RESUMEN
BACKGROUND AND PURPOSE: Our goal was to evaluate MR imaging findings after local intracerebral gene therapy in patients with glioblastoma and differentiate postoperative contrast enhancement phenomena. METHODS: In all, 26 patients with supratentorial single lesion glioblastoma underwent tumor resection and intracerebral injection of murine retroviral vector-producer cells for gene therapy with the herpes simplex virus type I thymidine kinase gene/ganciclovir system. Serial contrast-enhanced MR studies were obtained before treatment and postoperatively on day 1 or 2; weeks 2, 4, 9, 13, 17, 25, and 33; and every 8 weeks thereafter. Iodomethyltyrosine single-photon emission CT (IMT-SPECT) investigations also were performed in selected cases. RESULTS: Twelve patients showed nontumorous enhancement of various intensities after treatment, arising within 18 to 72 hours and persisting at 3 to 10 months. It was characterized by a strong local enhancement up to 20 mm thick, which was initially nodular and later linear along the resection cavity wall and surrounded by massive perifocal edema. This "flare" enhancement had features that clearly differed from those of residual tumor enhancements and benign postsurgical enhancements. The IMT-SPECT investigations showed increased amino acid uptake in patients with enhancement from residual or relapsing tumor, but not in patients with flare. CONCLUSION: After local gene therapy, a unique dynamic, transient perifocal flare enhancement can occur on MR images. IMT-SPECT may help to differentiate between tumorous and nontumorous flare enhancements in patients with enhancing tissue on MR images after gene therapy for glioblastoma.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Terapia Genética , Glioblastoma/diagnóstico , Glioblastoma/terapia , Imagen por Resonancia Magnética , Tomografía Computarizada de Emisión de Fotón Único , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Neoplasias Encefálicas/patología , Diagnóstico Diferencial , Femenino , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Neoplasia Residual/diagnóstico , Procedimientos Neuroquirúrgicos , Periodo Posoperatorio , Factores de RiesgoRESUMEN
Somatic gene therapy with the herpes simplex virus type I thymidine kinase gene/ganciclovir (HSV-Tk/GCV) system and murine retroviral vector producer cells (VPCs) was introduced as a new adjuvant treatment modality to treat tumor bulk and to prevent tumor recurrence in patients harboring malignant glioma. The single-center experience after treatment of 27 patients undergoing tumor resection followed by intracerebral VPC injection for HSV-Tk suicide gene therapy will be presented focused on findings of systematic and close MRI follow-up and a few histological specimens. The data indicate that hemorrhagic necrosis due to endothelial cell transfection mediated vessel necrosis and that local inflammatory immune response occurs frequently after gene therapy. These phenomena seem to be specific because none of the patients of a control group showed any similar features. The prognosis (time to progression, survival) of the patients with "bystander effects" after gene therapy was better, but compared to those patients without bystander effects, they were also privileged by a favorable constellation of prognostic factors. Therefore, the appearance of these neuroradiologic features cannot serve as an indicator for treatment effectiveness and outcome.
