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Biomedical subjects

V Alfaro

Publications and source records attributed to V Alfaro.

At least 19 recordsLinked to original sources
PubMed2022

Lurbinectedin, a selective inhibitor of oncogenic transcription, in patients with pretreated germline BRCA1/2 metastatic breast cancer: results from a phase II basket study.

BACKGROUND: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer. PATIENTS AND METHODS: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Confirmed partial response (PR) was observed in six patients [ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2%] who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%)]. Clinical benefit rate (PR + SD ≥ 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia). CONCLUSIONS: This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted.

Humans↗
PubMed2003

Nucleotides modulate renal ischaemia-reperfusion injury by different effects on nitric oxide and superoxide.

1. The present study investigated the effects of kidney ischaemia duration on nitric oxide (NO) and superoxide (O2-) generation at reperfusion and the role of xanthine and adenosine as mediators of NO/O2- generation. 2. The effect of the duration of ischaemia on renal nucleotide levels was studied in two ischaemic groups (10 and 30 min). The role of adenosine and xanthine was studied in ischaemic-reperfused groups (subjected to 10 and 30 min ischaemia and 60 min reperfusion). 3. Tissue levels of adenosine decreased significantly after 30 min ischaemia, whereas xanthine/hypoxanthine levels increased concomitantly with renal dysfunction and histological damage. 4. Nitric oxide production increased significantly after 10 min ischaemia and 60 min reperfusion, whereas lipoperoxidation increased significantly after 30 min ischaemia and 60 min reperfusion. The administration of theophylline (40 mg/kg, i.p.) reversed the early increase in NO production. 5. Xanthine supplementation decreased renal function and increased lipoperoxidation. 6. In conclusion, NO/O2- production and the subsequent renal injury/dysfunction may be modified by changes in the adenosine and xanthine levels of the injured kidney, although the present data show a significant in vivo role only for xanthine.

Adenosine↗
PubMed2002

Extracellular pH affects inflammatory cell production of superoxide and nitric oxide.

Previous research has described how high cellular metabolism creates an acidic environment in inflammatory cells during respiratory burst. The aim of our work was to describe the acid-base dependence of exudate in superoxide (O2.-) and nitric oxide (NO.) generation by inflammatory cells from a carrageenan-granuloma. Although the carrageenan solution was alkaline (pH 7.74 when equilibrated with air) the exudate showed an acidification that stabilised at around 7 units of pH. A notable hypercapnia, but not hypoxia, was found in the exudate at up to 24 h. The effect of extracellular acidosis on O2.- and NO. production by inflammatory cells was also studied. The maximum O2.- production and the lowest levels of NO. were found at pH 7, which was closer to the pH of the granuloma-pouch. These results suggest that experiments with inflammatory cells ex vivo should be carried out at an identical pH to that found in vivo in order to reproduce the physiological mechanisms of free radical generation during inflammatory processes.

Animals↗
PubMed2001

CO2 in static mesenteric venous blood during intestinal ischemia and ischemic preconditioning in rats.

During intestinal ischemia, CO2 accumulates in tissue as a result of bicarbonate buffering of anaerobic acid generation. Previous studies have shown that nitric oxide (NO) generated during ischemic preconditioning acts as a glycolytic modulator, thus decreasing tissue lactate production. We studied if ischemic preconditioning induces NO-dependent changes in static mesenteric venous blood Pco2 values and CO2 accumulation during intestinal ischemia. Superior mesenteric venous (smv) acid base variables were studied in 4 groups of rats: a control group (C), an ischemic (90-min period of flow arrest) group (I), an ischemic group subjected to previous ischemic preconditioning (P), and an ischemic group subjected to previous ischemic preconditioning in which nitric oxide synthase (NOS) was inhibited by N-nitro-L-arginine methyl ester (L-NAME) administration (P+N). Preconditioning induced acidosis in smv blood during reperfusion before ischemia, but this effect was counteracted by L-NAME. Group P showed the lowest values of end-ischemic tissue lactate, smv blood CO2 accumulation, and LDH in perfusate, whereas group P+N showed the highest level of LDH in perfusate but the lowest end-ischemic smv blood Pco2 and acidity. We conclude that lower ischemic CO2 accumulation in static smv blood, but not lower end-ischemic Pco2, was related with the protective effect of ischemic preconditioning in our rat model. Thus, the use of stagnant smv blood Pco2 as an indicative of intestinal dysoxia can lead to misinterpretations if a broader acid-base picture is not considered.

