routes. Neither the pharmacological properties of the drugs used in association with anaesthesia nor clinical experience justify an interruption of breast-feeding.

Vinflunine: drug safety evaluation of this novel synthetic vinca alkaloid.

INTRODUCTION: Vinca alkaloid agents have been widely used in several different types of malignancies. However, cancer cells, ultimately, develop resistance to these agents. Therefore, the development of new agents with improved efficacy is warranted. Recently, a new synthetic vinca alkaloid, vinflunine, was developed through the addition of two fluor molecules by superacidic chemistry. AREAS COVERED: The authors describe the development of the new vinca alkaloid vinflunine from preclinical studies to the late-stage clinical trials, highlighting the most important clinical and safety data of vinflunine. In vitro and in vivo studies have shown a superior efficacy of vinflunine over other vinca alkaloids and with an improved safety profile. Early clinical trials have demonstrated a significant activity of vinflunine against different malignancies. Phase III trials showed that vinflunine increases survival in patients with advanced transitional cell carcinoma of the urothelium (TCCU) tract treated in the second-line and is as effective as docetaxel in second-line NSCLC. EXPERT OPINION: Vinflunine is currently approved in Europe for the treatment of second-line TCCU and is currently being developed in other malignancies. It has been shown to have predictable and manageable adverse effects, such as neutropenia, anemia, constipation and fatigue.

Impact of erythropoiesis-stimulating agent prescribing at an Asian cancer center, after release of safety advisories.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) provide symptom relief and decrease blood transfusion support among patients with chemotherapy-induced anemia. However, due to increased cardiovascular events associated with off-labeled usage of ESAs, the FDA incorporated black box warnings in 2007 to include the following key points: (a) ESAs should be used only to treat anemia due to concomitant chemotherapy of a noncurative intent and (b) target hemogloblin level should not exceed 12 g/dL. Thus, this study was designed to compare the prescribing of epoetin alfa at National Cancer Centre Singapore before and after FDA black box updates. The secondary objective of this study was to evaluate the appropriateness of efficacy and toxicity monitoring of epoetin alfa. METHODS: This was a retrospective, single-centered, drug utilization review. Patients who received at least one dose of epoetin alfa were included in this study. Utilization of epoetin alfa was segregated into two time periods: January 1, 2005 to October 15, 2007 (S1, Pre-safety advisories changes) and October 16, 2007 to December 10, 2009 (S2, Post-safety advisories changes). RESULTS: A total of 171 patients were prescribed epoetin alfa at NCCS during the two time periods. However, only 139 patients were eligible for analysis, with 91 and 48 patients in S1 and S2 respectively. After safety advisory changes, there were more (18.2%) metastatic patients and fewer (19.1%) patients with cardiovascular co-morbidities who were prescribed epoetin alfa, the mean hemogloblin level when epoetin alfa was initiated was lowered by 0.46 g/dL, more (43%) dose adjustments were made for 'excessive' responders and more (40.7%) patients had fewer blood transfusions after epoetin alfa therapy (p < 0.05). However, blood pressure control, iron studies, and supplementation did not improve (p > 0.05). CONCLUSION: This study suggested that oncologists have generally adopted the new ESA safety warnings and adjusted prescribing habits.

Second-line treatment in the Malawi antiretroviral programme: high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline.

OBJECTIVES: The Malawi antiretroviral therapy (ART) programme uses the public health approach to identify ART failure. Advanced disease progression may occur before switching to second-line ART. We report outcomes for patients evaluated and initiated on second-line treatment in Malawi. METHODS: Patients meeting Malawi immunological or clinical criteria for ART failure in two large urban ART clinics were evaluated for virological failure (viral load >400 HIV-1 RNA copies/mL) and, if failure was confirmed, initiated on second-line ART (zidovudine/lamivudine/tenofovir/lopinavir/ritonavir). Patients were seen monthly and laboratory evaluations were performed quarterly and as needed. We performed logistic regression modelling to identify factors associated with mortality, mortality or new HIV illnesses, and virological suppression at 12 months. RESULTS: Of the 109 patients with confirmed virological failure, five patients died prior to initiation, three declined switching and 101 patients initiated second-line treatment. Over 12 months, 10 additional patients died, 34 patients experienced 45 HIV-related events, and 19 patients experienced grade 3 or 4 toxicities. Among survivors, 85.2% had HIV-1 RNA<400 copies/mL at 12 months. While power to distinguish differences was limited, response rates were similar regardless of baseline resistance level. The median CD4 count increase was 142 cells/microL. World Health Organization clinical failure at baseline [odds ratio (OR) 3.47; 95% confidence interval (CI) 1.14-10.59] and body mass index <18.5 (OR 4.43; 95% CI 1.15-17.12) were risk factors for death. Baseline CD4 count <50 cells/microL was associated with increased risk for death or morbidity at 12 months (OR 2.57; 95% CI 1.01-6.52). CONCLUSIONS: Second-line treatment in Malawi was associated with substantial mortality, morbidity and toxicity but, among survivors, virological outcomes were favourable.

