RESUMO
In the current study, hemostatic compositions including a combination of chitosan and kaolin have been developed. Chitosan is a marine polysaccharide derived from chitins, a structural component in the shells of crustaceans. Both chitosan and kaolin have the ability to mediate a quick and efficient hemostatic effect following immediate application to injury sites, and thus they have been widely exploited in manufacturing of hemostatic composites. By combining more than one hemostatic agent (i.e., chitosan and kaolin) that act via more than one mechanism, and by utilizing different nanotechnology-based approaches to enhance the surface areas, the capability of the dressing to control bleeding was improved, in terms of amount of blood loss and time to hemostasis. The nanotechnology-based approaches utilized to enhance the effective surface area of the hemostatic agents included the use of Pluronic nanoparticles, and deposition of chitosan micro- and nano-fibers onto the carrier. The developed composites effectively controlled bleeding and significantly improved hemostasis and survival rates in two animal models, rats and rabbits, compared to conventional dressings and QuikClot® Combat Gauze. The composites were well-tolerated as demonstrated by their in vivo biocompatibility and absence of clinical and biochemical changes in the laboratory animals after application of the dressings.
Assuntos
Quitosana/administração & dosagem , Desenho de Fármacos , Hemostasia/efeitos dos fármacos , Hemostáticos/administração & dosagem , Caulim/administração & dosagem , Nanocompostos/administração & dosagem , Animais , Bandagens , Quitosana/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Hemorragia/tratamento farmacológico , Hemorragia/fisiopatologia , Hemostasia/fisiologia , Hemostáticos/síntese química , Caulim/síntese química , Masculino , Nanocompostos/química , Coelhos , Ratos , Ratos Sprague-DawleyRESUMO
CONTEXT: The World Health Organization set the recommended daily vitamin C intake, henceforth referred to as ascorbic acid (AA), on the basis of scurvy prevention. Double-blind AA depletion-repletion studies suggest that this recommended AA dose may be too low to prevent microvascular fragility. OBJECTIVES: (1) To conduct a systematic review and meta-analysis of controlled clinical trials on whether AA supplementation leads to a reduced gingival bleeding tendency, a manifestation of microvascular fragility; and (2) to relate AA plasma levels to retinal hemorrhaging, another manifestation of microvascular fragility. DATA SOURCES: Data were reviewed from 15 trials conducted in 6 countries with 1140 predominantly healthy participants with measures of gingival bleeding tendency, and from the National Health and Nutrition Examination Survey (NHANES) III of 8210 US residents with measures of retinal hemorrhaging. RESULTS: In clinical trials, AA supplementation reduced gingival bleeding tendency when estimated baseline AA plasma levels were < 28 µmol/L (standardized mean difference [SMD], -0.83; 95%CI, -1.16 to -0.49; P < 0.002). Supplementation with AA did not unequivocally reduce gingival bleeding tendency when baseline estimated AA plasma levels were >48 µmol/L or unknown (respective standardized mean differences: -0.23, 95%CI, -0.45 to -0.01, P < 0.05; and -0.56; 95%CI: -1.19 to 0.06, P < 0.08). In NHANES III, prevalence of both retinal hemorrhaging and gingival bleeding tendency increased when AA plasma levels were within the range that protects against scurvy (11-28 µmol/L; respective prevalence ratios adjusted for age and sex: 1.47; 95%CI: 1.22-1.77; and 1.64; 95%CI: 1.32-2.03; P < 0.001 for both). CONCLUSION: Consistent evidence from controlled clinical trials indicates that setting human AA requirements based on scurvy prevention leads to AA plasma levels that may be too low to prevent an increased gingival bleeding tendency. Gingival bleeding tendency and retinal hemorrhaging coincide with low AA plasma levels and thus may be reflective of a systemic microvascular pathology that is reversible with an increased daily AA intake.