Anaerobiosis↗
PubMed2000

The clinical uroselectivity of alfuzosin is not significantly affected by the age of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

OBJECTIVE: To assess the effect of the age of patients with benign prostatic hyperplasia (BPH) on the clinical uroselectivity of alfuzosin during general medical practice. PATIENTS AND METHODS: The present national, multicentre, open-labelled, observational study involved 4018 Spanish outpatients with BPH, i.e. showing lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction. The patients received sustained release (SR) alfuzosin, 5 mg twice daily, for 2 months. The primary efficacy criteria were symptomatic improvements, as assessed by the International Prostate Symptom Score (IPSS) and quality of life (QoL) index. Safety was assessed by monitoring cardiovascular data and adverse events. RESULTS: The patients were divided into four age groups, i.e. < 56, 56-65, 66-75 and > 75 years. All groups of patients showed a mean IPSS decrease of 11-12 (55.8-65.4% from baseline) at the end of the study, while the QoL decreased by 2-3 points (55.6-63.6% from baseline). There were no relevant effects of age on the efficacy of the treatment. Moreover, alfuzosin was well tolerated independently of the age of the patient; 1.2% of the patients enrolled withdrew because of adverse events. The qualitative distribution of vasodilatory/nonvasodilatory adverse events was similar in all age groups. The incidence of asymptomatic orthostatic hypotension was low (0.58%) and not affected by the age of the patients. CONCLUSION: This study confirms that the clinical uro-selectivity of SR-alfuzosin, already described in ran-domized controlled studies, is not significantly affected in clinical practice by the age of the patients. This is considered particularly relevant to the characteristics of patients with BPH, as they are mostly elderly men.

Adrenergic alpha-Antagonists↗
PubMed2000

Safety and efficacy of sustained-release alfuzosin on lower urinary tract symptoms suggestive of benign prostatic hyperplasia in 3,095 Spanish patients evaluated during general practice.

OBJECTIVES: This general practitioner-run study assess the security as well as the efficacy and impact on health-related quality of life of a sustained-release (SR) form of alfuzosin in Spanish patients suffering from lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). MATERIAL AND METHODS: 3,095 patients with symptomatic BPH were enrolled into a national, multicentric, open, phase IV observational study. The period of active treatment studied (5 mg, twice daily) was 60 days. Safety was assessed by monitoring blood pressure and spontaneous adverse events. Symptoms were assessed using a validated Spanish International Prostate Symptom Score (I-PSS). Impact of symptoms on health-related quality of life was assessed using the quality of life index (L). RESULTS: 101 adverse events were reported in 82 patients (2.6%). 28 adverse events (2.6%) were classified as severe. 49 patients (1.6%) dropped out of the study due to adverse events but only 17 of these patients (0.5%) showed adverse events related to vasodilation. Incidence of postural events (vertigo, postural hypotension/hypotension, headache and dizziness) was low (55 patients, 1.8%) and effects on sexual function were found not significant: no retrograde ejaculation was reported and only 1 patient (0.03%) showed impotence. Blood pressure or heart rate showed no clinically significant changes. All the I-PSS scores decreased significantly during the treatment with alfuzosin, improvement being excellent in 60% of the patients. Symptomatic improvement was associated with a significant improvement in health-related quality of life. CONCLUSIONS: This large study conducted during general practice on Spanish BPH patients confirms the efficacy on LUTS and good safety profile of SR alfuzosin, especially its low incidence of postural symptoms and no deleterious effect on sexual function.

Adrenergic alpha-Antagonists↗
PubMed2000

Age-stratified analysis of I-PSS and QoL values in spanish patients with symptoms potentially related to BPH.

