RESUMEN
A conventional nomogram, based on serum creatinine (sCr) and age, was developed in order to determine the correct initial dosage regimen for meropenem (MEPM) infusions in elderly patients with severe community-acquired pneumonia (CAP), using a target minimum inhibitory concentration (MIC) of 2 mg/L. A correlation between age and actual bodyweight (BW) in a development cohort of 44 males and 45 females was performed by linear regression using the least-squares method (male: y=-0.4676x+80.281, R(2)=0.4888; female: y=-0.4373x+77.502, R(2)=0.3194). There were no significant differences between actual BW and the BW (e-BW) estimated using this equation in this cohort (male: e-BW 41.6±3.1 kg, BW 41.7±3.5 kg, p=0.93; female: e-BW 39.5±2.1 kg, BW 39.5±3.7 kg, p=0.20). By integrating these equations using the Monte Carlo simulation method, a dosage regime was calculated which would have an 80% probability of maintaining plasma drug levels above the MIC for more than 40% of the time (>40%TAM), using only the age and sCr of individual patients. This relationship was summarized as a nomogram. The nomogram was validated using an independent validation cohort (n=28) of patients. An optimized dosage regimen could be predicted in 84 patients (94.4%) in the development cohort and 25 patients (89.3%) in the validation cohort. This nomogram may be a useful tool for clinicians and pharmacists in determining an initial MEPM regimen in elderly patients with severe CAP, based only on age and sCr.
Asunto(s)
Envejecimiento/sangre , Antibacterianos/administración & dosificación , Creatinina/sangre , Método de Montecarlo , Nomogramas , Tienamicinas/administración & dosificación , Tienamicinas/sangre , Factores de Edad , Anciano , Anciano de 80 o más Años , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Peso Corporal , Infecciones Comunitarias Adquiridas/sangre , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Modelos Lineales , Masculino , Meropenem , Tienamicinas/uso terapéuticoRESUMEN
BACKGROUND: Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen. PATIENTS AND METHODS: The subjects were postmenopausal Japanese patients who had undergone surgery for node-negative breast cancer. Toremifene or tamoxifen was administered for 2 years. The primary endpoint was demonstration of the non-inferiority of toremifene compared with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events. RESULTS: A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were well-balanced. Median follow-up was 66.5 months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9 %; 90 % confidence interval -3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3 %, log-rank test P = 0.9458; 88.4 vs. 90.6 %, log-rank test P = 0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated. CONCLUSION: Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.
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Neoplasias de la Mama/tratamiento farmacológico , Tamoxifeno/uso terapéutico , Toremifeno/uso terapéutico , Anciano , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/uso terapéutico , Pueblo Asiatico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/cirugía , Femenino , Humanos , Persona de Mediana Edad , Posmenopausia , Moduladores Selectivos de los Receptores de Estrógeno/efectos adversos , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/efectos adversos , Toremifeno/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: Toremifene and tamoxifen have been used for adjuvant therapy in post-menopausal patients with breast cancer in Japan. Dyslipidemias are common in post-menopausal women. However, limited data are available on the effects of these agents on lipid profiles in Japanese patients. The Japan Toremifene Cooperative Study Group has been conducting a Phase III randomized trial of post-menopausal patients with breast cancer. One of its secondary endpoints is to confirm the effects of these agents on serum lipid profiles. METHODS: The subjects were post-menopausal Japanese patients who had undergone surgery for early breast cancer. Toremifene or tamoxifen was administered for 2 years. Lipid levels were measured before and up to 24 months after initiation. RESULTS: Compared with baseline, at 24 months, the toremifene group (n = 123) showed significantly decreased total cholesterol (P < 0.001) and low-density lipoprotein cholesterol levels (P < 0.001), and significantly increased high-density lipoprotein cholesterol levels (P < 0.001). Their triglyceride levels were not affected (P = 0.677). The tamoxifen group (n = 120) also showed significantly decreased total cholesterol (P < 0.001) and low-density lipoprotein cholesterol levels (P < 0.001); no significant changes occurred in high-density lipoprotein cholesterol (P = 0.297) or triglyceride levels (P = 0.120). CONCLUSIONS: Distinct differences between two selective estrogen receptor modulators on lipids were observed. Toremifene improved lipid profiles, particularly as an enhancer of high-density lipoprotein cholesterol. To a large extent, tamoxifen improved low-density lipoprotein cholesterol levels. The impact of these improved lipid profiles on the risk of cardiovascular diseases needs further confirmation.