Assuntos
Ácido Ascórbico , Gengiva , Hemorragia , Ácido Ascórbico/uso terapêutico , Gengiva/patologia , Hemorragia/fisiopatologia , Hemorragia/prevenção & controle , Humanos , Inquéritos Nutricionais , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Heat stress followed by an accompanying hemorrhagic challenge may influence hemostasis. We tested the hypothesis that hemostatic responses would be increased by passive heat stress, as well as exercise-induced heat stress, each with accompanying central hypovolemia to simulate a hemorrhagic insult. In aim 1, subjects were exposed to passive heating or normothermic time control, each followed by progressive lower-body negative pressure (LBNP) to presyncope. In aim 2 subjects exercised in hyperthermic environmental conditions, with and without accompanying dehydration, each also followed by progressive LBNP to presyncope. At baseline, pre-LBNP, and post-LBNP (<1, 30, and 60 min), hemostatic activity of venous blood was evaluated by plasma markers of hemostasis and thrombelastography. For aim 1, both hyperthermic and normothermic LBNP (H-LBNP and N-LBNP, respectively) resulted in higher levels of factor V, factor VIII, and von Willebrand factor antigen compared with the time control trial (all P < 0.05), but these responses were temperature independent. Hyperthermia increased fibrinolysis [clot lysis 30 min after the maximal amplitude reflecting clot strength (LY30)] to 5.1% post-LBNP compared with 1.5% (time control) and 2.7% in N-LBNP ( P = 0.05 for main effect). Hyperthermia also potentiated increased platelet counts post-LBNP as follows: 274 K/µl for H-LBNP, 246 K/µl for N-LBNP, and 196 K/µl for time control ( P < 0.05 for the interaction). For aim 2, hydration status associated with exercise in the heat did not affect the hemostatic activity, but fibrinolysis (LY30) was increased to 6-10% when subjects were dehydrated compared with an increase to 2-4% when hydrated ( P = 0.05 for treatment). Central hypovolemia via LBNP is a primary driver of hemostasis compared with hyperthermia and dehydration effects. However, hyperthermia does induce significant thrombocytosis and by itself causes an increase in clot lysis. Dehydration associated with exercise-induced heat stress increases clot lysis but does not affect exercise-activated or subsequent hypovolemia-activated hemostasis in hyperthermic humans. Clinical implications of these findings are that quickly restoring a hemorrhaging hypovolemic trauma patient with cold noncoagulant fluids (crystalloids) can have serious deleterious effects on the body's innate ability to form essential clots, and several factors can increase clot lysis, which should therefore be closely monitored.
Assuntos
Desidratação/fisiopatologia , Exercício Físico/fisiologia , Hemorragia/fisiopatologia , Hemostasia/fisiologia , Temperatura Alta/efeitos adversos , Adulto , Pressão Arterial/fisiologia , Transtornos de Estresse por Calor/fisiopatologia , Resposta ao Choque Térmico/fisiologia , Humanos , Hipertermia Induzida/métodos , Hipovolemia/fisiopatologia , Pressão Negativa da Região Corporal Inferior/métodos , MasculinoAssuntos
Comportamento Compulsivo/tratamento farmacológico , Hemorragia/complicações , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Sertralina/uso terapêutico , Comportamento Sexual/efeitos dos fármacos , Tálamo/fisiopatologia , Comportamento Compulsivo/etiologia , Hemorragia/fisiopatologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
This study examined characteristics and treatment persistence among patients prescribed oral anticoagulants (OACs) for stroke prevention in non-valvular atrial fibrillation (NVAF). We identified 15,244 patients (51.8% male, 72.7% aged ≥70) with NVAF and no prior OAC therapy who were prescribed apixaban (n = 1,303), rivaroxaban (n = 5,742), dabigatran (n = 1,622) or vitamin-K antagonists (VKAs, n = 6,577) between 1-Dec-2012 and 31-Oct-2014 in German primary care (IMS® Disease Analyzer). We compared OAC persistence using Cox regression over patients' entire follow-up and using a data-driven time-partitioned approach (before/after 100 days) to handle non-proportional hazards. History of stroke risk factors (stroke/transient ischaemic attack [TIA] 15.2%; thromboembolism 14.1%; hypertension 84.3%) and high bleeding risk (HAS-BLED score≥3 68.4%) was common. Apixaban-prescribed patients had more frequent history of stroke/TIA (19.7%) and high bleeding risk (72.6%) than other OACs. 12-month persistence rates were: VKA 57.5% (95% confidence interval (CI) 56.0-59.0%), rivaroxaban 56.6% (54.9-58.2%), dabigatran 50.1% (47.2-53.1%), apixaban 62.9% (58.8-67.0%). Over entire follow-up, compared to VKA, non-persistence was similar with apixaban (adjusted hazard ratio 1.08, 95% CI 0.95-1.24) but higher with rivaroxaban (1.21, 1.14-1.29) and dabigatran (1.53, 1.40-1.68). Using post-hoc time-partitioned approach: in first 100 days, non-persistence was higher with apixaban (1.37, 1.17-1.59), rivaroxaban (1.41, 1.30-1.53) and dabigatran (1.91, 1.70-2.14) compared to VKA. Compared to apixaban, rivaroxaban non-persistence was similar (1.03, 0.89-1.20), dabigatran was higher (1.39, 1.17-1.66). After 100 days, apixaban non-persistence was lower than VKA (0.66, 0.52-0.85); rivaroxaban (0.97, 0.87-1.07) and dabigatran (1.10, 0.95-1.28) were similar to VKA. Furthermore, rivaroxaban (1.46, 1.13-1.88) and dabigatran (1.67, 1.26-2.19) non-persistence was higher than apixaban. This study describes real-world observations on OAC use, particularly early apixaban use following approval for NVAF, in Germany. We identified potential differential OAC prescribing and higher persistence with apixaban than other OACs after 100 days' treatment. Larger studies are needed with longer follow-up to establish long-term patterns.
Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/uso terapêutico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Idoso , Fibrilação Atrial/fisiopatologia , Estudos de Coortes , Feminino , Alemanha , Hemorragia/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Atenção Primária à Saúde , Fatores de Risco , Tromboembolia/fisiopatologia , Vitamina K/antagonistas & inibidoresRESUMO
Major haemorrhage is a leading cause of death in critically ill or injured patients requiring medical retrieval and presents significant clinical and logistic challenges irrespective of patient location, primary pathophysiology or mode of transport. It is essential that all care providers involved in the retrieval patient pathway, including referring hospitals, ambulance services, retrieval teams and tertiary receiving centres, adopt a common approach to the management of this complex patient group through the use of retrieval-specific, integrated protocols. These should incorporate the latest clinical evidence base, recognise the differences between primary and inter-facility missions and clearly define the roles and responsibilities of the retrieval clinical coordinator. By unifying the response across services, the aim is to facilitate seamless transition of care with ongoing damage control resuscitation from point of referral, during transfer and on arrival at the receiving centre.
Assuntos
Prestação Integrada de Cuidados de Saúde/métodos , Serviços Médicos de Emergência/métodos , Hemorragia/terapia , Ressuscitação/métodos , Continuidade da Assistência ao Paciente/normas , Hemorragia/fisiopatologia , Humanos , Hipotensão/fisiopatologia , Hipotensão/terapia , Medicina Transfusional/métodos , Medicina Transfusional/tendênciasRESUMO
NEW FINDINGS: What is the central question of this study? Combined increases in skin and core temperatures reduce tolerance to a simulated haemorrhagic challenge. The aim of this study was to examine the separate and combined influences of increased skin and core temperatures upon tolerance to a simulated haemorrhagic challenge. What is the main finding and its importance? Skin and core temperatures increase during many occupational settings, including military procedures, in hot environments. The study findings demonstrate that both increased skin temperature and increased core temperature can impair tolerance to a simulated haemorrhagic challenge; therefore, a soldier's tolerance to haemorrhagic injury is likely to be impaired during any military activity that results in increased skin and/or core temperatures. Tolerance to a simulated haemorrhagic insult, such as lower-body negative pressure (LBNP), is profoundly reduced when accompanied by whole-body heat stress. The aim of this study was to investigate the separate and combined influence of elevated skin (Tskin ) and core temperatures (Tcore ) on LBNP tolerance. We hypothesized that elevations in Tskin as well as Tcore would both contribute to reductions in LBNP tolerance and that the reduction in LBNP tolerance would be greatest when both Tskin and Tcore were elevated. Nine participants underwent progressive LBNP to presyncope on four occasions, as follows: (i) control, with neutral Tskin (34.3 ± 0.5°C) and Tcore (36.8 ± 0.2°C); (ii) primarily skin hyperthermia, with high Tskin (37.6 ± 0.2°C) and neutral Tcore (37.1 ± 0.2°C); (iii) primarily core hyperthermia, with neutral Tskin (35.0 ± 0.5°C) and high Tcore (38.3 ± 0.2°C); and (iv) combined skin and core hyperthermia, with high Tskin (38.8 ± 0.6°C) and high Tcore (38.1 ± 0.2°C). The LBNP tolerance was quantified via the cumulative stress index (in millimetres of mercury × minutes). The LBNP tolerance was reduced during the skin hyperthermia (569 ± 151 mmHg min) and core hyperthermia trials (563 ± 194 mmHg min) relative to control conditions (1010 ± 246 mmHg min; both P < 0.05). However, LBNP tolerance did not differ between skin hyperthermia and core hyperthermia trials (P = 0.92). The lowest LBNP tolerance was observed during combined skin and core hyperthermia (257 ± 106 mmHg min; P < 0.05 relative to all other trials). These data indicate that elevated skin temperature, as well as elevated core temperature, can both contribute to reductions in LBNP tolerance in heat-stressed individuals. However, heat stress-induced reductions in LBNP tolerance are greatest in conditions when both skin and core temperatures are elevated.
