Recurrent limp in a young boy.
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Child, Preschool↗
Biomedical subjects
A Lippi
Publications and source records attributed to A Lippi.
Pharmacological profile of MEN 11066, a novel potent and selective aromatase inhibitor.
MEN 11066 is a new non-steroidal compound which potently inhibits human placenta (K(i)=0.5 nM) and rat ovarian (K(i)=0.2 nM) aromatase in vitro. In vivo, a single oral dose of 0.3 mgkg(-1) significantly decreased uterus weight in immature rats after stimulation of uterus growth by androstenedione. MEN 11066 reduced in a dose-dependent manner plasma estradiol levels in adult female rats treated with pregnant mare serum gonadotropin (PMSG). After 2 weeks of repeated daily treatment in adult rats, a significant decrease in uterine weight was observed together with a 65% decrease in plasma estradiol, whereas plasma levels of testosterone, progesterone, aldosterone, corticosterone, cholesterol, LH and FSH were not affected. The lack of any effect by MEN 11066 on adrenal steroids was confirmed by the unchanged plasma corticosterone and aldosterone levels in immature rats and also in adult rats when the repeated treatment with MEN 11066 (15 days) was followed by the administration of a synthetic ACTH analogue. No change in 11beta-hydroxylase or 21-hydroxylase activities was produced in vitro by the addition of 10 microM MEN 11066. Fifteen-day treatment with MEN 11066 did not produce changes in several rat hepatic enzymatic activities involved in the metabolism of xenobiotics. These results demonstrated that MEN 11066 is a potent inhibitor of aromatase which does not interfere with the cytochrome P450 involved in the synthesis of other steroids or in the metabolism of xenobiotics.
Administration, Oral↗
Pro- and anti-inflammatory actions of ricinoleic acid: similarities and differences with capsaicin.
We have investigated the pro- and anti-inflammatory effects of ricinoleic acid (RA), the main active principle of castor oil, in an experimental model of blepharitis induced by intradermal injection of carrageenan in the guinea-pig eyelid and its possible capsaicin-like mode of action on acutely dissociated rat dorsal root ganglia (DRG) neurons in vitro. Topical treatment with RA (10-100 mg/guinea-pig) or capsaicin (1-10 mg/guinea-pig) caused eyelid reddening and oedema. At lower doses (0.3-3 mg/guinea-pig and 0.009-0.09 mg/guinea-pig for RA and capsaicin, respectively) both drugs significantly potentiated the eyelid oedema induced by carrageenan. The tachykinin NK1 receptor antagonist FK 888 (0.59 mg/kg s.c.) abolished the potentiation of carrageenan-induced eyelid oedema induced by either RA or capsaicin. The neutral endopeptidase inhibitor, thiorphan (1.3 mg/kg i.v.) significantly enhanced the potentiation of carrageenan-induced eyelid oedema produced by RA. This potentiating effect was abolished by FK 888. Repeated (8 days) topical application of RA (0.9 mg/guinea-pig) or capsaicin (0.09 mg/guinea-pig) inhibited the carrageenan-induced eyelid oedema. This anti-inflammatory effect was accompanied by a reduction (75%-80% of SP and 46%-51% of NKA) in tachykinin content of the eyelids, as determined by radioimmunoassay. In dissociated rat DRG neurons, RA (0.1 mM for 5 min) significantly inhibited the inward currents induced by application of capsaicin (1 microM) and/or low pH (5.8), without inducing any currents by itself or changing voltage-dependent currents. Moreover, after 24-h incubation, RA (0.1 mM) significantly decreased the capsaicin (1 microM)-induced calcitonin gene-related peptide (CGRP) release from rat DRG neurons, whereas acute drug superfusion did not evoke CGRP release by itself. Summarizing, RA possesses capsaicin-like dual pro-inflammatory and anti-inflammatory properties which are observed upon acute and repeated application, respectively. However, unlike capsaicin, RA does not induce inward current in DRG neurons and it is devoid of algesic properties in vivo.
