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We use diffuse and inelastic x-ray scattering to study the formation of an incommensurate charge-density-wave (I-CDW) in BaNi_{2}As_{2}, a candidate system for charge-driven electronic nematicity. Intense diffuse scattering is observed around the modulation vector of the I-CDW, Q_{I-CDW}. It is already visible at room temperature and collapses into superstructure reflections in the long-range ordered state where a small orthorhombic distortion occurs. A clear dip in the dispersion of a low-energy transverse optical phonon mode is observed around Q_{I-CDW}. The phonon continuously softens upon cooling, ultimately driving the transition to the I-CDW state. The transverse character of the soft-phonon branch elucidates the complex pattern of the I-CDW satellites observed in the current and earlier studies and settles the debated unidirectional nature of the I-CDW. The phonon instability and its reciprocal space position are well captured by our ab initio calculations. These, however, indicate that neither Fermi surface nesting, nor enhanced momentum-dependent electron-phonon coupling can account for the I-CDW formation, demonstrating its unconventional nature.
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We study the elastoresistance of the highly correlated material CsFe_{2}As_{2} in all symmetry channels. Neutralizing its thermal expansion by means of a piezoelectric-based strain cell is demonstrated to be essential. The elastoresistance response in the in-plane symmetric channel is found to be large, while the response in the symmetry-breaking channels is weaker and provides no evidence for a divergent nematic susceptibility. Rather, our results can be interpreted naturally within the framework of a coherence-incoherence crossover, where the low-temperature coherent state is sensitively tuned by the in-plane atomic distances.
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BACKGROUND: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma (MM) patients <65 years. Safety and outcome of ASCT for patients >65 years is currently uncertain, especially since the introduction of novel agents for induction and maintenance therapy. Furthermore, there are no conclusive data available on risk assessment in elderly patients treated with HDT. PATIENTS AND METHODS: We retrospectively analyzed 202 patients ≥60 years with newly diagnosed MM who underwent ASCT at our institution. Patients were stratified by age into three groups (60-64, 65-69 and 70-75 years). For safety assessment, we compared data about hospitalization, hematopoetic reconstitution and early mortality. Remission before and after ASCT was analyzed according to age and application of novel agents. Event-free (EFS) and overall survival (OS) were analyzed to identify impact of age, remission before/after ASCT and maintenance therapy as well as ISS score and cytogenetic aberrations on outcome in elderly patients. RESULTS: The assessment of safety, remission before/after ASCT as well as EFS and OS showed no significant differences between the three groups (median EFS: 60-64 years: 27 months; 65-69 years: 23 months; 70-75 years: 23 months; median OS: not reached). Patients receiving novel agents as part of induction therapy achieved significantly higher nCR + CR rates than patients treated without novel agents. In Cox regression analysis, ISS and cytogenetics as well as remission after ASCT had the highest prognostic impact on EFS and OS. Maintenance therapy was associated with longer EFS in uni- and multivariate analyses. CONCLUSION: ASCT is feasible for selected patients >65 and >70 years without increased mortality. Age at transplantation has no prognostic significance on outcome after ASCT. Novel agents during induction therapy and maintenance therapy improves outcome of older patients eligible for ASCT. ISS and cytogenetic analysis should be carried out routinely for risk assessment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/terapia , Transplante de Células-Tronco , Idoso , Autoenxertos , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Humanos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Uniaxial pressure provides an efficient approach to control charge density waves in YBa2Cu3Oy. It can enhance the correlation volume of ubiquitous short-range two-dimensional charge-density-wave correlations, and induces a long-range three-dimensional charge density wave, otherwise only accessible at large magnetic fields. Here, we use x-ray diffraction to study the strain dependence of these charge density waves and uncover direct evidence for a form of competition between them. We show that this interplay is qualitatively described by including strain effects in a nonlinear sigma model of competing superconducting and charge-density-wave orders. Our analysis suggests that strain stabilizes the 3D charge density wave in the regions between disorder-pinned domains of 2D charge density waves, and that the two orders compete at the boundaries of these domains. No signatures of discommensurations nor of pair density waves are observed. From a broader perspective, our results underscore the potential of strain tuning as a powerful tool for probing competing orders in quantum materials.