Assuntos
Temperatura Corporal/fisiologia , Febre/fisiopatologia , Pele/fisiopatologia , Adulto , Feminino , Transtornos de Estresse por Calor/fisiopatologia , Resposta ao Choque Térmico/fisiologia , Hemorragia/fisiopatologia , Humanos , Hipertermia Induzida/métodos , Pressão Negativa da Região Corporal Inferior/métodos , Masculino , Síncope/fisiopatologiaRESUMO
OBJECTIVES: To report a series of consecutive patients that developed retroperitoneal hemorrhage (RPH) and persistent hypotension treated with endovascular approach. BACKGROUND: RPH is a rare complication of percutaneous cardiovascular interventions associated with high morbidity and mortality. The standard approach to treat this complication has been a conservative management for stable patients, and urgent vascular surgery for those with persistent hypovolemic shock. Percutaneous endovascular treatment has evolved as an alternative treatment option. METHODS: We implemented a management algorithm for patients with suspected RPH and persistent hypotension which embraced systematic use of emergency endovascular evaluation and treatment following clinical assessment without the use of non-invasive diagnostic testing. We report a series of 8 consecutive patients that developed RPH with persistent hypotension. RESULTS: Successful percutaneous treatment was achieved in all cases with the use of a covered stent. No patient required vascular surgery. The average blood transfusion was 3.4 ± 2.7 units per patient. There were no deaths; one patient experienced acute stent thrombosis that was successfully treated via endovascular approach. At 1-year follow-up, no further events were reported. CONCLUSION: The incorporation of a standardized protocol using only clinical evaluation followed by emergency percutaneous approach without delays attributed to non-invasive diagnostic work-up showed to be feasible and associated with favorable outcomes. © 2016 Wiley Periodicals, Inc.
Assuntos
Procedimentos Endovasculares , Hemodinâmica , Hemorragia/terapia , Hipotensão/terapia , Intervenção Coronária Percutânea/efeitos adversos , Choque Hemorrágico/terapia , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Angiografia , Procedimentos Clínicos , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Feminino , Hemorragia/diagnóstico por imagem , Hemorragia/etiologia , Hemorragia/fisiopatologia , Humanos , Hipotensão/diagnóstico , Hipotensão/etiologia , Hipotensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Espaço Retroperitoneal , Choque Hemorrágico/diagnóstico , Choque Hemorrágico/etiologia , Choque Hemorrágico/fisiopatologia , Stents , Resultado do TratamentoRESUMO
This study tested the hypothesis that the hypothalamus participates in the decompensatory phase of hemorrhage by measuring Fos immunoreactivity and by inhibiting neuronal activity in selected hypothalamic nuclei with lidocaine or cobalt chloride. Previously, we reported that inactivation of the arcuate nucleus inhibited, but did not fully prevent, the fall in arterial pressure evoked by hypotensive hemorrhage. Here, we report that hemorrhage (2.2 ml/100g body weight over 20 min) induced Fos expression in a high percentage of cells in the paraventricular, supraoptic and arcuate nuclei of the hypothalamus as shown previously. Lower densities of Fos immunoreactive cells were also found in the medial preoptic area (mPOA), anterior hypothalamus, lateral hypothalamus (LH), dorsomedial hypothalamus, ventromedial hypothalamus (VMH) and posterior hypothalamus. Bilateral injection of lidocaine (2%; 0.1 µl or 0.3 µl) or cobalt chloride (5mM; 0.3 µl) into the tuberal portion of the LH immediately before hemorrhage was initiated reduced the magnitude of hemorrhagic hypotension and bradycardia significantly. Lidocaine injection into the VMH also attenuated the fall in arterial pressure and heart rate evoked by hemorrhage although inactivation of the mPOA or rostral LH was ineffective. These findings indicate that hemorrhage activates neurons throughout much of the hypothalamus and that a relatively broad area of the hypothalamus, extending from the arcuate nucleus laterally through the caudal VMH and tuberal LH, plays an important role in the decompensatory phase of hemorrhage.
Assuntos
Hemorragia/fisiopatologia , Hipotálamo/metabolismo , Hipovolemia/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Bradicardia/patologia , Bradicardia/fisiopatologia , Cobalto/farmacologia , Modelos Animais de Doenças , Hemorragia/patologia , Hemostáticos/farmacologia , Hipotálamo/patologia , Hipovolemia/patologia , Lidocaína/farmacologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-DawleyRESUMO
On selection of external bleeding models for preclinical evaluation of the effectiveness of local haemostatic agents (literature review). To temporarily stop of external bleeding traditionally use a pressure bandage or tourniquet, but not for all types of wounds it is possible and appropriate to apply these dressings. In recent times there has been significant progress in the development and improvement of local haemostatic agents used for the first aid. There are currently conflicting information about their effectiveness, presented by various authors, requires standardization of experimental modelsforpre-clinical testing of medical devices in this class. Following a review of domestic and foreign literature DroDosed to standardize external bleeding model for assessing the effectiveness of local haemostatic agents.