Animals↗
The role of sensory neuropeptides in motor innervation of the hamster isolated urinary bladder.
In this study we have characterized the role of sensory fibers and of the sensory peptides, neurokinin A (NKA) and calcitonin gene-related peptide (CGRP), on the contractile responses evoked by single pulse electrical field stimulation (EFS) in the hamster urinary bladder. EFS of the hamster isolated urinary bladder produced twitch contractions which were unaffected by atropine but abolished by tetrodotoxin. The P2 purinoreceptor antagonist PPADS (30 microM) inhibited twitches by 66+/-4% on its own and by 78+/-3% in the presence of atropine. The selective tachykinin NK2 receptor antagonist nepadutant produced a slight but consistent reduction of twitch amplitude (-21+/-3%) at 1 microM. Addition of nepadutant to atropine and PPADS did not further increase their inhibitory effect. The application of hCGRP (10-300 nM) produced a concentration-dependent inhibition of twitches (Emax -38+/-3%, EC50=12 nM) and a small reduction of tone (0.5+/-0.09 mN). Similar effects were obtained with capsaicin (0.1-10 microM) which inhibited EFS-evoked contractions with an EC50 of 100.0 nM and a maximal effect of 34+/-4% inhibition at 1 microM. Under submaximal parameters of stimulation NKA (10 nM) increased the amplitude of twitches by 45+/-6% and produced a concentration-dependent tonic contraction (EC50=55.9 nM). The CGRP1 receptor subtype antagonist, hCGRP(8-37), increased by 29+/-8% the EFS-evoked contractions and significantly reduced the response to 0.1 microM CGRP. Capsaicin (10 microM) increased both CGRP-LI and NKA-LI release from superfused slices of hamster urinary bladder by about sixfold and by about 70%, over baseline, respectively. A second application of capsaicin was ineffective, indicating a complete desensitization of sensory nerve efferent function. In the hamster urinary bladder the sensory neuropeptides NKA and CGRP are co-released by sensory fibers after stimulation either by EFS or capsaicin. However, the role of CGRP appears functionally predominant.
Animals↗
Effect of the aromatase inhibitor, MEN 11066, on growth of two different MCF-7 sublines.
The racemate compound MEN 11066 (1-[(benzofuran-2-yl)(4'-cyanophenyl)methyl]-1H-1,2,4-triazole) and its enantiomers, (+)-MEN 11623 and (-)-MEN 11622, showed potent and selective aromatase activity on human placental microsomes. In addition, to better evaluate their potency as anticancer drugs, the compounds were assayed on testosterone-induced cell proliferation to measure their ability in inhibiting oestrogen-dependent tumour growth. Two different sublines originated from the human breast carcinoma MCF-7 were used. One, named MCF-7(tumour aromatase) (TA), that had maintained its intrinsic aromatase activity, was more sensitive to estradiol or testosterone-induced growth than the second subline named MCF-7(human placental aromatase) (hPA). The latter had been transfected with the human placental aromatase cDNA, after recognizing that the parental cells had aromatase activity reduced to undetectable levels. The MEN compounds completely reverted the testosterone-induced proliferation in both MCF-7(TA) and MCF-7(hPA) cells, while they did not affect the estradiol-triggered proliferation as a proof of their specificity for aromatase enzyme. Interestingly, MCF-7(TA) cells were more susceptible to the effects of aromatase inhibitors than the MCF-7(hPA) cell. These data suggest the efficacy of aromatase inhibitors in breast cancer when the growth dependency from oestrogen is high and a relatively low aromatase activity may be extremely important for tumour development.
Androstenedione↗
Antinociceptive activity of ricinoleic acid, a capsaicin-like compound devoid of pungent properties.
