RESUMO
BACKGROUND: Clostridium collagenase histolyticum (CCH) is being evaluated in women as a cellulite treatment. OBJECTIVE: To report preclinical safety and human pharmacokinetics (PK) and safety data for CCH. METHODS: Across 3 PK studies, 41 women received 12 subcutaneous injections per thigh/buttock in 1 session (up to 3.36 mg/dose). Blood samples were taken at baseline; at 5, 10, 20, and 30 minutes postdose; and at 1, 2, 4, 8, 12, 24, 48, 168, and 504 hours postdose. In a preclinical study, rats received 0, 0.029, 0.13, or 0.29 mg/dose of CCH intravenously (IV) every other day (QOD) for 16 days (total, 8 doses) and were evaluated for histopathologic changes. RESULTS: In human PK studies, no quantifiable plasma concentrations of AUX-I or AUX-II were observed postdose (n= 39 evaluable). Adverse events were injection site–related (bruising [97.6%], pain [87.8%], and edema/swelling [46.3%]). Antidrug antibodies were seen in most women at 504 hours postdose. In rats, plasma concentrations of AUX-I and AUX-II (CCH components) were measurable for 30 minutes and 1-2 hours, respectively, after IV administration. At ≥43× proposed human therapeutic dose on a mg/kg basis, rats experienced elevated liver enzyme levels, increased liver weights, and histologic changes that were mostly reversed during a 14-day recovery period. CONCLUSIONS: In human studies, no quantifiable circulating CCH levels were observed after a single subcutaneous dose of CCH up to 3.36 mg. Preclinical data indicated that repeat IV dosing (QOD; 8 doses) at ≥43× proposed human dose on a mg/kg basis for CCH was generally well tolerated.J Drugs Dermatol. 2020;19(9):852-856. doi:10.36849/JDD.2020.5048THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.
Assuntos
Celulite/tratamento farmacológico , Colagenase Microbiana/farmacocinética , Adulto , Idoso , Animais , Nádegas , Celulite/sangue , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Fertilidade/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Humanos , Injeções Intralesionais , Injeções Intravenosas , Masculino , Colagenase Microbiana/administração & dosagem , Colagenase Microbiana/sangue , Colagenase Microbiana/toxicidade , Pessoa de Meia-Idade , Ratos , Coxa da Perna , Testes de Toxicidade Subaguda , Resultado do TratamentoRESUMO
Neuroinflammation significantly contributes to brain injury and neurological deterioration following intracerebral hemorrhage (ICH). MicroRNA-152(miR-152) was reported to be downregulated in ICH patients and to possess anti-inflammatory properties in other diseases. In this study, we aimed to explore the role of miR-152 in ICH, and the underlying mechanisms, using a collagenase-induced rat ICH model and hemin-exposure as a cell model. We first confirmed that miR-152 was consistently downregulated in both models. Overexpression of miR-152 in microglial BV2 cells reduced hemin-induced inflammatory response and reactive oxygen species (ROS) generation, thus protecting co-cultured neuronal HT22 cells. Moreover, overexpression of miR-152 by intracerebroventricular lentivirus injection in ICH rats significantly alleviated neurodecifits, brain edema, and hematoma. These changes were associated with a marked reduction in ICH-induced neuronal death, as detected by co-staining of NeuN and TUNEL, and ICH-induced neuroinflammation, as revealed by inflammatory cytokine levels as well as by the number of Iba1 positive-stained cells in the perihematomal region. Mechanistically, miR-152 significantly inhibited ICH-induced TXNIP expression, and its overexpression blocked the interaction between TXNIP and NOD-like receptor pyrin domain containing 3(NLRP3), thus inhibiting NLRP3-driven inflammasome activation to attenuate neuroinflammation in vivo and in vitro. Moreover, the results of si-TXNIP transfection further confirmed that TXNIP inhibition was involved in the reduction of NLRP3 inflammasome activation by the overexpression of miR-152. Collectively, the present study demonstrates that miR-152 confers protection against ICH-induced neuroinflammation and brain injury by inhibiting TXNIP-mediated NLRP3 inflammasome activation, indicating a potential strategy for ICH treatment.
