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Biomedical subjects

R Bruno

Publications and source records attributed to R Bruno.

At least 37 records · Page 2Linked to original sources
PubMed2000

Transfusion-transmitted virus infection in HIV-1-seropositive patients.

OBJECTIVES: To investigate the prevalence, persistence and genome heterogeneity of transfusion-transmitted (TTV) in HIV-1-infected patients, a group at high risk both of contracting blood-borne viruses and having viral persistence relating to immunodepression. METHODS: Plasma samples from 238 HIV-1 seropositive subjects and 226 healthy blood donors were examined for TTV-DNA both by polymerase chain reaction (PCR) using primers from the conserved regions in the N22 clone and PCR using primers deduced from the untranslated region (UTR). Direct DNA sequencing and phylogenetic analysis were used to characterize 27 TTV isolates from HIV-1 patients or healthy controls. RESULTS: Using PCR with the UTR primers, TTV DNA was detected in a very high percentage (> 80%) of samples both from HIV-1 seropositive subjects and from blood donors. Using PCR with N22 primers, shown to detect viral strains associated with hepatitis of unknown etiology, TTV DNA was found in 103 of 238 (43.3%) HIV-1-infected patients and in 22 of 226 (9.7%) blood donors. There was no difference in the prevalence of the TTV DNA in HIV seropositive subjects with regard to clinical features related to immunosuppression, markers of HCV infection or intravenous drug use; presence of TTV DNA was associated significantly only with male gender (P = 0.003). Persistent or intermittent viremia was detected in plasma samples taken up over a period of 19 months in all (15 of 15) HIV-infected patients tested. CONCLUSIONS: The persistence and high frequency of infection detected by PCR with N22 primers in HIV-1 seropositive patients suggest that further clinical investigation of immunocompromised hosts will provide information to clarify the pathogenic role of TTV.

Blood Donors↗
PubMed2000

Clinical trial simulation of docetaxel in patients with cancer as a tool for dosage optimization.

BACKGROUND: Pharmacokinetic and pharmacodynamic analyses conducted during the development of docetaxel showed that patients with non-small-cell lung cancer with high baseline alpha1-acid glycoprotein levels had shorter time to progression and time to death. To assess whether such patients might benefit from dose intensification, we initiated a series of clinical trial simulations. METHODS: Pharmacokinetic and pharmacodynamic models for time to progression, death, and drop-out were developed and validated with the use of phase II data from 151 patients with non-small-cell lung cancer. The simulation process, in which these models were combined with a previously reported model for safety, was evaluated by comparison of the original phase II data with the predicted results. Simulations were undertaken for the evaluation of whether a trial (phase III) of 125 mg/m2 of docetaxel versus 100 mg/m2 of docetaxel in patients with high alpha1-acid glycoprotein levels would show improved survival. RESULTS: The hazard models showed that lower alpha1-acid glycoprotein levels, fewer number of organs involved, and higher docetaxel cumulative area under plasma concentration-time curve were significantly associated with enhanced time to progression and time to death. The simulation process produced data patterns similar to actual patterns. In the simulated phase III trial, although median survival was slightly longer in the 125 mg/m2 docetaxel group than in the 100 mg/m2 group (5.49 months versus 5.31 months, respectively), the difference was significant in only 6 of 100 trials. CONCLUSIONS: The low power to detect a difference due to dose intensification was the basis for the decision not to perform such a trial. The simulation exercise yielded valuable insight into how pharmacokinetic- and pharmacodynamic-based simulation of clinical trials may have an impact on decision making in drug development.

Adult↗
PubMed2000

Pharmacokinetics of ifosfamide are changed by combination with docetaxel: results of a phase I pharmacologic study.