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Lípidos/sangre , Tamoxifeno/uso terapéutico , Toremifeno/uso terapéutico , Anciano , Neoplasias de la Mama/sangre , Quimioterapia Adyuvante , Femenino , Humanos , Japón , Persona de Mediana Edad , PosmenopausiaRESUMEN
BACKGROUND: To compare the cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and the anthracycline-containing regimen cyclophosphamide, epirubicin, and fluorouracil (CEF) to evaluate the efficacy and safety of the latter. METHODS: A total of 294 patients with axillary node-positive primary breast cancer of STAGE I-IIIa were randomly assigned to either CEF [cyclophosphamide (CPA) 500 mg/m(2) i.v. days 1 and 8; epirubicin (EPI) 60 mg/m(2) i.v. day 1; and 5-fluorouracil (5-FU) 500 mg/m(2) i.v. days 1 and 8] or CMF [CPA 500 mg/m(2) i.v. days 1 and 8; methotrexate (MTX) 40 mg/m(2) i.v. days 1 and 8; and 5-FU 500 mg/m(2) i.v. days 1 and 8]. Both treatment regimens were comprised of six cycles at 4-week intervals. Tamoxifen (TAM) 20 mg/day was concomitantly given to estrogen receptor (ER)-positive patients and those with undetermined ER status for 2 years. RESULTS: The overall 5-year survival was 77.1% for CEF and 71.4% for CMF [p = 0.24; hazard ratio 0.79 (95% CI 0.50-1.24)], and the 5-year disease-free survival was 55.7% for CEF and 48.9% for CMF [p = 0.15; hazard ratio 0.80 (95% CI 0.57-1.12)]. Although the log-rank test did not show a significant difference, both overall and disease-free survivals were higher for CEF according to the point estimates. Adverse drug reactions (ADRs) occurred more frequently in CEF. CONCLUSION: Whereas CEF had a good trend compare with CMF, it could not be proven statistically significant. The principal cause of the failure seems to be insufficient power, that is, the dose intensity (EPI: 60 mg/m(2)) set 10 years ago, when the trial began, was low, and the number of trial subjects was small because of the background of the times, which made the accumulation of cases extremely difficult. However, the trial should be considered to be meaningful, as it was the first, formally conducted controlled trial on chemotherapy in Japan.
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Adenocarcinoma Escirroso/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Papilar/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adenocarcinoma Escirroso/mortalidad , Adenocarcinoma Escirroso/secundario , Adulto , Axila , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Papilar/mortalidad , Carcinoma Papilar/secundario , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Japón , Metástasis Linfática , Metotrexato/administración & dosificación , Persona de Mediana Edad , Receptores de Estrógenos/metabolismo , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Goserelin (GOS) therapy in an adjuvant setting for estrogen receptor(ER)-positive premenopausal patients with breast cancer was assessed in a randomised comparative study. METHODS: ER positive premenopausal patients with n + or n 0 and T > or = 3 cm received tamoxifen (TAM) 20 mg/day, GOS 3.6 mg/4 weeks or GOS + TAM for 2 years, and the clinical efficacy and safety of these regimens were assessed. RESULTS: In the data analysis of total 207 patients, hazard ratios of disease free survival (DFS) and overall survival (OS) in the GOS group compared to the TAM group were 0.87 and 2.10,respectively. The incidence of adverse drug reactions was similar (42-55%) in all three groups. Since the number of patients in this study did not reach the target number, the efficacy could not be assessed from a statistical aspect. Therefore,meta-analysis with similar foreign studies(ZIPP) was implemented. The results of meta-analysis showed that the hazard ratios of DFS and OS in the GOS group compared to the non-GOS group were 0.83 and 0.85, respectively. CONCLUSION: Although the analysis of 207 patients did not show any statistically significant difference between each of the treatment groups, the results of meta-analysis showed a significant prolongation of DFS in the GOS group. Also high tolerability of GOS was suggested. From these results, GOS was considered highly useful in adjuvant therapy for ER-positive premenopausal patients with breast cancer.
