Reações cutâneas provocadas por imunomoduladores injetáveis associadas ao tratamento de esclerose múltipla

Pós-graduação em Enfermagem (mestrado profissional) - FMB

Relapse of Intravenous Drug Use Triggered by Enfuvirtide, a Parenteral Antiretroviral Medication

Fuzeon (R) (enfuvirtide; Hoffmann-LaRoche, Nutley, NJ) is a parenteral medication prescribed to antiretroviral-experienced HIV patients. Clinicians are frequently concerned when prescribing enfuvirtide to former drug addicts because of the risk of triggering relapse, however, no previous report has described this adverse event. We describe two HIV-infected patients, previously abstinent from injection drug use, who experienced relapse or near-relapse situations after starting treatment with enfuvirtide. Along with the concerns related to adherence and to injection site reactions, clinicians who prescribe enfuvirtide should consider and discuss the risk of triggering relapse among former or recovering drug addicts.

Local inflammatory events induced by Bothrops atrox snake venom and the release of distinct classes of inflammatory mediators

Bothrops atrox is responsible for most accidents involving snakes in the Brazilian Amazon and its venom induces serious systemic and local effects. The local effects are not neutralized effectively by commercial antivenoms, resulting in serious sequelae in individuals bitten by this species. This study investigates the local inflammatory events induced in mice by B. atrox venom (Bay), such as vascular permeability, leukocyte influx and the release of important inflammatory mediators such as cytokines, eicosanoids and the chemokine CCL-2, at the injection site. The effect of Bay on cyclooxygenase (COX-1 and COX-2) expression was also investigated. The results showed that intraperitoneal (i.p.) injection of BaV promoted a rapid and significant increase in vascular permeability, which reached a peak 1 h after venom administration. Furthermore, BaV caused leukocyte infiltration into the peritoneal cavity between 1 and 8 h after i.p. injection, with mononuclear leukocytes (MNs) predominating in the first 4 h, and polymorphonuclear leukocytes (PMNs) in the last 4 h. Increased protein expression of COX-2, but not of COX-1, was detected in leukocytes recruited in the first and fourth hours after injection of BaV. The venom caused the release of eicosanoids PGD(2), PGE(2), TXA(2) and LTB4, cytokines TNF-alpha, IL-6, IL-10 and IL-12p70, but not IFN-gamma, and chemokine CCL-2 at different times. The results show that Bay is able to induce an early increase in vascular permeability and a leukocyte influx to the injection site consisting mainly of MNs initially and PMNs during the later stages. These phenomena are associated with the production of cytokines, the chemokine CCL-2 and eicosanoids derived from COX-1 and COX-2. (c) 2012 Elsevier Ltd. All rights reserved.

Treatment of Pythiosis in Equine Limbs Using Intravenous Regional Perfusion of Amphotericin B

Objective To evaluate the effects of intravenous regional limb perfusion (IRLP) administration of amphotericin B in horses to treat pythiosis after surgical excision and thermocautery. Study Design Case series. Animals Horses (n = 12) with Pythium insidiosum infection of the distal aspect of the thoracic or pelvic limbs. Methods After surgical excision of granulation tissue and thermocautery, 50 mg amphotericin B was administered by IRLP through a catheter placed in a superficial vein of the affected limb next to the lesion after placing a tourniquet above the injection site. The lesions and locomotor system were evaluated before treatment and at 7, 14, 21, 28, 35, and 60 days. Results Ninety-two percent of horses treated with amphotericin B had complete lesion resolution 35 or 60 days after 1 or 2 IRLP treatments, respectively. IRLP induced limb edema and pain during regional palpation in 42%, and inflammation of the injection site in 33% of horses; however these signs resolved after 14 days. Conclusions IRLP administration of amphotericin B was effective for treating pythiosis in equine limbs, resolving infection with manageable side effects.

