Home About us Contact
|
Home About us Contact | ||
|
|
||
Systemic Toxicity (systemic + toxicity)
Selected AbstractsSystemic toxicity of tacrolimus given by various routes and the response to dose reductionCLINICAL & EXPERIMENTAL OPHTHALMOLOGY, Issue 1 2005Laboratory Science Abstract Purpose:,To evaluate the long-term systemic toxicity of tacrolimus (FK-506) administered by various routes, and to assess the effect of dose reduction on toxicity. Methods:,The study animals were 120 experimentally naďve adult female Wistar rats weighing 200,250 g each. The rats were randomly divided into 10 equal groups (n = 12 in each) and treated with tacrolimus administered topically (in drops, 0.3%, q.i.d.), intravitreally (0.5 mg/kg bodyweight/week), intramuscularly (1 mg/kg bodyweight/week), low-dose intravenously (1 mg/kg bodyweight/week) and in high-dose intravenously (2 mg/kg bodyweight/week) for 3 months. The rats in the control groups (one for each different route of administration) were treated with 0.9% NaCl. The blood concentration of tacrolimus, complete blood count and biochemistry parameters were measured each month for the 3-month study period. Results:,The rats in the control groups and experimental groups administered topical and intravitreal tacrolimus did not demonstrate any systemic toxic effects. The rats that developed certain toxic effects (hyperglycaemia, hyperkalaemia and nephrotoxicity) in the groups given low-dose or high-dose i.v. tacrolimus responded well to dose reduction. Following dose reduction, blood glucose concentrations decreased from 247.4 ± 42.3 mg/dL to 189.6 ± 37.9 mg/dL (P < 0.05), and from 237.4 ± 41.1 mg/dL to 182.3 ± 22.7 mg/dL (P < 0.05) in the low- and high-dose i.v. tacrolimus-treated rats, respectively. The rats that developed impaired hepatic function after high-dose tacrolimus did not respond to dose reduction. Baseline cholesterol concentrations for the intramuscular and low- and high-dose i.v. tacrolimus-treated groups, demonstrated decreases, respectively, from 87.4 ± 14.0 mg/dL, 86.4 ± 14.0 mg/dL and 90.4 ± 14.3 mg/dL to 53.6 ± 9.8 mg/dL, 52.1 ± 12.5 mg/dL and 63.5 ± 11.7 mg/dL by the end of the second month. The differences were found to be statistically significant (P < 0.05 for each result). Conclusion:,Topical or intravitreal administration of tacrolimus seems to be systemically safe whereas parenteral administration can cause some systemic haematological changes such as dose-dependent decreased serum cholesterol concentrations. Dose reduction may prevent such adverse effects. [source] Long-lasting infiltration anaesthesia by lidocaine-loaded biodegradable nanoparticles in hydrogel in ratsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2009Q.-Q. YIN Background: Infiltration of a long-lasting anaesthetic is helpful during the post-operative period. The recently developed local drug delivery system, biodegradable nanoparticles in a thermo-sensitive hydrogel (nanogel system), may possibly provide an extended duration of drugs. Therefore, we evaluated whether prolonged infiltration anaesthesia could be achieved by loading lidocaine into this delivery system. Methods: Thirty male rats were randomized into five groups of six rats each: saline; 2% hydrochloride lidocaine solution; lidocaine-loaded nanogel system and its compositing formulations, namely lido,nano gel; lido,nano; and lidogel. Durations of local anaesthesia with subcutaneously injected agents were measured by tail flick latency tests in a randomized, blind fashion. Results: Lido,nano gel produced effective anaesthesia for 360±113 min, compared with 150±33 min by lidogel, 180±37 min by lido,nano, and 110±45 min by lidocaine solution (P<0.001, means±SD), and elicited complete sensory blockade for 300±114 min, compared with 75±37 min by lidogel, 105±53 min by lido,nano, and 60±33 min by lidocaine solution (P<0.001, means±SD) without severe skin/systemic toxicity. Conclusion: Lidocaine-loaded biodegradable nanoparticles in hydrogel produced prolonged infiltration anaesthesia in rats without severe toxicity, indicating a possible way to develop long-lasting local anaesthetics. [source] Peptide-doxorubicin conjugates specifically degraded by matrix metalloproteinases expressed from tumorDRUG DEVELOPMENT RESEARCH, Issue 5 2006Gee Young Lee Abstract Specific peptide-doxorubicin conjugates were developed for targeting matrix metalloproteinases (MMPs) expressed from tumors. The peptide-doxorubicin conjugates were designed to be cleaved by MMP-2 and MMP-9 in order that doxorubicin or the active form that acts as an anticancer agent was released free from the peptide fragment at the tumor site. Three types of peptide-doxorubicin conjugates were synthesized using the peptides: GPLG (Gly-Pro-Leu-Gly), GPLGV (Gly-Pro-Leu-Gly-Val), and GPLGPAG (Gly-Pro-Leu-Gly-Pro-Ala-Gly). The synthesized peptide-doxorubicin conjugates were characterized for their degradation behavior and bioactivity in vitro, and their antitumoral activity was assessed using the Lewis lung carcinoma (LLC) model, which expresses MMP-2 and MMP-9. After incubation with active MMP-2 for 24,h, GPLG-doxorubicin was barely degraded, whereas GPLGV-doxorubicin and GPLGPAG-doxorubicin were considerably degraded by active MMP-2. Consequently, all peptide-doxorubicin conjugates had significantly low cytotoxicity compared to doxorubicin, but tumor growth suppression was exhibited only by GPLGV-doxorubicin and GPLGPAG-doxorubicin. The tumor growth suppression by the two conjugates was higher compared to control, although it did not exceed the suppression level shown by doxorubicin. The low toxicity exhibited by peptide-doxorubicin conjugates resulted in only slight body weight loss in mice, whereas doxorubicin greatly reduced body weight and induced severe side effects. Therefore, we propose MMPs-specific peptide-doxorubicin conjugates in targeting anti-cancer drug delivery that could reduce systemic toxicities. Drug Dev. Res. 67:438,447, 2006. © 2006 Wiley-Liss, Inc. [source] Efficacy and Safety of Drug-Eluting Stents: Current Best Available EvidenceJOURNAL OF CARDIAC SURGERY, Issue 6 2006Shahzad G. Raja M.R.C.S. Drug-eluting coronary stents deliver effective local concentrations of antiproliferative drugs (thus avoiding systemic toxicities), without substantially modifying the technique of percutaneous coronary intervention. Studies involving several different stent platforms and antiproliferative drug coatings have recently demonstrated