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Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Goserelina/administración & dosificación , Premenopausia , Adulto , Antineoplásicos Hormonales/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Esquema de Medicación , Goserelina/efectos adversos , Guanosina Trifosfato/sangre , Sofocos/inducido químicamente , Humanos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Calidad de Vida , Receptores de Estrógenos/análisis , Tasa de Supervivencia , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversosRESUMEN
A late phase II clinical study (II) of a novel vinca alkaloid derivative KW-2307 (vinorelbine ditartrate) in advanced/recurrent breast cancer patients was performed at 22 institutions throughout Japan. An intravenous dose of KW-2307, 20 mg/m2, was administered once a week. Of the 60 patients enrolled in the study, 58 were eligible and 56 were evaluable. The response rate was 33.9% (19/56; 95% confidence interval: 21.8 to 47.8%) with one CR and 18 PRs. The response rate was as high as 37.0% (17/46; 95% confidence interval: 23.2 to 52.5%) when KW-2307 was used as a first-line chemotherapy for advanced/recurrent disease. The most common adverse event was myelosuppression including leukopenia in 96.4% (54/56) and neutropenia in 94.3% (50/53). Other events observed were increased GOT in 51.8% (29/56), increased GPT in 55.4% (31/56), LDH increased in 50.0% (27/54), serum total protein decrease in 39.3% (22/56), anorexia in 41.1% (23/56), nausea and vomiting in 66.1% (37/56), constipation in 30.4% (17/56), alopecia in 33.9% (19/56) and general fatigue in 46.4% (26/56). None of them were serious. This study demonstrated that KW-2307 was an effective and safe treatment for advanced/recurrent breast cancer patients.
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Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Vinblastina/análogos & derivados , Vinblastina/uso terapéutico , Adulto , Anciano , Alopecia/inducido químicamente , Anorexia/inducido químicamente , Antineoplásicos Fitogénicos/efectos adversos , Médula Ósea/efectos de los fármacos , Esquema de Medicación , Femenino , Humanos , Leucopenia/inducido químicamente , Persona de Mediana Edad , Náusea/inducido químicamente , Neutropenia/inducido químicamente , Vinblastina/efectos adversos , VinorelbinaRESUMEN
A 3-month-old female tortoise-shell cat showing azotemia died with a marked swollen abdomen. Necropsy revealed a huge perirenal cyst (8.5 x 6.0 x 4.5 cm) on the ventral aspect of the right kidney. The cyst was filled with the pellucid yellow fluid with a smell of urine. The lumen was connected with irregularly dilated renal pelvis by a narrow channel passing through the renal parenchyma. The cyst was lined by epithelial cells and its wall was consisted of collagen fibers and smooth muscle cells as that of the renal pelvis and ureter. Renal parenchyma adjacent to the channel showed interstitial infiltration of the lymphoid cells. The cyst was a diverticulum of the renal pelvis due to an impaired development.
