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KEY MESSAGE: The widely divergent species 4xTrifolium ambiguum and 2xT.occidentale are inter-fertile long after speciation (including polyploidisation) has occurred. Tri-species hybrids (T. repens × T. ambiguum × T. occidentale) have the potential to achieve introgression of stress resistant traits from both wild species into white clover. Trifolium ambiguum and T. occidentale are geographically, adaptionally and phenotypically contrasting species in the white clover section (Trifoliastrum) of the genus. T. ambiguum occurs as a high-altitude polyploid series (2x, 4x, 6x) in W Asia and NE Europe. T. occidentale is a diploid coastal species, occurring at sea level in W Europe. This study investigated hybridisation between 4xT. ambiguum and 2xT. occidentale and considered the significance of the hybrids for introgression breeding of white clover. Partially fertile F1 hybrids between 4xT. ambiguum and 2x and 4xT. occidentale were generated by embryo rescue. Hybrid plant morphology and fertility varied widely and hybrids generally expressed traits from both species. Advanced generation (F2-F5) 4x hybrids were highly fertile and constitute a new synthetic allotetraploid species. FISH analyses of 4x hybrids showed multivalent chromosome configurations with homoeologous associations between T. ambiguum and T. occidentale chromosomes. Crosses of the hybrids with T. repens produced fertile tri-species progeny. These very divergent species remain inter-fertile long after speciation (including polyploidisation) has occurred. Tri-species hybrids have the potential to achieve introgression of stress resistance traits from both wild species into white clover.
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Genoma de Planta , Hibridização Genética , Melhoramento Vegetal/métodos , Poliploidia , Trifolium/genética , Genótipo , Geografia , Fenótipo , Trifolium/crescimento & desenvolvimentoRESUMO
BACKGROUND: Labiaplasty is an increasingly popular surgical intervention but little is known about the characteristics and motivation of women who seek the procedure or the psychosexual outcome. METHOD: A total of 55 women seeking labiaplasty were compared with 70 women who did not desire labiaplasty. Various general measures of psychopathology as well as specific measures (Genital Appearance Satisfaction; Cosmetic Procedure Screening for labiaplasty) were used. Labia measurements of the women seeking labiaplasty were also obtained. RESULTS: Women seeking labiaplasty did not differ from controls on measures of depression or anxiety. They did, however, express increased dissatisfaction towards the appearance of their genitalia, with lower overall sexual satisfaction and a poorer quality of life in terms of body image. Women seeking labiaplasty reported a significantly greater frequency of avoidance behaviours on all the domains assessed, and greater frequency of safety-seeking behaviours for most of the domains. Key motivations reported for labiaplasty were categorized as cosmetic, functional or sexual. Of the 55 women seeking labiaplasty, 10 met diagnostic criteria for body dysmorphic disorder. CONCLUSIONS: This is the first controlled study to describe some of the characteristics and motivations of women seeking labiaplasty. We identified a wide range of avoidance and safety-seeking behaviours, which occurred more frequently in the labiaplasty group than the control group. These could be used clinically as part of a psychological intervention for women seeking labiaplasty.
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Transtornos Dismórficos Corporais/epidemiologia , Imagem Corporal/psicologia , Motivação , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Cirurgia Plástica/psicologia , Vulva/cirurgia , Adolescente , Adulto , Ansiedade/epidemiologia , Aprendizagem da Esquiva , Transtornos Dismórficos Corporais/psicologia , Estudos de Casos e Controles , Depressão/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , Comportamento de Redução do Risco , Índice de Gravidade de Doença , Comportamento Sexual/psicologia , Cirurgia Plástica/tendências , Inquéritos e Questionários , Fatores de Tempo , Vulva/anatomia & histologia , Vulva/fisiopatologia , Adulto JovemRESUMO
As research evolves in prodromal AD, the need to validate sufficiently sensitive outcome measures, e.g. the Alzheimer's Disease Composite Score (ADCOMS) is clear. In the LipiDiDiet randomized trial in prodromal AD, cognitive decline in the study population was much less than expected in the timeframe studied. While the primary composite endpoint was insufficiently sensitive to detect a difference in the modified intention to treat population, the per-protocol population showed less decline in the active than the control group, indicating better treatment effects with regular product intake. These results were further strengthened by significant benefits on secondary endpoints of cognition and function, and brain atrophy. The present post-hoc analysis investigated whether ADCOMS could detect a difference between groups in the LipiDiDiet population (138 active, 140 control). The estimated mean change in ADCOMS from baseline (standard error) was 0.085 (0.018) in the active and 0.133 (0.018) in the control group; estimated mean treatment difference -0.048 (95% confidence intervals -0.090, -0.007; p=0.023), or 36% less decline in the active group. This suggests ADCOMS identified the cognitive and functional benefits observed previously, confirming the sensitivity of this composite measure.