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Teclistamab, a B-cell maturation antigen (BCMA) × CD3 directed bispecific antibody, has shown high response rates and durable remissions in the MAJESTEC-1 trial in patients with relapsed and refractory multiple myeloma (RRMM). We retrospectively assessed efficacy and tolerability in 123 patients treated at 18 different German centers to determine whether outcome is comparable in the real-world setting. Most patients had triple-class (93%) or penta-drug (60%) refractory disease, 37% of patients had received BCMA-directed pretreatment including idecabtagene vicleucel (ide-cel) CAR-T cell therapy (21/123, 17.1%). With a follow-up of 5.5 months, we observed an overall response rate (ORR) of 59.3% and a median progression-free survival (PFS) of 8.7 months. In subgroup analyses, we found significantly lower ORR and median PFS in patients with extramedullary disease (37%/2.1 months), and/or an ISS of 3 (37%/1.3 months), and ide-cel pretreated patients (33%/1.8 months). Nonetheless, the duration of response in ide-cel pretreated patients was comparable to that of anti-BCMA naive patients. Infections and grade ≥3 cytopenias were the most frequent adverse events. In summary, we found that teclistamab exhibited a comparable efficacy and safety profile in the real-world setting as in the pivotal trial.
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Anticorpos Biespecíficos , Antineoplásicos , Mieloma Múltiplo , Neoplasias de Plasmócitos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B , Estudos Retrospectivos , Alemanha , Imunoterapia AdotivaRESUMO
The magnetic exchange in hole-doped ferromagnetic cobaltates is investigated by studying the magnetic and electronic properties of La0.7Sr0.3CoO3 films as a function of epitaxial strain. We found a strong-coupling double exchange mechanism between Co3+ (4t(2g) ââ2e(g)) and Co4+ (3t(2g) ââ2e(g)) high-spin states mediated by t(2g) electrons--in contrast to the moderate coupling provided by the e(g) exchange in manganites. The strong sensitivity of the Curie temperature TC to the bulk compression can be explained by the small bandwidth of the t(2g)-derived states. A strain-induced Jahn-Teller effect is likewise observed. The experimental results clarify the magnetic exchange mechanism in the cobaltates.
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The exchange coupling of a single spin localized at the central ion of Cu-tetraazaporphyrin on a magnetite(100) surface has been studied using x-ray magnetic circular dichroism (XMCD). Sum rule analysis of the XMCD spectra results in Cu spin and orbital magnetic moments as a function of the applied external field at low temperatures (20 K). The exchange coupling is positive for magnetization direction perpendicular to the surface (ferromagnetic) while it is negative for in-plane magnetization direction (antiferromagnetic). We attribute the anisotropy of the Heisenberg exchange coupling to an orbitally dependent exchange Hamiltonian.
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Using neutron reflectometry and resonant x-ray techniques we studied the magnetic proximity effect (MPE) in superlattices composed of superconducting YBa2Cu3O7 and ferromagnetic-metallic La0.67Ca0.33MnO3 or ferromagnetic-insulating LaMnO(3+δ). We find that the MPE strongly depends on the electronic state of the manganite layers, being pronounced for the ferromagnetic-metallic La0.67Ca0.33MnO3 and almost absent for ferromagnetic-insulating LaMnO(3+δ). We also detail the change of the magnetic depth profile due to the MPE and provide evidence for its intrinsic nature.