Assuntos
Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Hemorragia Cerebral Intraventricular/genética , Inflamassomos/imunologia , MicroRNAs/metabolismo , Tiorredoxinas/genética , Animais , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Hemorragia Cerebral Intraventricular/induzido quimicamente , Hemorragia Cerebral Intraventricular/imunologia , Hemorragia Cerebral Intraventricular/patologia , Ventrículos Cerebrais/imunologia , Ventrículos Cerebrais/patologia , Técnicas de Cocultura , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Técnicas de Silenciamento de Genes , Hemina/imunologia , Humanos , Inflamassomos/metabolismo , Injeções Intraventriculares , Masculino , Camundongos , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Colagenase Microbiana/administração & dosagem , Colagenase Microbiana/toxicidade , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios , Ligação Proteica/genética , Ligação Proteica/imunologia , RNA Interferente Pequeno/metabolismo , Ratos , Tiorredoxinas/metabolismoRESUMO
Cerebral iron overload contributes to free-radical damage and secondary brain injury following intracerebral hemorrhage (ICH). Phlebotomy most effectively removes iron from the human body, compared with any pharmacological agent (e.g., chelator), and does not impact mean arterial blood pressure. For centuries, this ancient method was a treatment for stroke. This is the first controlled scientific evaluation of this approach after ICH. Femoral catheterization occurred at 30 min following collagenase infusion. Three different exsanguination volumes were tested: 1, 2, 3 ml (approximately 5-15 % (normotensive) loss of total blood volume; or 3.33-10 ml/kg) compared with ICH and sham controls. Brain water content, hemorrhage size, and neuroscore were measured 24 h later. Preliminary analysis of the data demonstrated that therapeutic phlebotomy occurring shortly after ICH in adult rats significantly decreased brain edema and hemorrhagic size at 1 day after the brain injury. However, the neuroscore was unchanged compared with untreated animals. Therefore, exsanguination therapy after ICH using the traditional phlebotomy approach may eventually ameliorate early brain injury (hemorrhage and edema) in further human studies, despite equivocal changes in the short-term neurological functional ability. In meantime, translational studies must further delineate the involvement of specific neuroprotective molecules, sympathetic responses, hemodynamic-vasoactive mediators, or neuroendocrine factors involved in this apparent postconditioning approach following ICH in rodents.
Assuntos
Edema Encefálico/prevenção & controle , Hemorragia Cerebral/terapia , Flebotomia/métodos , Animais , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Exsanguinação , Masculino , Colagenase Microbiana/toxicidade , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de DoençaRESUMO
Germinal matrix hemorrhage (GMH) is the most common and devastating neurological injury of premature infants, and current treatment approaches are ineffective. Remote ischemic postconditioning (RIPC) is a method by which brief limb ischemic stimuli protect the injured brain. We hypothesized that RIPC can improve outcomes following GMH in rats. Neonatal rats (P7) were subjected to either stereotactic ganglionic eminence collagenase infusion or sham surgery. Groups were as follows: sham (n = 0), GMH non-RIPC (n = 10), GMH + 1 week RIPC (n = 10), GMH + 2 weeks RIPC (n = 10). Neurobehavior analysis at the fourth week consisted of Morris water maze (MWM) and rotarod (RR). This was followed by euthanasia for histopathology on day 28. Both 1- and 2-week RIPC showed significant improvement in FF and RR motor testing compared with untreated animals (i.e., GMH without RIPC). RIPC treatment also improved cognition (MWM) and attenuated neuropathological ventricular enlargement (hydrocephalus) in juvenile animals following GMH. RIPC is a safe and noninvasive approach that improved sensorimotor and neuropathological outcomes following GMH in rats. Further studies are needed to evaluate for mechanisms of neuroprotection.
