Spectrum of digoxin-induced ocular toxicity: a case report and literature review.

BACKGROUND: Digoxin intoxication results in predominantly digestive, cardiac and neurological symptoms. This case is outstanding in that the intoxication occurred in a nonagenarian and induced severe, extensively documented visual symptoms as well as dysphagia and proprioceptive illusions. Moreover, it went undiagnosed for a whole month despite close medical follow-up, illustrating the difficulty in recognizing drug-induced effects in a polymorbid patient. CASE PRESENTATION: Digoxin 0.25 mg qd for atrial fibrillation was prescribed to a 91-year-old woman with an estimated creatinine clearance of 18 ml/min. Over the following 2-3 weeks she developed nausea, vomiting and dysphagia, snowy and blurry vision, photopsia, dyschromatopsia, aggravated pre-existing formed visual hallucinations and proprioceptive illusions. She saw her family doctor twice and visited the eye clinic once until, 1 month after starting digoxin, she was admitted to the emergency room. Intoxication was confirmed by a serum digoxin level of 5.7 ng/ml (reference range 0.8-2 ng/ml). After stopping digoxin, general symptoms resolved in a few days, but visual complaints persisted. Examination by the ophthalmologist revealed decreased visual acuity in both eyes, 4/10 in the right eye (OD) and 5/10 in the left eye (OS), decreased color vision as demonstrated by a score of 1/13 in both eyes (OU) on Ishihara pseudoisochromatic plates, OS cataract, and dry age-related macular degeneration (ARMD). Computerized static perimetry showed non-specific diffuse alterations suggestive of either bilateral retinopathy or optic neuropathy. Full-field electroretinography (ERG) disclosed moderate diffuse rod and cone dysfunction and multifocal ERG revealed central loss of function OU. Visual symptoms progressively improved over the next 2 months, but multifocal ERG did not. The patient was finally discharged home after a 5 week hospital stay. CONCLUSION: This case is a reminder of a complication of digoxin treatment to be considered by any treating physician. If digoxin is prescribed in a vulnerable patient, close monitoring is mandatory. In general, when facing a new health problem in a polymorbid patient, it is crucial to elicit a complete history, with all recent drug changes and detailed complaints, and to include a drug adverse reaction in the differential diagnosis.

New cationic nanovesicular systems containing lysine-based surfactants for topical administration: Toxicity assessment using representative skin cell lines

Many strategies for treating diseases require the delivery of drugs into the cell cytoplasm following internalization within endosomal vesicles. Thus, compounds triggered by low pH to disrupt membranes and release endosomal contents into the cytosol are of particular interest. Cationic nanovesicles have attracted considerable interest as effective carriers to improve the delivery of biologically active molecules into and through the skin. In this study, lipid-based nanovesicles containing three different cationic lysine-based surfactants were designed for topical administration. We used representative skin cell lines and in vitro assays to assess whether the cationic compounds modulate the toxic responses of these nanocarriers. The nanovesicles were characterized in both water and cell culture medium. In general, significant agglomeration occurred after 24 h incubation under cell culture conditions. We found different cytotoxic responses among the formulations, which depended on the surfactant,cell line (3T3, HaCaT, and THP-1) and endpoint assayed (MTT, NRU, and LDH). Moreover, no potential phototoxicity was detected in fibroblast or keratinocyte cells, whereas only a slight inflammatory response was induced, as detected by IL-1a and IL-8 production in HaCaT and THP-1 cell lines, respectively. A key finding of our research was that the cationic charge position and the alkyl chain length of the surfactants determine the nanovesicles resulting toxicity. The charge on the a-amino group of lysine increased the depletion of cell metabolic activity, as determined by the MTT assay, while a higher hydrophobicity tends to enhance the toxic responses of the nanovesicles. The insights provided here using different cell lines and assays offer a comprehensive toxicological evaluation of this group of new nanomaterials.

Cardiac Toxicity in Selective Serotonin Reuptake Inhibitor Users.

Several classes of recreational and prescription drugs have been associated with an increased risk of cardiovascular disease and the occurrence of arrhythmias, which may be involved in sudden deaths in chronic users even at therapeutic doses. The study presented herein focuses on pathological changes involving the heart, which may be caused by selective serotonin reuptake inhibitor use and their possible role in the occurrence of sudden cardiac death. A total of 40 cases were included in the study and were divided evenly into 2 groups: 20 cases of patients treated with selective serotonin reuptake inhibitors and 20 cases of sudden deaths involving patients void of any drug treatment. The first group included 16 patients treated with citalopram and 4 with sertraline. Autopsies, histology, biochemistry, and toxicology were performed in all cases. Pathological changes in selective serotonin reuptake inhibitor users consisted of various degrees of interstitial and perivascular fibrosis as well as a small degree of perineural fibrosis within the myocardium of the left ventricle. Within the limits of the small number of investigated cases, the results of this study seem to confirm former observations on this topic, suggesting that selective serotonin reuptake inhibitors may play a potential, causative role in the pathogenesis of sudden deaths in chronic users even at therapeutic concentrations.