Assuntos
Modelos Animais de Doenças , Hemorragia/tratamento farmacológico , Técnicas Hemostáticas , Hemostáticos/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Hemorragia/patologia , Hemorragia/fisiopatologia , HumanosRESUMO
Effective tissue hemostasis in periapical surgical site is important in the procedures. Plants with large amount of tannins may act as a local hemostatic agent. We aimed to compare the hemostatic effect of the extract of Quercus persica with one of the common hemostatic material used in periapical surgery. Six standardized bone holes were prepared in the calvaria of 5 Burgundy rabbits. Two hemostatic medicaments were tested for their hemostatic effect and were compared with control defects: Group 1, cotton pellet soaked in 15.5% ferric sulfate solution; Group 2, cotton pellet soaked in pure ethanolic extract of Q. persica. Bleeding score between the groups was compared. The ferric sulfate group exhibited significantly less bleeding than the other 2 groups. Q. persica was found to cause more hemostasis than the control group at 4 and 5 minutes but there were no significant differences between normal saline and Q. persica extract in bleeding control.
Assuntos
Compostos Férricos/uso terapêutico , Hemorragia/tratamento farmacológico , Hemostáticos/uso terapêutico , Extratos Vegetais/uso terapêutico , Quercus/química , Crânio/lesões , Animais , Compostos Férricos/administração & dosagem , Hemorragia/fisiopatologia , Hemostáticos/administração & dosagem , Extratos Vegetais/administração & dosagem , Coelhos , Taninos/administração & dosagem , Taninos/uso terapêuticoRESUMO
This study investigated the effects of the long-term dietary fish oil supplementation or the acute administration of the omega-3 fatty acid docosahexaenoic acid (DHA) in the mouse hemorrhagic cystitis (HC) induced by the anticancer drug cyclophosphamide (CYP). HC was induced in mice by a single CYP injection (300mg/kg ip). Animals received four different diets containing 10% and 20% of corn or fish oil, during 21days. Separated groups received DHA by ip (1µmol/kg) or intrathecal (i.t.; 10µg/site) routes, 1h or 15min before CYP. The behavioral tests (spontaneous nociception and mechanical allodynia) were carried out from 1h to 6h following CYP injection. Bladder inflammatory changes, blood cell counts and serum cytokines were evaluated after euthanasia (at 6h). Immunohistochemistry analysis was performed for assessing spinal astrocyte and microglia activation or GPR40/FFAR1 expression. Either fish oil supplementation or DHA treatment (ip and i.t.) markedly prevented visceral pain, without affecting CYP-evoked bladder inflammatory changes. Moreover, systemic DHA significantly prevented the neutrophilia/lymphopenia caused by CYP, whereas this fatty acid did not significantly affect serum cytokines. DHA also modulated the spinal astrocyte activation and the GPR40/FFAR1 expression. The supplementation with fish oil enriched in omega-3 fatty acids or parenteral DHA might be interesting nutritional approaches for cancer patients under chemotherapy schemes with CYP.
Assuntos
Ciclofosfamida/efeitos adversos , Cistite/prevenção & controle , Ácidos Graxos Ômega-3/farmacologia , Hemorragia/prevenção & controle , Dor/prevenção & controle , Animais , Cistite/induzido quimicamente , Cistite/complicações , Cistite/fisiopatologia , Ácidos Graxos Ômega-3/administração & dosagem , Hemorragia/induzido quimicamente , Hemorragia/complicações , Hemorragia/fisiopatologia , Masculino , Camundongos , Dor/etiologia , Peroxidase/metabolismo , Bexiga Urinária/enzimologiaRESUMO
Uncaria tomentosa is widely used in folk medicine for the treatment of numerous diseases, such as urinary tract disease. Hemorrhagic cystitis (HE) is an inflammatory condition of the bladder associated with the use of anticancer drugs such as cyclophosphamide (CYP). Sodium 2-mercaptoethanesulfonate (Mesna) has been used to prevent the occurrence of HE, although this compound is not effective in established lesions. It has been demonstrated that the purinergic system is involved in several pathophysiological events. Among purinergic receptors, P2X7 deserves attention because it is involved in HE induced by CYP and, therefore, can be considered a therapeutic target. The objective of this study was to investigate the potential therapeutic effect of the quinovic acid glycosides purified fraction (QAPF) from U. tomentosa in the mouse model of CYP-induced HE. Pretreatment with QAPF not only had a protective effect on HE-induced urothelial damage (edema, hemorrhage and bladder wet weight) but was also able to control visceral pain, decrease IL-1ß levels and down-regulates P2X7 receptors, most likely by inhibit the neutrophils migration to the bladder. This research clearly demonstrates the promising anti-inflammatory properties of QAPF, supporting its use as complementary therapy. QAPF represents a promising therapeutic option for this pathological condition.