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Animales Recién Nacidos , Enfermedades de los Gatos/patología , Divertículo/veterinaria , Cálices Renales/anomalías , Animales , Gatos , Divertículo/diagnóstico , Resultado Fatal , Inmunohistoquímica/veterinaria , Cálices Renales/patologíaRESUMEN
BACKGROUND: Fulvestrant ('Faslodex') is a new type of oestrogen receptor (ER) antagonist that down-regulates the ER and has no known agonist effects. PATIENTS AND METHODS: In this open-label, Phase II trial, 30 postmenopausal Japanese women with hormone-sensitive advanced breast cancer, who had progressed on tamoxifen/toremifene following an initial response, received fulvestrant (250 mg; once-monthly intramuscular injection). Primary endpoints were objective tumour response rate (complete or partial response) and assessment of tolerability; secondary endpoints included clinical benefit (objective response, or stable disease > or = 24 weeks), duration of response and pharmacokinetic analysis. RESULTS: The objective response rate was 23.3% and 60.0% of patients experienced clinical benefit. Adverse events were generally mild; the most common were pharyngitis (26.7%), headache (23.3%) and nausea (20.0%). Pharmacokinetic data were similar to a Western study of postmenopausal patients. CONCLUSION: Fulvestrant 250 mg/month is effective and well-tolerated in Japanese patients who have relapsed after one prior endocrine treatment.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Estradiol/análogos & derivados , Estradiol/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/efectos adversos , Estradiol/efectos adversos , Moduladores de los Receptores de Estrógeno/efectos adversos , Moduladores de los Receptores de Estrógeno/uso terapéutico , Femenino , Fulvestrant , Humanos , Persona de Mediana Edad , PosmenopausiaRESUMEN
It has been found that alpha-effects in nucleophilic reactions, unexpectedly large nucleophilicity due to adjacent unpaired electrons, are strongly dependent on the structure of substrate. The nucleophilic cleavages of 4-nitrobenzoate esters and 4-methylbenzoate esters by HOO- have been systematically investigated in detail. When the leaving groups of substrates are sufficiently good (aryl, 2,2,2-trifluoroethyl, and 2,2-dichloroethyl esters), alpha-effect is evident. However, this effect drastically decreases as the leaving group gets poorer, and is only marginal for the cleavages of 2-fluoroethyl and methyl esters. In the nucleophilic cleavages by salicylaldoxime and acetohydroxamic acid, alpha-effect is also notable only for the esters having good leaving groups. These enormous dependences of alpha-effects on the substrate-structure have been interpreted in terms of the difference in the position of transition-state in the reaction coordinate.
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Benzoatos/química , Ésteres/química , Peróxido de Hidrógeno/química , Cinética , Estructura MolecularRESUMEN
Two histologic types of mammary cancer were encountered in an aged captive California sea lion (Zalophus californianus). A cancer with myoepithelial cell proliferation, which had metastasized to distant viscera, was located in the left cranial mammary region. Another cancer without myoepithelial cell proliferation was located in the right posterior mammary region, formed secondary nodules, and had metastasized to a regional lymph node. The presence of two different neoplasms in this sea lion is unusual.
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Carcinoma/veterinaria , Neoplasias Mamarias Animales/diagnóstico , Mioepitelioma/veterinaria , Neoplasias Primarias Múltiples/veterinaria , Leones Marinos , Animales , Animales de Zoológico , Carcinoma/diagnóstico , Carcinoma/patología , Resultado Fatal , Femenino , Inmunohistoquímica/veterinaria , Metástasis Linfática , Neoplasias Mamarias Animales/patología , Neoplasias Mamarias Animales/secundario , Mioepitelioma/diagnóstico , Mioepitelioma/patología , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/patologíaRESUMEN
PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.