Asunto(s)
Neoplasias Encefálicas/terapia , Encéfalo/irrigación sanguínea , Efecto Espectador , Encefalitis/etiología , Ganciclovir/uso terapéutico , Terapia Genética/efectos adversos , Glioma/terapia , Herpesvirus Humano 1/enzimología , Timidina Quinasa/genética , Transfección/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Neoplasias Encefálicas/diagnóstico , Encefalitis/diagnóstico , Encefalitis/inmunología , Femenino , Vectores Genéticos , Glioma/diagnóstico , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neovascularización Patológica/diagnóstico , Retroviridae/genéticaRESUMEN
This study was conducted to investigate immunological components of somatic gene therapy for primary glioblastoma multiforme (GBM) in adults. It involved 13 patients treated by surgical resection of tumor with subsequent radiation therapy. Seven of them received additional herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) gene therapy by direct intracerebral injection of retrovirus (RV) vector producing cells (VPC) during tumor surgery and subsequent systemic administration of GCV. Peripheral blood for FACS immunophenotyping, isolation of peripheral mononuclear cells (PMNC), and serum ELISA assays for IL-12 and soluble Fas ligand (sFasL) was collected daily during the first 4 post-operative weeks. Tumor specimens were obtained at primary or recurrent surgery and at autopsy. Tumors from gene therapy patients showed varying degrees of peritumoral necrosis around the former tumor resection cavity. Numbers of tumor-infiltrating lymphocytes found weeks after gene therapy were not significantly increased compared with primary tumors. Mitotic tumor cells were sparse close to the VPC injection sites, but abundant in brain areas somewhat distant from these sites. Serum ELISA revealed significantly increased sFasL and IL-12 levels in the gene therapy group compared with controls. Immunophenotyping of PMNC did not show a significant activation of T cells or NK cells during gene therapy. Interferon gamma secretion was evaluated by ELISPOT assays employing PMNC cocultivated with autologous tumor cells. It demonstrated an antitumor immune response in the gene therapy group, but not in the control group. These findings support the concept of in vivo induction of a systemic immune response by local intracerebral HSV-tk/GCV pharmacogene therapy for primary human GBM.
Asunto(s)
Neoplasias Encefálicas/terapia , Terapia Genética/métodos , Glioblastoma/terapia , Simplexvirus/enzimología , Timidina Quinasa/genética , Transfección/métodos , Anciano , Antivirales/uso terapéutico , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/inmunología , Estudios de Casos y Controles , Terapia Combinada , Proteína Ligando Fas , Femenino , Ganciclovir/uso terapéutico , Vectores Genéticos/administración & dosificación , Glioblastoma/sangre , Glioblastoma/inmunología , Humanos , Inyecciones Intralesiones , Interferón gamma/inmunología , Interleucina-12/sangre , Masculino , Glicoproteínas de Membrana/sangre , Persona de Mediana Edad , Retroviridae/genética , Resultado del TratamientoRESUMEN
The availability of hematopoietic growth factors has greatly facilitated the mobilization and collection of peripheral blood stem cells (PBSC). It was the aim of this double-blind study to compare the PBSC-mobilizing efficacy of recombinant human G-CSF and GM-CSF when administered post-chemotherapy. Twenty-six patients with relapsed Hodgkin's disease were included in the study. Their median age was 31 years (range, 22-59) and 14 patients were males and 12 were females. Patients were pretreated with a median of eight cycles of cytotoxic chemotherapy, while 18 patients had undergone extended field irradiation. The patients received dexamethasone 24 mg days 1-7, melphalan 30 mg/m2 day 3, BCNU 60 mg/m2 day 3, etoposide 75 mg/m2 days 4-7, Ara-C 100 mg/m2 twice daily days 4-7 (Dexa-BEAM). Twelve patients were randomized to receive 5/microg/kg/day G-CSF and 14 patients to receive 5 microg/kg/day GM-CSF, both administered subcutaneously starting on day 1 after the end of Dexa-BEAM. Primary endpoints of the study were the number of CD34+ cells harvested per kg body weight on the occasion of six consecutive leukaphereses and the time needed for hematological reconstitution following autografting. Twenty-one patients completed PBSC collection, and six patients of the G-CSF group and nine of the GM-CSF group were autografted. No difference was observed with respect to the median yield of CFU-GM and CD34+ cells: 32.5 x 10(4)/kg vs 31.3 x 10(4)/kg CFU-GM, and 7.6 x 10(6)/kg vs 5.6 x 10(6)/kg CD34+ cells, for G-CSF and GM-CSF, respectively (U