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Biomedical subjects

R Riccardi

Publications and source records attributed to R Riccardi.

At least 109 records · Page 6Linked to original sources
PubMed1986

Influence of food intake on bioavailability of oral 6-mercaptopurine in children with acute lymphoblastic leukemia.

Plasma levels of 6-mercaptopurine (6-MP) were measured after oral administration in 17 children with acute lymphoblastic leukemia (ALL). In the fasting state or after a breakfast consisting of 250 ml milk and 50 g biscuits, 6-MP was administered at a dose of 75 mg/m2. In patients studied in a fasting state, the mean time to plasma peak (tmax) level was 1.2 h, whereas in patient studied after breakfast the mean tmax was 2.3 h. This difference is statistically significant (p less than 0.001). Moreover, the 6-MP peak plasma concentration (cmax) and the areas under the plasma concentration time curves (AUC) were significantly reduced when the drug was administered after breakfast. The mean Cmax +/- SD were 0.98 +/- 0.54 microM and 0.63 +/- 0.48 microM, respectively (p less than 0.05). The mean 6-MP AUC +/- SD in patients studied in a fasting state and after breakfast were 143 +/- 69 microM min and 105 +/- 68 microM, respectively (p less than 0.01). These results indicated that 6-MP should be taken in a fasting state to optimize drug absorption in children undergoing chemotherapy for ALL.

Administration, Oral↗
PubMed1985

Long-term neuropsychologic sequelae of childhood leukemia: correlation with CT brain scan abnormalities.

Previous studies have failed to establish a direct relationship between behavioral disorders and organic pathology in long-term survivors of childhood acute lymphoblastic leukemia. We evaluated 23 long-term survivors who received central nervous system preventive therapy with cranial irradiation and intrathecal chemotherapy, using neuropsychologic tests and computed tomographic brain scans. The patients were in continuous first remission for 7 to 11 years, and none were receiving chemotherapy. On the basis of their CT scan findings, they were divided into three groups: 10 with normal CT findings, five with intracerebral calcifications, and eight with cortical atrophy. Neuropsychologic test results allowed prediction of CT scan findings with an 87% accuracy (P less than 0.001), indicating a strong correlation between the presence and type of CT scan abnormality and neuropsychologic functioning. Tests that measured verbal memory, attention, and functions correlated with frontal lobe integrity were most powerful in discriminating between groups.

Adolescent↗
PubMed1985

Plasma and cerebrospinal fluid pharmacokinetics of recombinant interferon alpha A in monkeys: comparison of intravenous, intramuscular, and intraventricular delivery.

Interferons are currently undergoing clinical testing in patients with cancer and other diseases. A variety of routes of administration are being utilized, and there is particular interest in delivery of interferon to the central nervous system. A biphasic decline in plasma concentrations was observed in monkeys following an i.v. bolus, with initial half-times of 15 to 33 min and terminal half-times of 1.7 to 4.6 hours. Total body clearance ranged from 24 to 39 ml/sq. m/min and steady-state volume of distribution was similar to extracellular space. CSF exposure was 1% or less than that of plasma. Intramuscular injections produced lower peak concentrations and more sustained levels, but there was substantial variation in bioavailability (range 19-103%). Levels in the CSF were not detectable for the i.m. route. For intraventricular doses, CSF exposure was 3,000-fold greater than for i.v. doses, despite a 20-fold lower dose.

Animals↗
PubMed1985

Abnormal computed tomography brain scans in children with acute lymphoblastic leukemia: serial long-term follow-up.

In a previous study we reported the occurrence of computed tomographic (CT) brain-scan abnormalities in a group of asymptomatic children with acute lymphoblastic leukemia (ALL) who had received prophylactic cranial irradiation and maintenance intrathecal chemotherapy. One or more of four types of CT-scan abnormalities were observed: ventricular dilatation (VD), subarachnoid space dilatation (SAD), areas of parenchymal decreased attenuation coefficient (DAC), and intracerebral calcifications (CALs). To study the natural history of these findings, serial CT scans were obtained on 24 of the original 32 patients who were available for long-term follow-up. CT scanning was performed for a minimum of seven years from the initiation of CNS preventive therapy. Review of the CT scans showed that VD (n = 5) and SAD (n = 7) were stable over the time of follow-up. DAC, originally observed in two patients, was no longer present on follow-up scans. In contrast, five patients developed CALS from five to seven years after initiation of CNS preventive therapy. All occurred in children who were less than 8 years of age at the time of diagnosis (P less than .01). These data indicate that CALs may develop many years after the cessation of CNS preventive therapy and suggest that long-term CT-scan follow-up should be considered in children who have received CNS preventive therapy.