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OBJECTIVE: Oxcarbazepine (Trileptal) is an antiepileptic drug used as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children. The primary objective of this study was to assess the bioequivalence of Trileptal oral suspension formulation vs. the film-coated tablet after single and multiple twice-daily administrations in fasted, healthy Chinese male subjects. METHODS: This was an open-label, randomized, two-period crossover study in 19 healthy Chinese male subjects. Treatment periods consisted of a single dose of 300 mg oxcarbazepine (either oral suspension formulation or film-coated tablet) on Day 1, b.i.d. administrations of 300 mg from Day 4 to Day 8 inclusive, and a final dose of 300 mg on the morning of Day 9. A 1-week washout period was implemented between treatment periods. Plasma levels of 10-monohydroxy derivative (MHD), the main metabolite mediating the pharmacologic activity of oxcarbazepine, were measured by a validated liquid chromatography tandem mass spectrometry method. Bioequivalence was assessed by the MHD areas under the concentration time curve (AUCs) and maximum concentrations (Cmax) of the oral suspension vs. the film-coated tablet. Safety was evaluated throughout the study. RESULTS: Trileptal oral suspension formulation was bioequivalent to film-coated tablet after single dose and multiple b.i.d. administrations, as assessed by MHD AUCs and Cmax. The 90% confidence intervals (CI) of the geometric mean of the MHD individual ratios were within the bioequivalence CI limits (0.80 - 1.25). No safety concerns were raised. CONCLUSIONS: Trileptal oral suspension formulation and film-coated tablets are bioequivalent in healthy Chinese males.
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Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Carbamazepina/análogos & derivados , Adolescente , Adulto , Anticonvulsivantes/sangue , Área Sob a Curva , Povo Asiático , Carbamazepina/administração & dosagem , Carbamazepina/sangue , Carbamazepina/farmacocinética , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Humanos , Masculino , Pessoa de Meia-Idade , Oxcarbazepina , Suspensões , Comprimidos com Revestimento Entérico , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto JovemRESUMO
BACKGROUND: In a large number of studies a positive family history is documented as one of the main risk factors for the development of prostate cancer. In a US population an association between early-onset prostate cancer among familial patients and a more differentiated tumour was shown. The aim of this study was to compare clinical parameters between sporadic and familial or hereditary patients with an age at diagnosis < or =55 years. MATERIAL AND METHODS: The clinical data of prostate cancer patients with an age at diagnosis < or =55 years and who were recruited between July 1999 and the end of June 2004 to the database "familial prostate cancer in Germany" were analysed. The following data were documented for all patients: PSA at diagnosis, histopathological stage, grading, Gleason score and progression-free survival. RESULTS: The clinical data of 685 patients could be completed: 222 (32.4%) had one first-degree relative with prostate cancer, 48 of whom (7.0%) were hereditary; 463 (67.6%) were sporadic. The median age at diagnosis in the hereditary patients was 51.6 (41-55) years, in the familial patients 51.1 (35-55) years and in the sporadic patients 52.0 (38-55) years. The median follow-up was 24 months in hereditary, 36 months in familial and 35 months in sporadic patients. An initial curative therapy with radical prostatectomy or radiotherapy/brachytherapy was planned in 657/685 (95.9%) of the patients. There were no clear differences regarding PSA at diagnosis, the postoperative parameters (organ-confined disease, lymph node involvement, Gleason score, grading) and the progression-free survival in sporadic and familial or hereditary patients. CONCLUSIONS: Patients with an age at diagnosis < or =55 years have a positive family history more often than all prostate cancer patients in Germany. No association could be shown between pathohistological stage or clinical course and a positive family history in patients with an age at diagnosis < or =55 years.
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Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Medição de Risco/métodos , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Alemanha/epidemiologia , Heterozigoto , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/patologia , Fatores de RiscoRESUMO
OBJECTIVE(S): The aim of this study was to investigate the bleeding pattern and cycle control of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a combined oral contraceptive (COC) containing 0.02 mg EE and 0.1 mg levonorgestrel (LNG). STUDY DESIGN: In this phase III, randomized, controlled, double-blind, double-dummy, multicenter trial, healthy women aged 18-45 years (smokers aged 18-35 years) received either the EE/GSD patch and a placebo tablet (n=171), or a placebo patch and the COC (n=175) for seven 28-day cycles. Bleeding control was assessed in two 90-day reference periods. RESULTS: Mean number of bleeding/spotting days was comparable across treatment groups in both reference periods (p>.05). Mean number of bleeding/spotting episodes was also comparable in reference period 1; however, there were fewer bleeding/spotting episodes for COC in reference period 2 (3.4 versus 3.1; p=.01). Mean length of bleeding/spotting episodes was comparable across treatment groups for both reference periods (p>.05). Withdrawal bleeding occurred consistently in both groups over the entire treatment period, but its absence was more common in the COC group in cycles 4 and 6 of reference period 2 (p<.01). Intracyclic bleeding was comparable between groups. CONCLUSION(S): Bleeding pattern and cycle control with the EE/GSD patch was comparable to an EE/LNG-containing COC. IMPLICATIONS STATEMENT: The findings suggest that bleeding patterns with the EE/GSD patch are similar to an EE/LNG-containing COC, except for absence of withdrawal bleeding, which was less common in patch users. The EE/GSD patch may constitute an additional contraceptive option for women.