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Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Floxuridina/uso terapéutico , Administración Oral , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Floxuridina/administración & dosificación , Floxuridina/efectos adversos , Humanos , Japón , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Meta-analysis of 5 studies on postoperative breast cancer cases (2 studies on surgery alone vs. tegafur plus uracil (UFT) and 3 studies on tamoxifen (TAM) alone vs. TAM + UFT) were carried out to evaluate the anticancer drug UFT in oral postoperative adjuvant chemotherapy. Of the 1973 patients enrolled, 1898 were eligible and 75 were excluded (exclusion rate 3.8%). There was no bias in major background factors in either the UFT-treated (965) or non-UFT-treated (933) groups. The reduction in the odds of death and the odds of recurrence were 17 +/- 17% (p = 0.33) and 21 +/- 11% (p = 0.060), respectively. Multivariate analysis using Cox's proportional hazards model emphasized the effectiveness of UFT treatment for suppression of recurrence compared with non-treatment with UFT (p = 0.038). Suppression of recurrence was remarkable in the group treated with UFT for 2 years. (the reduction in the odds of recurrence: 23 +/- 11%, p = 0.048) Stratified analysis was applied concerning recurrence, and improved results were obtained in premenopausal cases (the reduction in the odds of recurrence: 33 +/- 11%, p = 0.019). These results suggested that UFT treatment for 2 years was effective as postoperative adjuvant chemotherapy for stage I - IIIA breast cancer for the prolongation of the recurrence-free survival period.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Adulto , Anciano , Antimetabolitos Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Tasa de Supervivencia , Tegafur/administración & dosificación , Resultado del Tratamiento , Uracilo/administración & dosificaciónRESUMEN
We investigated the livers, spleens, kidneys and lungs collected from 24 cynomolgus macaques (Macaca fascicularis) naturally infected with Ebola virus subtype Reston (EBO-R) during the Philippine outbreak in 1996, in order to reveal the histopathologic findings. These macaques showed necrotic hepatocytes with inclusions, slight to massive fibrin deposition in splenic cords, depletion of lymphoid cells in the white pulp of the spleen, and fibrin thrombi in some organs. Immunohistochemical analysis using anti-leukocyte antigen L1 antibody revealed an increase in blood-derived macrophages/monocytes in the livers, kidneys and lungs of EBO-R infected macaques. EBO-R NP antigens were detected in the macrophages/monocytes, endothelial cells and fibroblasts in the liver, spleen, kidney and lung. These results indicate that EBO-R infection is characterized by systemic coagulopathy and an increase in blood-derived macrophages/monocytes in accordance with the EBO-R propagation in macrophages/monocytes.
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Fiebre Hemorrágica Ebola/patología , Fiebre Hemorrágica Ebola/veterinaria , Macaca fascicularis , Enfermedades de los Monos/patología , Animales , Animales de Laboratorio , Brotes de Enfermedades , Ebolavirus/aislamiento & purificación , Fiebre Hemorrágica Ebola/epidemiología , Fiebre Hemorrágica Ebola/virología , Complejo de Antígeno L1 de Leucocito , Macrófagos , Enfermedades de los Monos/epidemiología , Enfermedades de los Monos/virología , Monocitos , Filipinas/epidemiología , Factores de TiempoRESUMEN
A single-dose administration study of a new type of aromatase inactivator, exemestane, was performed in normal healthy postmenopausal Japanese women. The study was conducted to investigate the safety, effect on serum and urinary estrogen concentrations, and pharmacokinetics of exemestane at 25 or 50 mg. A crossover study using a single dose (25 mg) was also conducted in order to study the effect of meals on these parameters. Adverse events, in which a causal relationship with the study drug could not be excluded, were as follows: hot flushes (2/4), sleepiness (1/4), and glycogeusia (1/4), all of which were mild and transient. There were no clinically significant laboratory test or physical finding abnormalities with either dose, except for one patient in the 50 mg group who had an increase in levels of GPT, ALP and gamma-GTP. Maximal suppression of serum estrogen concentration (22-37% suppression) was achieved 3-4 days after single-dose administration of exemestane (25 mg or 50 mg), and almost no suppression was observed 2 weeks later. A significant decrease in the amount of urinary estrogen excretion occurred on day 4 and day 8 after exemestane administration. The level of urinary estrogen excretion almost returned to baseline levels in the 25 mg group and returned to 65% of baseline levels in the 50 mg group 2 weeks after drug administration. Both serum estrogen concentration and the amount of urinary estrogen excreted decreased in a similar fashion under both fasting and fed conditions, suggesting no effect of meals on the suppression of estrogen concentrations. Exemestane was adsorbed immediately after single-dose administration, and this was followed by a gradual decrease in serum concentrations in a multiphase pattern. An increase in Cmax and AUC0-tz values was observed after meals compared with those values obtained under fasting conditions, yet the increase was not statistically significant, suggesting that the increase was not clinically relevant. The results of this study verified the safety and the estrogen suppressive effects on serum and urinary concentrations of estrogen of a single dose of exemestane up to 50 mg. Furthermore, results suggest that the suppression of serum and urinary estrogen concentrations and pharmacokinetics of exemestane were not affected by food.