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Atividades Cotidianas , Doença de Alzheimer/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Testes Neuropsicológicos , Avaliação de Resultados em Cuidados de Saúde , Fosfolipídeos/uso terapêutico , Sintomas Prodrômicos , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Cognição , Progressão da Doença , Humanos , Testes de Estado Mental e Demência , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Preliminary information has suggested that megestrol acetate leads to appetite stimulation and nonfluid weight gain in patients with breast cancer, other cancers, and AIDS. Pursuant to this, we developed a randomized, double-blind, placebo-controlled trial of megestrol acetate in patients with cancer-associated anorexia and cachexia. We randomly assigned 133 eligible patients to receive 800 mg of megestrol acetate per day or a placebo. Patients assigned to megestrol acetate more frequently reported improved appetite (P = .003) and food intake (P = .009) when compared with patients receiving the placebo. A weight gain of 15 lb or more over baseline was seen in 11 of 67 (16%) patients receiving megestrol acetate compared with one of 66 (2%) given the placebo (P = .003). Patients receiving megestrol acetate reported significantly less nausea (13% vs. 38%; P = .001) and emesis (8% vs. 25%, P = .009). No clinically or statistically significant toxic reactions were ascribed to megestrol acetate, with the exception of mild edema. This study convincingly demonstrated that megestrol acetate can stimulate appetite and food intake in patients with anorexia and cachexia associated with cancer, leading to significant weight gain in a proportion of such patients.
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Anorexia/tratamento farmacológico , Caquexia/tratamento farmacológico , Transtornos da Alimentação e da Ingestão de Alimentos/tratamento farmacológico , Megestrol/análogos & derivados , Neoplasias/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Anorexia/etiologia , Antineoplásicos/uso terapêutico , Apetite/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Caquexia/etiologia , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Seguimentos , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Megestrol/uso terapêutico , Megestrol/toxicidade , Acetato de Megestrol , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
An alternating regimen for the treatment of extensive-disease small-cell lung cancer (SCLC) was compared with standard treatment with cyclophosphamide, doxorubicin, and vincristine (CAV) in 170 patients. Overall severity of toxicity was similar in both arms, with four toxic deaths in each arm (4.7%). Response results were also similar, with 54% complete and partial responses with the standard regimen and 53% complete and partial responses with the alternating regimen. Median survival time was 6.9 months with the standard regimen and 9.2 months with the alternating regimen (P = .078). The 2-year survival rate was 1.2% for the standard regimen and 4.7% for the alternating regimen. Survival benefit for treatment with the alternating regimen reached statistical significance only in those subsets of patients with poorer prognosis (male sex, performance status 3, liver metastases, bone marrow metastases, and oat cell histologic subtype).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Células Pequenas/mortalidade , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
PURPOSE: To evaluate the efficacy of three hormonal manipulations in the palliation of chemoresistant ovarian cancer, and to analyze the results in the light of other clinical trials. PATIENTS AND METHODS: Three sequential phase II trials were performed in patients with refractory epithelial ovarian carcinoma, using high-dose megestrol acetate (800 mg/d for 30 days, then 400 mg/d), high-dose tamoxifen (80 mg/d for 30 days, then 40 mg/d), and aminoglutethimide (1 g/d plus tapering doses of hydrocortisone). Results were compared with those described in the world literature from trials of the same or similar agents. RESULTS: No responses were seen among 30 assessable patients treated with megestrol acetate, and most (but not all) similar trials have reported low response rates. Five responses (17%) were seen among 29 patients treated with tamoxifen. Two responses exceeded 5 years in duration. No responses were seen among 15 patients treated with aminoglutethimide. CONCLUSION: Antiestrogen therapy may offer the possibility of useful and, occasionally, long-term palliation of refractory epithelial ovarian carcinoma, with little toxicity. There may be a trend toward a dose-response effect, which represents a suitable topic for a future prospective trial.