Adolescent↗
PubMed1984

Attentional deficits in long-term survivors of childhood acute lymphoblastic leukemia (ALL).

Simple alerted auditory reaction time (SRT) behavior with various foreperiods was investigated in a group of long-term survivors of childhood ALL who were in continuous first remission. As part of therapy, the patients had received cranial irradiation and intrathecal chemotherapy to prevent the development of central nervous system leukemia. The patients were divided into three groups on the basis of CT brain scan findings: (1) those with normal CT scans (n = 10); (2) those with evidence of cortical atrophy (n = 8), and (3) those with intracerebral calcifications (n = 5). The SRT results indicated significant differences between patients with normal and abnormal CT scans. Specifically, patients with abnormal scans reacted slower, and this latency was exaggerated by increasing the length of the warning interval. Furthermore, they reacted with larger variability which increased with the prolongation of testing. Moreover, the severity of impairment was related to the type of CT-scan abnormality: patients with calcifications performed more poorly than patients with evidence of atrophy. The present results revealed a strong correlation between the presence and type of CT-scan abnormalities and attentional performance in long-term survivors of childhood ALL.

Adolescent↗
PubMed1984

Intrathecally administered m-AMSA in the rhesus monkey.

4'-(9-Acridinylamino)-methanesulfon-m-anisidide (m-AMSA) is an acridine compound that has been found useful in the systemic treatment of acute leukemia. This paper specifically investigates the CSF pharmacokinetics of m-AMSA following both intravenous and intraventricular administration in a subhuman primate model. Following intravenous administration, m-AMSA crossed the blood-brain barrier poorly; cerebrospinal fluid (CSF) concentrations were only 1-3% of systemic concentrations. Intraventricular administration of drug achieved high initial ventricular fluid concentrations, but the drug was rapidly cleared with a half-life of 115 min. Following 500 micrograms of intraventricular drug, CSF concentrations of m-AMSA remained above 1 microM for only 6 h. These data suggest that m-AMSA has potential as an intrathecal agent against meningeal leukemia refractory to more conventional therapy, but detailed toxicology and neurohistopathology will be required before intra-CSF m-AMSA can be considered for human use.

Aminoacridines↗
PubMed1982

Influence of tetrahydrouridine on the pharmacokinetics of intrathecally administered 1-beta-D-arabinofuranosylcytosine.

Tetrahydrouridine (THU), a potent inhibitor of cytidine deaminase, has been shown to increase the antitumor activity of 1-beta-D-arabinofuranosylcytosine (ara-C) both in vitro and in vivo. In initial studies, which examined the cerebrospinal fluid (CSF) pharmacokinetics of intrathecally (i.t.) administered THU, the drug was found to be slowly cleared from the CSF with alpha and beta half-lives of 1 and 8 hr, respectively. In subsequent experiments, both i.v. pretreatment with THU and concomitant i.t. injection of THU were found to retard the disappearance of i.t. ara-C from the CSF, although the effect of i.t. THU was more profound. ara-C given alone was cleared from CSF with alpha and beta half-lives of 27.5 +/- 6.7 and 115.6 +/- 0.4 (S.D.) min, respectively. Pretreatment with i.v. THU resulted in alpha and beta half-lives of 10.4 +/- 1.5 and 85.7 +/- 11.1, respectively, whereas concomitant administration of i.t. THU resulted in a single half-life of 96 +/- 0.7. The mean calculated clearance rates for ara-C alone, ara-C plus i.v. THU, and ara-C plus i.t. THU were 7.5, 6.2, and 4.2 ml/hr, respectively. This effect appeared to be primarily due to THU inhibition of ara-C deamination, since a decrease in formation of 1-beta-D-arabinofuranosyluracil in the CSF was observed when ara-C was given in the presence of THU (either i.t. or i.v.). No acute neurotoxicity was noted after administration of either i.t. THU alone or i.t. THU with ara-C. The ability of THU to alter CSF ara-C pharmacokinetics may have potential therapeutic value.

Animals↗
PubMed1982

Cerebrospinal fluid levels of 2'-deoxycoformycin after systemic administration in monkeys.