The antinociceptive effect of ricinoleic acid ([R-(Z)]-12-hydroxy-9-octadecenoic acid) in comparison with capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) has been investigated in several "in vivo" tests. Acute topical application of capsaicin, but not ricinoleic acid, produced by itself an hyperalgesic effect detected as a decrease in paw withdrawal latency in response to a painful (heat) stimulus in mice. Capsaicin, but not ricinoleic acid at any dose tested, showed an irritant effect in the wiping test in guinea pig conjunctiva after local application and in the paw licking test in mice after intradermal injection. Whereas acute application of ricinoleic acid or capsaicin decreased paw withdrawal latency to heat in the presence of a pre-existing inflammation (injection of carrageenan in the mouse paw), the repeated local treatment for 8 days with either compounds markedly increased paw withdrawal latency. In a chronic model of inflammation (complete Freund's adjuvant arthritis in mice), the repeated topical and intradermal treatments with both ricinoleic acid and capsaicin increased paw withdrawal latency to heat, the antinociceptive effect of ricinoleic acid being more persistent than that of capsaicin. Antinociceptive effect of 8 days of treatment with ricinoleic acid and capsaicin was observed in acetic acid-induced writhing in mice, capsaicin-induced foot licking in mice and capsaicin-induced wiping movements in guinea pig conjunctiva. A decrease of substance P tissue levels in the mouse paw was found after repeated treatment with ricinoleic acid. In conclusion, ricinoleic acid seems to be a new antinociceptive agent lacking the pungent and acute hyperalgesic properties of capsaicin.
Administration, Topical↗
Effect of ricinoleic acid in acute and subchronic experimental models of inflammation.
Observational studies indicate that topical application of ricinoleic acid (RA), the main component of castor oil, exerts remarkable analgesic and anti-inflammatory effects. Pharmacological characterization has shown similarities between the effects of RA and those of capsaicin, suggesting a potential interaction of this drug on sensory neuropeptide-mediated neurogenic inflammation. The aim of this study was to assess RA anti-inflammatory activities in comparison with capsaicin in several models of acute and subchronic inflammation. The acute inflammation was induced by intradermal injection of carrageenan in the mouse or by histamine in the guinea-pig eyelid. In either experiment, the extent of the oedema thickness was measured. Subchronic oedema was induced by complete Freund's adjuvant injection in the ventral right paw of mice. Tissue substance P (SP) was measured in the carrageenan experiments by radioimmunoassay (RIA). It was found that the acute topical application of RA (0.9 mg/mouse) or capsaicin (0.09 mg/mouse) significantly increased the mouse paw oedema induced by carrageenan, while an 8-day repeated topical treatment with the same doses of both compounds resulted in a marked inhibition of carrageenan-induced paw oedema matched by a reduction in SP tissue levels. Similar effects were found against histamine-induced eyelid oedema in guinea-pigs after acute or repeated application of RA or capsaicin. RA and capsaicin given for 1-3 weeks reduced the established oedema induced by Freund's adjuvant, a subchronic model of inflammation, particularly if given by the intradermal route. Either in mouse paw or in guinea-pig eyelid, capsaicin but not RA by itself produced a slight hyperemia and activation of a behavioural response (e.g. scratching of the eyelids). On the basis of the present results, RA may be seen as a new capsaicin-like, non-pungent anti-inflammatory agent suitable for peripheral application.
Acute Disease↗
Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO)
About 30% of patients with severe aplastic anaemia (SAA) unresponsive to one course of immunosuppressive (IS) therapy with antithymocyte or antilymphocyte globulin can achieve complete or partial remission after a second IS treatment. Among various second-line treatments, rabbit ATG (r-ATG) could represent a safe and effective alternative to horse ALG (h-ALG). In a multicentre study, 30 patients with SAA (17 males and 13 females, median age 21 years, range 2-67) not responding to a first course with h-ALG plus cyclosporin (CyA) and granulocyte colony stimulating factor (G-CSF), were given a second course using r-ATG (3.5 mg/kg/d for 5 d), CyA (5 mg/kg orally from day 1 to 180) and G-CSF (5 microg/kg subcutaneously from day 1 to 90). The median interval between first and second treatment was 151 d (range 58-361 d). No relevant side-effects were observed, but one patient died early during treatment because of sepsis. Overall response, defined as transfusion independence, was achieved in 23/30 (77%) patients after a median time of 95 d (range 14-377). Nine patients (30%) achieved complete remission (neutrophils >/=2.0 x 109/l, haemoglobin >/=11 g/dl and platelets >/=100 x 109/l). The overall survival rate was 93% with a median follow-up of 914 d (range 121-2278). So far, no patient has relapsed. Female gender was significantly associated with a poorer likelihood to respond (P = 0.0006). These data suggest that r-ATG is a safe and effective alternative to h-ALG for SAA patients unresponsive to first-line IS treatment.