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Aminoglutetimida/uso terapêutico , Megestrol/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Cuidados Paliativos , Tamoxifeno/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Carcinoma/tratamento farmacológico , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Hidrocortisona/uso terapêutico , Megestrol/uso terapêutico , Acetato de MegestrolRESUMO
PURPOSE: Vaginal dryness and dyspareunia are significant estrogen-depletion symptoms that affect many breast cancer survivors. The present trial was developed to evaluate the nonhormonal vaginal lubricating preparation, Replens, for alleviating these symptoms. MATERIALS AND METHODS: A double-blind, crossover, randomized clinical trial was developed. Patients received 4 weeks of Replens (Columbia Research Laboratories, Rockville Centre, NY) followed by a 1-week washout period followed by 4 weeks of a placebo lubricating product, or vice versa. Weekly patient-completed diaries were used for measuring efficacies and toxicities of therapy. RESULTS: The 45 assessable patients provided well-balanced treatment groups. During the first 4 weeks, average vaginal dryness decreased by 62% and 64% in the placebo and Replens groups, respectively (P = .3). Average dyspareunia scores also improved by 41% and 60%, respectively (P = .05). Crossover analysis indicated that the bulk of the beneficial effects appeared within the first 2 weeks of the first treatment and remained constant thereafter. Both treatments were relatively well tolerated. CONCLUSION: Both Replens and the placebo appear to substantially ameliorate vaginal dryness and dyspareunia in breast cancer survivors.
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Dispareunia/tratamento farmacológico , Vagina/efeitos dos fármacos , Cremes, Espumas e Géis Vaginais/uso terapêutico , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Lubrificação , Pessoa de Meia-Idade , Vagina/metabolismoRESUMO
PURPOSE: A minority of cancer survivors develops long-term postsurgical neuropathic pain. Based on evidence that capsaicin, the pungent ingredient in hot chili peppers, might be useful for treating neuropathic pain, we developed the present clinical trial. PATIENTS AND METHODS: Ninety-nine assessable patients with postsurgical neuropathic pain were entered onto this study. After stratification, patients were to receive 8 weeks of a 0.075% capsaicin cream followed by 8 weeks of an identical-appearing placebo cream, or vice versa. A capsaicin/placebo cream was to be applied to the painful site four times daily. Treatment evaluation was performed by patient-completed weekly questionnaires. RESULTS: During the first 8-week study period, the capsaicin-cream arm was associated with substantially more skin burning, skin redness, and coughing (P < .0001 for each). Nonetheless, treatment was stopped for patient refusal or toxicity just as often while patients were receiving the placebo as compared with the capsaicin. The capsaicin cream arm had substantially more pain relief (P = .01) after the first 8 weeks, with an average pain reduction of 53% versus 17%. On completion of the 16-week study period, patients were asked which treatment period was most beneficial. Of the responding patients, 60% chose the capsaicin arm, 18% chose the placebo arm, and 22% chose neither (P = .001). CONCLUSION: A topical capsaicin cream decreases postsurgical neuropathic pain and, despite some toxicities, is preferred by patients over a placebo by a three-to-one margin among those expressing a preference.