Assuntos
Unha-de-Gato/química , Ciclofosfamida/efeitos adversos , Cistite/complicações , Cistite/tratamento farmacológico , Glicosídeos/uso terapêutico , Hemorragia/tratamento farmacológico , Triterpenos/uso terapêutico , Animais , Comportamento Animal , Cistite/induzido quimicamente , Cistite/fisiopatologia , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Hemorragia/induzido quimicamente , Hemorragia/complicações , Hemorragia/fisiopatologia , Interleucina-1beta/metabolismo , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Peroxidase/metabolismo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Receptores Purinérgicos P2X7/metabolismo , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Bexiga Urinária/efeitos dos fármacos , Vísceras/efeitos dos fármacosRESUMO
The effects and methods of acupuncture on promoting blood circulation and removing stasis and its importance for modern clinical acupuncture are explored and explained. The acupuncture theory of promoting blood circulation and removing stasis in Internal Canon of Yellow Emperor and the ancient medical scholars' knowledge of acupuncture for promoting blood circulation and removing stasis are traced, and then the principles and characteristics of acupuncture for promoting blood circulation and removing stasis are explored and summarized. The methods and common tools of prompting blood circulation and removing stasis of modern clinical acupuncture are summed up as well. It is considered that the treatment principles and methods of acupuncture for prompting blood and removing stasis deserve to be paid attention to and applied by all departments of clinical acupuncture.
Assuntos
Terapia por Acupuntura , Hemorragia/terapia , Terapia por Acupuntura/história , Circulação Sanguínea , China , Hemorragia/história , Hemorragia/fisiopatologia , História Antiga , Humanos , Medicina na Literatura , Qi/históriaRESUMO
Vector capsid dose-dependent inflammation of transduced liver has limited the ability of adeno-associated virus (AAV) factor IX (FIX) gene therapy vectors to reliably convert severe to mild hemophilia B in human clinical trials. These trials also identified the need to understand AAV neutralizing antibodies and empty AAV capsids regarding their impact on clinical success. To address these safety concerns, we have used a scalable manufacturing process to produce GMP-grade AAV8 expressing the FIXR338L gain-of-function variant with minimal (<10%) empty capsid and have performed comprehensive dose-response, biodistribution, and safety evaluations in clinically relevant hemophilia models. The scAAV8.FIXR338L vector produced greater than 6-fold increased FIX specific activity compared with wild-type FIX and demonstrated linear dose responses from doses that produced 2-500% FIX activity, associated with dose-dependent hemostasis in a tail transection bleeding challenge. More importantly, using a bleeding model that closely mimics the clinical morbidity of hemophilic arthropathy, mice that received the scAAV8.FIXR338L vector developed minimal histopathological findings of synovitis after hemarthrosis, when compared with mice that received identical doses of wild-type FIX vector. Hemostatically normal mice (n=20) and hemophilic mice (n=88) developed no FIX antibodies after peripheral intravenous vector delivery. No CD8(+) T cell liver infiltrates were observed, despite the marked tropism of scAAV8.FIXR338L for the liver in a comprehensive biodistribution evaluation (n=60 animals). With respect to the role of empty capsids, we demonstrated that in vivo FIXR338L expression was not influenced by the presence of empty AAV particles, either in the presence or absence of various titers of AAV8-neutralizing antibodies. Necropsy of FIX(-/-) mice 8-10 months after vector delivery revealed no microvascular or macrovascular thrombosis in mice expressing FIXR338L (plasma FIX activity, 100-500%). These preclinical studies demonstrate a safety:efficacy profile supporting an ongoing phase 1/2 human clinical trial of the scAAV8.FIXR338L vector (designated BAX335).