dramatic reductions in restenosis rates, compared to conventional bare metal stents. Although the clinical benefits of drug-eluting stents are increasingly evident, important concerns about their long-term safety and costs have been raised. Furthermore, drug-eluting stents are being claimed to replace coronary artery bypass surgery in the near future. This review article evaluates the current best available evidence on the efficacy and safety of drug-eluting stents with a focus on the impact of this "revolutionary" new technology on the practice of coronary artery bypass surgery. [source] Exploring the feasibility of selective depletion of T lymphocyte subsets by whole blood immunoadsorption cytapheresisCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2007M. Belak Summary Normal turnover of T lymphocytes is slow relative to other blood cells. Consequently, the physical removal of circulating leucocytes by thoracic duct drainage, repeated leukapheresis or blood filtration results in T cell depletion and immunosuppression. However, clinical use of such procedures is impractical compared with immunosuppressive drugs or radiation. None the less, immunosuppression by physical depletion of T cells, avoiding the systemic toxicities of drugs and radiation, might have clinical advantages if immunophenotypically distinct T cell subsets could be depleted selectively. Recent advances in targeted plasma protein apheresis using adsorbent macrobead columns prompted us to determine whether analogous techniques might permit CD4+ T lymphocytes to be removed selectively from whole blood. To explore this possibility, we linked murine anti-human-CD4 and isotype-identical control monoclonal antibodies (mAbs) to agarose, polyacrylamide and polystyrene macrobeads (150,350 ,m) and then evaluated the selectivity, specificity and efficiency of macrobead columns to remove CD4+ T cells from anti-coagulated whole blood at varying mAb densities and flow rates. We also examined saturation kinetics and Fc-oriention versus random coupling of mAbs to macrobeads. Sepharose 6MB macrobead (250,350 ,m) columns proved to be most effective, selectively removing up to 98% of CD4+ T cells from whole blood. Moreover, depletion efficiency and selectivity were retained when these columns were reused after elution of adherent CD4+ cells. These studies indicate that selective depletion of T lymphocyte subsets by whole blood immunoadsorption apheresis using mAb-linked macrobead columns may be feasible on a clinical scale. It is possible that such apheresis techniques could achieve targeted forms of immunosuppression not possible with drugs or radiation. [source] Safety of Lidocaine 15% and Prilocaine 5% Topical Ointment Used as Local Anesthesia for Intense Pulsed Light TreatmentDERMATOLOGIC SURGERY, Issue 7 2010J. ALASTAIR CARRUTHERS MD BACKGROUND Literature cautions against applying lidocaine 15%/prilocaine 5% over an area larger than 300 cm2. The area of the face, neck, and chest is 400 cm2 or greater. OBJECTIVE To investigate the safety of lidocaine 15%/prilocaine 5% topical anesthetic ointment used as anesthesia for intense pulsed light (IPL) treatment. METHODS AND MATERIALS Lidocaine 15%/prilocaine 5% ointment was applied to the face only (n=10) for 30 ± 15 minutes or to the face, neck, and chest (n=10) for a total of 60 ± 15 minutes before IPL. Blood lidocaine and prilocaine levels were measured. Adverse events were recorded. RESULTS For the entire cohort, blood was drawn 25.6 ± 6.6 minutes after IPL was completed. In the face only group, the mean lidocaine level was 0.122 ± 0.125 ,g/mL, and the mean prilocaine level was 0.048 ± 0.029 ,g/mL. In the face, neck, and chest group, the mean lidocaine level was 0.272 ± 0.208 ,g/mL, and the mean prilocaine level was 0.087 ± 0.060 ,g/mL. No adverse events related to systemic toxicity were observed or reported to the nurse. At the 24-hour follow-up, no subject reported symptoms of systemic toxicity after leaving the clinic. CONCLUSION Under the conditions of this study, topical lidocaine 15%/prilocaine 5% produces low levels of systemic absorption. The authors have indicated no significant interest with commercial supporters. [source] pH-Activated Near-Infrared Fluorescence Nanoprobe Imaging Tumors by Sensing the Acidic MicroenvironmentADVANCED FUNCTIONAL MATERIALS, Issue 14 2010Cong Li Abstract Imaging tumors in their early stages is crucial to increase the surviving rate of cancer patients. Currently most fluorescence probes visualize the neoplasia by targeting the tumor-associated receptor over-expressed on the cancer cell membrane. However, the expression level of these receptors in vivo is hard to predict, which limits their clinical translation. Furthermore, the signal output of these receptor-targeting probes usually stays at a high level, which leads to a strong background signal in normal tissue due to non-specific binding. In contrast to receptors, characteristics of the tumor microenvironment , such as acidosis , are pervasive in almost all solid tumors and can be easily accessed. In this work, a novel biodegradable nanoprobe InNP1 that demonstrates pH-activated near-infrared (NIR) fluorescence in both human glioblastoma U87MG cancer cells in vitro and the subcutaneous U87MG tumor xenografts in vivo is developed. Bio-distribution, in vivo optical imaging, and autoradiography studies demonstrate that the pH-activated NIR fluorescence is the dominant factor responsible for the high tumor/normal tissue (T/N) ratio of InNP1 in vivo. Overall, the work provides a nanoprobe prototype to visualize the solid tumor in vivo with high sensitivity and minimal systemic toxicity by sensing the tumor acidic microenvironment. [source] Biscoclaurine alkaloid cepharanthine inhibits the growth of primary effusion lymphoma in vitro and in vivo and induces apoptosis via suppression of the NF-,B pathwayINTERNATIONAL JOURNAL OF CANCER, Issue 6 2009Naoko Takahashi-Makise Abstract Primary effusion lymphoma (PEL) is a unique and recently identified non-Hodgkin's lymphoma that was originally identified in patients with AIDS. PEL is caused by the Kaposi sarcoma-associated herpes virus (KSHV/HHV-8) and shows a peculiar presentation involving liquid growth in the serous body cavity and a poor prognosis. As the nuclear factor (NF)- ,B pathway is activated in PEL and plays a central role in oncogenesis, we examined the effect of a biscoclaurine alkaloid, cepharanthine (CEP) on PEL derived