Comments on serious anaphylaxis caused by nine Chinese herbal injections used to treat common colds and upper respiratory tract infections.

Reports describing severe allergic shock and fatality following treatment of a common cold or upper respiratory tract infection (URTI) with a Chinese herbal injection were collected. Our analysis of the risks associated with this treatment suggested that the potential risk of serious, or even lethal, anaphylaxis should preclude its use in treating common colds and URTIs. In light of our findings herein, we propose the following five suggestions for improving the clinical safety of delivering Chinese herbal injections as medical treatments. First, Chinese herbal injections should not be delivered in the clinic to treat patients in accordance with Bian zheng lun zhi (broad-spectrum application based on holistic Traditional Chinese Medicine (TCM) theory and methodology), but rather they should be administered to target specific indicated disease processes. Second, Chinese herbal injection indications should be based on the results of double-blind randomized controlled clinical trials. Third, Chinese herbal injections should be used only in cases involving severe disease or to rescue patients in critical condition; they should not be used to treat mild, relatively innocuous diseases, such as common colds and upper respiratory tract infections, given the risk of doing harm. Fourth, Chinese herbal injection formulas should include materials from only a single or a small number of plant sources in known quantities. Fifth, more studies examining the toxicology and allergenic potential of Chinese herbal injections are needed.

[Discussion on implications and research ideas of toxic theory in natural characteristics of Chinese herbal medicine].

The meaning of "poisonous" in Traditional Chinese Medicine (TCM) is different from that of modern medicine. Narrow meaning of "poisonous" in TCM refers to harmful reaction to human body. Otherwise, generalized meaning of "poisonous" has two main implications: general title of drug and eccentric nature for drug. To fully reveal the scientific content of Chinese herbal toxic theory, we should carry out our research on the relationship between Chinese herbal toxicity and body state under the guidance of TCM theory. Moreover, comprehensive study on toxic information is also necessary for clarifying the natural characteristics of Chinese herbal medicine.

Species selection considerations for preclinical toxicology studies for biotherapeutics.

BACKGROUND: Preclinical efficacy and safety studies, especially chronic studies, can be difficult to perform when the candidate therapeutic agent is a human protein due to the specificity of these molecules for the human target. The main issues are: i) the human protein or target may not be pharmacologically active in rodents or dogs, the standard toxicology species; or ii) the therapeutic agent may be so immunogenic in these species, that longer duration studies are not possible due to the formation of neutralizing antibodies. Thus, preclinical safety testing of biotherapeutics poses a particular challenge in selecting a relevant animal species for use in toxicology studies. OBJECTIVE: This article will discuss the considerations that are unique to safety assessment of biotherapeutics and will provide alternatives to the standard toxicity testing which is conducted for small molecules. METHODS: This article is based on published information with regards to species selection considerations as well as information from the FDA website on several marketed compounds. In addition, discussions of this topic that have occurred in public forums as well as the experience of the author are considered. CONCLUSION: The most important consideration in species selection for a biotherapeutic is that the drug is pharmacologically active in the preclinical species. This is a key consideration as biotherapeutics are highly targeted and rarely, if ever, demonstrate off-target toxicity. Because of this species specificity, nonhuman primates are often the only relevant species that can be used to assess the safety of a biotherapeutic. Other alternatives such as use of a homologous protein in rodents or the use of transgenic or knockout mice can also be used to assess safety although the caveats to these approaches must be considered.

Drug metabolite profiling and elucidation of drug-induced hepatotoxicity.