OBJECTIVE: The main goal of the present study was to determine age-related symptom changes using a validated Spanish International Prostate Symptom Score (I-PSS) and quality of life index (QoL) in Spanish patients with symptomatic benign prostatic hyperplasia (BPH). METHODS: A total of 2,875 patients with the clinical diagnosis of symptomatic BPH were evaluated. Data were collected during current medical practice in a national study. Patients were excluded if they had any previous prostate operation or suspicion of prostate cancer. I-PSS was self-administered and compared with the physician's global impression. RESULTS: I-PSS symptoms, both voiding and storage symptoms, increased significantly with age (p<0.0001) as well as QoL (p<0.0017). A change in the I-PSS categories (minor, moderate and severe) was found with age, increasing severe symptomatic patients in the oldest groups. A significant correlation was found between I-PSS and QoL (r = 0.49, p<0.001), being this relationship linear and not significantly influenced by age. CONCLUSIONS: This study confirms reliable results using a validated Spanish I-PSS in a large national representative sample of Spanish patients with BPH symptoms. The age-stratified analysis showed that the natural progression of BPH with age was related to an increased symptomatology and bothersomeness, well reflected by increases in the I-PSS and QoL values. Nevertheless, the effect of symptomatology on quality of life was not strongly influenced by the age of the patient.

Age Factors↗
PubMed2000

Acid-base analysis during experimental anemia in rats.

The present study evaluated the acid-base status of anemic rats by using two approaches of acid-base analysis: one based on the base excess (BE) calculation and the other based on Stewart's physicochemical analysis. Two sets of experimental data, derived from two different methods of inducing anemia, were used: repetitive doses of phenylhydrazine (PHZ) and bleeding (BL). A significant uncompensated respiratory alkalosis was found in both groups of anemic rats. BE increased slightly, whereas strong ion difference ([SID]) and weak acid buffers ([A(TOT)]) remained unchanged in anemic rats. The reasons for the absence of compensation for hypocapnia and the differences in the behaviour of acid-base variables are discussed. BE increase was considered paradoxical; its calculation was affected by the experimental conditions and BE had little physiological relevance during anemia. The absence of metabolic renal compensation in anemic rats could be due to a lower pH in the kidney due to anemic hypoxia. Finally, the changes in buffer strength related to low Hb and low P(CO2) might influence plasma [SID] through counteracted shifts of strong ions between erythrocytes and plasma, finally resulting in unchanged [SID] during anemia.

Acid-Base Imbalance↗
PubMed1999

Modification of glyceraldehyde-3-phosphate dehydrogenase in response to nitric oxide in intestinal preconditioning.

BACKGROUND: Previous studies have demonstrated that intestinal preconditioning is triggered by an initial increase in nitric oxide synthesis. This confers resistance to the organ in face of a subsequently sustained period of ischemia-reperfusion. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in the glycolytic cascade that could be modulated by nitric oxide. The purpose of the present study is to evaluate a possible inhibitory effect on intestinal GAPDH by the nitric oxide generated during preconditioning. This could lead to a reduction of lactate accumulation during subsequent ischemia. METHODS: GAPDH activity was measured after intestinal preconditioning, and the effect of nitric oxide synthase inhibition was evaluated. RESULTS: Preconditioning induced a significant, but transient, decrease in GAPDH activity. This effect appears to be correlated with a reduced amount of lactate accumulation during ischemia. Inhibition of nitric oxide synthesis reversed these changes. In addition, increased synthesis of nitric oxide was detected after preconditioning. CONCLUSIONS: In summary, this study indicates that nitric oxide generated during ischemic preconditioning could act as a glycolytic modulator during subsequent ischemia, through its effect on GAPDH activity.

Animals↗
PubMed1999

Acid-base disturbance during hemorrhage in rats: significant role of strong inorganic ions.