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Androstadienos/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Posmenopausia , Androstadienos/farmacocinética , Antineoplásicos/farmacocinética , Neoplasias de la Mama/metabolismo , Estudios Cruzados , Estrógenos/sangre , Ayuno , Femenino , Humanos , Persona de Mediana EdadRESUMEN
A multiple-dose administration study of exemestane (0.5-50 mg/day after breakfast for 7 days) was conducted in 32 normal healthy postmenopausal Japanese women using a single-blind, 3-step dose-titration method in order to investigate the safety, effect on serum concentration, amount of urinary estrogen excretion, and pharmacokinetics of the drug. Subjective/objective symptoms, in which a causal relationship with exemestane administration could not be excluded, were as follows: headache (8 cases: 1 each in the 0.5 and 25 mg groups, 2 in the 10 mg group and 4 in the 50 mg group), dizziness (2 cases: 1 each in the 0.5 and 25 mg groups), and fever (1 in the 25 mg group), all of which were mild and disappeared without treatment. The only abnormal laboratory findings were a mild increase in levels of GOT and GPT in 1 case and in the number of basophils in another case. There were no notable abnormal findings in vital signs, body weight or EKG. A dose-dependent decrease in serum estrogen level was observed between doses of 0.5 mg and 25 mg. The decrease was maximal at 25 mg, at which serum estrogen concentrations decreased to 14-27% of those observed at day 0. This decrease was maintained for one week, returning to baseline levels 2 weeks after the completion of drug administration. A similar result was also observed in the suppression of 24-hour urinary estrogen excretion. Exemestane was absorbed immediately after initial administration, reaching Cmax 0.9-2.6 hours post-administration. This was followed by a rapid decrease over the next 4-8 hours followed by a gradual decrease Cmax reached normal steady state values on day 5. Cmax and AUC0-24 values taken between administration of the first and final doses increased proportionally in a dose-dependent manner, suggesting that exemestane has a linear pharmacokinetic profile. Furthermore, results of the comparison of the trough concentrations of the initial dose with those of the final dose suggested no accumulative effects of the study drug.
Asunto(s)
Androstadienos/administración & dosificación , Antineoplásicos/administración & dosificación , Posmenopausia , Androstadienos/farmacocinética , Antineoplásicos/farmacocinética , Esquema de Medicación , Ingestión de Alimentos , Estrógenos/sangre , Estrógenos/orina , Femenino , Humanos , Persona de Mediana Edad , Método Simple CiegoRESUMEN
Exemestane was administered orally to postmenopausal women with advanced/recurrent breast cancer at a dose of 10 mg/day or 25 mg/day once daily for more than 8 weeks in order to evaluate the drug's anti-tumor effects and safety in a dose-finding study. The response rate (CR + PR) in the 10 mg and 25 mg group was 25.0% (8/32) and 31.4% (11/35), respectively, demonstrating no significant differences between the two groups, yet a higher efficacy rate was observed in 25 mg group. The efficacy rate in hormone-treatment-resistant patients within the 10 mg and 25 mg groups was 14.3% (3/21) and 26.1% (6/23), respectively, demonstrating more than a 20% response rate in 25 mg group. Incidences of the adverse events of which relevance to the drug could not be excluded were 30.6% (11/36) in the 10 mg group. 13.9% (5/36) in the 25 mg group and 22.2% (16/72) in the total group. The major adverse events were, hot flashes, numbness of the limbs, nausea, headache etc. Abnormal findings in clinical laboratory tests were as follows: ALP increase; GOT increase; GPT increase; gamma-GTP increase; total cholesterol increase; urinary sediment present. Abnormal findings in endocrine function were as follows: aldosterone decrease; testosterone.cortisol.DHEA-S decrease. But discontinuation due to abnormal laboratory findings was not found. No abnormal findings in physical tests were observed. A significant decrease in plasma estrogen concentration at week 4 was observed in both the 10 mg and 25 mg groups compared with baseline. These low levels were maintained throughout the study period. On the basis of these results, the efficacy of exemestane 25 mg/day was verified to be slightly higher than 10 mg/day. In addition the safety profile had no major adverse events to notice. In these patients with advanced/recurrent breast cancer, 25 mg/day was recommended as the most appropriate dose to be used clinically.