test, P= 0.837 and 0.696). High-dose chemotherapy consisted of cyclophosphamide 1.7 g/m2 days 1-4, BCNU 150 mg/m2 days 1-4, etoposide 400 mg/m2 days 1-4. All patients transplanted with more than 5 x 10(6) CD34+ cells/kg had a rapid platelet recovery (20 x 10(9)/l) between 6 and 11 days and neutrophil recovery (0.5 x 10(9)/1) between 9 and 16 days, while patients transplanted with less than 5 x 10(6)/kg had a delayed reconstitution, regardless of the kind of growth factor used for PBSC mobilization. In conclusion, our data indicate that in patients with Hodgkin's disease G-CSF and GM-CSF given after salvage chemotherapy appear to be not different in their ability to mobilize PBSC resulting in a similar time needed for hematological reconstitution when autografted following high-dose therapy.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Método Doble Ciego , Femenino , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/farmacología , Trasplante AutólogoRESUMEN
The present phase II study was undertaken to assess antitumoral activity, safety and tolerability of recombinant human interleukin-6 (rh IL-6) in patients with advanced renal cell cancer. Rh IL-6 was administered as a daily subcutaneous injection at a fixed dose of 150 micrograms/day for a maximum of 42 consecutive days. 12 patients with metastatic renal cell cancer without previous immunotherapy were enrolled and were evaluated for response. No objective clinical responses were observed in the trial. Toxicity was moderate and reversible and mainly comprised fever, influenza-like symptoms, fatigue and moderate hepatotoxicity. Anaemia, leucocytosis, thrombocytosis and induction of an acute phase response were observed in most patients. In conclusion, prolonged subcutaneous administration of rh IL-6 on an outpatient basis is safe and feasible. However, rh IL-6 exhibited no antitumoral activity in patients with metastastic renal cell cancer. Profound regulatory effects on haematopoiesis and inflammatory response of rh IL-6 were observed.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/terapia , Interleucina-6/uso terapéutico , Neoplasias Renales/terapia , Adulto , Anciano , Proteína C-Reactiva/metabolismo , Carcinoma de Células Renales/sangre , Femenino , Humanos , Neoplasias Renales/sangre , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Insuficiencia del TratamientoRESUMEN
Coexistence of Philadelphia chromosome (Ph)-negative, primitive hematopoietic progenitor cells with their malignant counterparts in chronic myelogenous leukemia (CML) has been reported. As most of the Ph-negative progenitor cells do not express the HLA-DR antigen, selection of them might be possible. Peripheral blood progenitor cells (PBPC) from eight early chronic phase (CML) patients were mobilized by ICE chemotherapy followed by simultaneous administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human interleukin 3 (rhIL-3). PBPCs were collected by leukapheresis in the early phase of hematopoietic recovery after chemotherapy, CD34 selected and cultured in vitro. The content of Ph chromosome-positive cells in leukapheresis products as well as after CD34 enrichment and after in vitro culture was analyzed by interphase fluorescence in situ hybridization (FISH) and RT-PCR. The percentage of Ph chromosome-positive PBPC was reduced after each purification step in almost all samples. A substantial number of PBPC samples were negative for the bcr/abl mRNA rearrangement as analyzed by RT-PCR. The present study demonstrates the feasibility of mobilizing Ph-negative PBPC during the early phase of hematopoietic recovery after ICE chemotherapy and simultaneous administration of rhIL-3 and rhG-CSF.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Interleucina-3/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adulto , Antígenos CD34/sangre , Médula Ósea/patología , Células Cultivadas , Cisplatino/administración & dosificación , Terapia Combinada , Etopósido/administración & dosificación , Femenino , Proteínas de Fusión bcr-abl/genética , Reordenamiento Génico , Células Madre Hematopoyéticas/patología , Humanos , Ifosfamida/administración & dosificación , Inmunofenotipificación , Interferón-alfa/uso terapéutico , Leucaféresis , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Reacción en Cadena de la Polimerasa , Proteínas Recombinantes/uso terapéuticoRESUMEN
Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) has been successfully used in different clinical settings. We evaluated the tolerability of rhGM-CSF treatment in addition to its efficacy in preventing myelosuppression and reducing infectious complications after standard-dose chemotherapy of various tumors. Of the patient group analyzed (n = 308), 75% had solid tumors and 25% had hematological malignancies. In 27.9% of these patients an infection occurred after the first cycle of chemotherapy and between 8.2 and 19.0% in later cycles with a mean duration of fever (above 38.5 degrees C) of 3.6 days. Treatment with rhGM-CSF was well-tolerated. After the completion of treatment, the investigators assessed the efficacy of rhGM-CSF in 83.7% of the patients as 'very good' or 'good', and as 'moderate' or 'bad' in only 11.5% of patients as well as the tolerability as 'very good' or 'good' in 87.0% of the patients and in 9.4% 'moderate' or 'bad'. We conclude that rhGM-CSF proved to be an effective and well-tolerated tool in preventing myelosuppression and infectious complications after standard-dose chemotherapy of various tumors.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/toxicidad , Humanos , Infecciones/complicaciones , Infecciones/tratamiento farmacológico , Infecciones/epidemiología , Recuento de Leucocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
Interleukin-3 (IL-3) is a multipotent hematopoietic growth factor, which exhibits stimulatory effects on leucocytes, reticulocytes and platelets. Due to its pronounced induction of megakaryopoiesis, IL-3 is thought to be a cytokine with the potential to prevent and to overcome chemotherapy-induced thrombocytopenia. We report on four cases (two of metastatic breast cancer, one of metastatic ovarian cancer and one of Hodgkin's disease) with prolonged chemotherapy-induced thrombocytopenia in whom rhIL-3 in combination with either recombinant human (rh) granulocyte macrophage colony stimulating factor (GM-CSF) or rh granulocyte colony stimulating factor (G-CSF) was administered. In all cases, a steady and clinically significant increase in platelet counts could be observed. No major side effects, neither due to the application of rhIL-3 nor due to rhGM-CSF or rhG-CSF, occurred; only flu-like symptoms were seen, which could effectively be treated with paracetamol. This report highlights the efficacy of combined treatment with rhIL-3 plus rhGM-CSF or rhG-CSF in chemotherapy-induced thrombocytopenia, where megakaryopoiesis could be stimulated efficiently by rhIL-3. Based on this experience, the authors conclude that established thrombocytopenia as a major side effect of myelosuppressive chemotherapy should be considered as an indication for the use of rhIL-3 in interventional treatment. Further investigations in this area are encouraged.
Asunto(s)
Antineoplásicos/efectos adversos , Interleucina-3/uso terapéutico , Trombocitopenia/terapia , Adulto , Neoplasias de la Mama/sangre , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Combinada , Femenino , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Enfermedad de Hodgkin/sangre , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Interleucina-3/efectos adversos , Persona de Mediana Edad , Neoplasias Ováricas/sangre , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/tratamiento farmacológico , Recuento de Plaquetas , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Trombocitopenia/inducido químicamenteRESUMEN
Antihypertensive Efficacy and Tolerability of Isradipine in Patients with Severe Hypertension/Results of an open multicenter study. In this open multicentre study 55 patients (mean age 51.2 years) with severe hypertension (diastolic blood pressure > 115 mmHg) were treated for seven weeks with the calcium antagonist of the dihydropyridine type isradipine (CAS 75695-93-1, Lomir). If necessary, metoprolol or enalapril were added to the regimen. Before inclusion into the active treatment phase, responsiveness of the patients to a single administration of isradipine (5 mg) was compared with placebo. Preexisting antihypertensive therapy (18 patients) was to be maintained during the study period. Blood pressure was recorded with an automatic device. During the 7-week period blood pressure decreased from 173.7/124.8 mmHg to 143.2/97.8 mmHg. Both the group with isradipine monotherapy (n = 32) and the combination group (n = 11) showed a significant reduction in systolic and diastolic blood pressure. Diastolic blood pressure response, defined as a decline of more than 15 mmHg, was noted in 87.5% (monotherapy) and 72.7% (combination group) of patients. On the whole, blood pressure was normalized in 27.9% of the participants. Nineteen patients experienced 43 adverse events, most of which were rated mild to moderate. Therapy was withdrawn in only one patient (due to ankle edema). The most frequent adverse event was headache (20.9%).