Assuntos
Hemorragia Cerebral/terapia , Pós-Condicionamento Isquêmico/métodos , Animais , Animais Recém-Nascidos , Comportamento Animal , Encéfalo/fisiopatologia , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Extremidades , Aprendizagem em Labirinto , Colagenase Microbiana/toxicidade , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-RodRESUMO
Intracerebral hemorrhage (ICH) is the most fatal stroke subtype, with no effective therapies. Hematoma expansion and inflammation play major roles in the pathophysiology of ICH, contributing to primary and secondary brain injury, respectively. Fucoidan, a polysaccharide from the brown seaweed Fucus vesiculosus, has been reported to activate a platelet receptor that may function in limiting bleeding, and to exhibit anti-inflammatory effects. As such, the aim of the present study was to examine the effects of fucoidan on hemorrhaging and neurological outcomes after ICH. Male CD-1 mice were subjected to experimental ICH by infusion of bacterial collagenase. Animals were randomly divided into the following groups: sham, ICH + vehicle, ICH + 25 mg/kg fucoidan, ICH + 75 mg/kg fucoidan, and ICH + 100 mg/kg fucoidan. Brain water content, neurobehavioral outcomes, and hemoglobin content were evaluated at 24 h post ICH. Our findings show that fucoidan failed to attenuate the ICH-induced increase in BWC. The neurological deficits that result from ICH also did not differ in the treatment groups at all three doses. Finally, we found that fucoidan had no effect on the hemoglobin content after ICH. We postulate that fucoidan treatment did not improve the measured outcomes after ICH because we used crude fucoidan, which has a high molecular weight, in our study. High-molecular-weight fucoidans are reported to have less therapeutic potential than low molecular weight fucoidans. They have been shown to exhibit anti-coagulant and pro-apoptotic properties, which seem to outweigh their anti-inflammatory and potential procoagulant abilities. We propose that using a low-molecular-weight fucoidan, or fractionating the crude polysaccharide, may be effective in treating ICH. Future studies are needed to confirm this.
Assuntos
Anticoagulantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Hemorragia Cerebral/metabolismo , Fucus , Polissacarídeos/farmacologia , Animais , Encéfalo/patologia , Edema Encefálico/patologia , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/fisiopatologia , Hemoglobinas/efeitos dos fármacos , Hemoglobinas/metabolismo , Masculino , Camundongos , Colagenase Microbiana/toxicidade , Tamanho do ÓrgãoRESUMO
Bradykinesia in upper extremities is associated with a wide variety of motor disorders; however, there are few tasks that assay forelimb movement speed in rodent models. This study describes the bradykinesia assessment task, a novel method to quantitatively measure forelimb speed in rats. Rats were trained to reach out through a narrow slot in the cage and rapidly press a lever twice within a predefined time window to receive a food reward. The task provides measurement of multiple parameters of forelimb function, including inter-press interval, number of presses per trial, and success rate. The bradykinesia assessment task represents a significant advancement in evaluating bradykinesia in rat models because it directly measures forelimb speed. The task is fully automated, so a single experimenter can test multiple animals simultaneously with typically in excess of 300 trials each per day, resulting in high statistical power. Several parameters of the task can be modified to adjust difficulty, which permits application to a broad spectrum of motor dysfunction models. Here we show that two distinct models of brain damage, ischemic lesions of primary motor cortex and hemorrhagic lesions of the dorsolateral striatum, cause impairment in all facets of performance measured by the task. The bradykinesia assessment task provides insight into bradykinesia and motor dysfunction in multiple disease models and may be useful in assessing therapies that aim to improve forelimb function following brain damage.
Assuntos
Membro Anterior/fisiopatologia , Hipocinesia/diagnóstico , Transtornos dos Movimentos/fisiopatologia , Animais , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/complicações , Isquemia Encefálica/fisiopatologia , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/complicações , Hemorragia Cerebral/fisiopatologia , Condicionamento Operante , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Endotelina-1/toxicidade , Desenho de Equipamento , Feminino , Hipocinesia/fisiopatologia , Colagenase Microbiana/toxicidade , Córtex Motor/fisiopatologia , Transtornos dos Movimentos/etiologia , Desempenho Psicomotor , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
PrtV is an extracellular metalloprotease of Vibrio parahaemolyticus and regarded as a collagenase. Inductively coupled plasma-optical emission spectrometry analysis indicated that the recombinant PrtV contains 1 mol of zinc per mol of the native enzyme. On the basis of a kinetic study using 2-furanacryloyl-Leu-Gly-Pro-Ala (FALGPA, the specific substrate for bacterial collagenase) as a substrate, it was suggested that metal ions may play a significant role in the binding and catalytic steps of the substrate. PrtV hydrolyzed type I, II, III, and IV collagens; however, it did not hydrolyze type V. In addition, the hydrolysis of native proteins and synthetic substrates revealed that PrtV possesses higher activity toward collagen and collagen-like sequences. The result of the thermal stability study indicated that PrtV was thermostable up to 40 C; at 50 C, stability gradually decreased. In addition, PrtV showed higher storage stability at -20 and 4 C, respectively, than at 25 C. Compared with collagenases from Clostridium histolyticum and Vibrio alginolyticus, PrtV was immunologically different and had no significant effect on the growth of CHO, HeLa, and Vero cells. Taken together, the results of the studies described in this paper advance our knowledge concerning the metal content and biochemical properties of PrtV.