Asunto(s)
Androstadienos/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Posmenopausia , Administración Oral , Androstadienos/efectos adversos , Androstadienos/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias de la Mama/metabolismo , Esquema de Medicación , Estrógenos/sangre , Femenino , Cefalea/inducido químicamente , Sofocos/inducido químicamente , Humanos , Persona de Mediana Edad , Náusea/inducido químicamente , Receptores de Estrógenos/análisisRESUMEN
The aim of this study was to analyze the pharmacokinetics and pharmacodynamics (PK/PD) of 6- O-(3-ethoxypropionyl)-3',4'- O-exo-benzylidene-chartreusin (IST-622) and its metabolites, and to develop limited sampling models (LSM). Based on the data from 18 patients with breast cancer who were treated orally with 280 or 525 mg/m(2) of IST-622 once daily after breakfast for five consecutive days, we analyzed the relationship between the area under the plasma concentration versus time curve (AUC) and toxicities using a sigmoid E-max model and logistic regression. Plasma concentrations of IST-622 and its metabolites, 3',4'- O-exo-benzylidene-chartreusin (A-132) and 3"-demethyl-3',4'- O-exo-benzylidene-chartreusin (A-132M), were measured at 1, 2, 4, 8 and 24 h after administration on day 1. The AUC was calculated using the trapezoidal method. We also developed a LSM using stepwise linear regression analysis. IST-622 was detected in very few patients, and its concentration was very low and could be disregarded. It was suggested that meals promoted absorption of IST-622. AUCs of A-132 plus A-132M showed a better correlation with the rates of decrease and nadir counts of leukocytes, neutrophils and platelets than the AUC of each metabolite separately. Patients with the sum of AUCs more than 70 microg.h/ml showed severe myelotoxicities. Moreover, logistic regression analysis showed that grade 4 myelotoxicities would be seen in 30% of patients at an AUC of 65 microg.h/ml. We also developed an unbiased and precise LSM: AUC0-24h=C8hx17.6-0.95, where C(8h) denotes the sum of plasma concentrations of A-132 and A-132M. Myelotoxicities showed a good correlation with AUC(0-24h), and based on the results, it was decided that the target AUC was 65 microg.h/ml. The LSM was very convenient for estimating AUC(0-24h) and sufficiently accurate. These results show the possibility of predicting toxicities and dose adaptation for interpatient variability using LSM.
Asunto(s)
Benzopiranos/farmacología , Benzopiranos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Glicósidos/farmacología , Glicósidos/farmacocinética , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Área Bajo la Curva , Benzopiranos/administración & dosificación , Benzopiranos/química , Monitoreo de Drogas , Femenino , Glicósidos/administración & dosificación , Glicósidos/química , Humanos , Persona de Mediana Edad , Distribución TisularRESUMEN
To determine the recommended clinical dose of CGS20267 (Letrozole), we conducted a randomized comparative study as a late phase II study (first part) in postmenopausal women with advanced or recurrent breast cancer. Forty-one patients were randomly assigned to receive 0.5 mg or 1.0 mg once daily. There were no statistically significant differences in background between the two groups. Although there was no significant difference in the objective response rates between the two groups, the rate was higher at 1.0 mg (44.4%) than at 0.5 mg (38.1%). We also combined these data with the results of an early phase II study. The objective response rates (CR + PR) were 31.4% at 0.5 mg and 42.2% at 1.0 mg, and response rates consisting of CR, PR, and NC for longer than 6 months were significantly higher at a dose of 1.0 mg (68.9%) than 0.5 mg (41.2%). Side effects included drug-related adverse events in 36.8% at 0.5 mg and in 31.6% at 1.0 mg. All of the events were grade 2 or lower, indicating a favorable tolerability of CGS20267. These results demonstrated that CGS20267 1.0 mg once daily is more effective than 0.5 mg, and has comparable safety, in the treatment of postmenopausal women with advanced or recurrent breast cancer. We conclude the recommended clinical dose of CGS20267 should be 1.0 mg once daily.