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/tratamiento farmacológico , Isradipino/uso terapéutico , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/efectos adversos , Estudios Cruzados , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Isradipino/administración & dosificación , Isradipino/efectos adversos , Masculino , Persona de Mediana EdadRESUMEN
Tyrothricin, a polypeptide antibiotic, is active against yeast cells. Tyrothricin was rapidly fungicidal towards Candida albicans. Concentration of four times the minimum inhibitory (25 mg l-1) reduced the yeast numbers by more than 3 log10 within 1 h. Similar results were obtained in a flow cytometric antifungal activity assay using the new two-colour probe for yeast viability, FUN-1, which measures impairment of metabolic activity. The respiratory activity of Candida albicans, measured in a XTT kinetic assay, was significantly reduced in comparison with controls by 3.12 mg l-1 of the substance. Because fungicidal concentrations of tyrothricin are locally achievable in patients, an evaluation of the local effect of tyrothricin in patients suffering from mucosal infections with Candida species should be considered.
Asunto(s)
Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Tirotricina/farmacología , Candida/efectos de los fármacos , Candida/aislamiento & purificación , Candida/metabolismo , Candida albicans/aislamiento & purificación , Candida albicans/metabolismo , Candidiasis/tratamiento farmacológico , Humanos , Cinética , Pruebas de Sensibilidad Microbiana , Membrana MucosaRESUMEN
The effects of isradipine (Lomir, CAS 75695-93-1) and metoprolol (CAS 37350-58-6) on geometry and arterial compliance of the arteria brachialis of 14 patients each with essential hypertension were compared acutely and after three months of therapy by means of pulsed Doppler sonography and the determination of pulse wave velocity. A calculation model was used that allowed to determine the drug-specific effects on arterial diameter and compliance under isobaric conditions. Isradipine increased measured and isobaric diameter during short-term (p < 0.05) and long-term administration (p < 0.05) whereas metoprolol did not change it. Isradipine increased measured and isobaric compliance during short-term (p < 0.05) and long-term administration (p < 0.05). Metoprolol reduced measured compliance acutely (p < 0.01) and isobaric compliance acutely (p < 0.05) and long-term (p < 0.05). Drug-specific effects on compliance were different during short-term and long-term administration (p < 0.01); the diameter was influenced differently only during short-term administration (p < 0.05). These opposite drug effects on the A. brachialis are probably due to a vasoselective relaxation of smooth muscle in large arteries by isradipine and-in the case of metoprolol-arterial constriction. The increase of arterial compliance by isradipine reduces very effectively the load on the heart and could form the basis for the improvement in the prognosis of the hypertensive patient.
Asunto(s)
Arterias/fisiopatología , Hipertensión/tratamiento farmacológico , Isradipino/uso terapéutico , Metoprolol/uso terapéutico , Adulto , Anciano , Arterias/diagnóstico por imagen , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/diagnóstico por imagen , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Ultrasonografía , Resistencia Vascular/efectos de los fármacosRESUMEN
In this multicenter, placebo-controlled study, 16 patients with mild to moderate essential hypertension were treated with 10 mg/day isradipine retard (PN 200-110, Lomir SRO, CAS 75695-93-1) for 3 weeks. The study started with a 2 week placebo wash out phase. 