Biomedical subjects

G Corona

Publications and source records attributed to G Corona.

At least 19 recordsLinked to original sources

PubMed2006

Innovative schedule of oral idarubicin in elderly patients with metastatic breast cancer: comprehensive results of a phase II multi-institutional study with pharmacokinetic drug monitoring.

BACKGROUND: To determine if protracted low-dose oral idarubicin (IDA), feasible in a previous dose-finding study, would result in similar activity and a better toxicity profile in patients with metastatic breast cancer. PATIENTS AND METHODS: Elderly women (> or=65 years) with metastatic breast carcinoma were treated with 7.5 mg/day for 21 consecutive days, every 4 weeks. After the first fourteen patients, due to excessive toxicity, the protocol was amended to 5 mg/day. IDA and Idarubicinol (IDOL) plasma concentrations (C(trough)) were investigated in all patients. RESULTS: Between April 1999 and June 2004, 47 elderly patients were accrued in this two-part study (14 and 33 patients respectively). The median age was 74 and 75 years respectively. Visceral involvement was present in most patients. A partial response was noted in 7/31 patients (22%; 95% CI, 9.6-41.1%). Eleven patients had stable disease (33%). At the dose of 5 mg/day the treatment was well tolerated. Neutropenia grade 4 was present in only 6% of patients; alopecia > grade 1 and cardiotoxicity did not occur. The median time to progression was 3 months and the median overall survival was 17 months. IDA C(trough) and IDOL C(trough) levels were significantly associated with haematologic toxicity. CONCLUSION: This study shows that idarubicin at the dose of 5 mg/day for 21 consecutive days is feasible and effective in elderly breast cancer patients but do not demonstrate an improvement in efficacy. A determination of the IDA and IDOL plasma levels (C(trough)) is predictive for toxicity.

Administration, Oral↗

PubMed2006

Oral etoposide in elderly patients with advanced non small cell lung cancer: a clinical and pharmacological study.

Seventeen elderly patients with advanced progressive non small cell lung cancer (NSCLC) were treated with oral etoposide at the daily dose of 100 mg for 14 days every 3-4 weeks with pharmacokinetic monitoring. One partial response and 6 stabilizations were documented with a median overall duration of 13 weeks (range 8-32). The median survival was 24 weeks with an apparent advantage for non-progressive patients (40 weeks vs. 18 weeks). The treatment was well tolerated especially by those patients without concomitant illness, suggesting the crucial role of a careful selection of the geriatric population. Toxicity was not related to the etoposide plasma level, but was clearly dependent on comorbidity. A geriatric assessment rather than chronological age therefore appears to be more reliable in the selection of elderly patients for clinical trials. The easy self-management, favorable toxicity profile and synergy with other compounds makes oral etoposide suitable for further clinical-pharmacological studies in elderly patients.

Administration, Oral↗

PubMed2005

The therapeutic dilemma: how to use psychotherapy.

Organic, marital and intrapsychic disturbances mutually interact in the pathogenesis of erectile dysfunction (ED). Sexual psychotherapy (SP) should be considered a useful chance on all occasions. When non-organic causes are predominant, SP could help in solving the problem. Conversely, when ED is mainly a symptom of organic diseases, SP should be considered as an important support, reducing the net contribution of marital and/or intrapsychic components and improving responsiveness and compliance to medical treatments. A correct diagnosis is a crucial step in the evaluation of patients reporting ED, in order to quantify the contribution of different pathogenetic factors. Structured Interview on Erectile Dysfunction (SIEDY) is a useful instrument for the first screening of ED patients, providing scores for organic, marital and intrapsychic components. Other instruments, such as body paint or sexuality tree, might also be used to further analyse the problem and to choose the most effective SP intervention for the patient himself or for the couple. In our view, medical and psychosexual therapies are not indeed two distinct therapeutic entities to be used in different clinical settings, but are two important tools to be simultaneously considered (and often simultaneously employed) to fully rescue the sexual satisfaction of the couple.

Erectile Dysfunction↗

PubMed2005

The impotent couple: low desire.

