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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
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: 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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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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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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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
The white clover ( Trifolium repens) nuclear genome (n = 2x = 16) is an important yet under-characterised genetic environment. We have developed simple sequence repeat (SSR) genetic markers for the white clover genome by mining an expressed sequence tag (EST) database and by isolation from enriched genomic libraries. A total of 2,086 EST-derived SSRs (EST-SSRs) were identified among 26,480 database accessions. Evaluation of 792 EST-SSR primer pairs resulted in 566 usable EST-SSRs. Of these, 335 polymorphic EST-SSRs, used in concert with 30 genomic SSRs, detected 493 loci in the white clover genome using 92 F1 progeny from a pair cross between two highly heterozygous genotypes--364/7 and 6525/5. Map length, as estimated using the joinmap algorithm, was 1,144 cM and spanned all 16 homologues. The R (red leaf) locus was mapped to linkage group B1 and is tightly linked to the microsatellite locus prs318c. The eight homoeologous pairs of linkage groups within the white clover genome were identified using 96 homoeologous loci. Segregation distortion was detected in four areas (groups A1, D1, D2 and H2). Marker locus density varied among and within linkage groups. This is the first time EST-SSRs have been used to build a whole-genome functional map and to describe subgenome organisation in an allopolyploid species, and T. repens is the only Trifolieae species to date to be mapped exclusively with SSRs. This gene-based microsatellite map will enable the resolution of quantitative traits into Mendelian characters, the characterisation of syntenic relationships with other genomes and acceleration of white clover improvement programmes.
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Mapeamento Cromossômico , Genoma de Planta , Repetições de Microssatélites/genética , Trifolium/genética , Cruzamentos Genéticos , Primers do DNA , Etiquetas de Sequências Expressas , Biblioteca GênicaRESUMO
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.
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Transfusão de Sangue , Eritrócitos , Humanos , Medição de Risco , Reação TransfusionalRESUMO
In this investigation the authors assessed what physicians do when planning for and delivering bad news to patients. Seventy-three physicians responded to a series of statements about the behaviors, thoughts, and feelings they might have had while preparing for and delivering bad medically-related news. Data were also obtained about how well they thought the transaction had gone, how much stress they had experienced, and what they thought the experience was like from the patient's perspective. Physicians reported that these transactions were only moderately stressful, with 18.1% and 18.7% indicating that preparation stress or delivery stress, respectively, were above the midpoint on the scale. Slightly over 42% of the sample indicated that the stress they experienced lasted from several hours to three or more days. Thirty-six delivery-related statements were typical (with endorsement rates of at least 80% in a given direction) for at least one of the two recall groups.
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Comunicação , Acontecimentos que Mudam a Vida , Relações Médico-Paciente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
Many cancer patients are undermedicated and inappropriately managed for pain, leading to a diminished quality of life. Patients with moderate to severe pain often require opioid analgesics. Recently published guidelines emphasize individualization of opioid treatment to provide the drug and route of administration that meet the needs of the particular patient. Intolerable side effects, ineffective pain relief, or a change in the patient's clinical status can dictate the need for a new pain management regimen. Physicians must be able to readily quantify relative analgesic potency when converting from one opioid to another or from one route of administration to another. Transdermal fentanyl (Duragesic) is an opioid agonist that has been shown to be safe and effective for the treatment of cancer pain. However, clinicians should realize that the manufacturer's recommendations for equianalgesic dosing of transdermal fentanyl may result in initial doses that are too low in some patients, and in a titration period that is too long. Under these circumstances, the patient is likely to experience unrelieved pain. An alternative dosing algorithm that considers both a review of the literature and our combined clinical experience with transdermal fentanyl should help clinicians individualize the treatment of pain.
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Analgésicos Opioides/administração & dosagem , Fentanila/administração & dosagem , Neoplasias/complicações , Dor/tratamento farmacológico , Dor/etiologia , Administração Cutânea , Algoritmos , HumanosRESUMO
This article reports the results of an investigation designed to obtain descriptive information about what typically transpires in bad news transactions between patients and physicians. A sample of 115 health care providers who were attending a 1-day workshop on palliative care issues responded to questions regarding bad news transactions between physicians and patients. Results indicated that giving the news in person, giving the news in a private place, having patient support providers present, and using a warm and caring tone are highly typical of bad news transactions, whereas exploring patient emotional reactions, relying on touch, delivering the news at the patient's pace, and providing written information are less typical. Nurses and physicians diverged in the perceptions about what typically transpires, suggesting that studies focusing only on physician reports or recommendations may be misleading. These data also point to the need to obtain other views of bad news transactions, and they argue for research designed to assess the relation between actual patient-physician encounters and subsequent patient-related outcomes.
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Cuidados Paliativos , Relações Médico-Paciente , Percepção Social , Revelação da Verdade , Adulto , Feminino , Humanos , Masculino , New England , Enfermeiras e Enfermeiros , Pesquisa em EnfermagemRESUMO
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
"Breakthrough pain" is a common clinical term that has not been conclusively defined or described. Breakthrough pain is a transitory flare of pain experienced when baseline pain has been reduced to a mild or moderate level. Breakthrough pain may be characterized by its relationship to a fixed around-the-clock (ATC) opioid dose, rapid onset and short duration, precipitating events, predictability, pathophysiology (with nociceptive pain being most easily controlled), and etiology. The only prospective study of breakthrough pain conducted to date found a 63% prevalence of breakthrough pain in cancer patients referred to a pain service. Although prevalence figures from other studies vary widely, partly due to the populations chosen, all of the studies verify that breakthrough pain is a serious problem in cancer patients. In fact, several studies have listed incident pain, a subset of breakthrough pain, as a predictor of poor response to analgesic therapy. Breakthrough pain is currently managed with oral or parenteral breakthrough pain medications given in addition to the ATC analgesic regimen. The ATC dosage may also be increased until limited by side effects. Newer agents with a more rapid onset of analgesia and shorter duration of effect may help in the management of breakthrough pain.
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Neoplasias/fisiopatologia , Dor/fisiopatologia , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Esquema de Medicação , Previsões , Humanos , Injeções Intravenosas , Nociceptores/fisiopatologia , Dor/classificação , Dor/tratamento farmacológico , Clínicas de Dor , Prevalência , Prognóstico , Estudos Prospectivos , Encaminhamento e ConsultaAssuntos
Anestesia Geral , Procedimentos Cirúrgicos Cardíacos , Avaliação de Resultados em Cuidados de Saúde , Gestão de Riscos , Anticoagulantes/uso terapêutico , Encéfalo/fisiologia , Ponte Cardiopulmonar/efeitos adversos , Cateterismo de Swan-Ganz , Heparina/uso terapêutico , Antagonistas de Heparina/uso terapêutico , Humanos , Inflamação , Monitorização Intraoperatória , Protaminas/uso terapêutico , Segurança , Medula Espinal/fisiologiaRESUMO
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
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.