RESUMEN
ANX005 is a humanized immunoglobulin G4 recombinant antibody against C1q that inhibits its function as the initiating molecule of the classical complement cascade. The safety and tolerability of ANX005 are currently being evaluated in a phase I trial in healthy volunteers ( www.clinicaltrials.gov Identifier: NCT03010046). Inhibition of C1q can be applied therapeutically in a broad spectrum of diseases, including acute antibody-mediated autoimmune disease, such as Guillain-Barré syndrome (GBS), and in chronic diseases of the central nervous system involving complement-mediated neurodegeneration, such as Alzheimer's disease (AD). To support the clinical development of ANX005, several studies were conducted to assess the pharmacology, pharmacokinetics, and potential toxicity of ANX005. ANX-M1, the murine precursor of ANX005, functionally inhibits the classical complement cascade both in vitro and in vivo, to protect against disease pathology in mouse models of GBS and AD. Toxicology studies with ANX005, itself, showed that intravenous administration once weekly for 4 weeks was well tolerated in rats and monkeys, with no treatment-related adverse findings. Serum levels of ANX005 in monkeys correlate with a reduction in free C1q levels both in the serum and in the cerebrospinal fluid. In summary, ANX005 has shown proof of concept in in vitro and in vivo nonclinical pharmacology models, with no toxicity in the 4-week repeat-dose studies in rats and monkeys. The no observed adverse effect level was 200 mg/kg/dose, which is 200-fold higher than the first-in-human starting dose of 1 mg/kg in healthy volunteers.
Asunto(s)
Anticuerpos Monoclonales Humanizados/toxicidad , Enfermedades Autoinmunes/tratamiento farmacológico , Complemento C1q/inmunología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedades Autoinmunes/inmunología , Complemento C1q/metabolismo , Vía Clásica del Complemento/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Inyecciones Intravenosas , Macaca fascicularis , Masculino , Enfermedades Neurodegenerativas/inmunología , Ratas Sprague-Dawley , Especificidad de la EspecieRESUMEN
INTRODUCTION: Moving teeth rapidly and avoiding posttreatment relapse are fundamental goals of orthodontic treatment. In-vitro and animal studies suggest that the human hormone relaxin might increase the rate of movement and the stability through its effect on the periodontal ligament. The purpose of this study was to compare relaxin and a placebo with regard to tooth movement and stability in human subjects. METHODS: A single-center, blinded, placebo-controlled, randomized clinical trial was used to examine the effect of relaxin on tooth movement and stability. Forty subjects were randomized 1:1 and received weekly injections of 50 µg of relaxin or a placebo for 8 weeks. Aligners programmed to move a target tooth 2 mm during treatment were dispensed at weeks 0, 2, 4, and 6. Movement was measured weekly on polyvinyl siloxane impressions that were scanned and digitized. The subjects were followed through week 12 to assess relapse. RESULTS: Tooth movement over the 8-week treatment period did not differ by treatment group (P = 0.995). By using an intent-to-treat analysis, we found that the mean tooth movement for both groups was 0.83 mm (SE, 0.08 for relaxin and 0.09 for the placebo). Relapse from weeks 8 to 12 was the same in both groups (P = 0.986), and the mean was -0.75 (SE, 0.07 for relaxin and 0.08 for theplacebo). CONCLUSIONS: No differences in tooth movement over 8 weeks of treatment or relapse at 4 weeks posttreatment were detected when comparing subjects who received weekly injections of relaxin with those who received a placebo. In both groups, an average of less than half of the programmed tooth movement was obtained after 8 weeks of treatment. The local doses of relaxin might have been too low to affect tooth movement or short-term relapse.