Adolescent↗
Potassium removal increases the QTc interval dispersion during hemodialysis.
This study was planned to clarify the mechanism(s) by which hemodialysis increases the QTc dispersion, a marker of risk of ventricular arrhythmias. To this aim, 10 uremic patients, without any relevant heart diseases, underwent two different types of hemodialysis schedules. In the first, 1 h of isolated high rate ultrafiltration preceded the standard diffusive procedure. In the second, during the first hour of standard bicarbonate hemodialysis, the decrease of plasma potassium concentration was prevented by increasing K+ concentration in the dialysate, according to its pre dialysis plasma levels. During the high rate ultrafiltration period, together with ECG signs of increased sympathetic nervous system activity and catecholamines secretion, the QTc dispersion did not change significantly. Instead, an evident increment was observed 1 h after the start of the diffusive hemodialysis, then slowly progressing until the end of the dialysis and finally returning to the pre dialysis values within 2 h after the end of the session. To the contrary, the increase of the QTc dispersion was totally blunted during a standard hemodialysis procedure in absence of plasma K+ decrease, but appeared again when the K+ dialysate fluid concentration was restored to 2 mmol/l. This study provides evidence that the increase of QTc dispersion occurring on hemodialysis is mainly related to the diffusive process, more precisely to the K+ removal. This is one more reason to focus attention on K+ removal rate especially when hemodialysis treatment is given in uremics affected by cardiac diseases with high risk of arrhythmias.
Blood Pressure↗
Elbow arthritis: a rare inaugural manifestation of acute leukemia.
We report four cases of swelling of the elbow in children in whom the final diagnosis was acute leukemia. We believe that elbow arthritis in children, especially when isolated, is an unusual finding that is unlikely to indicate juvenile idiopathic arthritis and should suggest alternative diagnoses including neoplastic disease.
Adolescent↗
Characterization of the antibronchoconstrictor activity of MEN 11420, a tachykinin NK2 receptor antagonist, in guinea-pigs.
We have investigated the antibronchoconstrictor activity of a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist, MEN 11420 c¿[(beta-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2beta-5beta++ +)¿, as compared to MEN 10627 c[(Met-Asp-Trp-Phe-Dpr-Leu)c(2beta-5beta)] and to the nonpeptide antagonist SR 48968 ((S)-N-methyl-N[4-acetylamino-4-phenylpiperidino-2-3,4-dichlorophenyl)bu tyl] benzamide. In the guinea-pig isolated bronchus MEN 11420 (pK(B) 8.40+/-0.07) and MEN 10627 (pK(B) 8.67+/-0.09) competitively antagonized the contraction induced by the tachykinin NK2 receptor agonist, [betaAla8]neurokinin A-(4-10). SR 48968 showed an apparent pK(B) of 9.57+/-0.2. The atropine-resistant response to electrical stimulation was reduced in a concentration-dependent manner by MEN 11420, MEN 10627 and SR 48968. In urethane-anaesthetized guinea-pigs, MEN 11420 produced a dose-dependent inhibition of bronchoconstriction induced by [betaAla8]neurokinin A-(4-10). Comparable inhibitory effects were observed after i.v. administration of SR 48968 and MEN 10627. Bilateral electrical stimulation of the vagi (20 Hz for 20 s) induced a bronchoconstriction that was dose-dependently inhibited by i.v. MEN 11420, SR 48968 and MEN 10627. MEN 11420 was also effective in inhibiting the capsaicin (20 nmol/kg i.v.)-induced bronchoconstriction. MEN 11420 (1.1 micromol/kg i.v.) showed a longer plasma half-life and a greater area under the plasma concentration-time curve value (AUC) than those of MEN 10627. These findings indicate that MEN 11420 is a potent and selective antagonist of the tachykinin NK2 receptor in guinea-pig airways with a long duration of action.