Hypoactive sexual desire (HSD) is the deficiency of sexual fantasies and desire that should be considered as a disorder if it causes distress to the couple. In the general population, it is the most widespread sexuality-related problem. It is generally accepted that testosterone and prolactin regulate sexual desire. We recently reported that other psychobiological factors associate with HSD in a sample of almost 500 male patients attending our Outpatient Clinic for sexual dysfunction, by using SIEDY structured interview. We now originally extend investigation to a threefold broader patient sample. Considering marital parameters, perceived partner's libido and climax, patient's partner diseases, conflictual or even prolonged couple relationship were all significantly associated with an impairment of patients' sexual desire. Moreover, other lifestyle factors as satisfaction at work and/or domestic inhabitant relationship were significantly correlated to hypoactive sexual desire disorder (HSDD). Among hormonal parameters, severe hyperprolactinaemia (>700 mU/L), although rarely diagnosed (<2.0%), seems to play a greater role than the more common (23%) endocrine disease hypogonadism (testosterone < 12 nm) to the pathogenesis of HSD (RR = 7.5 [2.5-22.4] vs. 1.5 [1.1-1.9], respectively). Both mental disorders and use of medication interfering with sexual function were also significantly associated with HSDD, as well as depressive and anxiety symptoms. Finally, HSD was inversely correlated to sexual and masturbation frequency attempts. In conclusion, HSD is associated with several biological, psychological, and relational factors that can be simultaneously identified and quantified using the SIEDY structured interview.

Climacteric↗

PubMed2005

Testosterone and sexual activity.

Male sexual activity is characterized by a synchronization of sexual desire arising in the brain and its transmission to the periphery, resulting in penile tumescence necessary for sexual intercourse. Testosterone (T) has been claimed for so long as a pivotal hormone in regulating male sexual function, acting both at central and peripheral level. We believe that T is indeed the main synchronizer of sexual activity regulating libido and enzymes as nitric oxide synthase (NOS) and phosphodiesterase type 5 (PDE5), which are crucial for the erectile process. In fact, NOS increases cyclic guanosine monophosphate (cGMP) levels, while PDE5 reduces it. Because T positively controls both the initiation and the end of the penile erection, its net effect on erection is null. In fact, penile erections are often present even without T. The main action of T is to timely adjust the erectile process as a function of sexual desire, therefore finalizing erections to sex.

Animals↗

PubMed2004

Erectile dysfunction: symptom or disease?

Erectile dysfunction (ED) has been defined by the National Institute of Health (NIH) as the inability to achieve and/or to maintain an erection for a sufficiently long period of time so as to permit satisfactory sexual intercourse. ED affects millions of men throughout the world and could have a negative influence on the individual's well-being as well as on the quality of life of affected subjects. Discordant data have been reported on ED epidemiology with prevalence ranging from 12% to 52%, probably depending on the different criteria utilized in the different studies for patient selection. ED is a symptom, sometimes the first, of different pathological conditions. In 15.7% of 45-yr-old patients with vascular ED a dynamic ergometric test has shown electrocardiographic alterations in the absence of any cardiac symptom. In 15% of the patients with ED, high fasting glucose plasma levels are discovered for the first time and in patients with ED and normal fasting glucose plasma levels the prevalence of undiagnosed diabetes mellitus is 12.1% after an oral glucose tolerance test (OGTT). The different risk factors are often additive in the possible development of systemic vasculopathy, neuropathy and ED. ED, underestimated in clinical practice due to archaic prejudice which hinders the patient in spontaneously revealing the problem and the physicians in investigating it, can mark the point where evaluation and prevention of important diseases (such as diabetes, arterial hypertension, atherosclerosis) hitherto unknown by the patients, can begin. The physicians' cultural baggage must include the ability to identify the pathology that can determine ED and the ability to program a specific diagnostic workup. In this paper the different specialists involved in ED diagnosis agreed that a clinical approach which allows the identification of systemic pathologies contributing to the development of ED constitutes an improvement in disease prognosis and may either induce a spontaneous reduction of ED or facilitate its specific treatment.

Adult↗

PubMed2004

Organic, relational and psychological factors in erectile dysfunction in men with diabetes mellitus.

INTRODUCTION AND OBJECTIVES: Diabetes mellitus-induced erectile dysfunction (DMED) is thought to be multifactorial in aetiology and to include vascular, neurological, and psychological components. The aim of the present study is to determine the contribution of organic, relational, and intrapsychic components to the pathogenesis of ED in diabetic in comparison with non-diabetic patients. METHODS: We studied a consecutive series of 1027 using SIEDY structured interview. A complete physical examination and a series of metabolic, biochemical, hormonal, psychometric, penile vascular tests and nocturnal penile tumescence and rigidity evaluations were performed. RESULTS: 15% of patient studied were affected by DMED. Diabetic patients with DMED have a greater severity of erectile dysfunction and are more likely to have an organic, rather than an intrapsychic, component. Impaired sexual desire is less frequent in these patients and they had an higher prevalence of hypogonadism than non-diabetic individuals. CONCLUSION: Diabetic patients seeking treatment for erectile dysfunction have a greater severity of disease, less impaired sexual desire, suggesting that the need for medical care in diabetic patients with ED could be even greater than in their non-diabetic counterparts. Considering the higher prevalence of obesity-related decrease of testosterone levels in DMED, an appropriate screening and treatment of hypogonadism might improve the outcome of pharmacotherapy for ED in diabetic patients.