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Anticoncepcionais Femininos/administração & dosagem , Estrogênios/administração & dosagem , Etinilestradiol/administração & dosagem , Ciclo Menstrual/efeitos dos fármacos , Norpregnenos/administração & dosagem , Progestinas/administração & dosagem , Adesivo Transdérmico , Adolescente , Adulto , Amenorreia/induzido quimicamente , Anticoncepcionais Femininos/efeitos adversos , Anticoncepcionais Orais Combinados/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Estrogênios/efeitos adversos , Etinilestradiol/efeitos adversos , Feminino , Humanos , Levanogestrel/administração & dosagem , Levanogestrel/efeitos adversos , Menorragia/induzido quimicamente , Metrorragia/induzido quimicamente , Norpregnenos/efeitos adversos , Pacientes Desistentes do Tratamento , Progestinas/efeitos adversos , Adesivo Transdérmico/efeitos adversos , Estados Unidos , Adulto JovemRESUMO
OBJECTIVE(S): To investigate the bleeding pattern and cycle control parameters of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a patch containing 0.6 mg EE and 6 mg norelgestromin (NGMN). STUDY DESIGN: In this phase III, open-label, randomized, parallel-group trial, healthy women aged 18-35 years (smokers aged 18-30 years) received either the EE/GSD patch (n=200) or the EE/NGMN patch (n=198). Treatment consisted of one patch per week for 3 weeks followed by a 7-day, patch-free interval for seven cycles. Bleeding control was assessed in two 90-day reference periods. RESULTS: In reference period 1, mean number of bleeding/spotting days was comparable across treatment groups (p>0.05). However, in reference period 2, there were fewer bleeding/spotting days in the EE/GSD patch group (15.7 versus 18.4; p<0.0001). Mean number of bleeding/spotting episodes was comparable across groups for both reference periods, but bleeding/spotting episodes were shorter for the EE/GSD patch than the EE/NGMN patch during reference period 1 (5.13 days versus 5.53 days, respectively; p<0.05) and reference period 2 (5.07 versus 5.66; p=0.0001). Both treatment groups showed a similar frequency of withdrawal bleeding episodes; however, across all seven cycles, the length of these episodes was consistently shorter with the EE/GSD patch (p<0.01). There were no notable treatment differences in intracyclic bleeding. CONCLUSION(S): Bleeding pattern and cycle control achieved with the EE/GSD patch was similar to that of the EE/NGMN patch. IMPLICATIONS STATEMENT: The paper presents data on the bleeding pattern and cycle control parameters of an investigational transdermal contraceptive patch containing EE and GSD compared with an approved contraceptive patch containing EE and NGMN. This descriptive study found that bleeding patterns associated with the EE/GSD patch were similar to those of an EE/NGMN patch providing higher EE exposure.