Engraftment of human adipose derived stem cells delivered in a hyaluronic acid preparation in mice

PURPOSE: To evaluate the implant of human adipose derived stem cells (ADSC) delivered in hyaluronic acid gel (HA), injected in the subcutaneous of athymic mice. METHODS: Control implants -HA plus culture media was injected in the subcutaneous of the left sub scapular area of 12 athymic mice. ADSC implants: HA plus ADSC suspended in culture media was injected in the subcutaneous, at the contra lateral area, of the same animals. With eight weeks, animals were sacrificed and the recovered implants were processed for extraction of genomic DNA, and histological study by hematoxilin-eosin staining and immunufluorescence using anti human vimentin and anti von Willebrand factor antibodies. RESULTS: Controls: Not visualized at the injection site. An amorphous substance was observed in hematoxilin-eosin stained sections. Human vimentin and anti von Willebrand factor were not detected. No human DNA was detected. ADSC implants - A plug was visible at the site of injection. Fusiform cells were observed in sections stained by hematoxilin- eosin and both human vimentin and anti von Willebrand factor were detected by immunofluorescence. The presence of human DNA was confirmed. CONCLUSION: The delivery of human adipose derived stem cells in preparations of hyaluronic acid assured cells engraftment at the site of injection.

A phase I randomized, double-blind, controlled trial of 2009 influenza A (H1N1) inactivated monovalent vaccines with different adjuvant systems

Methods We conducted a phase I, multicenter, randomized, double-blind, placebo-controlled, multi-arm (10) parallel study involving healthy adults to evaluate the safety and immunogenicity of influenza A (H1N1) 2009 non-adjuvanted and adjuvanted candidate vaccines. Subjects received two intramuscular injections of one of the candidate vaccines administered 21 days apart. Antibody responses were measured by means of hemagglutination-inhibition assay before and 21 days after each vaccination. The three co-primary immunogenicity end points were the proportion of seroprotection >70%, seroconversion >40%, and the factor increase in the geometric mean titer >2.5. Results A total of 266 participants were enrolled into the study. No deaths or serious adverse events were reported. The most commonly solicited local and systemic adverse events were injection-site pain and headache, respectively. Only three subjects (1.1%) reported severe injection-site pain. Four 2009 influenza A (H1N1) inactivated monovalent candidate vaccines that met the three requirements to evaluate influenza protection, after a single dose, were identified: 15 μg of hemagglutinin antigen without adjuvant; 7.5 μg of hemagglutinin antigen with aluminum hydroxide, MPL and squalene; 3.75 μg of hemagglutinin antigen with aluminum hydroxide and MPL; and 3.75 μg of hemagglutinin antigen with aluminum hydroxide and squalene. Conclusions Adjuvant systems can be safely used in influenza vaccines, including the adjuvant monophosphoryl lipid A (MPL) derived from Bordetella pertussis with squalene and aluminum hydroxide, MPL with aluminum hydroxide, and squalene and aluminum hydroxide.

La terapia demetilante con 5-azacitidina nelle sindromi mielodisplastiche: esperienza clinica del Nostro Istituto e correlazione con i dati biologici

Sulla base delle evidenze della letteratura (Fenaux, 2009; Lyons, JCO 2009), a partire da Settembre 2004 nel Nostro Istituto sono stati trattati 57 pazienti affetti da Sindrome Mielodisplastica (MDS) mediante terapia demetilante con 5-Azacitidina. Sono stati utilizzati differenti regimi terapeutici a seconda della classe di rischio IPSS: i pazienti a rischio basso/intermedio-1 hanno ricevuto Azacitidina 75 mg/mq/die sottocute per 5 giorni/mese (schema 5) per 8 cicli; i pazienti a rischio alto/intermedio-2 hanno ricevuto Azacitidina 50 mg/mq/die sottocute per 10 giorni/mese (schema 5+2+5) o Azacitidina 75 mg/mq/die per 7 giorni/mese (schema 7) fino a perdita della risposta. Su una casistica totale di 57 pazienti (15 a rischio basso/int-1; 41 rischio alto/int-2), l’87.7% (50 pazienti) sono risultati valutabili. Tra questi le risposte osservate sono state del 68% (34 pazienti), di cui il 14% (7 pazienti) ha ottenuto una Remissione Completa (CR) ed il 54% (27 pazienti) ha ottenuto un Hematologic Improvement (HI). La valutazione della risposta è stata eseguita secondo i criteri dell’International Working Group 2006 (IWG, Cheeson 2006). Le principali tossicità osservate sono state rappresentate da reazioni cutanee locali nel sito d’iniezione, tossicità gastrointestinale (stipsi e/o diarrea), mielotossicità, neutropenia febbrile, sepsi (3 pazienti). Tra i pazienti trattati abbiamo osservato la presenza di risposta ematologica prolungata (≥ 20 mesi) in 10 pazienti (20% dei pazienti valutabili). Inoltre, grazie alla collaborazione con il Dipartimento di Anatomia Umana dell’Università di Bologna (Prof. L. Cocco, Dott.ssa M.Y. Follo), tutti i pazienti trattati sono stati valutati per i livelli di espressione genica e metilazione del gene della fosfolipasi PI-PLC-beta1. I dati biologici così ottenuti sono stati correlati con quelli clinici, evidenziando la presenza di una correlazione tra i livelli di espressione genica e mutilazione della PI-PLC-beta1 e la risposta alla terapia demetilante con 5-Azacitidina.