The pharmacokinetics of the combination of docetaxel and ifosfamide were studied in a phase I study. Docetaxel was given to cancer patients as a 1-hour infusion followed by a 24-hour infusion of ifosfamide (schedule A). After the dose-limiting toxicity of the combination was reached, ifosfamide was administered as a 24-hour infusion followed after 24 hours by a 1-hour infusion of docetaxel (schedule B). Cycle duration was 21 days. Docetaxel was determined by high-performance liquid chromatography, and ifosfamide and its metabolites, by gas chromatography-mass spectrometry. Twenty-seven patients were treated according to schedule A, and 6 according to schedule B. Combining the two drugs did not change their respective plasma half-lives. The sequence of drug administration did not affect the clearance and the area under the curve (AUC) of docetaxel. There was a decrease in the AUC of ifosfamide in schedule A compared with schedule B, resulting from an increase in the clearance of ifosfamide. The pharmacokinetics of docetaxel are not influenced by combination with ifosfamide, regardless of the drug sequence, but ifosfamide pharmacokinetics are changed by docetaxel, depending on the sequence of administration. The increase of clearance in schedule A may be due to the pretreatment with corticosteroids.

Adult↗
PubMed2000

Health-related quality of life in asymptomatic patients with HIV. Evaluation of the SF-36 health survey in Italian patients.

OBJECTIVE: To investigate the psychometric performance and clinical validity of the 36-Item Short Form (SF-36) health survey when completed by asymptomatic HIV-positive Italian patients and to compare their health profile with a representative sample of 2031 Italian citizens (the Italian norm). PATIENTS AND METHODS: This was an observational, multicentre, cross-sectional survey. Microbiologists throughout Italy recruited asymptomatic HIV-positive individuals who were aged at least 18 years and aware of their infection. Investigators collected demographic, social, clinical and treatment data. Patients, classified into 2 clinical categories (A1 and A2) according to explicit pre-defined criteria, completed the SF-36 health survey in the context of a medical visit. RESULTS: Between April and July 1996, 46 microbiologists recruited 214 patients (201 evaluable). No inconsistent responses were observed in 96% of the sample. The usually recommended psychometric standards were satisfied, and the internal consistency reliability indices were always greater than 0.70. Weak to moderate associations were found between SF-36 health survey scores and physicians' estimates of patients' physical performance, while no significant associations were found with CD4+ counts. On average, HIV-positive patients reported lower scores than the Italian norm, and patients in category A2 showed lower scores than patients in A1. These differences were more relevant in scales describing role limitations, general health perception, and psychological well-being. CONCLUSION: Our study showed that the SF-36 health survey maintained its psychometric properties in a sample of Italian asymptomatic HIV-positive patients and produced data that showed its validity and robustness in such a setting.

Adolescent↗
PubMed2000

The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance.

Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors. Patients given a standard dose of docetaxel exhibit wide interpatient variation in clearance (CL) and toxic effects. Docetaxel undergoes metabolism by cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxicity and CL. Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4 activity in each patient was measured by the [14C-N-methyl]erythromycin breath test (ERMBT). Blood samples were taken at selected times over the next 24 h for pharmacokinetic analysis. Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean, 2.53%; range, 0.25-5.35%), which is similar to a normal control population. CL of docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1 liters/h/m2). The ERMBT was the best predictor of CL when compared with serum alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotein. The natural log of ERMBT accounted for 67% of the interpatient variation in CL. Multivariate analysis showed that the natural log of ERMBT and albumin together accounted for 72% of the interpatient variation in CL. The greatest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4 activity is the strongest predictor of docetaxel CL and accounts for the majority of interpatient differences in CL. Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel. Those with high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals.

Adult↗
PubMed2000

Pharmacokinetics/pharmacodynamics in drug development: an industrial perspective.

In a health care environment dominated by the growth of managed care organizations, generic competition, therapeutic substitution and drug utilization review, drug development is an extremely risky proposition. Consequently, it is imperative to incorporate a mechanistic approach to drug development that combines a thorough understanding of a drug at the molecular/cellular level with a rigorous preclinical, and clinical pharmacology program. This should enable the sponsor to evaluate multiple hypotheses during the early "learning" phases of clinical development (Phases I and IIA) and to eliminate nonpromising candidates early on while drug development costs are low. Clinical research done properly in the early stages of drug development will also set the stage for designing and conducting optimal "confirming" registrational Phase IIB/III studies for promising drug candidates. Pharmacokinetics (PK) and pharmacodynamics (PD) modeling and simulation are crucial components of a mechanistic approach to optimal drug development and their application has significant impact in both early and late development efforts. This communication describes several applications of pharmacokinetics and pharmacodynamics modeling and simulation that were important in guiding, optimizing and ensuring the success of development efforts for drug candidates in the therapeutic areas of cardiology and oncology. These examples are used to illustrate and discuss the use of the current state-of-the-art in pharmacokinetics and pharmacodynamics modeling and simulation at numerous stages in the development cycle and to postulate on future directions in this area.