The present study tests the hypothesis that changes in the strong inorganic ion concentrations contribute significantly to the acid-base disturbance that develops during hemorrhage in the arterial plasma of rats in addition to lactate concentration ([Lac-]) increase. The physicochemical origins for this acid-base disorder were studied during acute, graded hemorrhage (10, 20, and 30% loss of blood volume) in three groups of rats: conscious, anesthetized with ketamine, and anesthetized with urethan. The results support the hypothesis examined: strong-ion difference (SID) decreased in the arterial plasma of all groups studied because of an early imbalance in the main strong inorganic ions during initial hemorrhagic phase. Moreover, changes in plasma [Lac-] contributed to SID decrease in a later hemorrhagic phase (after 10% hemorrhage in urethan-anesthetized, after 20% hemorrhage in ketamine-anesthetized, and after 30% hemorrhage in conscious group). Inorganic ion changes were due to both dilution of the vascular compartment and ion exchange with extravascular space and red blood cells, as compensation for blood volume depletion and hypocapnia. Nevertheless, anesthetized rats were less able than conscious rats to preserve normal arterial pH during hemorrhage, mainly because of an impaired peripheral tissue condition and incomplete ventilatory compensation.

Acid-Base Equilibrium↗
PubMed1997

Components of the blood acid-base disturbance that accompanies urethane anaesthesia in rats during normothermia and hypothermia.

1. We have studied the components of the metabolic acidosis that accompanies urethane anaesthesia in rats, both with and without the hypothermia that results from this anaesthesia. 2. Acid-base disturbances were analysed with an approach based on Stewart's analysis of acid-base chemistry. 3. The pH fall in the blood of normothermic anaesthetized rats (body temperature Tb) = 37 degrees C) was related to increases in plasma anions (lactate and [Cl-]), which decreased the strong ion difference ([SID]), as well as to increase the weak acid buffers due to increases in albumin. 4. A stronger metabolic acidosis was found in the blood of rats with hypothermia induced by urethane (Tb = 32 degrees C). Although plasma lactate was unchanged in hypothermic rats, [SID] decreased due to alterations in the plasma ionic balance. The metabolic acidosis found in hypothermia was also associated with increased weak acid buffers due to increases in albumin and inorganic phosphate. Further to hyperphosphataemia, signs of acute renal disfunction, such as increases in plasma [Mg2+] and blood urea nitrogen were found. Plasma retention of endogenous acids together with the retention of acid end-products of the metabolism of urethane because of acute renal failure may have contributed to strengthening the fall in pH and [HCO3-] found in urethane-induced hypothermic rats.

Acidosis↗
PubMed1997

Long-term domiciliary treatment with nasal intermittent positive-pressure ventilation plus supplemental oxygen in COPD with severe hypercapnia.

An effective treatment of advanced states of chronic obstructive pulmonary disease (COPD) has yet to be established. We report the case of a COPD patient with severe hypoxemia (pO2 = 32.0 mm Hg) and hypercapnia (pCO2 = 90.0 mm Hg) who was successfully treated for 8 months with nasal intermittent positive-pressure ventilation (NIPPV) plus supplemental O2 in a domiciliary treatment. The reduction of hypoxemia parallel to the alleviation of hypercapnia reversed the patient's continuously declining condition.

Blood Gas Analysis↗
PubMed1996

Factors influencing the acid-base changes in the air-pouch exudate following carrageenan induced inflammation in rats.

The interactions between the acid-base variables that contribute to exudate acidosis were studied in the subcutaneous air-pouch after carrageenan injection in rats. We studied the concurrent changes of exudate gases (PCO2 and PO2), main ions ([Na+], [K+], [Ca2+], [Mg2+], [Cl-] and [Lac-]), inorganic phosphate (P(i)) and albumin in acutely inflamed rats (4, 8, 12, 24 and 48 h of inflammation). A notable hypercapnia was found in the exudate after only 8 h (exudate PCO2 = 64.3 +/- 2.9 mm Hg) but this hypercapnia decreased after 48 h (32.9 +/- 12.7 mm Hg), coincident with the greatest increase in exudate cells. With respect to the metabolic acid-base variables, the most important changes found were a parallel decrease in the strong ion difference ([SID]) and exudate pH, as well as increases in the exudate weak acid buffers ([ATOT]) due to albumin and inorganic phosphate (P(i)) increases. However, after 12 h, the exudate acidosis was stable at around pH 7. A similar acid pH was obtained after 24 h of inflammation when the carrageenan solution injected was previously adjusted to a physiological pH (7.4). This pH, analogous to that of the exudate, was the result of compensation by the acid-base independent variables, a fact which suggests that acid pH may be a beneficial condition for cells taking part in inflammatory processes.