Assuntos
Dependovirus/genética , Fator IX/genética , Terapia Genética/métodos , Vetores Genéticos/farmacocinética , Hemofilia B/terapia , Hemorragia/prevenção & controle , Animais , Anticorpos Neutralizantes/análise , Capsídeo/química , Capsídeo/imunologia , Ensaios Clínicos como Assunto , Dependovirus/imunologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fator IX/metabolismo , Fator IX/farmacocinética , Expressão Gênica , Engenharia Genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/química , Hemofilia B/sangue , Hemofilia B/genética , Hemofilia B/fisiopatologia , Hemorragia/sangue , Hemorragia/genética , Hemorragia/fisiopatologia , Humanos , Fígado/imunologia , Fígado/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacocinética , Cauda , Distribuição Tecidual , Vírion/genéticaRESUMO
PURPOSE: To verify the effects of different catecholamines on volemic expansion and on the autonomic nervous system in rabbits that were subjected to hemorrhage. METHODS: Twenty four rabbits subjected to hemorrhage (with a 25% loss of blood volume) and were randomly divided into four experimental groups: 1) HEMO Group underwent replacement with their own blood in an equal volume; 2) SS Group underwent replacement with saline solution (SS) in a volume that corresponded to three times the removed blood volume; 3) ISP Group underwent replacement with SS and isoprenaline; 4) FNL Group underwent replacement with SS and phenylephrine. Spectral Analysis of the heart rate and heart rate variability were performed from the recorded data. Hematocrit was measured throughout the experiment. RESULTS: Replacement with SS and an α- or ß-agonist did not produce differences in the intravascular retention compared to replacement with SS alone. An analysis of HRV showed that the FNL group maintained the LF/HF ratio better than ISP and SS. CONCLUSIONS: No difference in vascular retention when α- or ß- agonists were added to SS during post-hemorrhagic recovery. The animals in the FNL group maintained the integrity of the autonomic response within normal physiological standards during hemorrhagic stress.
Assuntos
Volume Sanguíneo/efeitos dos fármacos , Catecolaminas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hemorragia/fisiopatologia , Cloreto de Sódio/farmacologia , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Transfusão de Sangue Autóloga , Análise de Fourier , Frequência Cardíaca/fisiologia , Hematócrito , Hemorragia/etiologia , Hemorragia/terapia , Isoproterenol/farmacologia , Fenilefrina/farmacologia , Coelhos , Distribuição Aleatória , Valores de Referência , Reprodutibilidade dos Testes , Análise Espectral , Fatores de TempoRESUMO
PURPOSE: To verify the effects of different catecholamines on volemic expansion and on the autonomic nervous system in rabbits that were subjected to hemorrhage. METHODS: Twenty four rabbits subjected to hemorrhage (with a 25% loss of blood volume) and were randomly divided into four experimental groups: 1) HEMO Group underwent replacement with their own blood in an equal volume; 2) SS Group underwent replacement with saline solution (SS) in a volume that corresponded to three times the removed blood volume; 3) ISP Group underwent replacement with SS and isoprenaline; 4) FNL Group underwent replacement with SS and phenylephrine. Spectral Analysis of the heart rate and heart rate variability were performed from the recorded data. Hematocrit was measured throughout the experiment. RESULTS: Replacement with SS and an α- or β-agonist did not produce differences in the intravascular retention compared to replacement with SS alone. An analysis of HRV showed that the FNL group maintained the LF/HF ratio better than ISP and SS. CONCLUSIONS: No difference in vascular retention when α- or β- agonists were added to SS during post-hemorrhagic recovery. The animals in the FNL group maintained the integrity of the autonomic response within normal physiological standards during hemorrhagic stress. .
Assuntos
Animais , Coelhos , Volume Sanguíneo/efeitos dos fármacos , Catecolaminas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hemorragia/fisiopatologia , Cloreto de Sódio/farmacologia , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Transfusão de Sangue Autóloga , Análise de Fourier , Hematócrito , Frequência Cardíaca/fisiologia , Hemorragia/etiologia , Hemorragia/terapia , Isoproterenol/farmacologia , Fenilefrina/farmacologia , Distribuição Aleatória , Valores de Referência , Reprodutibilidade dos Testes , Análise Espectral , Fatores de TempoRESUMO
Massive haemorrhage requires massive transfusion (MT) to maintain adequate circulation and haemostasis. For optimal management of massively bleeding patients, regardless of aetiology (trauma, obstetrical, surgical), effective preparation and communication between transfusion and other laboratory services and clinical teams are essential. A well-defined MT protocol is a valuable tool to delineate how blood products are ordered, prepared, and delivered; determine laboratory algorithms to use as transfusion guidelines; and outline duties and facilitate communication between involved personnel. In MT patients, it is crucial to practice damage control resuscitation and to administer blood products early in the resuscitation. Trauma patients are often admitted with early trauma-induced coagulopathy (ETIC), which is associated with mortality; the aetiology of ETIC is likely multifactorial. Current data support that trauma patients treated with higher ratios of plasma and platelet to red blood cell transfusions have improved outcomes, but further clinical investigation is needed. Additionally, tranexamic acid has been shown to decrease the mortality in trauma patients requiring MT. Greater use of cryoprecipitate or fibrinogen concentrate might be beneficial in MT patients from obstetrical causes. The risks and benefits for other therapies (prothrombin complex concentrate, recombinant activated factor VII, or whole blood) are not clearly defined in MT patients. Throughout the resuscitation, the patient should be closely monitored and both metabolic and coagulation abnormalities corrected. Further studies are needed to clarify the optimal ratios of blood products, treatment based on underlying clinical disorder, use of alternative therapies, and integration of laboratory testing results in the management of massively bleeding patients.