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Capsaicina/administração & dosagem , Neoplasias/cirurgia , Neuralgia/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Administração Tópica , Idoso , Capsaicina/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/etiologia , Pomadas , Medição da DorRESUMO
OBJECTIVES: The purpose of this study was to determine risk factors for adverse events following protamine administration after cardiopulmonary bypass. BACKGROUND: Intravenous protamine administration is associated with a risk of severe systemic reactions. However, risk factors for these events have not been well delineated, thus hampering development of preventive strategies. METHODS: A case-control study nested within a cohort of consecutive patients undergoing surgery requiring cardiopulmonary bypass was performed. The primary case definition included those events (pulmonary hypertensive and systemic hypotensive) occurring within 10 min of protamine administration in the absence of other measurable causes of hemodynamic compromise. RESULTS: Comparing the 53 cases to the 223 control subjects, three risk factors were independently associated with events (multivariable odds ratio [95% confidence interval]): neutral protamine Hagedorn insulin use (8.18 [2.08, 32.2]); fish allergy (24.5 [1.24, 482.3]), and a history of nonprotamine medication allergy (2.97 [1.25, 7.07]). These risk factors demonstrated an increasingly strong association with progressively more specific case definitions. An estimated 39% of cardiopulmonary bypass patients had one or more of these risk factors. Prior intravenous protamine, central venous pressure prior to protamine, preoperative ejection fraction and the need for inotropes when coming off bypass did not exhibit statistically significant associations with events (all p > 0.15). Prior protamine allergy was associated specifically with an increased risk of pulmonary hypertension (multivariable odds ratio 189; 95% confidence interval 13, 2,856). CONCLUSIONS: Immunologic factors are important in predisposing individuals to protamine reactions, and a substantial proportion of patients are at considerably increased risk Strategies to reduce the risk of protamine-associated events are needed.
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Ponte Cardiopulmonar , Antagonistas de Heparina/efeitos adversos , Protaminas/efeitos adversos , Estudos de Casos e Controles , Intervalos de Confiança , Hemodinâmica , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Período Pós-Operatório , Fatores de RiscoRESUMO
BACKGROUND: Several randomized trials have demonstrated superiority of memantine-cholinesterase inhibitor combination therapy in patients with moderate to severe Alzheimer's disease, yet a recent publication reported no additional benefit of add-on memantine therapy compared to donepezil alone. OBJECTIVES: In this post hoc analysis, we sought to re-evaluate the results from the DOMINO study using common statistical tools and to apply the statistical models used in the DOMINO study to a pooled data set of 24- to 28-week randomized trials of memantine in patients with moderate to severe AD in order to explore the robustness of the primary findings from the DOMINO study. DESIGN: DOMINO study: Randomized, double-blind, placebo-controlled trial (Current Controlled Trial number, ISRCTN49545035); Memantine Clinical Trial Program: Pooled analysis from four randomized, double-blind, placebo-controlled trials. SETTING: DOMINO study: United Kingdom; Memantine Clinical Trial Program: Multinational. PARTICIPANTS: DOMINO study: 295 participants enrolled during the period of February 2008 to March 2010; Memantine Clinical Trial Program: 1417 participants enrolled between August 1998 and January 2008. MEASUREMENTS: In the DOMINO study, the co-primary outcome measures were scores on the Standardized Mini-Mental State Examination and the Bristol Activities of Daily Living Scale; Neuropsychiatric Inventory was a secondary measure. In the Memantine Clinical Trial Program, outcome measures included the Severe Impairment Battery, the 19-item Alzheimer's Disease Cooperative Study - Activities of Daily Living scale, Neuropsychiatric Inventory, and a 4-Domain Composite Index (Z-score; a post hoc assessment). RESULTS: Both the pooled analysis of the Memantine Clinical Trial Program and the re-assessment of the DOMINO study with common statistical tools showed that adding memantine to donepezil therapy is associated with benefits across multiple clinical domains. CONCLUSIONS: The current analyses suggest that the results of the DOMINO study do not contradict previous studies which investigated the combined effects of memantine-cholinesterase inhibitor treatment.