Acid-Base Equilibrium↗
PubMed1996

Acute mild hypothermia in awake unrestrained rats induces a mixed acid-base disorder.

The interactions between components that contribute to acid-base homeostasis were studied in the first steps of acute hypothermia [body temperature (Tb) 37-31 degrees C] in awake unrestrained rats as an experimental model of accidental hypothermia in mammals. The concurrent changes in blood gases, plasma ions, and plasma protein concentrations in arterial blood were analyzed. Acute decreases in Tb decreased PCO2 and increased pH. The ratio of Na+ concentration to Cl- concentration increased at 35-33 degrees C Tb, leading to an increase in the plasma strong ion difference ([SID]). These increases were transient, and levels returned to baseline at lower Tb (31 degrees C). Lack of change in hematocrit, hemoglobin, plasma osmolality, or plasma protein concentration indicated stability in plasma volume. Therefore, [SID] changes were related to ionic shifts with respect to the extravascular space and not to ionic depletion. A feasible role in this ionic exchange for contracting skeletal muscle during shivering thermogenesis is given. Significant decrease in HCO3- concentration at lower Tb (31 degrees C) was related to an apparent increase in relative ventilation (lung ventilation per unit of CO2 removed). It is concluded that, during the first stages of body cooling, the blood acid-base status of conscious hypothermic rats is affected by PCO2 changes, apparently because of uncoupled changes between ventilation and metabolism, but it is also affected by a transitory metabolic disorder due to ion imbalance.

Acid-Base Imbalance↗
PubMed1996

Blood sampled in rats from right ventricle may not always be truly representative of a mixed venous sample.

Blood samples from the right ventricle (RV) in rats are usually assumed to be representative of mixed venous blood. However, results presented here suggest that this assumption may not be true in all experimental circumstances. Nineteen male Wistar rats were anaesthetized with urethane and mechanically ventilated. The six gases used in the multiple inert gas elimination technique (MIGET) were administered continuously and samples of mixed expired air and blood from the left carotid artery and RV were simultaneously withdrawn. While inert gas concentrations in arterial blood and mixed expired air were almost homogeneous, those obtained from RV blood showed a high variability, specially evident for the less soluble gases in blood. As inert gases are cleared in the lungs according to their solubility in blood and they are only replaced through the lower systemic circulation, higher or lower concentrations found in RV samples than those expected suggests a preferential collection of blood from the lower or upper systemic circulation, respectively.

Animals↗
PubMed1996

Blood acid-base changes during acute experimental inflammation in rats.

Acidosis has often been reported in inflamed tissues, and changes in strong relevant ions at the site of inflammation may provoke alterations in blood acid-base status. We measured changes in blood acid-base variables during carrageenan-induced inflammation in rats. We found a mixed acid-base disorder in rat blood during acute inflammation (12, 24, and 48 h). A metabolic acid contribution was found during the first 12 h and maintained further, as revealed by a decrease in plasma strong ion concentration difference ([SID]) and an increase in plasma weak acid concentration due to a rise in inorganic phosphate ([ATOT]P(i)). Plasma [SID] and [ATOT]P(i) changes were probably due to exchange of Na+ and P(i) between the inflammatory exudate and rat blood. A secondary respiratory compensation for the metabolic acid changes occurred in the blood of inflamed rats, resulting in significant hypocapnia. Furthermore, a progressive decrease in the total weak acid buffer concentration due to a decrease in plasma albumin ([ATOT]Alb) also counteracted the impact of changes in [SID] and P(i) to increase blood acidity. Therefore, despite the metabolic acid-base disorders induced by inflammatory processes, hydrogen ion (H+) homeostasis was maintained, and blood pH remained essentially unchanged in the inflamed rats.

Acid-Base Imbalance↗