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Anticoncepcionais Femininos/administração & dosagem , Estrogênios/administração & dosagem , Etinilestradiol/administração & dosagem , Ciclo Menstrual/efeitos dos fármacos , Norpregnenos/administração & dosagem , Progestinas/administração & dosagem , Adesivo Transdérmico , Adolescente , Adulto , Amenorreia/induzido quimicamente , Amenorreia/epidemiologia , Áustria/epidemiologia , Anticoncepcionais Femininos/efeitos adversos , República Tcheca/epidemiologia , Combinação de Medicamentos , Estrogênios/efeitos adversos , Etinilestradiol/efeitos adversos , Feminino , Humanos , Incidência , Mastodinia/induzido quimicamente , Mastodinia/epidemiologia , Menorragia/induzido quimicamente , Menorragia/epidemiologia , Metrorragia/induzido quimicamente , Metrorragia/epidemiologia , Países Baixos/epidemiologia , Norgestrel/administração & dosagem , Norgestrel/efeitos adversos , Norgestrel/análogos & derivados , Norpregnenos/efeitos adversos , Pacientes Desistentes do Tratamento , Progestinas/efeitos adversos , Adesivo Transdérmico/efeitos adversos , Adulto JovemRESUMO
We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, P<0.001). Neuropathy rates (⩾2°) were higher in the PAd group (14.9 versus 8.4%, P=0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAd group (32.7 versus 24.0%, P=0.04 and 2.8 versus 0.4%, P=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ⩾VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Ácidos Borônicos/administração & dosagem , Bortezomib , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Mobilização de Células-Tronco Hematopoéticas , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Pirazinas/administração & dosagem , Indução de Remissão , Taxa de SobrevidaRESUMO
BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy. RESULTS: A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. CONCLUSIONS: Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens.
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Antivirais/administração & dosagem , Ciclosporina/administração & dosagem , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Ciclosporina/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Ribavirina/efeitos adversos , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
In the secondary prevention of coronary artery disease (CAD) the beneficial effect of lipid lowering is no longer controversial. LDL-apheresis is a feasible therapy for effective lipid lowering in patients refractory to diet and cholesterol lowering drugs. To assess the impact of the HELP-therapy (heparin-induced, extracorporeal LDL precipitation) on patients' clinical outcome and coronary angiography, we set up a prospective trial, in which patients with advanced coronary atherosclerosis and severe hypercholesterolemia resistant to diet and drug therapy were treated with LDL-apheresis. A total of 44 patients were treated with adjunctive weekly HELP-therapy for 15.5 +/- 9.5 months. The mean levels of total cholesterol (Chol), LDL-cholesterol (LDL-C), Lp(a), and fibrinogen at baseline were 308.0 +/- 69.7, 231.8 +/- 72.7, 82.2 +/- 54.1, and 356.1 +/- 94.1 mg/dl, respectively. LDL-apheresis caused a mean per treatment reduction of 44.8 +/- 8.7, 55.5 +/- 8.6, 60.8 +/- 10.2, and 53.8 +/- 6.5% of Chol, LDL-C, Lp(a), and fibrinogen, resulting in mean treatment interval values of 190.4 +/- 33.7, 116.3 +/- 28.9, 51.9 +/- 33.1, and 213.7 +/- 148.9 mg/dl, respectively. Improvement of the clinical status (exercise tolerance, anti-anginal drug use, angina pectoris) was found in 73%, no change in 11%, and deterioration in 16% of the cases. Four patients died cardiac death. The maximal bicycle exercise work load of the patients increased significantly from 101 +/- 41 to 119 +/- 46 W (P < 0.001). Ten (40%) out of 25 patients who underwent follow-up angiography revealed CAD progression, whereas two (8%) patients had CAD regression. Despite angiographic deterioration eight out of ten progressors (80%) improved clinically. In patients with advanced coronary atherosclerosis and severe hypercholesterolemia HELP-therapy can safely and effectively lower LDL-C, Lp(a), and fibrinogen. The chronic weekly HELP-treatment results in clinical improvement in the majority of patients, even in those patients with angiographically shown CAD progression.
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Remoção de Componentes Sanguíneos , Doença da Artéria Coronariana/terapia , Circulação Extracorpórea , Heparina/uso terapêutico , Hipercolesterolemia/terapia , Lipoproteínas LDL/análise , Adulto , Precipitação Química , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Fibrinogênio/análise , Humanos , Hipercolesterolemia/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
This report concerns a heart transplant patient with hypercholesterolemia who showed rapid development of a severe transplant coronary artery disease. The patient received 10 mg pravastatine per day. Quantitative coronary angiography analyses of 4 serial angiograms clearly demonstrated that in the first 2.5 years following surgery, there was a rapid simultaneous progression in both the transplant coronary disease, involving the entire coronary system, and the development of segmental stenotic lesions. During one year of weekly heparin-mediated extracorporeal LDL-cholesterol precipitation (HELP) therapy in addition to diet and pravastatine therapy, the serum low density lipoprotein (LDL), lipoprotein (a) (Lp(a)), and fibrinogen levels could be reduced from 185 +/- 45 mg/dl, 138 mg/dl and 248 mg/dl, respectively, to interval values of 136 +/- 17 mg/dl, 48 +/- 15 mg/dl, and 185 +/- 44 mg/dl, respectively [interval value = (the concentration after HELP + the concentration before the next HELP treatment):2]. This therapy halted further progression of coronary diameter throughout the whole coronary system and brought about marked regression of segmental obstructive lesions.