Diabetes Complications↗

PubMed2004

Psycho-biological correlates of rapid ejaculation in patients attending an andrologic unit for sexual dysfunctions.

INTRODUCTION AND OBJECTIVES: Rapid ejaculation (RE) is the most common sexual dysfunction in males. The aim of the present study is to determine the contribution of intrapsychic, organic and relational factors to the pathogenesis of RE and the relationship between RE and erectile dysfunction (ED) in a sample of patients attending for the first time to an Outpatient Clinic for sexual dysfunction. METHODS: We studied a consecutive series of 755 patients using Structured Interview on Erectile Dysfunction (SIEDY), a brief, recently validated, multidimensional instrument specifically designed by our group for the study of pathogenetic factors of ED. RE was defined as ejaculation within 1 minute of vaginal intromission and its severity was categorized on a 4-point scale using a standard question. A complete physical examination and a series of biochemical, hormonal, psychometric, penile vascular and rigidometric evaluations were performed. RESULTS: Twenty-eight percent (n = 214) of patients attending to our sexology clinic reported RE of any degree. Patients reporting RE were younger (48.5 +/- 12.6 vs. 52.9 +/- 12.9 years old for RE and not RE respectively; p < 0.0001) and showed a higher prevalence of anxiety symptoms when compared to the rest of the sample. Among organic factors subjects with RE showed a higher prevalence of hyperthyroidism and significantly lower fasting plasma glucose (94 [87-110] and 98 [89-113] mg/dl for RE and non-RE respectively; p < 0.01). No difference among groups was observed for other hormones or clinical, biochemical and instrumental parameters. Finally RE patients showed a higher prevalence of partial erection sufficient for penetration when compared to the rest of the sample. Similar differences were observed between patients with and without RE when those without ED were excluded from the analysis. CONCLUSION: Our data suggest a minor involvement of organic factors to the pathogenesis of ED in patients with concomitant RE. On the other hand, in our sample, patients complaining about RE are younger, healthier than the rest of the sample and are characterized by high degree of anxiety symptoms and hyperthyroidism.

Analysis of Variance↗

PubMed2004

Psycho-biological correlates of hypoactive sexual desire in patients with erectile dysfunction.

We studied the psychological and biological correlates of hypoactive sexual desire (HSD) in a consecutive series of 428 patients with erectile dysfunction (ED), by using the structured interview SIEDY. A complete physical examination and a series of biochemical, hormonal, psychometric, and penile vascular tests were also performed. Among the patients studied, 22.8% reported a mild, 12.9% a moderate, and 4.6% a complete loss of sexual interest. Patients reporting HSD showed significantly lower testosterone (T) levels than the rest of the sample, although the prevalence of hypogonadism (T<10 nM) was comparable in the two groups. Only a minority (<2%) had severe hyperprolactinemia (>700 mU/l), which, nonetheless, was closely associated with a relevant HSD. Both mental disorders and use of medication interfering with sexual function were significantly associated with HSD, as well as depressive and anxiety symptoms. HSD patients showed significantly higher scores in SIEDY scale 2, which explores the relational component of ED. In particular, perceived partner's libido and climax were crucially associated with an impairment of patients' sexual desire. In conclusion, HSD in ED is associated with several biological, psychological, and relational factors that can be simultaneously identified and quantified using the SIEDY structured interview.

Adult↗

PubMed2004

Aging and pathogenesis of erectile dysfunction.