Vaccine hypersensitivity--update and overview

Concerns about possible reactions to vaccines or vaccinations are frequently raised. However, the rate of reported vaccine-induced adverse events is low and ranges between 4.8-83.0 per 100,000 doses of the most frequently used vaccines. The number of true allergic reactions to routine vaccines is not known; estimations range from 1 per 500,000 to 1 per 1,000,000 doses for most vaccines. When allergens such as gelatine or egg proteins are components of the formulation, the rate for serious allergic reactions may be higher. Nevertheless, anaphylactic, potentially life-threatening reactions to vaccines are still a rare event (approximately 1 per 1,500,000 doses). The variety of reported vaccine-related adverse events is broad. Most frequently, reactions to vaccines are limited to the injection site and result from a non specific activation of the inflammatory system by, for example, aluminium salts or the active microbial components. If allergy is suspected, an accurate examination followed by algorithms is the key for correct diagnosis, treatment and the decision regarding revaccination in patients with immediate-type reactions to vaccines.

Treatment of clinically diagnosed equine sarcoid with a mistletoe extract (Viscum album austriacus)

BACKGROUND: Equine sarcoids (ES) are common, difficult to treat, and have high recurrence rates. Viscum album extracts (VAE) are used in human cancer treatment. HYPOTHESIS: That therapy with VAE (Iscador P) is effective in the treatment of ES. ANIMALS: Fifty-three horses (444 ES); 42 were treated with VAE or placebo as monotherapy; 11 were treated with VAE or placebo after selective excision of ES. METHODS: Prospective, randomised, blinded, clinical trial. Horses were randomly assigned to treatment (VAE; n=32) or control group (Placebo; n=21). One milliliter of VAE (Iscador P) in increasing concentrations from 0.1 to 20 mg/mL or physiological NaCl solution was given SC 3 times a week over 105 days. Number, localization, and type of the ES were documented over 12 months. A subset of 163 clinically diagnosed equine sarcoid (CDES) lesions (95 VAE, 68 Placebo) was evaluated in detail, considering clinical findings and tumor volume. RESULTS: No undesired adverse effects were observed except for mild edema at the injection site in 5 of 32 horses (16%). Complete or partial regression was observed in 13 horses of the VAE group (41%) and in 3 of the control horses (14%; P<.05). After VAE treatment, 48 of 95 CDES (67%) showed an improvement compared with 17 of 68 CDES in the control group (40%; P<.01). Twenty-seven CDES had disappeared completely in the VAE group (38%) compared with 9 CDES in the control group (13% NS). CONCLUSIONS AND CLINICAL IMPORTANCE: VAE (Iscador P) represents a safe and effective treatment for CDES.

Humoral response to 2 inactivated bluetongue virus serotype-8 vaccines in South American camelids

BACKGROUND: Bluetongue virus serotype 8 (BTV-8) has caused disease in domestic ruminants in several countries of northern Europe since 2006. In 2008 a mass-vaccination program was launched in most affected countries using whole virus inactivated vaccines. OBJECTIVE: To evaluate 2 inactivated vaccines (Bovilis BTV 8; BTVPUR AlSap8) for immunogenicity and safety against BTV-8 in South American camelids (SAC) in a field trial. ANIMALS: Forty-two SAC (25 Alpacas, 17 Llamas) aged between 1 and 16 years. METHODS: The animals were vaccinated twice at intervals of 21 days. They were observed clinically for adverse local, systemic, or both reactions throughout the trial. Blood samples collected on days 0, 14, 21, 43, and 156 after vaccination were tested for the presence of BTV-8 virus by real time-polymerase chain reaction and of specific antibodies by competitive ELISA and a serum neutralization test. RESULTS: All vaccinated animals developed antibodies to BTV-8 after the 2nd administration of the vaccine. No adverse effects were observed except for moderate local swellings at the injection site, which disappeared within 21 days. Slightly increased body temperatures were only observed in the first 2 days after vaccination. The BTV was not detected in any of the samples analyzed. CONCLUSIONS AND CLINICAL IMPORTANCE: The administration of the 2 inactivated commercial vaccines was safe and induced seroconversion against BTV-8 in all vaccinated animals. The results of this study suggest that 2 doses injected 3 weeks apart is a suitable vaccination regimen for SAC.