Asunto(s)
Relaxina/uso terapéutico , Técnicas de Movimiento Dental/métodos , Adolescente , Adulto , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Incisivo/patología , Inyecciones , Masculino , Maloclusión/terapia , Modelos Dentales , Diseño de Aparato Ortodóncico , Ligamento Periodontal/efectos de los fármacos , Placebos , Proteínas Recombinantes , Recurrencia , Método Simple Ciego , Estrés Mecánico , Técnicas de Movimiento Dental/instrumentación , Adulto JovenRESUMEN
Vocacapsaicin is a novel prodrug of trans-capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) being developed as a nonopioid, long-lasting, site-specific treatment for postsurgical pain management. The objective of these studies was to examine the safety and tolerability of vocacapsaicin in an osteotomy model in two animal species and to evaluate bone healing parameters. Rats undergoing unilateral femoral osteotomy received a single perioperative administration (by instillation) of vocacapsaicin (vehicle, 0.15, 0.3, and 0.6 mg/kg). Rabbits undergoing unilateral ulnar osteotomy received a single perioperative administration (by infiltration and instillation) of vocacapsaicin (vehicle, 0.256 and 0.52 mg) alone or in combination with 0.5% ropivacaine. Clinical signs, body weights, food consumption, radiography, histopathologic examinations, ex vivo bone mineral density measurements (rats only), and biomechanical testing were evaluated at 4 and 8 weeks in rats and at 2 and 10 weeks in rabbits. Plasma samples were also collected in rabbits. There were no vocacapsaicin-related effects on mortality, clinical observations, body weight, or food consumption in either species. Systemic exposure to vocacapsaicin and its metabolites, including capsaicin, was transient. In rats, vocacapsaicin was devoid of deleterious effects on bone healing parameters, and there was a trend for enhanced bone healing in rats treated with the mid-dose. In rabbits, vocacapsaicin administered alone or in combination with ropivacaine did not adversely affect bone healing parameters. In conclusion, a single perioperative administration of vocacapsaicin in unilateral osteotomy models was well tolerated, locally and systemically, supporting its continued development as a novel, nonopioid treatment for postsurgical pain management.
Asunto(s)
Capsaicina , Profármacos , Animales , Capsaicina/farmacología , Curación de Fractura , Osteotomía , Dolor Postoperatorio , Profármacos/farmacología , Conejos , Ratas , Ropivacaína/farmacologíaRESUMEN
BACKGROUND: A novel formulation of > or = 98% pure capsaicin (4975) is currently undergoing clinical investigation using novel routes of delivery to provide selective analgesia lasting weeks to months with a single dose. We conducted this study to assess the safety and effects of instilled and injected 4975 in rat models of wound healing osteotomy repair and sensory-motor nerve function. METHODS: Adult male and female Sprague-Dawley rats were used. To assess the effects of 4975 on nerve or muscle, 0.0083 or 0.025 mg 4975 or vehicle (25% polyethylene glycol-300) was applied to exposed sciatic nerve, or 0.1 mg 4975 or vehicle was injected into the surrounding muscle (Group 1). To assess the effect of 4975 on bone healing, an osteotomy was made in one femur and 0.5 mg of 4975 or vehicle was instilled into the site (Group 2). Behavioral testing was performed on both groups of rats and histological evaluation of the sciatic nerve, and surrounding soft tissue and bone was done at days 3, 14, and 28 after surgery. Femurs from osteotomy rats were assessed using peripheral quantitative computed tomography and biomechanical testing. Standard statistical tests were used to compare groups. RESULTS: Rats with direct application of 4975 to the sciatic nerve and surrounding muscle were no different from the controls in nociceptive sensory responses (F = 0.910, P = 0.454), grip strength (F = 0.550, P = 0.654), or histology of the muscle or sciatic nerve. In osteotomy rats, there were no statistical differences between 4975 and vehicle-treated rats for bone area (H = 2.858, P = 0.414), bone mineral content (F = 0.945, P = 0.425), or bone mineral density (F = 0.87, P = 0.462) and no difference in soft tissue healing. There were neither differences in bone stiffness (F = 1.369, P = 0.268) nor were there noticeable differences in the macro- or microscopic appearance of the right femur osteotomy healing site and surrounding soft tissues between the control group and the 4975-treated animals. CONCLUSION: A single, clinically relevant application of instilled or injected 4975 has no observable adverse effect on wound and bone healing after osteotomy or on the structural integrity of exposed muscle and nerve.
