A monoclonal antibody against kininogen reduces inflammation in the HLA-B27 transgenic rat

The human leukocyte antigen B27 (HLA-B27) transgenic rat is a model of human inflammatory bowel disease, rheumatoid arthritis and psoriasis. Studies of chronic inflammation in other rat models have demonstrated activation of the kallikrein–kinin system as well as modulation by a plasma kallikrein inhibitor initiated before the onset of clinicopathologic changes or a deficiency in high-molecular-mass kininogen. Here we study the effects of monoclonal antibody C11C1, an antibody against high-molecular-mass kininogen that inhibits the binding of high-molecular-mass kininogen to leukocytes and endothelial cells in the HLA-B27 rat, which was administered after the onset of the inflammatory changes. Thrice-weekly intraperitoneal injections of monoclonal antibody C11C1 or isotype IgG(1 )were given to male 23-week-old rats for 16 days. Stool character as a measure of intestinal inflammation, and the rear limbs for clinical signs of arthritis (tarsal joint swelling and erythema) were scored daily. The animals were killed and the histology sections were assigned a numerical score for colonic inflammation, synovitis, and cartilage damage. Administration of monoclonal C11C1 rapidly decreased the clinical scores of pre-existing inflammatory bowel disease (P < 0.005) and arthritis (P < 0.001). Histological analyses confirmed significant reductions in colonic lesions (P = 0.004) and synovitis (P = 0.009). Decreased concentrations of plasma prekallikrein and high-molecular-mass kininogen were found, providing evidence of activation of the kallikrein–kinin system. The levels of these biomarkers were reversed by monoclonal antibody C11C1, which may have therapeutic potential in human inflammatory bowel disease and arthritis

Characteristics and drug responses of cochlear and vestibular adenylate cyclase

Die Aktivitäten von Adenylatzyklase in isolierten cochlearen und vestibulären Strukturen wurden in Inkubationen mit dem ATP-Analog Adenylylimidodiphosphat gemessen. Hohe Aktivitäten (pro mg protein) fanden sich in Stria vascularis und vestibulären Präparationen, geringere Aktivitäten im Ligamentum spirale, dem 8. Nerven und Cortischem Organ. In allen Präparationen wurde die Enzymaktivität stimuliert durch Fluorid, Guanylylimidodiphosphat oder Mangan(II)ionen und gehemmt durch Ethakrynsäure und Bleiionen. Das ototoxische Zytostatikum cis-Diammin-dichloroplatin hemmte die Zyklase von Stria vascularis signifikant. Adenylate cyclase activity of dissected cochlear and vestibular structures was assayed with the ATP-analog adenylyl imidodiphosphate as substrate. High activities (per mg protein) were found in stria vascularis and in vestibular preparations, lower activities in spiral ligament, VIIIth nerve, and organ of Corti. The enzyme from all structures was stimulated by fluoride, guanylyl imidodiphosphate or manganese(II) ions, and strongly inhibited by ethacrynate and lead ion. The anti-cancer drug cis-diammine-dichloro platinum significantly inhibited adenylate cyclase from stria vascularis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47263/1/405_2004_Article_BF00454231.pd

Marijuana Use in Epilepsy: The Myth and the Reality

Marijuana has been utilized as a medicinal plant to treat a variety of conditions for nearly five millennia. Over the past few years, there has been an unprecedented interest in using cannabis extracts to treat epilepsy, spurred on by a few refractory pediatric cases featured in the media that had an almost miraculous response to cannabidiol-enriched marijuana extracts. This review attempts to answer the most important questions a clinician may have regarding the use of marijuana in epilepsy. First, we review the preclinical and human evidences for the anticonvulsant properties of the different cannabinoids, mainly tetrahydrocannabinol (THC) and cannabidiol (CBD). Then, we explore the safety data from animal and human studies. Lastly, we attempt to reconcile the controversy regarding physicians' and patients' opinions about whether the available evidence is sufficient to recommend the use of marijuana to treat epilepsy

Ototoxicidade da cisplatina e otoproteção pelo extrato de ginkgo biloba às células ciliadas externas: estudo anatômico e eletrofisiológico Cisplatin ototoxycity and otoprotector to cilliated cells by ginkgo biloba extract: anatomic and eletrophisiologic study

A Cisplatina é uma potente droga antineoplásica, largamente utilizada para o tratamento do câncer, tanto em adultos quanto em crianças. Dentre seus efeitos colaterais, a ototoxicidade se apresenta como um dos mais importantes e leva à perda auditiva irreversível, bilateral, para as altas freqüências (4KHz#8KHz). Estudos têm tentado identificar drogas que, associadas à cisplatina possam atuar como otoprotetores. Sabe-se que o mecanismo da ototoxicidade pela cisplatina está relacionado a alterações nos mecanismos antioxidantes das células ciliadas, principalmente as células ciliadas externas da cóclea. OBJETIVO: Nossa proposta foi de avaliar através de emissões otoacústicas, por produtos de distorção (EOAPD) e por microscopia eletrônica de superfície (ME), a ação do extrato de ginkgo biloba (EGB 761), que tem conhecida ação antioxidante, como possível otoprotetor, utilizando como modelo experimental cobaias albinas. FORMA DE ESTUDO: Experimental. MATERIAL E MÉTODO: Observamos EOAPD presentes pré e pós tratamento no grupo EGB (100 mg/Kg/dia via oral) e 90 minutos após cisplatina (80 mg/Kg/dia via intraperitoneal) por 8 dias. RESULTADO: Houve também manutenção da arquitetura ciliar nas células ciliadas externas em todas as espiras da cóclea, enquanto que no grupo tratado somente com cisplatina (80 mg/Kg/dia via intraperitoneal) por 8 dias, houve desaparecimento das EOAPD pós tratamento, com desaparecimento dos cilios das células ciliadas externas e distorção na arquitetura dos cílios remanescentes à ME. CONCLUSÃO: Concluímos que a EGB, por sua ação antioxidante, atua como fator otoprotetor à ototoxicidade pela cisplatina, devendo ser testada tal ação na prática clínica em pacientes que utilizam a cisplatina, pois o uso do EGB está extremamente difundido no tratamento de diferentes doenças.<br>Cisplatin is an antineoplastic drug for cancer treatment in children and adults. The side effects of cisplatin ototoxycity are important with irreversible auditory and bilateral damage to high frequencies (4kHz - 8 kHz). Reports recognize some drugs that are associated with cisplatin to obtain an otoprotector effect. The ototoxycity mechanisms of cisplatin are related to injury of conduct the hair cell oxidation mechanism, with particular injury to outer hair cells. AIM: We intend to studies using otoacoustic emissions - distortion products (DPOEA) and scanning microscopy to verify the action of ginkgo biloba (GBE-761) that has well known antoxidizing characteristics, that can function like otoprotector effects. STUDY DESIGN: Experimental. MATERIAL AND METHOD: We use an experimental guinea pig model. We found DPOEA positive before and after treatment in the GBE group (100 mg/ Kg/ day - oral) and after 90 minutes cisplatin (8,0 mg/ Kg/ day - intraperitoneal - 8 consecutive days). RESULTS: The normal cilium architecture of outer hair cells was supported in all cochlear spirals and in the group treated only with cisplatin (8,0 mg/ Kg/ day - intraperitoneal - 8 consecutive days), the DPOEA was not present and strong injury to cilium of outer hair cells showed cilium disorders upon scanning microscopy. CONCLUSION: We conclude that GBE has a potential otoprotector effect against cisplatin ototoxycity and could be used in clinical trials