Amino Acid Sequence↗
Characterization of [3H]MEN 11420, a novel glycosylated peptide antagonist radioligand of the tachykinin NK2 receptor.
[3H]MEN 11420, a radiolabeled glycosylated peptide antagonist of the tachykinin NK2 receptor, has been investigated in ligand-receptor binding assays using membranes of CHO cells transfected with the human tachykinin NK2 receptor. [3H]MEN 11420 bound to a single class of high affinity binding sites: its binding was inhibited by natural tachykinins (potency ranking: NKA >> SP > or = NKB), as well as by peptide (MEN 11420 > MEN 10376 >> R 396) and nonpeptide (SR 48968 > GR 159897) selective NK2 receptor antagonists. These data indicate that [3H]MEN 11420 is a potent radioligand for the human tachykinin NK2 receptor that may represent a useful tool for studying ligand-receptor interactions at the molecular level.
Animals↗
1,2-disubstituted cyclohexane derived tripeptide aldehydes as novel selective thrombin inhibitors.
A series of tripeptide arginine aldehydes was synthesized by replacement of proline with 1,2-disubstituted cyclohexane derivatives in the sequence of D-MePhe-Pro-Arg-H. Based on molecular modeling, further modification of the D-MePhe residue resulted in a potent and selective thrombin inhibitor.
Aldehydes↗
Depolarization evoked co-release of tachykinins from enteric nerves in the guinea-pig proximal colon.
The aim of this study was to assess at which extent an even co-release of the tachykinins, substance P (SP) and neurokinin A (NKA), occurs from enteric neurons/nerves of the guinea-pig proximal colon during graded depolarization. In this preparation, a sharply diverging NK1/NK2 receptor pattern of tachykininergic co-transmission has been observed in physiological studies. The experiments were performed in capsaicin-pretreated (10 microM for 15 min) mucosa-free smooth muscle of guinea-pig proximal colon, to exclude the mucosa and the peripheral endings of primary afferent nerves as possible sources of released tachykinins. The content of extractable tachykinins was measured as SP- and NKA-like immunoreactivities (-LI) by radioimmunoassay. Chromatographic characterization of aqueous acetic acid extracts showed one peak of SP-LI corresponding to authentic SP, whereas there were multiple peaks of NKA-LI, the major one co-eluting with authentic NKA. An increased outflow of both SP- and NKA-LI was evenly produced in a concentration-dependent manner when the preparations were superfused with a high potassium (K) medium in which NaCl had been replaced with equimolar amounts (20-100 mM) of KCl. The high K-evoked release of SP- and NKA-LI was dependent upon the presence of extracellular calcium and was inhibited by about 50% in the presence of the N-type voltage-dependent calcium channel blocker, omega-conotoxin GVIA (0.1 microM). Omega-conotoxin MVIIC (1 microM), a non-selective blocker of N-, P- and Q-type voltage-dependent calcium channels, likewise produced about 40% inhibition of evoked release of both peptides. No evidence for a role of L-type channels in tachykinin release was obtained, since the addition of nifedipine (1 microM) or Bay K8644 (1 microM) did not significantly affect the response to high K. Neither NK1 receptor agonist (septide, 0.1 microM) or antagonist (SR 140333, 10 nM) nor NK2 receptor agonists ([betaAla8]NKA(4-10) and GR 64349, 0.1 microM each) or antagonist (SR 48968, 10 nM) did affect the high K-evoked release of tachykinins. We conclude that SP and NKA are evenly co-released in response to graded depolarization of enteric nerves in the guinea-pig colon. Therefore, the specialization of tachykininergic transmission observed in functional studies does not originate at the prejunctional level. The co-release of tachykinins involves the influx of extracellular calcium via N-type but not L-type calcium channels. No evidence for the presence of NK1 or NK2 autoreceptors affecting tachykinin release from enteric neurons was obtained.