2'-Deoxycoformycin (DCF) is an inhibitor of the enzyme adenosine deaminase (ADA) and has shown promise as an antileukemia agent. For the assessment of the extent to which systemically administered DCF crosses into the central nervous system (CNS), rhesus monkeys were given iv boluses of DCF. Simultaneous blood and cerebrospinal fluid (CSF) samples were assayed for DCF levels at times ranging from 10 minutes to 6 hours after the drug was given. Average peak CSF drug levels of 5.5 X 10(-8) M and 3 X 10(-7) M were reached 1 1/2 - 2 hours following injections of 0.25 and 1.0 mg DCF/kg, respectively. The ratio of peak CSF to simultaneous plasma levels was 1 to 10. Data obtained from a patient who had acute lymphocytic leukemia and who was given iv DCF were comparable. Drug levels achieved within the CSF following iv administration of 0.25 mg DCF/kg are similar to those previously demonstrated to inhibit ADA. These results may be important both for understanding DCF-related CNS toxicity and for designing combination chemotherapy with DCF.

Animals↗
PubMed1982

Methotrexate levels in the interstitial space and seminiferous tubule of rat testis.

The ability of methotrexate (MTX) to pass from the blood into the interstitial space and seminiferous tubule of the rat was investigated using testicular micropuncture. MTX was administered to anesthetized adult Wister rats via a femoral vein cannula. Constant plasma levels of MTX were achieved by giving a priming dose followed by a constant infusion of 1, 10, or 100 mg/kg/hr with 6 to 27 rats studied at each dose. Blood (via a jugular vein cannula), testicular interstitial fluid, and seminiferous tubule fluid (via direct micropuncture) were periodically sampled during the 4 hr of drug infusion. Under steady-state conditions, when compared to corresponding plasma values, MTX levels were 2- to 4-fold lower in the testicular interstitial fluid and 18- to 50-fold lower in the seminiferous tubule. These results indicate that, in the rat, a significant blood-testis barrier to MTX exists at the tubular but probably not at the capillary-interstitial level. If these results can be extrapolated to humans, they do not provide a pharmacological explantation for the frequent occurrence of leukemic relapse in the interstitium of the testes in boys with acute lymphocytic leukemia.

Animals↗
PubMed1981

L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans.

L-Asparaginase has been widely used for the treatment of acute lymphoblastic leukemia. Therapeutic and toxic effects in the central nervous system have been noted with systemic treatment. In order to better define the relationship between L-asparaginase administration and cerebrospinal fluid (CSF) asparagine levels, L-asparaginase and asparagine were measured in the CSF of rhesus monkeys following intrathecal and i.v. administration. Following intrathecal injection, the enzyme activity of Escherichia coli L-asparaginase in the CSF demonstrated a more rapid terminal half-life than did that of 111In-labeled diethylenetriaminepentaacetic acid, a marker of CSF bulk flow [4 +/- 0.7 (S.D.) hr versus 5.8 +/- 0.2 hr]. Intrathecal injection of E. coli asparaginase resulted in complete depletion of CSF asparagine for at least 5 days. A similar period of CSF asparagine depletion was observed following i.v. administration of L-asparaginase. Similar results were found in seven patients undergoing systemic L-asparaginase therapy. The minimal plasma level of L-asparaginase necessary to deplete CSF asparagine in both species was 0.1 IU/ml. Two other enzymes, Erwinia L-asparaginase and succinylated Acinetobacter glutaminase-asparaginase, were cleared from the CSF at the same rate as bulk flow. These data indicate that systemic L-asparaginase therapy may be a feasible means of treating central nervous system involvement in patients with acute lymphoblastic leukemia and that there is no therapeutic advantage to using intrathecal L-asparaginase.

Animals↗
PubMed1980

Clinical implications of glucocorticoid receptor studies in childhood acute lymphoblastic leukemia.

We have performed in parallel, in 19 children with acute lymphoblastic leukemia, a quantitative determination of glucocorticoid levels, in vitro steroid induced inhibition of nucleic acid precursors, and a short-term clinical trial of corticosteroids alone, before the treatment was given, which included corticosteroids and other drugs. From our results it appears that high glucocorticoid receptor levels in acute lymphoblastic leukemia of children do not guarantee a clinical response to corticosteroids. On the other hand, glucocorticoid receptors may turn out to be of value in predicting a poor response to corticosteroids only if their levels are considerably low.

Adolescent↗