Assuntos
Metais/análise , Colagenase Microbiana/química , Colagenase Microbiana/metabolismo , Vibrio parahaemolyticus/enzimologia , Animais , Catálise , Linhagem Celular , Colágeno/metabolismo , Estabilidade Enzimática , Humanos , Metais/metabolismo , Metais/farmacologia , Colagenase Microbiana/genética , Colagenase Microbiana/toxicidade , Níquel/análise , Oligopeptídeos/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Temperatura , Vibrio parahaemolyticus/genética , Zinco/análiseRESUMO
The involvement of bradykinin, 5-hydroxytryptamine, substance P and prostanoids in the hyperalgesia elicited by collagenase in rat paw was investigated. Collagenase (100 micrograms) induced a slight hyperalgesia in kininogen deficient rats in comparison with the behavioural response obtained in normal rats. Lisinopril (10(-5) M), and angiotensin-converting enzyme inhibitor, increased the duration of the hyperalgesia elicited in normal rats. Ondansetron (0.5 to 5 mumol/kg), a 5-HT3 antagonist, suppressed the hyperalgesia as did methysergide (1.1 to 11 mumol/kg), a mixed 5-HT1 and 5-HT2 receptor antagonist. However, the hyperalgesia was not modified by RP 67580 (1.8 to 18 mumol/kg), a NK1 receptor antagonist, and was only slightly delayed by indomethacin (2 mg/kg), a cyclo-oxygenase inhibitor. The oedema-promoting effect of 5-HT (6 nmol) was inhibited by methysergide but not by ondansetron. The swelling induced by collagenase in rat paw was reduced by methysergide but not by ondansetron. We conclude that the behavioural response induced by collagenase depends on an interactions between bradykinin and 5-HT. Prostanoids play a minor role in the beginning of the reaction whereas substance P is not significantly involved in this hyperalgesia.
Assuntos
Bradicinina/metabolismo , Hiperalgesia/metabolismo , Colagenase Microbiana/toxicidade , Serotonina/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Bradicinina/fisiologia , Clostridium/enzimologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Membro Posterior , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Indóis/farmacologia , Indóis/uso terapêutico , Isoindóis , Cininogênios/deficiência , Lisinopril/farmacologia , Lisinopril/uso terapêutico , Metisergida/farmacologia , Metisergida/uso terapêutico , Antagonistas dos Receptores de Neurocinina-1 , Ondansetron/farmacologia , Ondansetron/uso terapêutico , Prostaglandinas/metabolismo , Prostaglandinas/fisiologia , Ratos , Ratos Wistar , Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Substância P/metabolismo , Substância P/fisiologiaRESUMO
Intracerebral hemorrhage occurs in tumors, stroke and head trauma. Proteolysis of the extracellular matrix around cerebral capillaries by naturally occurring mammalian 72-kDa type IV collagenase may initiate this pathologic event. To investigate this hypothesis adult rats underwent intracerebral injection of type IV collagenase purified from human melanoma cells. Histologically, at 4 h there was perivascular cellular infiltration with hemorrhage, and by 24 h there was infarction with necrosis, edema and hemorrhage. Ultrastructurally, the basal lamina of endothelial cells was disrupted at 2 h. Brain uptake of [14C]dextran and [3H]sucrose increased after intracerebral injection of type IV collagenase compared to controls (P less than 0.0001). Tissue inhibitor of metalloproteinase-2 (TIMP-2) reduced the tracer uptake (P less than 0.02). Metalloproteinase inhibitors reduce extracellular matrix proteolysis and protect the blood-brain barrier.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/patologia , Ventrículos Cerebrais/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Colagenase Microbiana/toxicidade , Proteínas de Neoplasias/farmacologia , Análise de Variância , Animais , Transporte Biológico/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Capilares/efeitos dos fármacos , Capilares/patologia , Capilares/ultraestrutura , Ventrículos Cerebrais/efeitos dos fármacos , Dextranos/metabolismo , Humanos , Injeções Intraventriculares , Masculino , Colagenase Microbiana/administração & dosagem , Colagenase Microbiana/antagonistas & inibidores , Proteínas de Neoplasias/administração & dosagem , Ratos , Ratos Endogâmicos , Sacarose/metabolismo , Inibidor Tecidual de Metaloproteinase-2RESUMO
One of the implantation problems in immunoprotected living cells is the appearance of local inflammatory phenomena around microcapsules. Some of the mediators released in such pathophysiological conditions were tested. A toxic action of compounds such as elastase, collagenase was evidenced. Interleukins 1 and 2 revealed no cytotoxicity within the test limits on the experimental cellular model chosen. These results underline the importance of inflammatory mediators released by adjacent cells of the implant.