cell lines (BCBL-1, TY-1 and RM-P1), in vitro and in vivo. An methylthiotetrazole assay revealed that the cell proliferation of PEL cell lines was significantly suppressed by the addition of CEP (1,10 ,g/ml). CEP also inhibited NF- ,B activation and induced apoptotic cell death in PEL cell lines. We established a PEL animal model by intraperitoneal injection of BCBL-1, which led to the development of ascites and diffuse infiltration of organs, without obvious solid lymphoma formation, which resembles the diffuse nature of human PEL. Intraperitoneal administration of CEP inhibited ascites formation and diffuse infiltration of BCBL-1 without significant systemic toxicity in this model. These results indicate that NF- ,B could be an ideal molecular target for treating PEL and that CEP is quite useful as a unique therapeutic agent for PEL. © 2009 UICC [source] Effect of lindane on CYP-mediated steroid hormone metabolism in male mice following in utero exposureJOURNAL OF APPLIED TOXICOLOGY, Issue 8 2009Emma Di Consiglio Abstract A wide number of pesticides, including highly persistent organochlorinated compounds, such as lindane (LIN), may induce reproductive and developmental alterations by directly binding to the estrogen/androgen receptors or altering steroid hormone metabolism. In the present work, we have investigated whether LIN in utero exposure of CD1 mice affects the reproductive system in male offspring by causing an impairment of the CYP-dependent steroid hormone metabolism. Dam exposure to 25 mg kg,1 b.w. LIN occurred during critical developmental periods, from gestational days 9 to 16. Effects on hepatic CYP-mediated testosterone (TST) hydroxylase, aromatase activities and testicular parameters were tested at postnatal days (PND 50, 65,69, 100) that are critical for sexual maturation in CD1 mice. In the adult F1 mice significant changes of male reproductive endpoints (testis weight, spermatid number) as well as dramatic effects on CYP-mediated TST metabolism were observed on PND 65,69, in the absence of any of systemic toxicity. The levels of TST 6, - and 2, -hydroxylation and dehydrogenation showed the highest level of reduction, suggesting CYP 3A and 2C families as the major target of LIN induced effects. All changes were almost recovered on PND 100. No effects on aromatase activity were evidenced. Overall, these findings provide useful information for a better characterization of the LIN mode of action. They suggest that LIN-induced toxicity in males is linked to an impairment of steroid hormone homeostasis, due to CYP-mediated TST catabolism modulation and differs from LIN receptor-mediated mechanism previously reported in females. Copyright © 2009 John Wiley & Sons, Ltd. [source] Evaluation of analogues of DRDE-07 as prophylactic agents against the lethality and toxicity of sulfur mustard administered through percutaneous routeJOURNAL OF APPLIED TOXICOLOGY, Issue 2 2006A. S. Kulkarni Abstract Sulfur mustard (SM), chemically bis (2-chloroethyl) sulfide is a bifunctional alkylating agent that causes serious blisters on contact with human skin. Although several antidotes have been reported for the systemic toxicity of SM in experimental animals none of them are approved so far and decontamination of SM immediately by physical or chemical means is recommended as the best protection. Two compounds amifostine [S-2(3-aminopropylamino) ethyl phosphorothioate] and DRDE-07 [S-2(2-aminoethylamino) ethyl phenyl sulfide] gave very good protection as an oral prophylactic agent against SM the in mouse model, but in the rat model the protection was only moderate. In the search for more effective and less toxic compounds, a number of analogues of DRDE-07 were synthesised and their protective efficacy was evaluated in mouse and rat models. The LD50 of S-aryl substitution was between 1 and 2 g kg,1 and S-alkyl substitution was more than 2 g kg,1. In the mouse model, DRDE-07, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 gave about 20 fold protection, and DRDE-23 and DRDE-38 gave less protection of 4.8 and 9.0 fold respectively, against percutaneously administered SM. In the rat model, DRDE-07, DRDE-09, DRDE-10 and DRDE-21 gave about two fold protection. Percutaneously administered SM (19.33 mg kg,1) significantly depleted the hepatic GSH content in mice. Pretreatment with DRDE-21 significantly elevated the levels. A 4.4 fold increase in % DNA fragmentation was observed 7 days after SM administration (19.33 mg kg,1) in mice. Pretreatment with DRDE-07, DRDE-09, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 significantly protected the mice from SM induced DNA damage. The histopathological lesions in liver and spleen induced by percutaneously administered SM was reduced by pretreatment with DRDE-07, DRDE-09, DRDE-10 and DRDE-21. These analogues may prove as prototypes for the designing of more effective prophylactic drug for SM. Copyright © 2006 John Wiley & Sons, Ltd. [source] Two-generation reproductive toxicity study of inhaled tertiary amyl methyl ether (TAME) vapor in CD® ratsJOURNAL OF APPLIED TOXICOLOGY, Issue 6 2003R. W. Tyl Abstract Under Of,ce of Prevention, Pesticides and Toxic Substances draft guidelines, CD® weanling F0 rats (30 of each gender per group) inhaled tertiary amyl methyl ether vapor at 0, 250, 1500 or 3000 ppm 5 days a week and 6 h a day for 10 weeks, with vaginal cytology evaluated for weeks 8,10. The F0 animals then produced F1 offspring, with exposure 7 days a week from mating through to lactation. During the F1 prebreed exposure period, vaginal patency, preputial separation (PPS) and vaginal cytology were evaluated. The F1 animals were mated, with F2 anogenital distance measured on postnatal day zero. At F2 weaning 30 of each gender per group were selected for postwean retention, with no exposures, through vaginal patency and PPS. Body weights, feed consumption and clinical signs were recorded throughout the study. Adult F0 and F1 systemic toxicity was present at 1500 and 3000 ppm. Minor adult male reproductive toxicity was present at 3000 ppm. There were no adult effects on vaginal cyclicity, estrous cycle length, mating, fertility, pregnancy, gestational length or ovarian and uterine weights. There were no treatment-related gross or histopathologic ,ndings in parental male or female systemic or reproductive organs. The F1 and F2 offspring toxicity was present at 1500 and 3000 ppm. The no-observable-adverse-effect level for adult systemic and