Clinical Trials as Topic↗
PubMed1999

Modulation of serotonin 5-HT3 receptor expression in injured adult rat spinal cord motoneurons.

The effects of sciatic nerve lesions on the expression of serotonin 5-HT3 receptor (5-HT3R) alpha subunit in motoneurons of the spinal cord was investigated by semi-quantitative immunohistochemistry. Following sciatic nerve crush, a significant reduction in density of staining in motoneurons was observed in longitudinal sections of the ventral horn at 3 and 15 days on the lesioned side when compared to the contralateral side (p<0.01). At 30 days after crush, after completion of sciatic nerve regeneration and reinnervation of peripheral targets, intensity of staining had returned to normal. Conversely, after sciatic nerve cut, a lesion that does not allow for target reinnervation, highly significant reductions were observed at 3, 15, 30 and 45 days. These results suggest a role for functional contacts with muscular targets in the maintenance of 5-HT3R expression in spinal motoneurons.

Animals↗
PubMed1999

Regulation of the p75 neurotrophin receptor in a rat myogenic cell line (L6).

Neurotrophins are expressed in muscle cells both during development and postnatally. Furthermore, during development muscle cells express high levels of the common p75 neurotrophin receptor, which binds all neurotrophins. Only fragmentary and controversial data are available regarding the responsiveness of muscle cells to neurotrophins and the importance of low-affinity p75 receptor in muscle development. The present study investigates in vitro the immunocytochemical expression of p75 in a rat myogenic cell line (L6) at various time points and in response to different coating substrates as a first step in elucidating the regulation of p75 in muscle. We found that in L6 myoblasts, p75 is expressed only at very early stages of maturation and its levels of expression are regulated by the nature of the coating substrates. p75 expression decreases in cells growing on substrates more suitable for myoblast fusion into myotubes. Time course analysis indicates a reverse correlation between myoblast fusion into myotubes and the levels of p75 expression. Myotubes were always p75 negative. Substrates not suitable for the fusion process induced a prolonged presence of p75 in myoblasts with an increase of their apoptosis. We conclude that expression of p75, at least in this in vitro condition, is regulated by the stages of myoblast differentiation and the nature of the coating substrates. According to the observed time- and substrate-related evidences, future studies should investigate in vivo both the regulation of p75 in the myoblast fusion and the effects and the importance of neurotrophins binding during myoblast differentiation.

Animals↗
PubMed1999

Phase I trial of intoplicine (RP 60475) administered as a 72 h infusion every 3 weeks in patients with solid tumors.

Intoplicine (RP 60475) was selected for a phase I evaluation because it inhibits topoisomerase I and II, and has exhibited antitumor activity against a variety of preclinical solid tumor models. Intoplicine is a 7H-benzo[e]pyrido[4,3-b]indole that inhibits DNA nicking and closing reactions by stabilizing the cleavable complex, a transient intermediate in the religation reaction involving topoisomerase I and II and DNA. Twenty-eight patients with refractory advanced malignancies who met standard phase I eligibility criteria were enrolled in a dose-escalation study of intoplicine, ranging from 7 to 420 mg/m2/day administered as a continuous 72 h i.v. infusion. Fifty-three courses were administered and evaluated. Myelosuppression (four patients, grade 3; two patients, grade 4) and hepatic toxicity (one patient, grade 3) were dose limiting at 336 mg/m2/day. No objective antitumor responses were observed. The pharmacokinetic parameters of intoplicine were investigated in 11 patients at dose levels of 112 (n=1), 224 (n=3), 336 (n=6) and 420 (n=1) mg/m2/day. Both the area under the plasma concentration versus time curves and the maximum plasma concentrations increased linearly within the dose range studied. Intoplicine content measured in whole blood exceeded that found in plasma by 3- to 7-fold, indicating that red blood cells may serve as a drug reservoir. Preclinical cytotoxic concentrations were not achieved at the dose levels studied.