Stereotactic body radiation therapy with helical tomotherapy for medical inoperable early-stage primary and second-primary non-small cell lung neoplasm : one-year outcome and toxicity analysis

Le cancer du poumon est la première cause de mortalité associée au cancer dans le monde. Le traitement curatif des tumeurs pulmonaires non-à-petites-cellules (NSCLC) diagnostiquées à un stade précoce se base sur une approche chirurgicale. Cependant, étant donné les comorbidités liées à la consommation de tabac, dont la bronchopneumopathie chronique occupe la première place, l'éligibilité chirurgicale pour ce type de cancer se trouve fréquemment limitée. Dans ce contexte, l'emploi de la radiothérapie stéréotaxique (SBRT) est une alternative valable chez les patients atteints d'un NSCLC primaire de stade précoce, et qui sont considérés inopérables à cause de leurs comorbidités. Depuis peu seulemement, le spectre de la SBRT a été élargi aux patients atteints d'un deuxième NSCLC primaire (SPLC), faisant suite à un premier NSCLC, traité avec un but curatif. Ils concernent donc des patients ayant déjà subits une intervention chirurgicale au préalable et qui présentent une réserve fonctionnelle pulmonaire extrêmement réduite. Le succès croissant de la SBRT résulte soit d'une efficacité thérapeutique comparables à la chirurgie, soit de sa toxicité qui semble limitée. À notre connaissance, seulement une étude a reporté des issues cliniques de patients affectés par des NSCLC primaires traités par SBRT. Cette dernière a utilisé la tomothérapie comme système d'irradiation (T-SBRT), sur un faible échantillon de patients (n = 27). Concernant l'irradiation des patients présentant des SPLC, la littérature disponible est pauvre et aucune publication a décrit l'utilisation de la T-SBRT. Ces éléments innovants ont donc motivé la rédaction d'un travail de thèse concernant les premières données cliniques de l'expérience faite au CHUV. Du point de vue des effets secondaires, si la pneumonie actinique précoce et tardive survenant au niveau du champ d'irradiation est désormais une complication iatrogène bien connue de la SBRT, une seule étude s'est intéressée à ce sujet dans le cadre de la T-SBRT. De plus, une entité bénigne et transitoire de pneumonie ( ?) a été reconnue depuis peu : la pneumonie organisée radio-induite (OP). Celle-ci semble se chevaucher comme un autre effet iatrogène à l'extérieur du champ d'irradiation. Originellement, cette dernière avait été rapportée dans les suites de la radiothérapie pour les cancer du sein. Elle a été décrite comme étant initialement limitée au champ d'irradiation et successivement pouvant s'étendre dynamiquement en dehors de celui-ci. Nous avons donc supposé que des infiltrats de OP peuvent être présents chez des patients asymptomatiques, et que ce dynamisme pourrait être identifié déjà au sein du champ d'irradiation. Notre étude a démontré que le traitement par T-SBRT garde des issues cliniques très encourageantes, aussi bien pour les tumeurs primaires que pour les SPLC. Entre autre, ce traitement semble avoir une toxicité limitée, et l'existence vraisemblable de la OP, déjà au sein du champ d'irradiation, peut aider les radiologues à différencier les infiltrats radio-induits d'une une récidive tumorale.

Selenomethionine incorporation into amyloid sequences regulates fibrillogenesis and toxicity.

The capacity of a polypeptide chain to engage in an amyloid formation process and cause a conformational disease is contained in its sequence. Some of the sequences undergoing fibrillation contain critical methionine (Met) residues which in vivo can be synthetically substituted by selenomethionine (SeM) and alter their properties.

Cancer therapy-related toxicity in the immature testis

Infertility is a common late effect of childhood cancer treatment. Testicular toxicity can clinically be first detected after the onset of pubertal maturation of the patients when the testis does not grow, spermatogenesis does not initiate and serum levels of gonadotrophins rise. Improved prognosis for childhood cancer has resulted in a growing number of childhood cancer survivors with late effects. In our study, we developed novel tools for detecting cancer therapy-related testicular toxicity during development. By using these methods the effects of the tyrosine kinase inhibitor imatinib mesylate, chemotherapy agent doxorubicin and irradiation on testicular development were investigated in rat and monkey. Patients with chronic myeloid leukemia and some patients with acute lymphoblastic leukemia have fusion gene BCR-ABL which codes for abnormal tyrosine kinase protein. Imatinib mesylate (Glivec®) inhibits activity of this protein. In addition, imatinib inhibits the action of the c-kit and PDGF –receptors, which are both important for the survival and proliferation of the spermatogonial stem cell pool. Imatinib exposure during prepubertal development disturbed the development and the growth of the testis. Spermatogonial stem cells were also sensitive to the toxic effects of doxorubicin and irradiation during the initiation phase of spermatogenesis. In addition, the effect of the treatment of acute lymphoblastic leukemia on germ cell numbers and recovery of reproductive functions after sexual maturation was investigated. Therapy for childhood acute lymphoblastic leukemia seldom results in infertility. The present study gives new information on the mechanisms by which cancer treatments exert their gonadal toxicity in immature testis.