Grafted neuronal precursor cells differentiate and integrate in injured hippocampus in experimental pneumococcal meningitis

Bacterial meningitis (BM) frequently causes persisting neurofunctional sequelae. Autopsy studies in patients dying from BM show characteristic apoptotic brain injury to the stem cell niche in the subgranular zone of the hippocampal dentate gyrus (DG), and this form of brain damage is associated with learning and memory deficits in experimental BM. With an eye to potential regenerative therapies, the survival, migration, and differentiation of neuronal precursor cells (NPCs) were evaluated after engraftment into the injured hippocampus in vitro and in vivo in an infant rat model of pneumococcal meningitis. Green fluorescent protein (GFP)-expressing NPCs were grafted into the DG of organotypic hippocampal slice cultures injured by challenge with live Streptococcus pneumoniae. Seven days after engraftment, NPCs had migrated from the site of injection into the injured granular layer of the DG and electro-functionally integrated into the hippocampal network. In vivo, GFP-expressing NPCs migrated within 1 week from the injection site in the hilus region to the injured granular layer of the hippocampal DG and showed neuronal differentiation at 2 and 4 weeks after transplantation. Hippocampal injury induced by BM guides grafted NPCs to the area of brain damage and provides a microenvironment for neuronal differentiation and functional integration.

Alternative vaccination against equine botulism (BoNT/C)

REASON FOR PERFORMING STUDY: In Europe the incidence of botulism in horses has increased in the last decade due to the growing popularity of haylage feeding. Recombinant vaccines are safer and less expensive to produce and are generally better tolerated than toxoids. OBJECTIVES: To investigate whether the recombinant C-terminal half of the heavy chain of the botulinum neurotoxin C (Hc BoNT/C) in combination with an immunstimulatory adjuvant is an appropriate vaccine candidate for horses by testing its efficacy to induce neutralising antibodies and by comparing its immunogenic properties and adverse reactions to a commercial toxoid vaccine. Formation of oedema and local pain reactions were assessed. ELISA and Western blot assay against Hc BoNT/C and testing of neutralising antibody induction in a mouse protection assay were used to evaluate the immune response. RESULTS: With the recombinant vaccine, only minor local swelling with full recovery after 5 days was noted after brisket injections. The toxoid vaccine produced local, painful reactions with longer recovery periods of up to 2 weeks. Horses vaccinated with either vaccine induced neutralising antibodies after the second booster vaccination, while seroconversion on ELISA and Western blot to Hc BoNT/C was apparent after the first recombinant vaccination, and at various time points in the vaccination schedule in horses that received commercial toxoid vaccine. CONCLUSION: The recombinant vaccine showed fewer adverse reactions compared to the only commercially available vaccine but induced similar concentrations of neutralising antibodies. There was no correlation between the serological response to Hc BoNT/C and the neutralising capacity of serum. POTENTIAL RELEVANCE: Recombinant Hc BoNT/C is an appropriate vaccine candidate to stimulate production of neutralising antibodies against botulinum neurotoxin C in horses and creates only minor local reactions at the injection site.

