Phase I-II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma.

BACKGROUND: This phase I-II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma. METHODS: The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m(-2) (n = 20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m(-2) on days 1, 8 and 15 q4wk combined with DTIC 800 mg m(-2) q4wk (n = 38). RESULTS: The overall response rate with plitidepsin/DTIC was 21.4%; all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ≤ 1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug-drug pharmacokinetic interactions were found. CONCLUSION: This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m(-2) fortnightly and DTIC 800 mg m(-2) q4wk is recommended.

[The contribution of diet and sun exposure to the nutritional status of vitamin D in elderly Spanish women: the five countries study (OPTIFORD Project)]. / Contribución de la dieta y la exposición solar al estatus nutricional de vitamina D en españolas de edad avanzada: Estudio de los Cinco Países (Proyecto OPTIFORD).

UNLABELLED: Vitamin D deficiency represents an important public health problem, especially among elderly people, by increasing the morbimortality. Because of the importance of this, in the year 2001 the "Five Countries Study" was put in place, within the European OPTIFORD project (Towards a strategy for optimal vitamin D fortification). This cross-sectional and observational study aims at knowing the vitamin D status in adolescent and elder women from five European countries, including Spain, according to different dietary and behavioral habits. OBJECTIVE: This work analyzes the relative contribution of sun exposure and diet to the vitamin D status in 53 Caucasian Spanish elder women (72 +/- 1.6 years), with an autonomous life, participating at the Five Countries Study. METHODOLOGY: The information was gathered in summer and winter time, by using homologated and validated questionnaires: health status and life style questionnaire; assessment of sun exposure by a standardized test and using a Viospor UV dosimeter (only in summer time); biochemical analysis of 25 hydroxyvitamin D (S-25-OHD) and parathyroid hormone; and questionnaire of frequency of selective intake. RESULTS: We observed a direct relationship between sun exposure measured with the dosimeter (741 +/- 624 J/m2) and the number of hours outdoors during the measuring week (3.4 +/- 1.9 hours/day) (p < 0.0001). The serum levels of S-25-OHD were higher in summer time than during the winter (40.32 +/- 20.39 nmol/L and 30.08 +/- 17.39 nmol/L, respectively), and 40% of the participants had worse vitamin status in winter as compared with summer time (p < 0.001). During the summer time, vitamin D deficiency (S-25-OHD < or = 25 nmol/L) affected 28% of the population, being virtually twice as much during the winter time. The higher the sun exposure, as assessed by the dosimeter, the higher the value of S-25-OHD, with clear differences between participants in the S-25-OHD < or = 25 nmol/L group and those in the S-25-OHD > 50 nmol/L (p = 0.01). There is also a direct association between the number of hours outdoors and S-25-OHD (p = 0.09), with differences between the participants in the S-25-OHD < or = 25 nmol/L group and the S-25-OHD > 50 nmol/L group. In more than 95% of the sample, mean dietary intakes of vitamin D (5.17 +/- 4.84 microg/day in summer time and 4.70+/- 4.72 microg/day in winter time), the main source of which being fish, did not cover the Recommended Allowances. We did not observe a relationship between the dietary intake and blood levels of vitamin D. By contrast, those participants taking vitamin D supplements presented higher S-25-OHD levels (summer = 69.64 nmol/L and winter = 55 nmol/L) than those not consuming it (summer = 36.83 nmol/L and winter = 25.82 nmol/L) (psummer =0.0003 and p winter < 0.001). CONCLUSIONS: The deficient status of vitamin D among the elderly female population has to be corrected, whenever possible, with appropriate sun exposure and an increase in vitamin D intake through the diet, assessing at each particular case the benefits of pharmacological supplementation.

The mechanism of the positive inotropic action of ketamine on isolated atria of the rat.