offspring toxicity was 250 ppm and 1500 ppm for male reproductive toxicity (females at >3000 ppm). Copyright © 2003 John Wiley & Sons, Ltd. [source] Percutaneous toxicokinetic and repeated cutaneous contact studies with ethylene glycol monohexyl etherJOURNAL OF APPLIED TOXICOLOGY, Issue 5 2003Bryan Ballantyne Abstract Ethylene glycol monohexyl ether (EGHE; CAS no. 112-54-4) is a liquid industrial chemical with a potential for skin contact. The toxicokinetics of EGHE was investigated in Fischer 344 rats and New Zealand White rabbits by intravenous (i.v.) and 48-h occluded epicutaneous dosing. Given i.v. to male rats (2.5,25 mg kg,1) [14C]EGHE demonstrated ,rst-order kinetics. Carbon-14 was eliminated mainly in urine (68,74%) as metabolites, with no free EGHE. The plasma free EGHE concentration declined rapidly post-dosing and was not detectable by 8 h. Similar results were obtained for [14C]EGHE given i.v. to male rabbits in the dosage range 1,10 mg kg,1, except that the metabolism of EGHE was more rapid, with no free EGHE being detectable in plasma by 1 h post-dosing. After cutaneous dosing of male and female rats with 25 mg kg,1, there was rapid percutaneous absorption, with >95% of the radiochemical dose being recovered. Percutaneous bioavailability was >75%. Carbon-14 was excreted in urine (21,33%) to a lesser extent than by the i.v. route, and 14CO2 and volatiles accounted for 15,18%. Carbon-14 recovery was low from tissues and organs (0.39,0.46%), with no preferential accumulation. Extensive metabolism was indicated by the rapid decline in plasma free EGHE, with none being detectable by 48 h. Free EGHE was not present in urine, and urinary radioactivity was associated with up to seven metabolites. After cutaneous dosing of male and female rabbits (10 mg kg,1) ca. 75% of the dose was recovered, most 14C being in urine (58,60%). Urine radioactivity was associated with up to nine metabolite peaks, but no free EGHE. The toxicokinetic ,ndings indicate a signi,cant percutaneous absorption of EGHE across both rat and rabbit skin, which is rapidly and extensively metabolized, with renal excretion being the principal route of elimination of metabolites. A 9-day repeated skin contact study in the male and female New Zealand White rabbit, using a dosage range of 44,444 mg kg,1 day,1, did not show any evidence for percutaneous systemic toxicity. Copyright © 2003 John Wiley & Sons, Ltd. [source] Life-threatening systemic toxicity and airway compromise from a common European adder bite to the tongueACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 10 2009L. C. G. HOEGBERG A 24-year-old man was bit on the tongue by a European common adder. Within 15 min following envenomation, he experienced tongue swelling, hypotension and impaired consciousness. Antihistamine, corticosteroid and crystalloids were administered. Within 105 min of envenomation, increasing oral, pharyngeal and facial oedema compromised the airway, leading to respiratory failure, concomitant with circulatory failure related to hypoxaemia and systemic toxic effects. Acute tracheotomy secured the airway, and two doses of antivenom successfully treated the systemic, toxic effects. The reaction was severe due to rapid and suspected high-dose uptake of venom, underlining the need for early advanced symptomatic treatment with airway control and early and eventually repeated dosing of antivenom. [source] Is brimonidine ophthalmic a safe therapy for infants?JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2006G. P. Daubert MD Summary Brimonidine is a topical alpha-2 agonist commonly used in the treatment of glaucoma. Brimonidine toxicity resembles that of clonidine overdose and is probably due to both imidazoline and alpha-2 adrenergic receptor effects. We report a case of a 6-week-old infant with congenital glaucoma who developed bradycardia and hypotension following the administration of brimonidine 0·15% ophthalmic solution. There are occasional reports of brimonidine toxicity in the paediatric population but its overall safety profile in children <2 years of age remains uncertain. Brimonidine is not dosed by weight and therefore paediatric patients may be at increased risk for systemic toxicity. It is recommended that the use of this medication be carefully considered in children <2 years of age. Physicians should be aware of its side effect profile because of its general use in the paediatric population. [source] Hydroquinone and its analogues in dermatology , a risk-benefit viewpointJOURNAL OF COSMETIC DERMATOLOGY, Issue 3 2006DABT, J L O'Donoghue VMD Summary Hydroquinone (HQ) has been used since the 1950s in commercially available over-the-counter skin lightener products and since the 1960s as a commercially available medical product. It is also used in cosmetic products such as hair dyes and products for coating finger nails. Beginning in 2001, HQ is no longer authorized for use in cosmetic skin lightening formulations in European Union countries, although products containing arbutin, an analogue of HQ, and botanicals, including plants that naturally contain HQ and arbutin, continue to remain available in European countries. The potential toxicity of HQ is dependent on the route of exposure, and toxicity in rodents is highly sex-, species-, and strain-specific. Subchronic and chronic toxicity in experimental animals is primarily limited to nephrotoxicity in male F-344 rats. Dermal toxicity studies, even those conducted in the sensitive male F-344 rat, are essentially devoid of systemic toxicity. Developmental and reproductive toxicity studies with HQ in rats and rabbits have not demonstrated significant effects. Cancer bioassay data for HQ demonstrate limited effects and are not sufficient to classify HQ for human carcinogenicity. Epidemiology and occupational studies of workers with extensive exposure to HQ have not reported any evidence of adverse systemic health effects or carcinogenicity. A risk-benefit approach is recommended for assessing the available data for HQ, arbutin, and other materials in use as, or proposed for use as, skin lighteners to provide optimal therapeutic benefits to patients with pigmentary changes of the skin. [source] Predicting and monitoring cancer treatment response with diffusion-weighted MRIJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 1 2010Harriet C. Thoeny MD Abstract An imaging biomarker that would provide for an early quantitative metric of clinical treatment response