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LDL-Colesterol/sangue , Doença das Coronárias/sangue , Doença das Coronárias/terapia , Transplante de Coração/fisiologia , Hipercolesterolemia/terapia , Arteriosclerose/diagnóstico por imagem , Arteriosclerose/fisiopatologia , Precipitação Química , LDL-Colesterol/isolamento & purificação , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Circulação Extracorpórea , Fibrinogênio/metabolismo , Seguimentos , Humanos , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Pravastatina/uso terapêutico , Fatores de TempoRESUMO
BACKGROUND: Serotonin and its type-4 (5-hydroxytryptamine4) receptor play a major role in the physiology of the gastrointestinal tract. The effect of intravenous and/or oral tegaserod, a 5-hydroxytryptamine4 receptor partial agonist, on gastric emptying, small bowel transit and colonic transit has not been studied in detail in humans. AIM: To assess the pharmacodynamic effects of repeated oral and intravenous administration of tegaserod on gastric emptying and small intestine and colonic transit. METHODS: A randomized, placebo-controlled, double-blind, three-way, crossover study of 6 mg oral and 0.6 mg intravenous tegaserod in 12 healthy male subjects was performed. Each treatment arm of the study involved 3 days of twice-daily administration and 1 day of daily administration of the study drugs. RESULTS: In comparison with placebo, oral and intravenous tegaserod significantly increased the gastric emptying rate (P < 0.01), accelerated colonic filling (P < 0.01) and shortened colonic transit at 48 h (P < 0.05). Tegaserod shortened the small intestine transit time by 30% after oral and by 37% after intravenous administration. CONCLUSIONS: In healthy subjects, tegaserod markedly accelerated gastric emptying and small intestinal transit, and induced a small but significant acceleration of colonic transit. Tegaserod can act as a promotile agent throughout the gastrointestinal tract.
Assuntos
Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Indóis/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Administração Oral , Adulto , Colo/efeitos dos fármacos , Colo/fisiologia , Estudos Cross-Over , Método Duplo-Cego , Humanos , Indóis/administração & dosagem , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Agonistas do Receptor de Serotonina/administração & dosagemRESUMO
BACKGROUND: The pathogenesis of transplant coronary artery disease (TxCAD) is probably multifactorial. Immune mechanisms may be the primary and triggering stimuli, whereas risk factors such as hyperlipoproteinemia or lipoprotein(a) elevation may accelerate the progression of the disease. With the heparin-induced-low-density lipoprotein-precipitation (HELP), low-density lipoprotein (LDL), fibrinogen, and lipoprotein(a) can be reduced about 55%, 50%, and 60%, respectively. METHODS: We treated eight heart transplant recipients (52.6 +/- 8.1 years old; all men) with weekly LDL-apheresis (HELP-system). At the beginning of the HELP treatment, all patients had survived at least 2 years after surgery, had LDL levels higher than 150 mg/dl in spite of 10 mg pravastatin per day and diet, and had development of significant coronary artery disease as shown by annual coronary angiography. We analyzed three angiograms in each patient taken 16.2 +/- 6.5 months before, at the beginning of (-0.5 +/- 6 months), and after 21.8 +/- 7.4 months of HELP therapy. Two hundred seventy-three coronary artery segments (34 +/- 6 per patient; 6 to 65 single measurements per segment) were analyzed by quantitative coronary angiography. Statistical significances of differences between the angiograms taken at the three time points were evaluated by the paired t test. RESULTS: Measurements of all coronary artery segments showed a significant decrease of mean luminal diameter during the last 1 to 2.5 years before the HELP treatment from 3.61 +/- 1.1 mm to 3.15 +/- 1 mm (p < 0.0001). During the following 1 to 2.5 years of HELP therapy, the mean luminal diameter increased to 3.4 +/- 1.15 mm (p < 0.0001). CONCLUSIONS: In long-term heart transplantation survivors with hyperlipidemia, who have development of a rapid progressive coronary artery disease, LDL-apheresis can lead to disease regression. Further studies will be needed to determine whether immunologic factors and growth factors involved in the TxCAD pathogenesis are also eliminated by the HELP therapy and whether HELP is also effective in patients with TxCAD without severe hypercholesterolemia.