1 The effect of ketamine (10-7 M-5 X10-4 M) on electrical and mechanical properties of isolated atria of the rat was investigated. 2. On spontaneously beating right atria, ketamine produced a dose-dependent positive inotropic effect which was accompanied by a progressive reduction in atrial rate. 3 In electrically driven left atria, ketamine produced a dose-dependent positive inotropic effect which was accompanied by a parallel increase in df/dtmax and by a prolongation in the time to peak tension and in the time for total concentration. The positive inotropic effect occurred concomitantly with an increase in the height and duration of the plateau phase of the action potential of atrial fibres. 4 The positive inotropic effect of ketamine varied with the concentration of Ca and Na in the bathing media and the rate of stimulation. 5 Ketamine decreased post-extrasystolic potentiation and the amplitude-interval relationship. 6 The positive inotropic effect of ketamine was inhibited by verapamil (10-6 M) and by caffeine (4 X10-3 M). 7 Ketamine, 5 X10-5M and 10-4M, increased 45Ca uptake in electrically driven left atria. At 10-4M and 5 X10-4M, ketamine also increased 45Ca efflux. 8 These results suggest that ketamine produces its positive inotropic effect by two possible mechanisms. One of these is presumed to be an effect on the cell membrane with leads to an increased Ca influx into atrial fibres; the other is probably related to the inhibition of Ca sequestration by the sarcoplasmic reticulum.

A comparison of josamycin with macrolides and related antibiotics on isolated rat atria.

The effects of macrolide (Josamycin, erythromycin, spiramycin and oleandomycin) and related antibiotics (clindamycin and lincomycin) were examined and compared in spontaneously beating right atrial preparations and in electrically driven left atrial preparations of rats. Josamycin and erythromycin (10(-7)-10(-4) M) produced a dose-dependent decrease in rate. contractile force and maximum following frequency and prolonged the sinus node recovery time and the refractory period. The negative inotropic effect of josamycin was not modified by pretreating the atria with atropine or with a mixture of antagonists containing phentolamine, practolol, diphenhydramine, cimetidine, methysergide and indomethacin. In isolated right atria, josamycin did not block the positive inotropic and chronotropic responses to isoprenaline but shifted the dose-response curve to Ca to the right. Josamycin and erythromycin reduced in a dose-dependent manner the slow responses induced in K-depolarized right atria by isoprenaline but this effect was reversed by increasing the Ca concentration in the bathing media. These findings demonstrate a direct negative inotropic effect of josamycin and suggest that this effect could in some way be explained by inhibiting transmembrane Ca influx into atrial cells. The clinical significance of these results is discussed.

[Concomitant hyperfractionation of drugs and irradiation in the treatment of advanced ENT cancers]. / Hiperfraccionamiento concomitante de drogas e irradiación en el tratamiento del cáncer avanzado del área O.R.L.

Considering the limited results achieved up to now in the treatment of advanced ENT-cancer, with the classic customary procedures, the AA. suggest a new therapeutic schedule (within the concurrent radio-chemotherapy context) in which the selected cytotoxic drug, the carboplatin, is a part of each therapeutic fraction. A group of 36 patients suffering advanced ENT-cancer (2 cases stage III and 34 stage IV) were studied between Mars 1993 and September 1995, and the outcomes assessed after a 18 months mean follow-up (30 months maximum). There were 11% surgically rescued cases, being the full dosage administered twice daily 8.050 cGy plus 700 mg carboplatin. Tolerance was very good, so 100% of the patients received a complete treatment. Initial response was also fine resulting 93% full remissions on primaries, 96% on neck adenopathies (6% surgical rescues). Regarding the actuarial control after 30 months were controlled 88% of neck adenopathies, control loco-regional amounted for 69%, control on primaries 63% and actuarial survival amounted 55%. The AA. drawn out 10 conclusions, underlining the good tolerance of the therapeutic sketch proposed, because the antineoplastic results are by far better than those experienced with whichever modality of management of tumors of these sites and staging.

Non-institutionalized nonagenarians health-related quality of life and nutritional status: is there a link between them?