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BACKGROUND: Optimized scales and composite outcomes have been proposed as a way to more accurately measure Alzheimer's disease related decline. AFFITOPE® AD02, is an amyloid-beta (Aß)-targeting vaccine to elicit anti-Aß antibodies. IMM-AD04, commonly known as Alum, originally designated as a control agent, appeared to have disease-modifying activity in a multicenter, parallel group phase II study in early AD patients. OBJECTIVES: To develop adapted outcomes for cognition, function and a composite scale with improved sensitivity to decline and treatment effects in early AD (mild plus prodromal AD) based on historical data and to assess these adapted outcomes in this phase II study. DESIGN: Data from public datasets was analyzed using a partial least squares model in order to identify an optimally weighted cognitive outcome, Adapted ADAS-cog, and an optimally weighted ADL outcome, Adapted ADCS-ADL which were prospectively defined as co-primary endpoints for the study and were also combined into a composite scale. Data from 162 patients in the placebo groups of ADCS studies and 156 mild patients in the ADNI I study were pooled for this analysis. The Adapted ADAS-cog scale considered 13 ADAS-cog items as well as several Neuropsychological test items and CogState items, the Adapted ADCS-ADL considered all ADCS-ADL items. After the pre-specified analyses were complete, additional adapted and composite scales were investigated in a post-hoc manner. Evaluation of the adapted and composite scales was performed on Phase II trial data for AFFITOPE® AD02 (AFF006, Clinical Trial Identifier: NCT01117818) and historic data in early AD. Least square means, standard deviations, and least squares mean to standard deviation ratios were compared among adapted and composite scales and traditional scales for the 5 treatment groups in the phase II study and overall for the historic data. Treatment effect sizes and p-values were also compared for the phase II study. RESULTS: Cognitive items that were selected for the adapted cognitive scale (aADAS-cog) and had the highest weights were Word Recall, Word Recognition, and Orientation. Delayed Word Recall and Digit Cancellation were among the items excluded due to lack of improved sensitivity to decline. Highly weighted ADL items included in the adapted functional scale (aADCS-ADL) were using the telephone, traveling, preparing a meal/snack, selecting clothing, shopping and using appliances. Excluded items were primarily basic ADLs such as eating, walking, toileting and bathing. Comparisons between traditional scales and primary outcome adapted scales show improved sensitivity to group differences with the adapted scales in the phase II trial. Most of the improvement in the sensitivity of the aADAS-cog and the aADCS-ADL is due to a larger treatment difference observed rather than the improved sensitivity to decline in the comparison groups. CONCLUSION: To our knowledge, this is the first study to prospectively use optimized scales as primary endpoints and to demonstrate the superior power of optimized scales and composites in early disease. Although it is possible that the treatment difference between randomized groups is due to a factor other than the treatment itself, for instance baseline imbalance, the improved power to detect these differences still argues in favor of the adapted scales. The issue of oversensitivity to detect treatment effects is controlled by selection of the alpha level for significance, and in our case will happen less than 5% of the time. Clinical relevance of the treatment difference should be assessed separately from statistical significance, and in this phase II study, is supported by significant or similar sizes of effect on function, behaviour and quality of life outcomes, which are important to patients and caregivers.
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OBJECTIVES: The primary objective of this clinical trial was to assess the clinical activity of various doses and formulations of AFFITOPE® AD02 following its repeated s.c. administration to patients with early Alzheimer´s disease (AD), based on the evaluation of cognitive and functional domains. DESIGN: It was designed as a randomized, placebo-controlled, parallel group, double blind, multicenter phase II trial with 10 regular outpatient visits and 6 telephone interviews. SETTING: The trial was performed at 32 sites in six countries. PARTICIPANTS: A total of 332 patients were enrolled and 265 patients completed the trial in 3 treatment groups with AD02 and 2 control groups with aluminum oxihydroxide, here named IMM-AD04. Patients were randomly assigned to 5 groups: two doses of IMM-AD04, 25µg AD02 (in two different formulations) and 75µg AD02. INTERVENTION: At months 0, 1, 2, 3, 9 and 15, each patient received a single s.c. injection of the corresponding preparations of AFFITOPE® AD02 or the control, IMM-AD04. MEASUREMENTS: Co-primary efficacy outcomes included a measure of cognition (adapted AD Assessment Scale cognitive [aADAS cog]), and a measure of function (adapted AD Cooperative Trial Activities of Daily Living [aADCS-ADL]). A primary composite score was the sum of these two scores. RESULTS: Treatments were generally well tolerated and adverse events (AEs) were seen at similar rates across all treatment groups, with the exception that more injection site reactions were seen in the groups with a higher level of adjuvant. None of the AD02 groups showed a benefit over the IMM-AD04 controls for primary or exploratory efficacy outcomes. The control groups differed on aADCS-ADL and therefore couldn't be pooled (p=0.039). Unexpectedly, the 2mg IMM-AD04 showed statistically significant effects over the other groups on several clinical outcomes including: aADAS-cog, aADL, Composite, ADAS-cog, CDR-sb, and QOL-AD Caregiver as well as two biomarker outcomes: right and total hippocampal volume (all p<0.05). 48% of patients in the IMM-AD04 2mg group had no decline in the composite outcome over 18 months compared to 17%-31% in the other groups, which is consistent with historical placebo groups. CONCLUSION: No significant treatment effects were seen for the investigational compound AD02. However, the IMM-AD04 2mg group showed statistically significant effects over all other groups on several clinical outcomes as well as a slowing of decline on right hippocampal volume. The data support further development of IMM-AD04 as a disease modifying agent in line with EMA/FDA definitions.