Adult↗
PubMed1999

Echinococcal liver cysts: treatment with echo-guided percutaneous puncture PAIR for echinococcal liver cysts.

In spite of recent progress, treatment for liver echinococcal cysts is still far from satisfying. In recent years, percutaneous drainage has been increasingly used for this purpose and it has been shown to be an effective alternative to surgery and chemotherapy alone. This technique is known as PAIR, from Puncture, Aspiration, Injection (of a scolecidal agent), Reaspiration: here we present our experience and the state of the art of PAIR. Patients from Italy and Turkana (Kenya), harbouring 233 Gharbi type I, II and III echinococcal cysts were successfully treated with PAIR: it was performed according to protocols established at the Division of Infectious and Tropical Diseases, IRCCS--Policlinico S. Matteo, University of Pavia. In Italy, one relapse was recorded, four years after the procedure; the patient was treated again with PAIR; no cases of anaphylactic shock or peritoneal dissemination were observed in a follow-up of 10 years; only 10 minor complications (biliary fistula, urticarioid reaction, abscessualization of the cyst, anaphylactoid reactions) were reported. Long-term results indicate that in Gharbi type I, II and III echinococcal cysts, and in developing countries, in particular, PAIR is a first choice method for the treatment of abdominal localizations of this disease.

Adolescent↗
PubMed1998

Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial (FMTC) disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by coexistence of MTC with other endocrine neoplasia. Activating mutations of the RET proto-oncogene, involving the somatic or the germinal cell lineage, are found in both inherited and acquired forms. In this study, RET mutations were screened in 47 individuals either affected by MTC or belonging to families with hereditary MTC. Exons 10, 11, 13, 14, 15 and 16 of the RET gene were amplified by polymerase chain reaction and examined by DNA sequence and/or restriction enzyme analysis to detect mutations in purified amplicons. Six MEN 2A families with a germline mutation at codon 634, one FMTC family carrying a mutation at codon 618 and two MEN 2B families with a mutation at codon 918 were identified. In affected members of a MEN 2A family no known RET mutations were observed. Besides, we identified a germline mutation in a patient with apparently sporadic MTC and in two out of three sons, indicating the presence of a sporadic misclassified familial disease. In all of the families examined we were able to distinguish the affected vs unaffected (not at risk) members. A somatic mutation of codon 918 was detected in three out of ten patients with apparently sporadic MTC.

Adult↗
PubMed1998

Evaluation of the linearity of docetaxel pharmacokinetics.

The taxanes, paclitaxel and docetaxel, have favorable response rates in patients with breast, gynecologic, and lung cancers and have demonstrated activity against a variety of malignancies. In human trials, paclitaxel pharmacokinetics are nonlinear and are best fit by a three-compartment model with nonlinear distribution into the second compartment as well as nonlinear elimination. This finding is important for patients receiving paclitaxel at high doses or as a short infusion, as it results in disproportionately high peak concentrations and delayed elimination. The presence of nonlinear processes in docetaxel pharmacokinetics has not previously been examined. Therefore, plasma concentration data obtained from 53 patients receiving docetaxel at 55-115 mg/m2 over 1-24 h as part of phase I studies were modeled using the nonlinear three-compartment model found most suitable for paclitaxel and the results were compared with those obtained using the linear version. Docetaxel disposition was best described by the three-compartment nonlinear model in 28 of 53 data sets (53%). However, the difference in curve fit observed between the two models was modest (did not improve Akaike criteria) and unlikely to be of relevance. This study suggests that nonlinear processes in docetaxel pharmacokinetics may exist, but, unlike the case of paclitaxel, they are not likely to have a significant impact at the dose and administration schedule used in routine clinical practice (60-100 mg/m2 given over 1 h by infusion). The presence of nonlinear docetaxel pharmacokinetics at doses above 115 mg/m2 will have to be determined in case of further dose escalation.

Antineoplastic Agents, Phytogenic↗