13 patients were randomised to an exclusive placebo therapy. After the placebo wash out phase, following the 1st medication in active therapy and after the end of therapy, 24-h blood pressure profiles were recorded. The profile under placebo on the 1st medication was separated by a one-week intervening placebo therapy for all patients. On active therapy, the systolic as well as the diastolic blood pressure (day time, night time and 24-h mean values) were significantly reduced. The antihypertensive effect of the active therapy became already manifest after the 1st medication and was augmented after 3 weeks of therapy. In the placebo group no parameter of the 24-h profiles changed significantly. The tolerability of treatment was excellent in 14 (87.5%) of the isradipine patients and in 10 (76.9%) of the placebo group. In one of 16 patients in the active group, adverse events (flush and ankle oedema) were observed. However, therapy could be continued. In one patient of the placebo group, oedema of the fingers was noticed, in another headache was documented. In the placebo group two patients discontinued the study due to inefficacy, in the isradipine group one patient for the same reason; a second patient was excluded from this group due to a concomitant disease unrelated to the study drug.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Ritmo Circadiano/fisiología , Hipertensión/tratamiento farmacológico , Isradipino/uso terapéutico , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/efectos adversos , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Isradipino/administración & dosificación , Isradipino/efectos adversos , Masculino , Persona de Mediana EdadRESUMEN
Antihypertensive efficacy and tolerability of a 4-week treatment each with the modified release formulation of the calcium antagonist isradipine (5 mg; Lomir SRO, CAS 75695-93-1) were compared with those of nitrendipine (20 mg) (both with morning intake) in 51 patients with mild to moderate hypertension using a double-blind, intraindividual crossover study. Blood pressure was measured over 24 h at the end of a 2-week placebo phase and after both treatment phases by means of a continuous ambulatory recording device. Upon statistical evaluation of all patients with 3 complete 24-h profiles (n = 44) and combined analysis of data from same treatments the following 24-h mean values were obtained: blood pressure (syst./diast.) was lowered from 151/98 mmHg to 141/91 mmHg by isradipine retard (IS) and to 141/92 mmHg by nitrendipine (NI), whereas heart rate remained nearly unchanged (78 vs 79 beats/min on both therapies). The 24-h profiles differed significantly between placebo and both therapies, the profile as a whole was more even on IS. Starting from a day-time mean value (6:00 a.m.-10:00 p.m.) on placebo of 155/102 mmHg blood pressure was reduced by IS to 143/94 mmHg and by NI to 144/95 mmHg; the corresponding night-time mean values were; placebo 138/85 mmHg, IS 132/82 mmHg, NI 134/83 mmHg. If one compares the area under the blood pressure curves during the hours from 6 p.m. to 12 p.m. significant differences (2p = 0.0128) were found for systolic pressure and borderline significance (2p = 0.0668) for diastolic differences in favour of IS.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Ritmo Circadiano/fisiología , Hipertensión/tratamiento farmacológico , Isradipino/uso terapéutico , Nitrendipino/uso terapéutico , Adolescente , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Humanos , Hipertensión/fisiopatología , Isradipino/administración & dosificación , Isradipino/efectos adversos , Masculino , Persona de Mediana Edad , Nitrendipino/administración & dosificación , Nitrendipino/efectos adversosRESUMEN
The comparative efficacy of the calcium antagonists isradipine and nifedipine in reducing left ventricular peak systolic wall tension was assessed in 25 patients with essential hypertension (20 men, 5 women; mean age: 49 years). After 2 weeks of treatment with either isradipine (2.5 mg twice daily) or slow-release nifedipine (20 mg twice daily), blood pressure was similarly reduced in both groups of patients whereas the thickness of the interventricular septum and left ventricular free wall did not change. Echocardiographic end-diastolic volume of the left ventricle showed no change whereas end-systolic volume significantly decreased with isradipine, but not with nifedipine retard. This led to a significant reduction in peak systolic wall tension in the isradipine group, but not in the nifedipine group. In conclusion, antihypertensive treatment with isradipine produces a reduction in peak systolic wall tension which is not seen with nifedipine, probably because of its negative inotropic effect.