INTRODUCTION: Nonagenarian population, clearly increasing, shows different characteristics from the rest of elderly people. Health-related quality of life is a way to study population health in physical, psychological and social dimensions. OBJECTIVES: To examine the relationship between nutritional status and health-related quality of life in a group of free-living nonagenarians. Differences with octogenarians were also studied. METHODS: Within Villanueva Older Health Study, 20 non-institutionalised people (92.5 ± 3.5 years; 80% women) make the nonagenarian subsample. Nutritional risk was assessed by Mininutritional Assessment questionnaire, dietary intake by a 24-hour dietary recall and health-related quality of life by EuroQoL-5D questionnaire. SPSS was used for statistical analysis. RESULTS: 40% nonagenarians were at risk of malnutrition. Dietary assessment showed magnesium, zinc, potassium, folic acid, vitamin D and vitamin E deficiencies. Problems in mobility were more frequently reported (80%). EQ-5Dindex was associated with MNA(p<0.05). Self-care dimension was associated with calcium and niacin(p<0.05), retinol and cholesterol(p<0.01) intake. Usual activities dimension was associated with niacin(p<0.01) and cholesterol(p<0.05) intake. Pain/discomfort dimension was associated with protein(p<0.01), energy, selenium and niacin(p<0.05) intake. Anxiety/depression was associated with protein(p<0.01) and selenium(p<0.05) intake. CONCLUSIONS: Risk of malnutrition is a factor associated to health-related quality of life. Results suggest that energy and some nutrient intakes could be possibly associated to health-related quality of life but further research on this influence is required.

Introducción: La población nonagenaria, en claro crecimiento, muestra características diferentes del resto de la población anciana. La calidad de vida relacionada con la salud es una forma de estudiar la salud de la población en sus dimensiones física, psicológica y social. Objetivos: Observar la relación entre el estado nutricional y la calidad de vida relacionada con la salud en un grupo de nonagenarios de vida independiente. También se estudian las diferencias con los octogenarios. Método: Dentro del Estudio sobre Salud en Mayores de Villanueva de la Cañada, 20 personas (92,5±3,5 años; 80% mujeres) forman la submuestra de nonagenarios. El riesgo nutricional fue valorado mediante el Mininutritional Assessment, la ingesta dietética mediante un recuerdo de 24 horas y la calidad de vida relacionada con la salud usando el cuestionario EuroQoL-5D (EQ-5D). Para el análisis estadístico se utilizó el programa SPSS. Resultados: 40% de los nonagenarios presentaban riesgo de malnutrición. Se detectaron posibles deficiencias de magnesio, cinc, potasio, ácido fólico, vitamina D y vitamina E. Los problemas de movilidad fueron los más frecuentes (80%). El EQ-5Dindice se asoció con el MNA(p.

Influence of nutritional status on health-related quality of life of non-institutionalized older people.

OBJECTIVES: Health-related quality of life (HRQoL) is a multidimensional health measurement and a key to optimal aging. The aim of this study was to examine the association of nutritional status with HRQoL in the elderly. DESIGN: Cross-sectional study. SETTING: Villanueva Older Health Study, a community-based study in Villanueva de la Cañada (Madrid, Spain). PARTICIPANTS: 83 (53 women) non-institutionalized inhabitants aged 80 years and above. MEASUREMENT: HRQoL was assessed by EuroQoL-5D (EQ-5D) questionnaire, nutritional risk by Mini Nutritional Assessment (MNA) questionnaire and dietary intake by 24-hour dietary recall. Statistical significance was evaluated at 95% confidence level (P<0.05). RESULTS: EQ-5D pointed out differences between men and women (0.782±0.235 and 0.633±0.247; p=0.02). Problems in mobility (total sample) and pain/discomfort (women) dimensions were most frequently reported. MNA (26.5±3.2 men and 24.3±3.2 women; p=0.03) revealed malnutrition in 3.3% of men and 1.9% of women, and risk of malnutrition in 6.7% and 37.7%, respectively. Total sample was at risk of folic acid, zinc, magnesium, vitamin D and vitamin E deficiency. EQ-5D was associated with MNA (p<0.001). EQ-5Dindex was associated with energy intake (p=0.04) and EQ-5Dvas was negatively correlated with body mass index (p=0.02). EQ-5D pain/discomfort dimension was associated with energy (p=0.006), protein (p=0.005), lipid (p=0.03), magnesium (p=0.032), phosphorus (p=0.012), selenium (p=0.043) and niacin (p=0.004) intake. CONCLUSIONS: Women showed poorer HRQoL and higher malnutrition risk. A relationship between HRQoL and risk of malnutrition was observed. Results suggest that when energy and protein, lipid, phosphorus, magnesium, selenium and niacin intake increase, HRQoL is promoted, although the increase does not seem to have a strong direct effect on it. The limited influence of energy and nutrient intake on HRQoL observed requires further research.