Animals↗
MEN 11420 (Nepadutant), a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist.
1. The pharmacological profile was studied of MEN 11420, or cyclo[[Asn(beta-D-GlcNAc)-Asp-Trp-Phe-Dap-Leu]cyclo(2beta-5beta )], a glycosylated derivative of the potent, selective, conformationally-constrained tachykinin NK2 receptor antagonist MEN 10627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2beta-5beta)). 2. MEN 11420 competitively bound with high affinity to the human NK2 receptor stably transfected in CHO cells, displacing radiolabelled [125I]-neurokinin A and [3H]-SR 48968 with Ki values of 2.5+/-0.7 nM (n = 6) and 2.6+/-0.4 nM (n = 3), respectively. 3. MEN 11420 showed negligible binding affinity (pIC50 < 6) at 50 different receptors (including tachykinin NK1 and NK3 receptors) and ion channels. 4. In the rabbit isolated pulmonary artery and rat urinary bladder MEN 11420 potently and competitively antagonized tachykinin NK2 receptor-mediated contractions (pK(B) = 8.6+/-0.07, n = 10, and 9.0+/-0.04, n = 12; Schild plot slope = -1.06 (95% c.l. = -1.3; -0.8) and -1.17 (95% c.l. = -1.3; -1.0), respectively). MEN 11420 produced an insurmountable antagonism at NK2 receptors in the hamster trachea and mouse urinary bladder. However, in both preparations, the effect of MEN 11420 was reverted by washout and an apparent pK(B) of 10.2+/-0.14, n = 9, and 9.8+/-0.15, n = 9, was calculated in the hamster trachea and mouse urinary bladder, respectively. 5. MEN 11420 showed low affinity (pK(B) < 6) at guinea-pig and rat tachykinin NK1 (guinea-pig ileum and rat urinary bladder) and NK3 (guinea-pig ileum and rat portal vein) receptors. On the whole, the affinities (potency and selectivity) showed by MEN 11420 for different tachykinin receptors, measured either in binding or in functional bioassays, were similar to those shown by the parent compound, MEN 10627. 6. The in vivo antagonism of the contractions produced by [betaAla8]neurokinin A(4-10) (1 nmol kg(-1)) was observed after intravenous (dose range: 1-10 nmol kg(-1)), intranasal (3-10 nmol kg(-1)), intrarectal (30-100 nmol kg(-1)) and intraduodenal (100-300 nmol kg(-1)) administration of MEN 11420. MEN 11420 was more potent (about 10 fold) and longer lasting than its parent compound MEN 10627, possibly due to a greater metabolic stability. 7. A dose of MEN 11420 (100 nmol kg(-1), i.v.), that produced potent and long lasting inhibition of the contraction of the rat urinary bladder induced by challenge with the NK2 selective receptor agonist [betaAla8]neurokinin A(4-10) (10-300 nmol kg(-1)), was without effect on the responses produced by the NK1 receptor selective agonist [Sar9]substance P sulphone (1-10 nmol kg(-1)). 8. These findings indicate that MEN 11420 is a potent and selective tachykinin NK2 receptor antagonist. The introduction of a sugar moiety did not produce major changes in the affinity profile of this antagonist as compared to MEN 10627, but markedly improved its in vivo potency and duration of action. With these characteristics, MEN 11420 is a suitable candidate for studying the pathophysiological significance of tachykinin NK2 receptors in humans.
Animals↗
Arthritis as a presenting feature of non-Hodgkin's lymphoma.
Leukaemia can present with joint swelling in the absence of abnormal haematological findings. Arthritis as a presenting sign of lymphoma, however, is extremely rare. Three children with non-Hodgkin's lymphoma who had joint swelling at the onset of their disease are reported. Two cases showed histological features of anaplastic large cell lymphoma (Ki-1/CD30 positive), and one of angioimmunoblastic T cell lymphoma. In all patients the unusual presentation delayed correct diagnosis.