Asunto(s)
Ventrículos Cardíacos/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Isradipino/uso terapéutico , Nifedipino/uso terapéutico , Volumen Cardíaco/efectos de los fármacos , Método Doble Ciego , Femenino , Humanos , Isradipino/farmacología , Masculino , Persona de Mediana Edad , Contracción Miocárdica/efectos de los fármacos , Nifedipino/farmacologíaRESUMEN
The cardiodepressant and vasodilator effects of an intravenous (i.v.) infusion of 0.5 mg isradipine or 2 mg nifedipine were interindividually (10 vs. 10 patients) compared in a double-blind study in patients with stable coronary heart disease. To minimize vasodilation-induced autonomic reflex mechanisms, which may counterbalance negative inotropic effects after acute administration of calcium antagonists, i.v. autonomic blockade was produced by 0.2 mg/kg propranolol and 0.04 mg/kg atropine. Systemic hemodynamics were measured before and 15 min after the end of the 15-min calcium antagonist infusion. After administration of both drugs, heart rate (HR) decreased similarly during the observation period (isradipine from 93 +/- 10 to 88 +/- 9 beats/min and nifedipine from 84 +/- 9 to 79 +/- 6 beats/min, both p less than or equal to 0.01). The reduction in total peripheral resistance (TPR) was significantly (p less than or equal to 0.01) greater after isradipine (from 1,376 +/- 285 to 1,002 +/- 224 dynes s cm-5) than after nifedipine (1,258 +/- 262 to 1,112 +/- 225 dynes s cm-5). Between the two drugs, the difference in the reduction of afterload independent dP/dt40, determined by tip-manometry, reached borderline significance (p = 0.08) (isradipine from 1,197 +/- 258 to 1,157 +/- 225 mm Hg/s, NS and nifedipine 1,228 +/- 226 to 1,109 +/- 227 mm Hg/s, p less than or equal to 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Bloqueo Nervioso Autónomo , Isradipino/uso terapéutico , Contracción Miocárdica/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Nifedipino/uso terapéutico , Vasodilatadores/farmacología , Depresión Química , Método Doble Ciego , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/fisiopatología , Resistencia Vascular/efectos de los fármacosRESUMEN
As isradipine is known to be less cardiodepressant than nifedipine, myocardial wall stress--an important determinant of cardiac oxygen demand--may also be more favorably influenced by isradipine. Therefore, the acute effects of an intravenous (i.v.) infusion of isradipine (0.4 mg) vs. nifedipine (2.0 mg) on cardiac hemodynamics and systolic wall stress were investigated in a crossover study of 12 hypertensive patients. Vasodilation-induced reflex activation was limited by pretreatment with i.v. propranolol at 0.1 mg/kg of body weight. The hemodynamic parameters measured were statistically comparable at baseline and after propranolol with both calcium antagonists, as was blood pressure reduction. However, the end-systolic volume decreased with isradipine, but not with nifedipine [before: 69 +/- 7.0 ml (mean +/- SEM); after: 61 +/- 6.1 ml; 2p less than 0.01 vs. before: 62 +/- 6.1 ml; after: 64 +/- 7.0 ml; NS, (difference between changes in response to treatments: 2p less than 0.05)]. The ejection fraction increased only with isradipine vs. nifedipine [before: 48 +/- 2.3%; after: 54 +/- 2.3%; 2p less than 0.001 vs. before: 52 +/- 2.0%; after: 52 +/- 2.3%; NS (difference between changes in response to treatments: 2p less than 0.05)]. Systolic wall stress decreased significantly more with isradipine than with nifedipine [before: 2,767 +/- 231; after: 2,153 +/- 162 relative units; 2p less than 0.001 vs. before: 2,636 +/- 212; after: 2,310 +/- 199 relative units; 2p less than 0.05 (difference between changes in response to treatments: 2p less than 0.05)]. These results suggest that isradipine, given acutely, unloads the heart more than does nifedipine.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/farmacología , Hemodinámica/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Nifedipino/farmacología , Anciano , Bloqueadores de los Canales de Calcio/administración & dosificación , Dihidropiridinas/administración & dosificación , Humanos , Infusiones Intravenosas , Isradipino , Persona de Mediana Edad , Nifedipino/administración & dosificaciónRESUMEN