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Anorexia and cachexia are common clinical problems of many patients with advanced cancer. Approximately 20 years ago, a controlled, clinical study demonstrated that dexamethasone could stimulate appetites of patients with advanced gastrointestinal cancer without causing any apparent effect on patient weight or survival. More recently, two double-blind, placebo-controlled trials investigated cyproheptadine and megestrol acetate in patients with cancer anorexia/cachexia. The first of these studies suggested that cyproheptadine could mildly stimulate appetite without causing any discernible effect on patient weight. Megestrol acetate, on the other hand, can clearly cause an increase in patient-perceived appetite and food intake and can also lead to substantial nonfluid weight gain in a proportion of patients with cancer anorexia/cachexia. Ongoing studies have been designed to better study the appetite-enhancing effects of megestrol acetate. In addition, current studies are evaluating the effect of the drug hydrazine sulfate on the appetite and weight status of patients with advanced lung or colon cancer.
Assuntos
Anorexia/tratamento farmacológico , Caquexia/tratamento farmacológico , Neoplasias/complicações , Anorexia/etiologia , Caquexia/etiologia , Ciproeptadina/uso terapêutico , Dexametasona/uso terapêutico , Método Duplo-Cego , Humanos , Hidrazinas/uso terapêutico , Neoplasias/patologia , Aumento de Peso/efeitos dos fármacosRESUMO
For patients with heparin-induced platelet activation, reexposure to heparin can result in profound thrombocytopenia, intravascular thrombosis, and hemorrhage. We compared the ability of aspirin to that of iloprost (ZK36374), an analogue of prostacyclin, in preventing heparin-induced platelet activation and thus permitting a cardiac operation in a patient with heparin-induced platelet activation. Despite abolishing thromboxane A2 synthesis, aspirin (4 mmol/L) failed to prevent either in vitro heparin-induced platelet aggregation (65.0% without versus 59% with aspirin) or carbon 14-serotonin release (81.8% without versus 59.7% with aspirin). In contrast, iloprost (0.01 mumol/L) prevented both in vitro heparin-induced platelet aggregation (65% without versus 5.0% with iloprost) and release (81.8% without versus 0% with iloprost). Consequently, a continuous infusion of iloprost was begun before administration of heparin, continued throughout cardiopulmonary bypass, and discontinued 15 minutes after administration of protamine. The whole blood platelet count (209,000/microliter) remained stable after intraoperative administration of heparin (238,000/microliter) and was 115,000/microliter after the operation. No spontaneous platelet aggregates were observed in samples of platelet-rich plasma after heparin administration, and no platelet transfusions were required. Plasma levels of platelet factor 4 rose from 27 to 725 ng/ml after heparin administration but then declined during bypass to 50 ng/ml. Beta thromboglobulin levels only rose from 92 to 496 ng/ml with administration of heparin. Fibrinopeptide A levels fell from 72 to 22 ng/ml after heparin and remained stable throughout bypass. The template bleeding time was 7.5 minutes preoperatively and 8.0 minutes postoperatively. The postoperative chest tube drainage (12 hours) was 475 ml, and platelets responded normally to adenosine diphosphate. In conclusion, iloprost but not aspirin completely prevented heparin-induced platelet activation in vitro. Furthermore, iloprost effectively prevented this syndrome clinically, which permitted a safe cardiac operation in this patient with heparin-induced platelet activation.