Assuntos
Remoção de Componentes Sanguíneos , Doença das Coronárias/terapia , Transplante de Coração/imunologia , Lipoproteínas LDL/sangue , Complicações Pós-Operatórias/terapia , LDL-Colesterol/sangue , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/imunologia , Vasos Coronários/imunologia , Fibrinogênio/metabolismo , Humanos , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/imunologia , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Transplant coronary artery disease is the major cause of late mortality after heart transplantation. The underlying mechanism probably involves various factors including immunologic and nonimmunologic factors. METHODS: The influence of various risk factors concerning both the development and the progression of transplant coronary artery disease was analyzed. Fifty-two heart transplant patients, who survived at least 2 years after transplantation (24 to 60 months), were included. RESULTS: Of these patients 38.5% had angiographic evidence of transplant coronary artery disease. They had significantly higher values of total cholesterol, low-density lipoprotein cholesterol, and log triglycerides than patients without evidence of the disease (p = 0.037, p = 0.002, and p = 0.015, respectively). In addition, preoperative diagnosis of coronary artery disease was a predictor of the development of transplant coronary artery disease, whereas significant differences were not found corresponding to recipient age, donor age, ischemic time, body mass index, lipoprotein (a) value, high-density lipoprotein cholesterol value, time after transplantation, number of postoperative rejection episodes, or prednisone dosage. A 12-month angiographic follow-up indicated disease progression in 25% of the patients. With respect to the majority of factors analyzed within the study, the differences between patients with and those without progression were comparable to the differences between patients in whom transplant coronary artery disease developed and those in whom it did not. However, patients exhibiting disease progression had a higher prednisone intake dosage (p = 0.006) and had significantly higher lipoprotein (a) values (p = 0.0229) than patients without progression. CONCLUSION: This study clearly shows that in heart transplant patients surviving more than 2 years, lipid disorder is one of the main risk factors of both the development and the progression of transplant coronary artery disease.
Assuntos
Doença das Coronárias/sangue , Sobrevivência de Enxerto , Transplante de Coração , Lipídeos/sangue , Adulto , Angiografia Coronária , Doença das Coronárias/epidemiologia , Doença das Coronárias/fisiopatologia , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Imunossupressores/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de RiscoRESUMO
In a retrospective analysis of 13 phase I multiple-dose trials, clinical data from 100 volunteers who received placebo were investigated for differences in routine safety laboratory parameters and vital signs between smokers and nonsmokers. Of the 100 subjects, 47 were classified as smokers (cigarettes only) and 53 were classified as nonsmokers. Objectives of the analysis were to offer a basis for decision whether certain deviations of laboratory values or vital signs might be related to smoking rather than to a study drug or some external influence, and to explore whether smokers tend to present changes in laboratory values or vital signs during a trial that are different from changes that occur in nonsmokers. Regarding baseline values, which were defined as the mean of values at screening and the first day of the in-house stay, clinically and statistically significant differences between smokers and nonsmokers were found for total leukocytes and triglycerides (mean greater for smokers than nonsmokers), and total bilirubin (mean greater for nonsmokers than smokers). Comparison of changes during the study in smokers and nonsmokers showed a statistically and clinically significant difference only for triglyceride levels. Smokers had a slight decrease in triglyceride levels, whereas nonsmokers showed a marked increase in the respective values during the trials. Prospective studies with sufficiently large sample sizes are required to confirm the results of this retrospective analysis on a wider basis, and to possibly achieve significance for further differences between smokers and nonsmokers.