Hemodynamic Effects of Isradipine and Nifedipine in Hypertension Myocardial wall tension is an important determinant of the oxygen demand, the function and the degree of hypertrophy of the left ventricle. Myocardial wall tension should be influenced more favourably by a non-cardiodepressive antihypertensive than by a potentially cardiodepressive one. Therefore, we investigated the effects of an intravenous infusion of the calcium antagonists isradipine (I; 0.4 mg; 3,5-pyridinecarboxylic acid, 4-[benzofurazanyl]-1,4-dihydro-2,6-dimethyl-,methyl-ethylester+ ++ [9CI]; CAS75695-93-1) and nifedipine (N; 2.0 mg) resp., on hemodynamics and myocardial wall tension in 12 hypertensives by an intraindividual comparison. The adrenergic reflex activation induced by vasodilation was limited by pre-medication with 0.1 mg propranolol/kg body weight (i.v.) before application of I and N. Baseline blood pressure of the patients and its changes in response to both calcium antagonists were statistically comparable, as were the left ventricular end-diastolic volumes. The end-systolic volumes, however, decreased significantly on I but not on N: before I: 69 +/- 7.0 (mean +/- standard error), after I: 61 +/- 6.1 ml, 2p less than 0,001; before N: 62 +/- 6.1, after N: 64 +/- 7.0 ml, n.s. (difference to I: 2 p less than 0.05). Stroke volume increased only on I (before I: 62 +/- 4.1, after I: 69 +/- 4.1 ml, 2p less than 0.001; before N: 64 +/- 3.5, after N: 65 +/- 3.8 ml, n.s. (difference to I: 2p less than 0.05)).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Dihidropiridinas/uso terapéutico , Hipertensión/fisiopatología , Nifedipino/uso terapéutico , Adulto , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Dihidropiridinas/administración & dosificación , Femenino , Corazón/anatomía & histología , Corazón/efectos de los fármacos , Pruebas de Función Cardíaca , Humanos , Hipertensión/tratamiento farmacológico , Inyecciones Intravenosas , Isradipino , Masculino , Persona de Mediana Edad , Contracción Miocárdica/efectos de los fármacos , Nifedipino/administración & dosificación , Propranolol/farmacología , Volumen Sistólico/efectos de los fármacosRESUMEN
In a randomized double-blind study, the haemodynamic and anti-ischaemic effects of the new dihydropyridine calcium channel blocker isradipine (5 mg and 10 mg thrice daily (t.i.d.) were investigated over 1 week in nine patients with coronary artery disease and chronic effort angina and compared with nifedipine (20 mg t.i.d.) and placebo. In standardized exercise stress tests and exercise radionuclide ventriculography, haemodynamics improved under medication compared with placebo: resting end-diastolic and end-systolic volume index decreased on isradipine 5 mg, 10 mg and on nifedipine, and ejection fraction at rest increased with all medications. Resting mean arterial pressure was reduced compared with placebo accompanied by a decrease in systemic vascular resistance (P less than 0.05) and systolic wall tension (P less than 0.05). Cumulative ST-segment depression was significantly reduced by all three medications (-48%, -23%, -36%), while the increase in work capacity was insignificant. No significant change was found for either heart rate, double product, cardiac index, or stroke work index. Resting plasma levels of noradrenaline, adrenaline and renin activity increased with all three medications (except adrenaline at isradipine 5 mg). Isradipine has favourable effects comparable with those of nifedipine in patients with chronic stable angina and can be safely administered in these patients.
Asunto(s)
Angina de Pecho/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/uso terapéutico , Hemodinámica/efectos de los fármacos , Nifedipino/uso terapéutico , Piridinas/uso terapéutico , Método Doble Ciego , Epinefrina/sangre , Prueba de Esfuerzo , Humanos , Isradipino , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Ventriculografía con Radionúclidos , Ensayos Clínicos Controlados Aleatorios como Asunto , Renina/sangreRESUMEN
The acute effect of a single oral dose of isradipine 5 mg on blood pressure, renal haemodynamics, electrolyte excretion and plasma renin activity was studied in 10 healthy males. Isradipine did not produce a significant change in systolic or diastolic blood pressure, and glomerular filtration rate, renal plasma flow, renal vascular resistance, and urinary albumin excretion remained constant. There was a marked natriuretic and diuretic effect about 1-3 h after isradipine. Plasma renin activity showed a slight, insignificant increase 1 h after dosing. Uric acid clearance and beta 2-microglobulin excretion showed no significant changes, despite an increase in sodium clearance, suggesting an additional mechanism of action other than the proximal tubular natriuretic effect of isradipine in normotensive volunteers.