The prevalence and the severity of erectile dysfunction (ED) increase with advancing age; different pathogenetic factors could contribute to age-related ED. We studied organic, relational and intrapsychic components of ED as a function of patients' age in a consecutive series of 977 patients with ED, using the specifically designed structured interview SIEDY. A complete physical examination and a series of biochemical, hormonal, psychometric and penile vascular tests were also performed. Relational factors seems to be more relevant in patients aged over 60 y, while intrapsychic disturbances play a major role in younger subjects. Organic factors are the most important determinant of ED in all age groups, but their contribution is more important in older patients. In fact, basal and dynamic peak cavernosal velocity at Doppler ultrasound penile examination was reduced in older patients. Among hormonal factors, the body mass index-dependent reduction of testosterone in older patients does not seem to play a crucial role in the pathogenesis of ED. No significant correlation was observed between testosterone level and the severity of ED, although patients reporting hypoactive sexual desire showed significantly lower testosterone levels when compared with the rest of the sample. A better understanding of the relative contribution of age-related pathogenetic factors of ED could be of help in the design of appropriate therapeutic approaches.

Adult↗

PubMed2004

Effect of highly active antiretroviral therapy (HAART) on pharmacokinetics and pharmacodynamics of doxorubicin in patients with HIV-associated non-Hodgkin's lymphoma.

BACKGROUND: We demonstrated that highly active antiretroviral therapy (HAART) increases the toxic effect of cyclophosphamide, vincristine, doxorubicin (DOX) and prednisone (CHOP) in HIV-patients with non-Hodgkin's lymphoma (NHL). To ascertain the cause of increased toxicity, we investigated the pharmacokinetics of DOX in HIV-patients with NHL treated with CHOP with and without HAART. METHODS: Complete pharmacokinetics and pharmacodynamic analysis was determined in 19 patients during 38 cycles of chemotherapy: 19 cycles with CHOP and 19 CHOP + HAART in a crossover-designed study. HAART included protease inhibitors indinavir (IDV) in nine patients, saquinavir (SQV) hard gel in six patients and nelfinavir (NFV) in four patients. RESULTS: No significant effects of HAART on pharmacokinetics parameters of DOX were observed. Similarly, no differential effect on DOX pharmacokinetics among IDV, SQV, and NFV was evidenced. Significant associations (P=0.012) were observed between DOX AUC0-infinity (area under the concentration curve) and G3-G4 WHO haematologic toxicity, in patients treated with CHOP alone, but not in those treated with CHOP + HAART (P = not significant). CONCLUSION: We demonstrated that HAART therapy has no significant effect on DOX pharmacokinetics. DOX AUC appears to be a predictor of toxicity only in patients treated with CHOP alone. Other factors beside DOX plasma levels are detrimental for toxicity after CHOP + HAART. Therefore, pharmacodynamic interactions between HAART and DOX should be considered.

Adult↗

PubMed2004

Pharmacokinetic comparison of 120-hour infusion versus hyperfractionated oral administration of idarubicin.

The aim of this study was to compare the pharmacokinetics of idarubicin (IDA) and its active metabolite idarubicinol (IDOL) after chronic oral and continuous intravenous (i.v.) IDA administration in order to establish the oral doses needed to reach the i.v. equiactive plasma drug exposure. The pharmacokinetic profile of IDA and IDOL was investigated in 23 patients receiving 12 mg/m2 IDA by 120-h i.v. infusion (2.4 mg/m2/day) combined with cyclophosphamide, etoposide and prednisone in comparison to 28 patients receiving oral IDA doses ranging from 2 to 10 mg/day for 21 days in a phase I study. We found that IDA AUC24h/dose/m2 was 4.7-fold greater during i.v. than oral administration, whereas IDOL AUC24h/dose/m2 was only about 2-fold higher after i.v. administration. The metabolic ratio between IDOL AUC24h and IDA AUC24h in plasma was about 3-fold higher after oral administration. Based on these results we were able to estimate that equiactive plasma drug exposure was reached with an approximately 2.5-fold greater oral dose/m2 of IDA than the corresponding i.v. dose.

Administration, Oral↗

PubMed2003

Structured interview on erectile dysfunction (SIEDY): a new, multidimensional instrument for quantification of pathogenetic issues on erectile dysfunction.

The aim of the present study is the definition of a brief structured interview (SI) providing scores useful for identification and quantification of pathogenetic factors of erectile dysfunction (ED). A SI was developed and applied to a consecutive series of 320 ED patients. A 13-item SI, with three-factor analysis-derived scales, was identified and applied for validation to an independent consecutive series of 194 ED patients. PGE(1) (10 microg) intracavernosal injection, penile duplex ultrasound (PDU), blood hormones, PSA, glycemia, and lipids were used for the assessment of an organic component (OC), and Middlesex Hospital Questionnaire (MHQ) modified for psychological disturbances. Scale 1, dealing with OC, showed a positive correlation with age, BMI, blood pressure, glycemia, and inverse correlation, with testosterone, PGE(1) and several parameters derived from PDU. Scale 2, related to partner's relationship, was not correlated with organic parameters. Scale 3, which measures psychopathological traits was correlated with MHQ scales. Scale 1 (>3) had a sensitivity of 67.9% and a specificity of 67.6% for OC. SIEDY((c)) provides information on ED pathogenesis and might assist physicians in diagnostic and therapeutic choices.