Asunto(s)
Capsaicina/administración & dosificación , Miembro Posterior/efectos de los fármacos , Osteotomía , Desempeño Psicomotor/efectos de los fármacos , Animales , Capsaicina/efectos adversos , Femenino , Miembro Posterior/patología , Miembro Posterior/fisiología , Inyecciones Intramusculares , Instilación de Medicamentos , Masculino , Osteotomía/métodos , Desempeño Psicomotor/fisiología , Ratas , Ratas Sprague-Dawley , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/fisiologíaRESUMEN
BAS Medical is investigating the use of relaxin to improve ortho-dontic treatments. Relaxin is well known for its effects on remodeling soft tissue, and we believe relaxin will be clinically useful in speeding tooth movement and preventing relapse. We investigated the use of relaxin in preventing relapse in a dog model. Dog maxillary second incisors were orthodontically rotated an average of 42 degrees, and then relaxin was administered by gingival injection to relieve the rotational memory in the connective tissues. Teeth were retained for 30 days to allow fibers to reform. Teeth then were released and relapse was measured by a series of impressions. Animals receiving relaxin gingival injections (n = 8) were compared with placebo-treated animals (n = 8) (exhibiting high relapse) and gingival fiberotomies (n = 8) (low relapse). Gingival fiberotomy is a surgical procedure to cut the gingival connective tissues away from the tooth and has been shown to be effective in preventing relapse clinically and in animal models. There was a significant difference in relapse between the fiberotomy and the placebo control groups, and the relaxin-treated group had an intermediate response between the two groups (nonsignificant). Dose and treatment optimization may improve the response in future studies. To study the underlying mechanisms, we have localized relaxin receptors on gingival and periodontal ligament fibroblasts in tissue slices and cell cultures. Relaxin was found to stimulate collagenase production by relaxin in human gingival fibroblast cultures. Taken together, the data support a role for relaxin therapy to speed tooth movement and prevent relapse in orthodontic practice.
Asunto(s)
Ortodoncia/métodos , Relaxina/farmacología , Relaxina/uso terapéutico , Técnicas de Movimiento Dental , Animales , Perros , Masculino , Modelos Animales , Receptores Acoplados a Proteínas G , Receptores de Péptidos/metabolismo , Prevención SecundariaRESUMEN
Highly purified capsaicin has emerged as a promising injectable compound capable of providing sustained pain relief following a single localized treatment during orthopedic surgical procedures. To further assess its reliability for clinical use, the potential effect of highly purified capsaicin on articular cartilage metabolism as well as tendon structure and function warrants clarification. In the current study, rabbits received unilateral supraspinatus transection and repair with a single 1 ml injection of capsaicin (R+C), PEG-only placebo (R+P), or saline (R+S) into the glenohumeral joint (GHJ). An additional group received 1 ml capsaicin onto an intact rotator cuff (I+C). At 18 weeks post-op, cartilage proteoglycan (PG) synthesis and content as well as cell viability were similar (p>0.05) across treatment groups. Biomechanical testing revealed no differences (p>0.05) among tendon repair treatment groups. Similarly, histologic features of both cartilage and repaired tendons showed minimal differences across groups. Hence, in this rabbit model, a single injection of highly purified capsaicin into the GHJ does not induce a deleterious response with regard to cartilage matrix metabolism and cell viability, or rotator cuff healing. These data provide further evidence supporting the use of injectable, highly purified capsaicin as a safe alternative for management of postoperative pain following GHJ surgery.