in cancer patients would provide for a paradigm shift in cancer care. Currently, nonimage based clinical outcome metrics include morphology, clinical, and laboratory parameters, however, these are obtained relatively late following treatment. Diffusion-weighted MRI (DW-MRI) holds promise for use as a cancer treatment response biomarker as it is sensitive to macromolecular and microstructural changes which can occur at the cellular level earlier than anatomical changes during therapy. Studies have shown that successful treatment of many tumor types can be detected using DW-MRI as an early increase in the apparent diffusion coefficient (ADC) values. Additionally, low pretreatment ADC values of various tumors are often predictive of better outcome. These capabilities, once validated, could provide for an important opportunity to individualize therapy thereby minimizing unnecessary systemic toxicity associated with ineffective therapies with the additional advantage of improving overall patient health care and associated costs. In this report, we provide a brief technical overview of DW-MRI acquisition protocols, quantitative image analysis approaches and review studies which have implemented DW-MRI for the purpose of early prediction of cancer treatment response. J. Magn. Reson. Imaging 2010. © 2010 Wiley-Liss, Inc. [source] Polymeric enhancers of mucosal epithelia permeability: Synthesis, transepithelial penetration-enhancing properties, mechanism of action, safety issuesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2008Giacomo Di Colo Abstract Transmucosal drug administration across nasal, buccal, and ocular mucosae is noninvasive, eliminates hepatic first-pass metabolism and harsh environmental conditions, allows rapid onset, and further, mucosal surfaces are readily accessible. Generally, however, hydrophilic drugs, such as peptides and proteins, are poorly permeable across the epithelium, which results in insufficient bioavailability. Therefore, reversible modifications of epithelial barrier structure by permeation enhancers are required. Low molecular weight enhancers generally have physicochemical characteristics favoring their own absorption, whereas polymeric enhancers are not absorbed, and this minimizes the risk of systemic toxicity. The above considerations have warranted the present survey of the studies on polymeric transmucosal penetration-enhancers that have appeared in the literature during the last decade. Studies on intestinal permeation enhancers are also reviewed as they give information on the mechanism of action and safety of polymers. The synthesis and characterization of polymers, their effectiveness in enhancing the absorption of different drugs across different epithelium types, their mechanism of action and structure-efficacy relationship, and the relevant safety issues are reviewed. The active polymers are classified into: polycations (chitosan and its quaternary ammonium derivatives, poly- L -arginine (poly- L -Arg), aminated gelatin), polyanions (N-carboxymethyl chitosan, poly(acrylic acid)), and thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil (PCP)-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates). © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 1652,1680, 2008 [source] Application of pharmacokinetic,pharmacodynamic modeling to predict the kinetic and dynamic effects of anti-methotrexate antibodies in miceJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2003Evelyn D. Lobo Abstract We have shown that intravenous (iv) administration of anti-methotrexate (MTX) antibodies (AMAb) reduces the systemic exposure of intraperitoneal (ip) MTX therapy, and we have proposed that AMAb effects on MTX systemic exposure would allow a reduction in MTX-induced systemic toxicity (i.e., producing a desirable antagonistic effect). However, many literature reports have shown that anti-toxin antibodies occasionally demonstrate unexpected agonist-like activity, increasing the extent of toxicity induced by their ligand. In this report, we have utilized a pharmacokinetic,pharmacodynamic (PKPD) model to predict the potential of AMAb to increase or decrease the magnitude of MTX-induced body weight loss in mice. Simulations predicted that both anti-MTX immunoglobulin G (AMI) and anti-MTX Fab fragments (AMF) would lead to increases or decreases in MTX toxicity, with effects dependent on the dosing protocol used. Based on the computer simulations, two protocols were selected for in vivo evaluation of predicted agonistic or antagonistic effects. Murine monoclonal AMI and AMF were produced, purified, and characterized. Agonistic effects were tested after 24-h infusion of ip MTX (10 mg/kg) and iv administration of an equimolar dose of AMI. Antagonistic effects were tested after 72-h infusion of ip MTX (5 mg/kg) and iv infusion of an equimolar dose of AMF. Consistent with model predictions of agonist-like activity, the 24-h AMI protocol led to significantly increased animal mortality (all animals died, p,<,0.005) and mean nadir weight loss (p,<,0.005). Also consistent with the predictions of the PKPD model, the 72-h AMF protocol significantly decreased animal mortality and mean nadir body weight loss (p,<,0.01). Thus, these studies demonstrate that agonistic and antagonistic effects of anti-toxin antibodies may be predicted through the use of an integrated PKPD model. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1665,1676, 2003 [source] Review article: new drug formulations, chemical entities and therapeutic approaches for the management of ulcerative colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2008S. C. NG Summary Background, Treatment options for ulcerative colitis (UC) are expanding with the development of novel drug formulations and dosing regimens and new chemical entities. Although the goals of medical therapy for UC remain unchanged, that is to induce and to maintain remission, focus has also centred on improving patient compliance, modifying the natural course of disease and healing the mucosa. Aim, To examine novel formulations, new chemical entities and novel therapeutic approaches to the management of UC. Methods, Searches for all studies related to UC treatment in Medline and abstracts from major national and international meetings published in the last 10 years. Results, 5-Aminosalicylic acids (5-ASA) remain the standard first-line treatment for patients with mild to moderately active UC. New formulations with altered delivery, and new dosing regimens have demonstrated possible improvements in efficacy compared with historically available preparations and dosing patterns. Once-daily dosing, micropellet formulations, and high-dose tablets offer enhanced efficacy and improved compliance. 