Adult↗

PubMed2003

Pharmacogenetics of irinotecan.

Pharmacogenetics focuses on intersubjects variation in therapeutic drug effects and toxicity depending on genetic polymorphisms. This is particularly interesting in oncology since anticancer drugs usually have a narrow margin of safety. Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin] is used in cancer chemotherapy as a topoisomerase I inhibitor and it is characterised by a sometimes unpredictable severe toxicity. It is mostly intestinal with nausea, vomit and diarrhoea or haematologic with leuko-thrombocytopenia. Its complex metabolism involves many proteins. Human carboxylesterase isoforms 1 and 2 (hCE1, hCE2) activate irinotecan to its metabolite SN-38 (7-ethyl-10-hydroxycamptothecin); cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5) mediate the oxidation of the parental compound to irinotecan; uridino-glucuronosil transferase isoform 1A1 (UGT1A1) catalyses glucuronidation of SN-38; the multi-resistance protein isoform 2 (MRP2) allows the cellular excretion of the SN-38 glucuronide (SN-38G) and the multi-drug resistance gene (MDR1), encoding for P-glycoprotein, is responsible for the excretion of irinotecan from the cell. Polymorphic structures in the genes encoding for all these proteins have been described. In particular, the UGT1A1*28 allele has been associated with an increased toxicity after irinotecan chemotherapy. Classical parameters used in the clinic, such as body-surface area, have no longer a meaningful correlation with clinical outcome. Hence it emerges the importance of studying the individual genotype to predict the toxicity and efficacy of irinotecan and to individualise therapy. In this review, we summarise the new developments on the study of the pharmacogenetics of irinotecan, stressing its importance in drug cytotoxic effect.

Antineoplastic Agents, Phytogenic↗

PubMed2001

Population pharmacokinetics and pharmacodynamics of oral etoposide.

AIMS: To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours. METHODS: A prospective, open label, cross-over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P-Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints. RESULTS: Mean clearance was 1.14 l h(-1) (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r(2) = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l(-1) h; CV 64%; range 0.4-9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l(-1) h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l(-1) h) than in patients with stable (2.1 mg l-1 h) or progressive disease (2.3 mg l-1 h) (P = 0.01). CONCLUSIONS: Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.

Administration, Oral↗

PubMed2001

Effects of melatonin treatment in septic newborns.

Free radicals have been implicated in the pathogenesis of neonatal sepsis and its complications. This study was conducted to determine the changes in the clinical status and the serum levels of lipid peroxidation products [malondialdehyde (MDA) and 4-hydroxylalkenals (4-HDA)] in 10 septic newborns treated with the antioxidant melatonin given within the first 12 h after diagnosis. Ten other septic newborns in a comparable state were used as "septic" controls, while 10 healthy newborns served as normal controls. A total of 20 mg melatonin was administered orally in two doses of 10 mg each, with a 1-h interval. One blood sample was collected before melatonin administration and two additional blood samples (at 1 and 4 h) were collected after melatonin administration to assess serum levels of lipid peroxidation products. Serum MDA + 4-HDA concentrations in newborns with sepsis were significantly higher than those in healthy infants without sepsis; in contrast, in septic newborns treated with melatonin there was a significant reduction (p < 0.05) of MDA + 4-HDA to the levels in the normal controls at both 1 and 4 h (p < 0.05). Melatonin also improved the clinical outcome of the septic newborns as judged by measurement of sepsis-related serum parameters after 24 and 48 h. Three of 10 septic children who were not treated with melatonin died within 72 h after diagnosis of sepsis; none of the 10 septic newborns treated with melatonin died. To our knowledge, this is the first study where melatonin was given to human newborns.

Apgar Score↗

PubMed2000

Resistance to methotrexate in SKOV-3 cell lines after chronic exposure to carbamazepine is associated with a decreased expression of folate receptor.