Asunto(s)
Capsaicina/uso terapéutico , Cartílago Articular/efectos de los fármacos , Manguito de los Rotadores/efectos de los fármacos , Traumatismos de los Tendones/tratamiento farmacológico , Tendones/efectos de los fármacos , Animales , Fenómenos Biomecánicos , Cartílago Articular/cirugía , Supervivencia Celular , Masculino , Dolor Postoperatorio , Presión , Proteoglicanos/metabolismo , Conejos , Manguito de los Rotadores/cirugía , Articulación del Hombro/patología , Estrés Mecánico , Traumatismos de los Tendones/cirugía , Tendones/cirugíaRESUMEN
BACKGROUND: Researchers typically search for disease markers using a "targeted" approach in which a hypothesis about the disease mechanism is tested and experimental results either confirm or disprove the involvement of a particular gene or protein in the disease. Recently, there has been interest in developing disease diagnostics based on unbiased quantification of differences in global patterns of protein and peptide masses, typically in blood from individuals with and without disease. We combined a suite of methods and technologies, including novel sample preparation based on carrier-protein capture and biomarker enrichment, high-resolution mass spectrometry, a unique cohort of well-characterized persons with and without Alzheimer disease (AD), and powerful bioinformatic analysis, that add statistical and procedural robustness to biomarker discovery from blood. METHODS: Carrier-protein-bound peptides were isolated from serum samples by affinity chromatography, and peptide mass spectra were acquired by a matrix-assisted laser desorption/ionization (MALDI) orthogonal time-of-flight (O-TOF) mass spectrometer capable of collecting data over a broad mass range (100 to >300,000 Da) in a single acquisition. Discriminatory analysis of mass spectra was used to process and analyze the raw mass spectral data. RESULTS: Coupled with the biomarker enrichment protocol, the high-resolution MALDI O-TOF mass spectra provided informative, reproducible peptide signatures. The raw mass spectra were analyzed and used to build discriminant disease models that were challenged with blinded samples for classification. CONCLUSIONS: Carrier-protein enrichment of disease biomarkers coupled with high-resolution mass spectrometry and discriminant pattern analysis is a powerful technology for diagnostics and population screening. The mass fingerprint model successfully classified blinded AD patient and control samples with high sensitivity and specificity.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Péptidos/química , Proteómica/métodos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/clasificación , Biomarcadores/sangre , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Péptidos/sangre , Péptidos/aislamiento & purificación , Sensibilidad y EspecificidadRESUMEN
A recent study demonstrated that gravi-incompetent coleoptile-less seedlings of rye exhibit gravi-competence after exogenous application of ethylene. Treatments and conditions which induce and interfere with this phenomenon were analysed in more detail. Aminocyclopropane-1-carboxylic acid (ACC) as a precursor of ethylene has similar gravicompetence-inducing effects and also appropriate conditions of light, which strongly enhances ethylene synthesis. Both effects can be inhibited by the ethylene-perception blocking agent methylcyclopropene (MCP) or inhibitors of ethylene synthesis such as aminovinylglycine (AVG), indicating that light exerts its gravicompetence-generating effect via induced/enhanced ethylene synthesis. Gain in gravicompetence is accompanied by the induced/enhanced occurrence of calreticulin and lipoxygenase as detected by 2D-gels and Q-TOFF-analyses. Previously gravicompetent, light-grown coleoptile-less seedlings are characterized by gravi-incompetent growth during subsequent horizontal gravistimulation when perception of ethylene is inhibited by MCP. The results demonstrate that continuous perception of ethylene is an indispensable step, permanently required for the regulation of gravitropic growth in germinating primary shoots of rye, either within the process of graviperception and/or of the transduction of the gravi-signal.
Asunto(s)
Etilenos/farmacología , Gravitropismo/fisiología , Brotes de la Planta/fisiología , Secale/fisiología , Secuencia de Aminoácidos , Gravitropismo/efectos de los fármacos , Luz , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/aislamiento & purificación , Brotes de la Planta/efectos de los fármacos , Brotes de la Planta/crecimiento & desarrollo , Secale/efectos de los fármacosRESUMEN
Fractionation enhances the resolution of proteins with similar characteristics by reducing the number of proteins that comigrate in gels, thus facilitating the detection of lower-abundance proteins and the accurate determination of quantitative and qualitative differences in disease and normal samples. An efficient, reproducible microscale fractionation protocol for complex protein mixtures using novel ion-exchange membrane chromatographic substrates (PerkinElmer, Boston, MA, USA; Vivascience, Carlsbad, CA, USA) is described. The fractionation techniques were used in combination with two-dimensional (2-D) gels and orthogonal matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry to identify differentially expressed proteins in brain samples from persons with and without Alzheimer's disease.