Arthritis↗
Pharmacokinetics of the bicyclic peptide tachykinin NK2 receptor antagonist MEN 11420 (nepadutant) in rats.
The pharmacokinetics of MEN 11420 [nepadutant, c[[(beta-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2beta-5beta++ +)]], a potent glycosylated analogue of the selective, bicyclic peptide, tachykinin NK2 receptor antagonist MEN 10627 [c[(Met-Asp-Trp-Phe-Dpr-Leu)c(2beta-5beta)]], were studied in rats after different routes of administration. The plasma concentration profile for MEN 11420 after iv administration (1 mg/kg) was compared with that for the parent compound MEN 10627. The mean plasma half-life (44 min) and AUC value (285 micrograms.min/ml) for MEN 11420 were almost 3-fold greater than those for MEN 10627, and the systemic clearance was reduced to one third. The absolute bioavailability of MEN 11420 after intranasal (1 mg/kg) or ip (1 mg/kg) administration was virtually complete. However, bioavailability was only approximately 5% after intrarectal treatment (5 mg/kg) and was too low to be quantified (<3%) after sublingual (1 mg/kg) or oral (10 mg/kg) doses. The urinary excretion of unchanged compound, after an iv dose of 1 mg/kg, was approximately 34% of the dose for MEN 11420 but was <2% for MEN 10627. This is in agreement with in vitro data showing that MEN 11420 is more resistant to hydrolytic and oxidative metabolism than is MEN 10627. It is concluded that the hydrophilic modification of MEN 10627 to produce MEN 11420 resulted in marked improvement in the pharmacokinetic and metabolic characteristics of the peptide.
Animals↗
Clinical relevance of CD10 expression in childhood ALL. The Italian Association for Pediatric Hematology and Oncology (AIEOP).
BACKGROUND AND OBJECTIVE: Previous studies have considered the prognostic significance of CD10 expression in childhood acute lymphoblastic leukemia (ALL) and showed its linkage to a more favorable prognosis. The aim of this study was to assess the independent significance of CD10 expression in a large population of ALL patients. DESIGN AND METHODS: We revised the independent clinical relevance of CD10 expression in 2038 children with acute lymphoblastic leukemia (ALL), who were consecutively entered in 4 sequential trials of the Italian Association for Pediatric Hematology and Oncology (i.e. AIEOP studies 82, 87, 88, 91); 1142 were males and 896 females, age ranged between 1 and 14 years (yrs) at diagnosis. Of the whole group, 1471 children (72.2%) were defined as having standard risk, 567 (27.8%) as having a high risk. RESULTS: CD10 was detected in blast cells from 1706 of 1784 (95.6%) patients with B-lineage ALL and 46 of 254 (18.1%) with T-cell ALL. In the B-lineage subgroup CD10 expression was associated with presenting features such as age < 9 yrs and inclusion in the standard risk category. No significant differences were found between CD10+ and CD10- cases in T-lineage ALL, concerning presenting features, except for FAB L2 in the former group. We compared the event-free survival (EFS) rates for patients with T-ALL or B-lineage ALL, regarding CD10 positivity, overall and by individual study. Patients with T-ALL fared worse than those with B-lineage ALL (5 and 10 yrs EFS: 46.8% vs. 68.5% and 44.5% vs. 63.7% respectively, p = 0.0001). In multivariate analysis of B-lineage subgroup poorer EFS was associated with male sex, higher WBC (> or = 20 x 10(9)/L), age > 9 yrs. Only WBC > or = 20 x 10(9)/L and age > 9 yrs were parameters linked to poorer EFS in the T-lineage subgroup. Finally, we compared EFS rates for four groups of patients categorized as having high or standard risk, and according to CD10+ and CD10- expression. High-risk patients fared statistically worse than standard risk patients both in the CD10- and in the CD10+ groups (42% vs. 50.7% and 63.6% vs. 66.8%, respectively). INTERPRETATION AND CONCLUSIONS: CD10 expression does not have independent prognostic significance in either the larger subgroup of B-ALL patients or in T-cell ALL.
Adolescent↗