5-ASA is now recognized as a ligand for peroxisome proliferator-activated receptor-, (PPAR-,) and it has a role as a chemo-preventive agent in long-standing UC. New colonic release corticosteroid formulations help to limit systemic toxicity; turmeric, tacrolimus and infliximab have shown promising results. New anti-inflammatory targeted therapies include an anti-CD3 antibody, selective integrin blockers, anti-IL-2 antibody and PPAR-, agonists. Conclusion, The evolution of novel oral 5-ASA formulations and dosage regimens, and recent development of new molecules have expanded the therapeutic armamentarium of UC. [source] Neopterin in renal cell carcinoma: inhalational administration of interleukin-2 is not accompanied by a rise of urinary neopterinLUMINESCENCE: THE JOURNAL OF BIOLOGICAL AND CHEMICAL LUMINESCENCE, Issue 4-5 2005Bohuslav Melichar Abstract Inhalational administration of interleukin-2 (IL-2) is effective in controlling renal cell carcinoma (RCC) lung metastases with minimal toxicity. Neopterin is an indicator of systemic immune activation in metastatic cancer and is increased after systemic IL-2 administration. Urinary neopterin was investigated in 13 patients with metastatic RCC and 18 controls. In seven patients, urinary neopterin was followed before and after treatment with inhalational IL-2. Neopterin was measured by highperformance liquid chromatography and creatinine was determined by Jaffé reaction. Urinary neopterin was significantly increased in patients with metastatic RCC compared to controls (257 ± 263 µmol/mol creatinine vs. 110 ± 41 µmol/mol creatinine; Mann,Whitney U-test, p < 0.05). Median survival was significantly longer in patients with urinary neopterin <173 µmol/mol creatinine compared to patients with neopterin ,173 µmol/mol creatinine (698 vs. 245 days; log-rank test, p < 0.05). No significant increase was observed after inhalational IL-2 therapy (147 ± 101 vs. 153 ± 54 µmol/mol creatinine). We conclude that urinary neopterin is increased in patients with metastatic RCC, and higher neopterin concentrations are indicative of poor prognosis. The absence of an increase in urinary neopterin after inhalational IL-2 therapy is in accord with the lack of significant systemic toxicity. Copyright © 2005 John Wiley & Sons, Ltd. [source] Recent developments in carbohydrate-decorated targeted drug/gene deliveryMEDICINAL RESEARCH REVIEWS, Issue 2 2010Hailong Zhang Abstract Targeted delivery of a drug or gene to its site of action has clear therapeutic advantages by maximizing its therapeutic efficiency and minimizing its systemic toxicity. Generally, targeted drug or gene delivery is performed by loading a macromolecular carrier with an appropriate drug or gene, and by targeting the drug/gene carrier to specific cell or tissue with the help of specific targeting ligand. The emergence of glycobiology, glycotechnology, and glycomics and their continual adaptation by pharmaceutical scientists have opened exciting avenue of medicinal applications of carbohydrates. Among them, the biocompatibility and specific receptor recognition ability confer the ability of carbohydrates as potential targeting ligands for targeted drug and gene delivery applications. This review summarizes recent progress of carbohydrate-decorated targeted drug/gene delivery applications. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 2, 270,289, 2010 [source] Chemical injuries: The Tasmanian burns unit experienceANZ JOURNAL OF SURGERY, Issue 1-2 2003Sophie Ricketts Background: Chemical burns account for relatively few admissions to a burns unit. These injuries, however, deserve separate consideration because of their ability to cause continuing tissue destruction, their potential to cause systemic toxicity and the value of early treatment with copious lavage. Widespread inexperience in the treatment of chemical burns highlights the potential for greater levels of general awareness and knowledge. Methods: A review of 31 patients with chemical injuries admitted to the Tasmanian Burns Unit at the Royal Hobart Hospital (RHH) was carried out for the years 1989,1999. Results: The majority of patients were men aged 20,49 years (mean age: 32 years). Fifty-one per cent of injuries occurred in a domestic and 38% in an industrial setting. The more common aetiological agents were cement (25%), sulphuric acid (16%) and hydrofluoric acid (16%). The upper and lower extremities were involved in all but four patients and the mean total body surface area affected was 3.4%. The mean length of hospital stay was 9 days with a range of 1,30 days. Management of injuries consisted of either surgical or conservative treatment. The former included debridement and split-thickness skin grafting or primary closure and the latter of topical treatment with 1% silver sulfadiazine cream and appropriate dressings. Conclusion: Widespread inexperience in the treatment of chemical injuries highlights the potential for greater levels of knowledge. This is particularly apparent in the early management of these injuries. [source] Liposome-bound APO2L/TRAIL is an effective treatment in a rabbit model of rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 8 2010Luis Martinez-Lostao Objective We previously observed that T lymphocytes present in synovial fluid (SF) from patients with rheumatoid arthritis (RA) were sensitive to APO2L/TRAIL. In addition, there was a drastic decrease in the amount of bioactive APO2L/TRAIL associated with exosomes in SF from RA patients. This study was undertaken to evaluate the effectiveness of bioactive APO2L/TRAIL conjugated with artificial lipid vesicles resembling natural exosomes as a treatment in a rabbit model of antigen-induced arthritis (AIA). Methods We used a novel Ni2+ -(N -5-amino-1-carboxypentyl)-iminodiacetic acid),containing liposomal system. APO2L/TRAIL bound to liposomes was intraarticularly injected into the knees of animals with AIA. One week after treatment, rabbits were killed, and arthritic synovial tissue was analyzed. Results Tethering APO2L/TRAIL to the liposome membrane increased its bioactivity and resulted in more effective treatment of AIA compared with soluble, unconjugated APO2L/TRAIL, with