Assuntos
Cápsulas/efeitos adversos , Inflamação/imunologia , Animais , Linhagem Celular/transplante , Citotoxicidade Imunológica , Técnicas In Vitro , Inflamação/enzimologia , Colagenase Microbiana/metabolismo , Colagenase Microbiana/toxicidade , Elastase Pancreática/metabolismo , Elastase Pancreática/toxicidade , RatosRESUMO
The influence of the endothelium on pulmonary venular responses to reduced oxygen tension has not been defined. To examine this question, endothelial injury was induced in small guinea pig pulmonary artery and venule segments (effective lumen radius, 174 +/- 5 and 122 +/- 2 microns, respectively) by perfusion with either a mixture of hypoxanthine (5 mM) and xanthine oxidase (0.05 U/ml) (HX/XO) or collagenase (2 mg/ml). HX/XO significantly (p less than 0.05) reduced the relaxation of precontracted pulmonary arteries by acetylcholine (ACH), bradykinin (BK), and A-23187, and the relaxations were restored by including superoxide dismutase (40 micrograms/ml) in the HX/XO solution. However, neither HX/XO nor collagenase affected vasodilation induced by ACH, BK, and A-23187 in precontracted pulmonary venules. In contrast, HX/XO significantly (p less than 0.05) augmented the sustained contraction of pulmonary venules to hypoxia (HX/XO, 3.2 +/- 1.0 mg/mm; control, 1.0 +/- 0.5 mg/mm) and anoxia (HX/XO, 35.1 +/- 6.6 mg/mm; control, 20.3 +/- 4.0 mg/mm). Collagenase also significantly (p less than 0.05) enhanced the anoxic contractions (collagenase, 36.0 +/- 3.7 mg/mm; control, 20.9 +/- 6.8 mg/mm). Superoxide dismutase (40 micrograms/ml) and catalase (323 micrograms/ml) abolished HX-XO-induced augmentation of the hypoxic and anoxic contractions of pulmonary venules. Collagenase removed 54 +/- 8% of the venular endothelium (control, 5 +/- 1%), whereas HX/XO-exposed endothelial cells contained numerous craters. Neither gossypol (5 microM) nor methylene blue (10 microM) affected pulmonary venular contractions to reduced PO2. Endothelial damage augments the PO2-dependent contractions of the pulmonary venule, and this augmentation does not appear to be due to decreased release of endothelium-derived relaxing factor.
Assuntos
Endotélio Vascular/fisiologia , Hipóxia/fisiopatologia , Oxigênio/fisiologia , Artéria Pulmonar/fisiologia , Veias Pulmonares/fisiologia , Animais , Cobaias , Hipoxantina , Hipoxantinas/toxicidade , Masculino , Colagenase Microbiana/toxicidade , Pressão Parcial , Vasoconstrição , Vênulas/fisiologia , Xantina Oxidase/toxicidadeRESUMO
Excorporal bovine eye has been resuscitated and sustained with an aim of its development as an alternative to whole animal in evaluating acute retinal toxicity of xenobiotics. As indicated by the stable ERG response, such preparation is functionally reactive to photic stimuli over a span of 6-12 h. Moreover, after experienced a 20 min hypoxia the reperfused eyes recovered fully. This functionally responsive preparation was used to evaluate the influence of a highly purified bacterial collagenase (Nucleolysin) on the integrity of vitreoretinal junction. Nucleolysin at concentrations between 120-600 U/ml was injected into the posterior chamber for 15 min. Retinal surfaces were irrigated and eyes were perfusion fixed with glutaraldehyde. Ultrastructural analysis indicated that thinning of the internal limiting membrane occurred when enzyme exceeded 480 U. At 600 U concentration, the principle subcellular change involved the end-foot region of the Muller cells. These studies suggest that the isolated, perfused bovine eye is a suitable model for evaluating acute retinal toxicity of xenobiotics.