Drug metabolism studies, together with pathologic and histologic evaluation, provide critical data sets to help understand mechanisms underlying drug-related hepatotoxicity. A common practice is to trace morphologic changes resulting from liver injury back to perturbation of biochemical processes and to identify drug metabolites that affect those processes as possible culprits. This strategy can be illustrated in efforts of elucidating the cause of acetaminophen-, troglitazone- and valproic acid-induced hepatic necrosis, microvesicular steatosis and cholestasis with the aid of information from qualitative and quantitative analysis of metabolites. From a pharmaceutical research perspective, metabolite profiling represents an important function because a structure-activity relationship is essential to rational drug design. In addition, drugs are known to induce idiosyncratic hepatotoxicity, which usually escapes the detection by preclinical safety assessment and clinical trials. This issue is addressed, at present, by eliminating those molecules that are prone to metabolic bioactivation, based on the concept that formation of electrophilic metabolites triggers covalent protein modification and subsequent organ toxicity. Although pragmatic, such an approach has its limitations as a linear correlation does not exist between toxicity and the extent of bioactivation. It may be possible in the future that the advance of proteomics, metabonomics and genomics would pave the way leading to personalized medication in which beneficial effect of a drug is maximized, whereas toxicity risk is minimized.

Preclinical cardiac safety assessment of drugs.

The heart is a frequent site of toxicity of pharmaceutical compounds in humans, and when developing a new drug it is critical to conduct a thorough preclinical evaluation of its possible adverse effects on cardiac structure and function. Changes in cardiac morphology such as myocardial necrosis, hypertrophy or valvulopathy are assessed in regulatory toxicity studies in laboratory animals, although specific models may be needed for a more accurate detection of the risk. The potential proarrhythmic risk of new drugs is a major subject of concern and needs to be fully addressed before treatment of volunteers or patients takes place. In vitro assays are conducted to determine the effects on cardiac ion channels, in particular I(Kr) potassium channel antagonism. Prolongation of the QT interval is assessed in vivo, generally in telemetered dogs. Together, these two tests are considered to detect most arrhythmic drugs. The results of this core battery can be refined by additional studies, in particular assays on isolated cardiac tissues determining changes in cardiac action potential duration, shape and variability over time. Triggering of arrhythmia is assessed in hypokalaemic dogs with artificially created bradycardia, or in vitro in isolated whole hearts. The proarrhythmic risk of the new compound is then evaluated by integrating the results of these different tests. Drug adverse effects on cardiac electrophysiological function, in particular impulse formation and conduction, are evaluated through changes in ECG, generally recorded in dogs, pigs or monkeys. Changes in cardiac contractility occurring either as a primary effect of the drug on cardiac function or as a consequence of cardiac lesions should also be carefully assessed. In telemetered or anaesthetised animals, cardiac contractility is evaluated by measurement of left ventricular pressure and its first derivative over time. Echocardiography allows non-invasive measurement of drug-induced changes in ventricular wall movements and cardiac haemodynamics indicative of effects on contractility. In conclusion, a reliable and accurate evaluation of the cardiac safety of a new pharmaceutical agent is based on the results of in vitro tests, with overall moderate to high throughput, and in vivo experiments assessing the effects of the drug on the heart in its physiological environment. The specific sensitivities of the animals used in these assays to cardiac adverse effects should also be considered. The final evaluation of the cardiac risk is therefore based on an integrated analysis of the results from a battery of tests.

Preclinical predictors of clinical safety: opportunities for improvement.

Toxicology studies in animals are required by regulatory authorities worldwide to provide assurances that clinical testing of pharmaceutical candidates can be conducted safely. Safety concerns from animal studies account for over 20% of attritions from drug development. As discordance between humans and animals is expected, two goals of safe and efficient drug development must be (1) to improve the human relevance of animal testing with new models and technologies, and (2) to advance quickly to clinical testing armed with improved safety biomarker tools.

QT prolongation in guinea pigs for preliminary screening of torsadogenicity of drugs and drug-candidates. II.

Experimental approaches on anaesthetised guinea pigs have been shown recently to be satisfactorily predictive of the torsadogenic risk of drugs. This work aimed at obtaining additional data, for a further understanding of the reliability and/or the limits of this model. Clonidine (non-torsadogenic in humans) induced a lengthening of the ECG parameter of RR in anaesthetised guinea pigs, without any corresponding increase of QT (corrected by the algorithms of Bazett and Fridericia). Thus, 'QT correct' prolonging effects produced by drugs torsadogenic in humans, on the guinea pig model are primarily due to inhibition of cardiac repolarisation. The corresponding RR prolongation is a consequence (not the cause) of this primary effect. Astemizole, haloperidol and terfenadine, torsadogenic in humans, produced in Langendorff perfused guinea pig hearts a prolongation of the QT interval. Chlorprotixene (non-torsadogenic) did not produce any significant effect on QT. These results are fully consistent with previous observations in anaesthetised guinea pigs. In Langendorff perfused hearts, pentobarbital does not affect cardiac repolarisation and does not potentiate the QT-prolonging effect of astemizole. Together with the findings reported by many authors, these data suggest that ECG recording in anaesthetised guinea pigs is a reliable model for cardiac safety studies evaluating the influence of drugs on the repolarisation process.