substantially reduced synovial hyperplasia and inflammation in rabbit knee joints. The results of biophysical studies suggested that the increased bioactivity of APO2L/TRAIL associated with liposomes was due to the increase in the local concentration of the recombinant protein, augmenting its receptor crosslinking potential, and not to conformational changes in the protein. In spite of this increase in bioactivity, the treatment lacked systemic toxicity and was not hepatotoxic. Conclusion Our findings indicate that binding APO2L/TRAIL to the liposome membrane increases its bioactivity and results in effective treatment of AIA. [source] Binding of quercetin with human serum albumin: A critical spectroscopic studyBIOPOLYMERS, Issue 6 2003Bidisa Sengupta Abstract Flavonols are plant pigments that are ubiquitous in nature. Quercetin (3,3,,4,,5,7-pentahydroxyflavone) and other related plant flavonols have come into recent prominence because of their usefulness as anticancer, antitumor, anti-AIDS, and other important therapeutic activities of significant potency and low systemic toxicity. Quercetin is intrinsically weakly fluorescent in aqueous solution, showing an emission maximum at ,538 nm. Upon binding to human serum albumin (HSA), quercetin undergoes dramatic enhancement in its fluorescence emission intensity, along with the appearance of dual emission behavior, consisting of normal and excited-state proton transfer (ESPT) fluorescence. In addition, the occurrence of a third emitting species has been noted for the first time. This is attributed to a electronic ground-state complex formed in the protein environment. High values of the fluorescence anisotropy (r) are obtained in the presence of HSA for the ESPT tautomer (r = 0.18), as well as the complex species (r = 0.37) of quercetin, indicating that the precursor ground-state molecules for both these emitting species of quercetin molecules are located in the motionally constrained sites of HSA. The steady-state emission data suggest that quercetin binds to two distinct sites in HSA from which the emissions from the normal tautomer and complex species take place. The preliminary results of studies on emission decay kinetics are also reported herein. Studies by far-UV circular dichroism spectroscopy reveal that binding of quercetin induces no significant perturbation in the secondary structure of HSA. © 2003 Wiley Periodicals, Inc. Biopolymers (Biospectroscopy), 2003 [source] Use of radiolabelled iododeoxyuridine as adjuvant treatment for experimental tumours of the liverBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 10 2003J. S. Zager Background The aim of the study was to determine whether hepatic regeneration stimulates growth of tumour residing within the liver, and whether a difference in the rate of DNA synthesis in liver and tumour may be used to target cancer using the radiolabelled thymidine analogue 5-iodo-2,-deoxyuridine (IUdR). Methods Partial hepatectomy was performed on Buffalo rats bearing solitary nodules of syngeneic Morris hepatoma. Liver and tumour DNA synthesis was measured by incorporation of radioactive IUdR. [125I]IUdR was tested as an adjuvant therapy after hepatectomy in Buffalo rats bearing diffuse microscopic Morris hepatomas to simulate the clinical situation. Results Liver regeneration enhanced liver and tumour DNA synthesis as measured by incorporation of radioactive IUdR. Liver DNA synthesis returned to baseline by 7 days, whereas tumour DNA synthesis remained above baseline level. Hepatectomy enhanced the growth of microscopic liver tumours. [125I]IUdR (250 µCi or 1 mCi/kg) administered 4 days after hepatectomy significantly reduced tumour growth without signs of systemic toxicity or liver dysfunction. Conclusion The local environment of the regenerating liver stimulates tumour growth. The thymidine analogue [125I]IUdR may be used preferentially to target tumour DNA synthesis in the regenerating liver, and may prove useful as an adjuvant therapy for hepatic tumours after surgical resection. Copyright © 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] A nonreplicating adenoviral vector that contains the wild-type p53 transgene combined with chemotherapy for primary breast cancerCANCER, Issue 5 2006Safety, biologic activity of a novel gene-therapy approach, efficacy Abstract BACKGROUND. Primary systemic therapy (PST) is the standard approach to the management of patients with locally advanced breast cancer (LABC). The authors hypothesized that the intratumoral administration of a nonreplicating adenoviral vector (Ad5) that contains the human wild-type p53, AdCMV- p53, combined with chemotherapy, could increase the efficacy of PST as measured by pathologic complete response. METHODS. In a prospective, open-label, Phase II trial, 13 patients with LABC were treated with 6 3-week cycles of PST, which consisted of intratumoral injections of Ad5CMV- p53 for 2 consecutive days plus docetaxel and doxorubicin followed by surgery. p53 status was determined at baseline and was assessed immediately after the first injection (up to 48 hours). Clinical response was assessed by clinical and radiologic methods. RESULTS. The trial was terminated early, because none of the patients achieved a pathologic complete response. The median age was 56 years (range, 39,71 years), and the median tumor size was 8 cm (range, 5,11 cm). Eight patients (73%) had a p53 mutation. Serial biopsies showed an increase in p53 messenger RNA (mRNA) and p21WAF1/Cip1 mRNA. All 12 evaluable patients achieved an objective clinical response. The surgical specimens revealed scattered tumor cells with extensive tumor-infiltrate leukocytes (predominantly T-lymphocytes). At a median follow-up of 37 months (range, 30,41 months), 4 patients (30%) developed systemic recurrence, and 2 patients died. The estimate breast cancer-specific survival rate at 3 years was 84% (95% confidence interval, 65.7,100%). There was no increase in systemic toxicity. CONCLUSIONS. Ad5CMV- p53 combined with PST is safe, active, and associated with local immunomodulatory effects. The promising clinical activity of this combination deserves further investigation in randomized studies. Cancer 2006. © 2006 American Cancer Society. [source] Hyperthermic intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin in patients who undergo cytoreductive surgery for peritoneal carcinomatosis and sarcomatosisCANCER, Issue 2 2002Phase I study Abstract BACKGROUND Hyperthermic