Assuntos
Retina/efeitos dos fármacos , Toxicologia/métodos , Alternativas aos Testes com Animais , Animais , Bovinos , Eletrorretinografia/efeitos dos fármacos , Técnicas In Vitro , Colagenase Microbiana/toxicidade , Consumo de Oxigênio/efeitos dos fármacos , Perfusão , Retina/ultraestrutura , Xenobióticos/toxicidadeRESUMO
An experimental model is described in which collagenase in different concentrations and volumes were applied epidurally or intrathecally in the rabbit lumbar spine. This made it possible to study the tissue effects in a situation similar to that of collagenase leaking from a disc or accidental epidural or intrathecal injection at chemonucleolysis. Epidurally applied collagenase, in higher concentration, caused a local thinning of the dura. This effect was reduced at lower concentrations and volumes. Intrathecally injected collagenase, even in small amounts, caused intrathecal hemorrhage and acute paraplegia in the hind limbs. Therefore, in the clinical situation, intrathecal injection of collagenase must be avoided.
Assuntos
Quimiólise do Disco Intervertebral/efeitos adversos , Colagenase Microbiana/administração & dosagem , Animais , Dura-Máter/efeitos dos fármacos , Feminino , Injeções Epidurais , Injeções Espinhais , Vértebras Lombares , Masculino , Colagenase Microbiana/toxicidade , Permeabilidade , Coelhos , Medula Espinal/efeitos dos fármacos , Raízes Nervosas Espinhais/efeitos dos fármacosRESUMO
Evidence is presented that the collagenase perfusion of adult rat liver results in significant damage to nuclear DNA as evaluated by the alkaline elution technique. The extent of the damage is related to the perfusion time as well as to the clostridial enzyme preparation used. The DNA structure of isolated cells is almost completely repaired within 12 h of their culture in chemically defined medium.
Assuntos
Reparo do DNA , Fígado/efeitos dos fármacos , Colagenase Microbiana/toxicidade , Mutação/efeitos dos fármacos , Animais , Fígado/fisiologia , Masculino , Perfusão , Ratos , Ratos EndogâmicosRESUMO
Electron microscopic analysis of intravitreal strands produced by the injection of autogenous fibroblasts showed thin, immature collagen after two weeks and the mature banded variety after four weeks. With the use of this intravitreal strand model, it was found that highly purified bacterial collagenase caused extensive digestion of scar tissue after incubation periods of 10, 15, and 30 minutes. There was no morphologic damage to cicatricial cellular elements or to the inner limiting membrane of the retina. A 45-minute exposure of retinas previously injured by photocoagulation to collagenase also did not result in morphologic evidence of damage. The use of collagenase as an adjunct to vitrectomy in cases of extreme vitreal scarring or retinal traction may decrease the complication rate of a procedure that is still extremely hazardous.
Assuntos
Colagenase Microbiana/uso terapêutico , Corpo Vítreo/cirurgia , Animais , Cicatriz/patologia , Fibroblastos/efeitos dos fármacos , Injeções , Fotocoagulação , Colagenase Microbiana/administração & dosagem , Colagenase Microbiana/toxicidade , Coelhos , Retina/efeitos dos fármacos , Retina/patologia , Fatores de Tempo , Corpo Vítreo/patologiaRESUMO
Animal experimental studies are reported in which the enzyme collagenase was used to digest the nucleus pulposus of the intervertebral disc in both dogs and monkeys. Studies in the same animals indicated a low risk toxicity. Clinical studies were started in 1979, in which the results in 82 patients are reported. All patients were subjected to rigid standards of selection. Of 78 patients followed, 80.4% had good results, 4.9% fair results, and 14.7% had poor results. There were no instances of toxicity. A double-blind study of 30 patients indicates clearcut superiority of collagenase over placebo in relieving the symptoms of herniated disc.
Assuntos
Disco Intervertebral/efeitos dos fármacos , Colagenase Microbiana/uso terapêutico , Animais , Cães , Haplorrinos , Humanos , Injeções Espinhais , Disco Intervertebral/diagnóstico por imagem , Disco Intervertebral/metabolismo , Colagenase Microbiana/toxicidade , RadiografiaRESUMO
This study reports the use of a purified form of the enzyme collagenase (Nucleolysin) to effect dissolution of the normal nucleus pulposus in a series of dogs and monkeys. A consistent dissolution effect has been observed. The toxicity of the enzyme to surrounding local tissues has been studied in the same species with an indication of safety in all areas other than intrathecal administration. A margin of safety in intrathecal administration between the effective dose and toxic dose has been suggested in the monkey. Mice LD50 studies and systemic toxicity studies in dogs show a satisfactory margin of safety for this enzyme. Guinea pig studies show no significant antigenicity.