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Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Procedimentos Cirúrgicos Cardíacos/métodos , Epoprostenol/uso terapêutico , Antagonistas de Heparina/uso terapêutico , Idoso , Feminino , Humanos , IloprostaRESUMO
The effects of cardiopulmonary bypass with bubble and membrane oxygenator systems on platelet function were studied in 26 patients who had elective coronary arterial bypass grafts. Fourteen patients were perfused with spiral coil membrane oxygenator systems, 12 with bubble oxygenator systems. During and after bypass, platelet counts decreased in both groups; however, when corrected for dilution, platelet counts did not change significantly in patients perfused with membrane oxygenators and increased slightly but significantly in those perfused with membrane oxygenators and increased slightly but significantly in those perfused with bubble oxygenator systems. During and 1 hour after bypass, the concentration of adenosine diphosphate (ADP) required to cause complete aggregation increased in both groups. Plasma low affinity platelet factor 4 (LA-PF4) increased significantly during and after bypass in both groups. However, the concentration of platelet adenine nucleotides and LA-PF4, measured only in patients perfused with membrane oxygenator systems, did not change. Bleeding times increased postoperatively in both groups and 18 hour blood losses were similar. Cardiopulmonary bypass with membrane and bubble oxygenator systems causes qualitatively similar losses in sensitivity to ADP and similar increases in bleeding times. The mechanism by which platelets are altered during cardiopulmonary bypass in obscure but is not due to partial depletion of granule contents in patients perfused with membrane oxygenators.
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Plaquetas/fisiologia , Ponte Cardiopulmonar , Oxigenadores , Difosfato de Adenosina/análise , Trifosfato de Adenosina/análise , Plaquetas/análise , Humanos , Pessoa de Meia-Idade , Oxigenadores de Membrana , Contagem de Plaquetas , Fator Plaquetário 4/análiseRESUMO
Recurrent thrombocytopenia, thrombosis, or sudden death may develop in patients with heparin-induced thrombocytopenia who are reexposed to heparin. Three patients came to us in whom a diagnosis of heparin-induced thrombocytopenia had been made on the basis of clinical and serologic evidence; these patients required reexposure to heparin because of urgent cardiac surgery. Therefore, we evaluated the ability of iloprost (ZK36374), a new analogue of prostacyclin, to prevent heparin-dependent activation of platelets and thereby permit obligatory heparinization for safe extracorporeal circulation. Before operation, we demonstrated that iloprost prevented both heparin-dependent platelet aggregation and tritiated (3H)-serotonin release in vitro. Therefore a continuous infusion of iloprost was begun 1 hour before heparinization and was continued throughout cardiopulmonary bypass and for an additional 15 minutes after protamine administration. The mean platelet count of 130,000/microliters before operation remained stable, and no spontaneous platelet aggregation was observed in samples of platelet-rich plasma obtained before cardiopulmonary bypass but after heparin administration. Similarly, after heparin administration but before bypass, platelet responsiveness to adenosine diphosphate remained unchanged when compared with preoperative values. Plasma levels of platelet factor 4 increased from 26 +/- 1 ng/ml (mean +/- standard error) to 843 +/- 383 ng/ml after heparin administration but actually decreased throughout cardiopulmonary bypass to 52 +/- 25 ng/ml. Beta-thromboglobulin levels increased from 103 +/- 16 to 244 +/- 94 ng/ml with heparinization. The mean bleeding time was 10.5 minutes preoperatively and 13.3 minutes postoperatively. The mean amount of postoperative chest tube drainage (duration: 12 hours) was 432 +/- 67 ml. Thus, despite the confirmed presence of heparin-dependent platelet-activating factor in the plasma of these three patients, iloprost prevented heparin-induced platelet activation during cardiopulmonary bypass while preserving platelet function, as would be desired for postoperative hemostasis.
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Ponte Cardiopulmonar , Fármacos Cardiovasculares/uso terapêutico , Epoprostenol/uso terapêutico , Heparina/efeitos adversos , Trombocitopenia/prevenção & controle , Adulto , Fibrinopeptídeo A/sangue , Humanos , Iloprosta , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas/efeitos dos fármacos , Fator Plaquetário 4/sangue , Trombocitopenia/induzido quimicamente , Tromboxano B2/sangueRESUMO
The value of red blood cell administration to increase oxygen carrying capacity is obvious to all clinicians. Nevertheless, there has never been a prospective, randomized, controlled study documenting the efficacy or conclusively defining the indications for red blood cell use. Considering the risks associated with allogeneic blood, careful consideration must be given before the administration of each unit of blood product.