[Comparative analysis of vitamin D status and solar exposition habits in adolescent and elderly Spanish women. The Five Countries Study (OPTIFORD Project)]. / Análisis comparativo del estado nutricional de vitamina D y de los hábitos de exposición solar de las participantes Españolas (adolescentes y de edad avanzada) del Estudio de los Cinco Países (Proyecto OPTIFORD).

INTRODUCTION: Vitamin D deficiency is known to be very common in adolescent girls and elderly women. AIM: To analyze vitamin D status, vitamin D intake and solar exposure of Spanish participants in The Five Countries Study of Optiford Project. METHODS: Questionnaires approved and validated of lifestyle and food consumption frequency applied. The biochemical analysis of 25-hidroxivitamin D and PTH and the evaluation of the solar exposure (dosymeter UV VioSpor) were carried out. RESULTS: The average solar exposure of adolescent girls (1,519 J/m²) was double than elderly women (740 J/m²). The vitamin D status of adolescent girls in summer and winter was better than elderly women. CONCLUSIONS: Solar exposure habits are different between the two age groups. This fact, jointly to the lower body's capacity to synthesize Vitamin D through exposure to the sun in the elderly, may justify the worse vitamin D status in this age group.

[Influence of sun exposure and diet to the nutritional status of vitamin D in adolescent Spanish women: the five countries study (OPTIFORD Project)]. / Influencia de la exposición solar y la dieta en el estado nutricional de vitamina D en adolescentes españolas: estudio de los cinco países (Proyecto OPTIFORD).

INTRODUCTION: Vitamin D deficiency is a big public health concern, especially among women. For this reason, "The Five Countries Study" was set up within the OPTIFORD project. This study aims at knowing the vitamin D status in adolescent and older women in five European countries according to their different dietary and behavioral habits. OBJECTIVES: To analyze the relative contribution of sun exposure and the diet to the vitamin D status among 47 Spanish adolescents participating in "The Five Countries Study". METHODS: Validated and standardized questionnaires (health, lifestyle, sun exposure, and frequency of food consumption), biochemical analysis (25-hydroxyvitamin D (S-25-OHD) and parathormone), and assessment of sun exposure (UV dosimeter). RESULTS: Serum levels of S-25-OHD were higher during the summertime than in winter (61.55±12.85 nmol/l and 45.81±9.29 nmol/l, respectively). Forty-five percent of the sample had a worsening of their vitamin status in the winter, as compared with the summer (p<0.0001). During the summer, vitamin D insufficiency (S-25-OHD≤50 nmol/l) affected 17% of the population, going up to 63% in the winter. Sixty-six percent of the sample did not reach the IR of vitamin D (5 g/day), being the fish the main dietary source of vitamin D. CONCLUSIONS: Only 34% of the participants had an adequate vitamin D status. Both adequate sun exposure and vitamin D dietary intake are recommended in order to correct deficient and insufficient situations.