Assuntos
Transfusão de Sangue , Hemorragia/terapia , Transtornos da Coagulação Sanguínea/etiologia , Fatores de Coagulação Sanguínea/uso terapêutico , Hemorragia/sangue , Hemorragia/fisiopatologia , Humanos , Tromboelastografia , Ácido Tranexâmico/uso terapêuticoRESUMO
BACKGROUND: As all anticoagulants, apixaban exposes to a bleeding risk, thus an effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), and fibrinogen concentrate (Fib) to reverse apixaban in a rabbit model of bleeding and thrombosis. METHODS: After a dose-ranging study to assess the minimal amount of apixaban increasing bleeding, 63 anaesthetized rabbits were randomized into 5 groups: control (saline), apixaban (apixaban and saline), rFVIIa (apixaban and rFVIIa), PCC (apixaban and PCC) and fibrinogen (apixaban and Fib). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis detected as cyclic flow reductions (CFRs) within 20 min. A number of parameters were recorded through ear immersion bleeding time (BT), clotting times (CT), thrombelastography, and thrombin generation time (TGT). Ultimately, a hepatosplenic section was performed to evaluate as primary endpoint the blood loss in 15 min. RESULTS: Apixaban increased blood loss (11.6 ± 3 g vs. 8.3 ± 3 g for control, p < 0.0003), lengthened BT, the prothrombin time (PT), thrombelastographic CT and decreased thrombin generation. Only rFVIIa reduced BT yet failed to improve blood loss. PCC and rFVIIa both shortened the PT, CT in thrombelastographic, and lag time in TGT. Fib improved clot firmness, enhanced thrombin generation but increased bleeding. Regarding safety, neither rFVIIa, PCC, nor Fib increased CFRs. CONCLUSION: rFVIIa, PCC, and Fib failed to reverse apixaban-induced bleeding. They only improved several laboratory parameters.
Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Fator VIIa/uso terapêutico , Fibrinogênio/uso terapêutico , Hemorragia/tratamento farmacológico , Pirazóis/toxicidade , Piridonas/toxicidade , Trombose/tratamento farmacológico , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Hemorragia/induzido quimicamente , Hemorragia/fisiopatologia , Masculino , Pirazóis/antagonistas & inibidores , Piridonas/antagonistas & inibidores , Coelhos , Proteínas Recombinantes/uso terapêutico , Trombose/induzido quimicamente , Trombose/fisiopatologiaRESUMO
Simulated haemorrhage, e.g. lower body negative pressure (LBNP), reduces central blood volume and mean arterial pressure, while ventilation increases. Passive whole-body heat stress likewise increases ventilation. The objective of this project was to test the hypothesis that ventilatory responses to reductions in central blood volume and arterial pressure during simulated haemorrhage are enhanced when individuals are heat stressed rather than normothermic. Eight healthy men (34 ± 9 years old, 176 ± 6 cm tall and 80.2 ± 4.2 kg body weight) underwent a simulated haemorrhagic challenge via LBNP until presyncope on two separate occasions, namely normothermic control and whole-body heat-stress trials. Baseline ventilation and core and mean skin temperatures were not different between trials (all P > 0.05). Prior to LBNP, heat stress increased core (from 36.8 ± 0.2 to 38.2 ± 0.2°C, P < 0.05) and mean skin temperatures (from 33.9 ± 0.5 to 38.1 ± 0.6°C, P < 0.05), as well as minute ventilation (from 8.01 ± 2.63 to 13.68 ± 6.68 l min(-1), P < 0.01). At presyncope, mean arterial pressure and middle cerebral artery blood velocity decreased in both trials (P < 0.05). At presyncope, ventilation increased to 23.22 ± 6.78 (P < 0.01) and 25.88 ± 10.16 l min(-1) (P < 0.01) in the normothermic and hyperthermic trials, respectively; however, neither the increase in ventilation from the pre-LBNP period nor the absolute ventilation was different between normothermic and hyperthermic trials (P > 0.05). These data suggest that the increase in ventilation during simulated haemorrhage induced via LBNP is not altered in heat-stressed humans.