Asunto(s)
Antineoplásicos/administración & dosificación , Inhibidores de la Aromatasa , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Nitrilos/administración & dosificación , Posmenopausia , Triazoles/administración & dosificación , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Estrógenos/sangre , Femenino , Humanos , Letrozol , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
In the first part of this late phase II study, we determined the recommended clinical dose of CGS20267 to be 1.0 mg once daily for the treatment of postmenopausal women with advanced or recurrent breast cancer. To further evaluate the efficacy and safety of CGS20267 at the derived or recommended clinical dose, 30 more patients were enrolled in the second part of the study, and were added to the patients treated at 1.0 mg in the first part. As a result of putting the first and second parts together, the objective response rate at 1.0 mg was found to be 38.3%, which was almost equal to that of the early phase II study (40.7%). Drug-related adverse events occurred in 35.4% of the patients at 1.0 mg, and all of the events were of grade 2 or lower. These results demonstrated that CGS20267 1.0 mg once daily is effective and well tolerated in the treatment of postmenopausal women with advanced or recurrent breast cancer.
Asunto(s)
Antineoplásicos/administración & dosificación , Inhibidores de la Aromatasa , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Nitrilos/administración & dosificación , Posmenopausia , Triazoles/administración & dosificación , Adulto , Anciano , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/mortalidad , Esquema de Medicación , Inhibidores Enzimáticos/uso terapéutico , Estrógenos/sangre , Femenino , Humanos , Letrozol , Persona de Mediana Edad , Nitrilos/uso terapéutico , Tasa de Supervivencia , Triazoles/uso terapéuticoRESUMEN
A multicenter, open labeled, randomized early Phase II study for CGS 20267 was conducted at the doses 0.5 mg once daily and 1.0 mg once daily in postmenopausal women with advanced breast cancer. Sixty-four patients were randomly assigned to the doses of either 0.5 mg once daily (n = 33) or 1.0 mg once daily (n = 31). Thirty-one patients were eligible for 0.5 mg group, and 29 for 1.0 mg group. A total of 57 patients (30 in the 0.5 mg group and 27 in the 1.0 mg group) were eligible for the evaluation of efficacy. There were 3 CR, 5 PR, 5 stable disease (SD: NC lasting over 24 weeks), 7 NC and 10 PD in the 0.5 mg group. The objective response rate (ORR) was 26.7%. There were 4 CR, 7 PR, 8 SD, 3 NC and 5 PD in the 1.0 mg group. The ORR was 40.7%. A total of 57 patients (29 in the 0.5 mg group and 28 in the 1.0 mg group) were eligible for safety evaluation. Adverse clinical events related to CGS 20267 in the 0.5 mg group were headache, nausea, cold sweat, sleepiness and muscle ache in the lower extremities (2 patients, incidence rate 6.9%) whereas those in the 1.0 mg group were generalized itching and generalized hot feeling (2 patients, incidence rate 7.1%). All of the adverse events were grade 1 except the generalized itching which was grade 2. CGS 20267-related abnormalities in the laboratory tests for the 0.5 mg group were a decrease in WBC, and increases in GOT, GPT, LDH and gamma-GTP (5 patients, 14.3%) whereas those in the 1.0 mg group were increases in GPT, gamma-GTP, alkaline phosphatase, and total bilirubin (1 patient, 3.6%). The increases in GOT and GPT were grade 2, but others were grade 1. The data show both CGS 20267 0.5 mg once daily and 1.0 mg once daily to be effective and tolerable in the treatment of postmenopausal women with advanced breast cancer.