intraperitoneal intraoperative chemotherapy (HIIC) combined with cytoreductive surgery (CS) has been proposed as a new multimodal treatment mainly for carcinomatosis of gastrointestinal origin. To evaluate whether this regimen could be used for other tumor types, the authors conducted a Phase I study on HIIC with doxorubicin and cisplatin in patients with peritoneal carcinomatosis or sarcomatosis. PATIENTS AND METHODS Thirty-one patients with peritoneal carcinomatosis or sarcomatosis (PCS) were enrolled for the study. After completion of CS, HIIC was administered with drug doses that were increased for each consecutive cohort following a three-patient cohort scheme. Thereafter, the accrual was stopped when Grade 4 locoregional or systemic toxicity was observed. The maximum tolerated dose (MTD) was considered the dose in the previous triplet. Drug pharmacokinetics and procedure costs also were analyzed. RESULTS After CS, residual tumors were not present or measured less than or equal to 3 mm (in dimension) in all cases. Maximum tolerated dose was 15.25 and 43.00 mg L,1 for doxorubicin and cisplatin, respectively. The perfusate/plasma area under the curve ratios were favorable for both drugs, at 162 ± 113 and 20.6 ± 6.0, respectively, for doxorubicin and cisplatin. Doxorubicin levels in the peritoneum were higher than in tumor or normal tissue samples. There were no postoperative deaths. Surgery-related complications were observed in 25% of cases. Findings at cost analysis showed that the length of stay in the operation room and intensive care unit were the major cost drivers. CONCLUSIONS Cytoreductive surgery combined with HIIC is an expensive but feasible therapeutic approach for locally advanced abdominal tumors. Because our preliminary findings for local disease control are encouraging, a Phase II study is now advisable to verify the activity of this promising treatment. Cancer 2002;94:492,9. © 2002 American Cancer Society. [source] Local interferon-, gene therapy elicits systemic immunity in a syngeneic pancreatic cancer model in hamsterCANCER SCIENCE, Issue 3 2007Hidehiko Hara The interferon (IFN) protein is a cytokine with pleiotropic biological functions that include induction of apoptosis, inhibition of angiogenesis and immunomodulation. We previously examined the two antitumor mechanisms, taking advantage of the fact that IFN-, did not show cross-species activity in its in vivo effect. In a nude mouse subcutaneous xenograft model using human pancreatic cancer cells, the expression of human IFN-, effectively induced cell death of human pancreatic cancer cells, whereas mouse IFN-, augmented antitumor immunity by stimulation of natural killer cells. Here, we extended our investigation to a syngeneic pancreatic cancer model, so that the integrated antitumor activity of local IFN-, gene therapy, including the antiproliferative, proapoptotic, antiangiogeneic and immunomodulatory effects, can be evaluated rigorously. When a recombinant hamster IFN-, adenovirus was injected into syngeneic subcutaneous tumors of hamster pancreatic cancer (PGHAM-1) cells in Syrian hamster, tumor growth was significantly suppressed due to cell death and T cell- and natural killer cell-mediated antitumor immunity. Moreover, in this case, tumor regression was observed not only for the injected subcutaneous tumors but also for the untreated tumors both in the peritoneal cavity and at distant sites. No significant systemic toxicity was observed in the treated hamsters. Moreover, the subcutaneous rechallenge of PGHAM-1 cells was rejected in three of four cured hamsters from the initial tumor challenge. This study further demonstrated that local IFN-, gene therapy is a promising therapeutic strategy for pancreatic cancer, due to its multiple mechanisms of antitumor activity and its lack of significant toxicity. (Cancer Sci 2007; 98: 455,463)) [source] 4364: Direct intra-arterial (ophthalmic artery) chemotherapy with melphalan for advanced intraocular retinoblastoma: the Italian experienceACTA OPHTHALMOLOGICA, Issue 2010T HADJISTILIANOU Purpose To report the preliminary results of the conservative treatment of advanced retinoblastoma (Stage Va e Vb) obtained with the melphalan protocol (direct intraarterial-ophthalmic artery infusion ). Methods 33 children (35 eyes) with advanced retinoblastoma who were eligible for enucleation were entered in phase two of one center open study-approved protocol of ophthalmic artery infusion of Melphalan to avoid enucleation (Italian Melphalan protocol, approved by the Ethic Commettee , University Hospital of Siena). Two cases have been treated bilaterally. 15 eyes were first diagnosis and 18 were relapses following chemo and/or radiotherapy. In two cases has not been possible to conclude the procedure due to haemodynamic problems. Results The ophthalmic artery was successfully cannulated in 35 eyes (total, 121 procedures). In 2 attempts was impossible to successfully conclude the procedure due to hemodynamic problems. Cannulation of the ophthalmic artery was performed by a femoral artery approach using microcatheters (magic 1.5) while the children were under general anesthesia and anticoagulated. Melphalan was infused into the artery over a 30-minute period (dose of 3-7 mg according to the age and size of the globe). Local and systemic toxicity have been evaluated and documented. Conclusion 33 children (35 eyes) with advanced retinoblastoma (Stage Va and Vb Reese classification) were eligible for the Melphalan Italian Protocol. The 78.7% of treated eyes is in complete remission. Superselective chemotherapy delivered through the ophthalmic artery can avoid enucleation, primary radiation or abuse of systemic chemotherapy. [source] Rotavirus gastroenteritis complicated with toxic megacolonACTA PAEDIATRICA, Issue 11 2009Chia-Wei Hung Abstract Rotavirus is a leading cause of gastroenteritis in young children, which may indicate hospitalization due to dehydration and electrolyte imbalance. Most cases are self-limited with good prognosis. The association between rotavirus and toxic megacolon has never been mentioned in the literature. We report a case of toxic megacolon secondary to rotavirus gastroenteritis. Conclusion:, Toxic megacolon can occur in patients with rotavirus gastroenteritis. An abdominal radiograph should be taken for patients with rotavirus gastroenteritis who have systemic toxicity and persistent abdominal fullness. [source] | ||||||||||||||||||||||||||||