Assuntos
Transfusão de Sangue , Eritrócitos , Humanos , Medição de Risco , Reação TransfusionalRESUMO
A directive from the Food and Drug Administration indicates that the use of plasma protein fraction (PPF) is contraindicated during cardiopulmonary bypass because of possible hypotension. Bradykinin has been implicated as the cause of this hypotension. Bradykinin levels were measured by radioimmunoassay in PPF and in 5% albumin and were found to be consistently elevated in the former and occasionally in the latter. The addition of PPF to pump primes resulted in significantly elevated levels of bradykinin, which rapidly cleared, indicating that extrapulmonary sites of bradykinin inactivation were efficient. The potential hypotensive effect of PPF was observed by determining the change in mean perfusion pressure in two groups of patients: one group with a 3,000 ml crystalloid prime and the other with a prime of 2,000 ml of crystalloid and 1,000 ml of PPF. There was no significant difference in the perfusion pressure between the two groups at any point, and the hypotensive effects seen in both groups were readily treated, suggesting that the directive against the use of PPF during cardiopulmonary bypass may be unnecessarily restrictive.
Assuntos
Proteínas Sanguíneas/administração & dosagem , Transfusão de Sangue , Bradicinina/sangue , Ponte Cardiopulmonar/efeitos adversos , Hipotensão/etiologia , Substitutos do Plasma/administração & dosagem , Albuminas/administração & dosagem , Pressão Sanguínea , Proteínas Sanguíneas/efeitos adversos , Bradicinina/efeitos adversos , Humanos , Substitutos do Plasma/efeitos adversos , Albumina Sérica Humana , Soroglobulinas , Cloreto de Sódio/administração & dosagemRESUMO
Heparin anticoagulation and its neutralization were monitored by three different techniques: a manual protamine titration, an automated activated coagulation time, and an automated protamine titration. All three techniques provided satisfactory information. The decision of which to use must be based on other considerations such as available manpower and cost of equipment. The effect of using the automated protamine titration test on heparin and protamine requirements, and on blood loss measured intraoperatively after bypass and in overnight chest bottle drainage in two groups of comparable patients undergoing coronary artery bypass operation was studied. The heparin requirements were similar (24,420 +/- 584 units, control group; 23,550 +/- 849 units, treatment group), but the protamine requirements were markedly different (429 +/- 14.7 mg, control; 258 +/- 10.4 mg, treatment; p < 0.05). There was no statistical difference in intraoperative blood loss or overnight chest bottle drainage.
Assuntos
Testes de Coagulação Sanguínea/métodos , Heparina/sangue , Protaminas/sangue , Autoanálise , Criança , Ponte de Artéria Coronária , Cardiopatias Congênitas/cirurgia , Hemorragia/diagnóstico , Humanos , Pessoa de Meia-Idade , Tempo de Coagulação do Sangue TotalRESUMO
For 11 patients with confirmed heparin-induced thrombocytopenia, we used reversible platelet inhibition with iloprost, a stable prostacyclin analogue, to permit safe heparin administration for cardiac (n = 9) or vascular (n = 2) operations. In vitro, iloprost (0.01 mumol/L) prevented both heparin-induced platelet aggregation and 14C-serotonin release in all patients. Therefore, intraoperatively, a continuous infusion of iloprost was started before administration of heparin and was continued until 15 minutes after administration of protamine. For cardiac patients, after heparin administration, the whole blood platelet count did not change (171,000 +/- 29,000/microL versus 174,000 +/- 29,000/microL, mean +/- standard error of the mean); no spontaneous platelet aggregation was observed, and plasma levels of the alpha-granule constituents platelet factor 4 and beta-thromboglobulin increased from 38 +/- 14 and 140 +/- 18 ng/mL to 591 +/- 135 and 235 +/- 48 ng/mL, respectively. Fibrinopeptide A levels actually decreased from 287 +/- 150 to 27 +/- 6 ng/mL. Furthermore, adenosine diphosphate-induced platelet activation was preserved, postoperative bleeding times were unchanged, and no heparin-related deaths occurred. Similar results were obtained in both vascular patients. We conclude that temporary platelet inhibition with iloprost now permits safe heparin administration in all patients with heparin-induced thrombocytopenia who require a cardiac or vascular operation.