The detrimental effect of chronic administration of carbamazepine (CBZ) on serum and erythrocyte folates of patients has been extensively analyzed. However, at present, no data have been reported on the effect of CBZ on the intracellular content and activity of antimetabolite cytotoxic agents that can be used together with CBZ in the treatment of cancer patients. To investigate this issue, we chronically exposed in vitro the human ovarian cancer cell line SKOV-3 (grown under physiological folate concentrations) to CBZ, thus selecting SKOV-CBZ clones (SKOV-CBZ-50-2, SKOV-CBZ-50-5 and SKOV-CBZ-100-2) able to grow in the continuous presence of the antiepileptic drug. All of the SKOV-CBZ clones were more resistant to methotrexate (MTX) than the parental cells. MTX resistance index, as determined by the ratio between MTX concentrations inhibiting cell growth by 50% (MTX IC(50)) in SKOV-CBZ clones and in the parental cells, ranged between 3- and 5-fold. This resistance was related to a reduced intracellular content of MTX. No alteration activity of the cellular enzymes directly involved in MTX cytotoxicity (dihydrofolate reductase, thymidylate synthase [TS] and folylpolyglutamate synthetase) was observed. SKOV-CBZ clones were cross-resistant to the TS inhibitors tomudex and CB3717, but not to the TS inhibitor 5-fluoro-deoxy uridine and other antineoplastic drugs (cisplatin, doxorubicin, vincristine and taxol), whose cellular uptake is derived from transmembrane transport mechanisms different from folate receptor alpha (FRalpha) or reduced folate carrier (RFC). FRalpha mRNA and protein levels were significantly lower in SKOV-CBZ clones than in the parental cells. The reduced level of FRalpha in SKOV-CBZ clones was associated with a decreased binding capacity of folic acid. No variation of mRNA RFC expression in the SKOV-CBZ clones as compared to the parental cells was observed. Thus, after chronic exposure to CBZ, SKOV-CBZ clones develop resistance towards MTX due to defective MTX uptake.

Biological Transport↗

PubMed2000

Dose-finding and pharmacologic study of chronic oral idarubicin therapy in metastatic breast cancer patients.

Oral idarubicin (IDA) is an active drug in metastatic breast cancer, but its role in the management of this tumor is yet not established completely. To investigate a new modality of IDA administration, a dose-finding study was designed with hyperfractionated doses. The purpose was to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the pharmacokinetics of this schedule. IDA was administered twice daily as outpatient therapy in cycles of 3 weeks followed by a 1-week rest. Thirty-one patients with progressive metastatic breast cancer and pretreated with chemotherapy (including epirubicin and doxorubicin) were enrolled. DLT was defined as G4 hematological toxicity or any other toxicity G3 or higher (Bloom and Richardson grading). Inter- and intrapatient dose increases were studied. Pharmacokinetics of IDA and its metabolite idarubicinol (IDOL) were evaluated. IDA dose was increased from 2 mg/day to 10 mg/day, by steps of 1 mg/day, with the larger dose given in the evening. MTD was reached at 10 mg/day. Overall, the therapy cycles were 69 (median/patient, 2; range, 1-6). DLTs were G4 neutropenia associated with leukopenia and thrombocytopenia in one patient and G3 diarrhea in another of the 5 patients in the 10 mg/day cohort. The two patients developing DLT at the daily dose of 10 mg received a dose normalized for body surface of 6.85 and 5.65 mg/m2/day, respectively. We considered 5.5 mg/m2/day to be the MTD. Other toxicities were nausea, vomiting, neutropenia, and diarrhea, grades G1 to G2. By univariate analysis, significant correlations were observed between absolute neutrophil count at nadir and IDA area under the curve (P = 0.022; r = -0.33), IDA Cmax (P = 0.0067; r = -0.38), IDOL area under the curve (P = 0.0009; r = -0.43), and IDOL Cmax (P = 0.0016; r = -0.41), respectively. By multivariate analysis, IDA Cmax was the strongest determinant for neutropenia (R2 = 0.14; P = 0.01). Among the 21 patients evaluable for response, 3 (14.3%) had partial response (lasting 3, 6, and 8 months, respectively), and 6 (28.6%) had a complete arrest of disease progression (lasting 2-6 months). In conclusion, the MTD of this schedule is 10 mg/day and the DLTs are neutropenia and diarrhea. Tolerance was good, and the treatment is feasible as home therapy. Some objective measurable responses were documented in this group of anthracycline-pretreated patients. IDOL could have a role for the pharmacological effect. Further evaluation of this schedule is warranted to assess the activity and toxicity of prolonged oral IDA administration.

Administration, Oral↗