Fluvial biofilms: a pertinent tool to assess β-blockers toxicity

Among increasingly used pharmaceutical products, β-blockers have been commonly reported at low concentrations in rivers and littoral waters of Europe and North America. Little is known about the toxicity of these chemicals in freshwater ecosystems while their presence may lead to chronic pollution. Hence, in this study the acute toxicity of 3 β-blockers: metoprolol, propranolol and atenolol on fluvial biofilms was assessed by using several biomarkers. Some were indicative of potential alterations in biofilm algae (photosynthetic efficiency), and others in biofilm bacteria (peptidase activity, bacterial mortality). Propranolol was the most toxic β-blocker, mostly affecting the algal photosynthetic process. The exposure to 531 μg/L of propranolol caused 85% of inhibition of photosynthesis after 24 h. Metoprolol was particularly toxic for bacteria. Though estimated No-Effect Concentrations (NEC) were similar to environmental concentrations, higher concentrations of the toxic (503 μg/L metoprolol) caused an increase of 50% in bacterial mortality. Atenolol was the least toxic of the three tested β-blockers. Effects superior to 50% were only observed at very high concentration (707 mg/L). Higher toxicity of metoprolol and propranolol might be due to better absorption within biofilms of these two chemicals. Since β-blockers are mainly found in mixtures in rivers, their differential toxicity could have potential relevant consequences on the interactions between algae and bacteria within river biofilms

Is Microtox R toxicity related to potentially harmful algae proliferation in Mediterranean salt marshes?

Mediterranean salt marshes are ecosystems that are highly influenced by sea changes and freshwater inputs from runoff. In these ecosystems, toxic and non-toxic algae blooms often produce large and unpredictable biomasses of phytoplankton. The Microtox R test has been described as a successful, quick method for detecting toxicity in various phytoplankton taxa. Ourstudy sought to test the efficiency of Microtox R in detecting toxic HAB in Mediterranean salt marshes. The results showed that the Microtox R test was able to detect toxic substances in the particulate matter of several lagoons in the Empordà salt marshes. This Microtox R toxicity coincided with periods when potentially harmful cyanobacteria, dinoflagellates andhaptophytes had a high biomass. The results suggest that potentially harmful phytoplankton cannot be ruled out as a source of Microtox R

Decolorization and toxicity of municipal waste by horseradish (Cochlearia armoracia)

The Municipal Station of Americana, SP, Brazil, treats a volume of 400 l s-1 of effluent, of domestic and textile origin, and produces about 20 t of sludge per day. The plant horseradish, which contains high amount of peroxidases, was able to decolorize this effluent in 2 h and the solid waste in 2 days, at concentrations of 10 and 50%, respectively. However, there was an increase in the toxicity for the bioassays with Hydra attenuatta, Selenastrum capricornutum and lettuce seeds, indicating formation of more toxic substances. Since horseradish showed the ability to decolorize these residues, it can be used as pre-treatment resulting in a sludge of less complex composition.

Ninety-day oral toxicity studies on two genetically modified maize MON810 varieties in Wistar Han RCC rats (EU 7th Framework Programme project GRACE)

The GMO Risk Assessment and Communication of Evidence (GRACE; www.grace-fp7.eu) project is funded by the European Commission within the 7th Framework Programme. A key objective of GRACE is to conduct 90-day animal feeding trials, animal studies with an extended time frame as well as analytical, in vitro and in silico studies on genetically modified (GM) maize in order to comparatively evaluate their use in GM plant risk assessment. In the present study, the results of two 90-day feeding trials with two different GM maize MON810 varieties, their near-isogenic non-GM varieties and four additional conventional maize varieties are presented. The feeding trials were performed by taking into account the guidance for such studies published by the EFSA Scientific Committee in 2011 and the OECD Test Guideline 408. The results obtained show that the MON810 maize at a level of up to 33 % in the diet did not induce adverse effects in male and female Wistar Han RCC rats after subchronic exposure, independently of the two different genetic backgrounds of the event

First secondary metabolites from Herissantia crispa L (Brizicky) and the toxicity activity against Artemia salina Leach

The phytochemical investigation of Herissantia crispa led to the isolation of seven compounds, identified as: sitosterol 3-O-β-D-glucopyranoside, stigmasterol 3-O-β-D-glucopyranoside, 3,5,7,4'-tetrahydroxyflavone (kaempferol), 3,5,7,3',4'-pentahydroxyflavone (quercetin), unpublished in the genus Herissantia, besides β-sitosterol, kaempferol 3-O-β-D-(6''-E-p-coumaroil) (tiliroside) glucopyranoside and kaempferol 3,7-di-O-α-L-ramnopyranoside (lespedin), described for the first time in the species. The structural determination of the compounds was made by means of spectroscopy methods such as Infrared Spectroscopy, ¹H and 13C Nuclear Magnetic Resonance, with the aid of two dimensional techniques, and by comparison with literature data. The toxicity activity of the MeOH extract and lespedin on Artemia salina Leach. was also carried out.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.