Safety of ondansetron loading doses in children with cancer

INTRODUCTION: In highly emetogenic chemotherapy, the recommended dose of the serotonin-receptor antagonist ondansetron (5 mg/m(2) q8h) may be insufficient to prevent chemotherapy-induced nausea and vomiting. In adults, ondansetron-loading doses (OLD) of 32 mg are safe. We aimed to evaluate in children the safety of an OLD of 16 mg/m(2) (top, 24 mg) i.v., followed by two doses of 5 mg/m(2) q8h. MATERIALS AND METHODS: This retrospective single-center study included all pediatric oncology patients having received >/=1 OLD between 2002 and 2005. Adverse events (AE) definitely, probably, or possibly related to OLD were studied, excluding AE not or unlikely related to the OLD. Associations between potential predictors and at least moderate AE were analyzed by mixed logistic regression. RESULTS: Of 167 patients treated with chemotherapy, 37 (22%) received 543 OLD. The most common AE were hypotension, fatigue, injection site reaction, headache, hot flashes/flushes, and dizziness. At least mild AE were described in 139 OLD (26%), at least moderate AE in 23 (4.2%), and severe AE in 5 (0.9%; exact 95% confidence interval [CI], 0.4-2.1). Life-threatening or lethal AE were not observed (0.0%; 0.0-0.6). At least moderate AE were significantly more frequent in female patients (odds ratio [OR] 3.5; 95% CI 1.4-8.8; p = 0.010), after erroneously given second OLD (17.0; 1.9-154; p = 0.012) and higher 24 h cumulative surface corrected dose (1.26 per mg/m(2); 1.06-1.51; p = 0.009). OLD given to infants below 2 years were not associated with more frequent AE. CONCLUSIONS: Ondansetron-loading doses of 16 mg/m(2) (top, 24 mg) i.v. seem to be safe in infants, children, and adolescents.

[Concurrent irradiation and DNA tumor vaccination in canine oral malignant melanoma: a pilot study].

Melanoma is the most common oral tumor in dogs, characterized by rapid growth, local invasion, and high metastatic rate. The goal of this study was to evaluate the combination of radiation therapy and DNA tumor vaccine. We hypothesized, that the concurrent use would not increase toxicity. Nine dogs with oral melanoma were treated with 4 fractions of 8 Gray at 7-day intervals. The vaccine was given 4 times every 14 days, beginning at the first radiation fraction. Local acute radiation toxicities were assessed according to the VRTOG toxicity scoring scheme over a time period of 7 weeks. In none of the evaluated dogs, mucositis, dermatitis and conjunctivitis exceeded grade 2. In 3 dogs mild fever, lethargy, and local swelling at the injection site were seen after vaccine application. In conclusion, the concurrent administration of radiation therapy and vaccine was well tolerated in all dogs.

Immunization against gonadotropin-releasing hormone in dairy cattle: Antibody titers, ovarian function, hormonal levels, and reversibility

Suppression of cyclic activity in cattle is often desired in alpine farming and for feedlot cattle not intended for breeding. A cattle-specific anti-GnRH vaccination (Bopriva, Zoetis Australia Ltd., West Ryde, Australia) is approved for use in heifers and bulls in New Zealand, Australia, Mexico, Brazil, Argentina, Turkey, and Peru. Eleven healthy, cyclic Swiss Fleckvieh cows were included in the study and vaccinated twice with Bopriva 4wk apart. Injection site, rectal body temperature, and heart and respiratory rates were recorded before and 3d following each vaccination. Blood samples were taken weekly for progesterone and estrogen analysis and to determine GnRH antibody titer. Ovaries were examined weekly, using ultrasound to count the number of follicles and identify the presence of a corpus luteum. Thirty weeks after the first vaccination, the cows were subjected to a controlled internal drug-releasing device-based Select-Synch treatment. The GnRH antibody titers increased after the second vaccination and peaked 2wk later. Estrogen levels were not influenced by vaccination, and progesterone level decreased in 7 of 11 cows up to 3wk after the second vaccination and remained low for 10 to 15wk following the second vaccination. The number of class I follicles (diameter ≤5mm) was not influenced by vaccination, whereas the number of class II follicles (diameter 6-9mm) decreased between 7 and 16wk after the first vaccination. Class III follicles (diameter >9mm) were totally absent during this period in most cows. The median period until recurrence of class III follicles was 78d from the day of the second vaccination (95% confidence interval: 60-92d). After vaccination, all cows showed swelling and pain at the injection site, and these reactions subsided within 2wk. Body temperature and heart and respiratory rates increased after the first and second vaccinations and returned to normal values within 2d of each vaccination. The cows in our study were not observed to display estrus behavior until 30wk after the first vaccination. Therefore, a Select-Synch protocol was initiated at that time. Ten cows became pregnant after the first insemination (the remaining cow was reinseminated once until confirmed pregnancy). Bopriva induced a reliable and reversible suppression of reproductive cyclicity for more than 2mo. The best practical predictor for the length of the anestrus period was the absence of class III follicles.