[Research and prospect on reducing the toxicity and enhancing the efficacy of Tipterygium wilfordii by combined use of Chinese medicine].

Researches in recent close to dozen years concerning Tripterygium wilfordii (TW) toxicity-reducing and efficacy-enhancing by combined use of Chinese medicine in treating intractable diseases such as rheumatoid arthritis, nephropathy, psoriasis etc. were summarized in this paper. Furthermore, the therapeutic mechanisms and adverse reaction of TW were elaborated and how to arrange properly the TCM hebal drugs used in combination was analyzed.

Protective effect of Andrographis paniculata and andrographolide on cyclophosphamide-induced urothelial toxicity.

The protective effect of Andrograhis paniculata and andrographolide (ANDLE) against cyclophosphamide (CTX)-induced urothelial toxicity was investigated in this study. Pretreatment of Swiss albino mice with A paniculata extract (10 mg/dose/animal intraperitoneally [ip]) and ANDLE (500 microg/dose/animal ip) could significantly reduce CTX (1.5 nmol/kg body weight)-induced urothelial toxicity. Morphological and histopathological analysis of urinary bladder of CTX-treated mice showed severe inflammation and dark coloration, whereas A paniculata and ANDLE-treated mice showed almost normal bladder morphology. Elevation of urinary protein level (7.33 +/- 0.3 g/L) by CTX administration was reduced by A paniculata (3.78 +/- 0.4 g/L) and ANDLE treatment (4.19 +/- 0.1 g/L). Urinary urea N2 level, which was elevated after 48 hours of CTX administration (24.25 +/- 0.2 g/L) was found to be reduced by the treatment with A paniculata (14.19 +/- 0.5 g/L) and ANDLE (15.79 +/- 0.4 g/L). A decreased level of reduced glutahione (GSH) content in liver (2.81 +/- 0.1 nmol/mg protein) and bladder (1.20 +/- 0.2 nmol/mg protein) after CTX administration was also increased by the treatment with A paniculata (liver: 5.78 +/- 0.3 nmol/mg protein; bladder: 2.96 +/- 0.2 nmol/mg protein) and ANDLE (liver: 5.14 +/- 0.3 nmol/mg protein; bladder: 2.84 +/- 0.2 nmol/mg protein). Production of the proinflammatory cytokine, tumor necrosis factor-alpha, which was elevated during CTX administration, was found to be inhibited by A paniculata and ANDLE treatment. The lowered level of interleukin-2 and interferon-gamma during CTX treatment was elevated by the administration of A paniculata and ANDLE.

Systemic toxicity from topically applied lidocaine in conjunction with fractional photothermolysis.

BACKGROUND: Topical anesthetics, unlike injectable anesthetics, can be applied painlessly and can provide sufficient pain control to maintain patient comfort throughout a variety of laser procedures. Although the use of topical lidocaine is considered relatively safe, instances of cardiotoxic and neurotoxic adverse events have been reported to occur. OBSERVATIONS: A 52-year-old woman underwent fractional photothermolysis for management of severe hypopigmentation and scarring of several years' duration. Shortly after termination of treatment to her face and neck, which required prolonged exposure to a 30% lidocaine gel compound both before and during surgery, she developed clinical signs and symptoms consistent with systemic lidocaine toxicity. The results of laboratory studies confirmed serum lidocaine levels within the toxic range. We postulate that the combination of the high concentration of topical lidocaine required to achieve sufficient anesthesia, together with the laser-induced disruption in epidermal barrier function, may have been responsible for this phenomenon. CONCLUSIONS: Application of a 30% topical lidocaine gel to a limited area in conjunction with fractional photothermolysis may generate serum lidocaine levels high enough to elicit systemic toxicity. Laser surgeons should be alert to this phenomenon, particularly in patients with underlying hepatic, endocrine, cardiac, or central nervous system/psychiatric dysfunction; in patients with a low body mass index; and in patients who are taking medications that may interfere with hepatic lidocaine metabolism.