Pharmacodynamics of ticlopidine in man in relation to plasma and blood cell concentration

Summary In 6 normal volunteers given single oral doses of 250, 500 and 1000 mg ticlopidine (T), the peak plasma level of unchanged drug was reached after about 2 h. There was no correlation between the plasma T level and its inhibitory effect on platelet function, expressed as % inhibition of ADP-induced aggregation. By means of HPLC and GC/MS significant concentrations of T were demonstrated in washed red cells, platelets and neutrophils, with a marked difference in the time course of the appearance of cell-associated drug. The time course of platelet-associated T very accurately fitted that of the antiaggregatory activity.After subacute oral administration (250 mg b. d. for 7 days), the maximum effect on platelet function was observed after 3 to 4 days, when a significant concentration of platelet-associated T had been reached. The pharmacological effect persisted as long as drug was detectable in platelet.An in vitro study strongly suggested that the antiaggregating effect was retained by treated washed platelets but not by treated plasma. It is suggested that the platelet compartment represents the pharmacological target of T via a specific uptake system.     

Intra-daily oscillations in dipropylacetic acid plasma levels with two or three daily doses of dipropylacetamide in epileptic patients

The diurnal fluctuations in dipropylacetic acid (DPA) plasma levels were examined in ten epileptic patients following a chronic treatment with 3 or 2 daily doses of dipropylacetamide (DPM). The highest/lowest DPA level ratios observed throughout 24 hrs were 1.18 and 1.36, respectively, but the difference in the data was not statistically significant (p>0.05). The present results indicate that a reduction of the frequency of the daily administrations of the drug can be made with consequent possible improvement in the patient's compliance. The clinical value of the oscillations in DPA serum levels is also revised in the light of the data reported in the literature.

---

Sommario Le fluttuazioni giomaliere dei livelli plasmatici di acido dipropilacetico (DPA) sono state esaminate in 10 pazienti epilettici in trattamento cronico con 3 o 2 dosi giomaliere di dipropilacetamide (DPM). I rapporti valore più alto/valore più basso di livello di DPA osservati nelle 24 ore sono risultati 1.18 e 1.36, rispettivamente, ma la differenza dei dati non è stata significativa (p>0.05). I presenti risultati indicano che può essere effettuata una riduzione della frequenza delle somministrazioni giomaliere del farmaco con un conseguente possibile miglioramento della compliance del paziente. Il valore clinico delle oscillazioni dei livelli serici di DPA è inoltre rivisto alla luce dei dati riportati in letteratura.

     

Genome analysis and gene expression profiling of neuroblastoma and ganglioneuroblastoma reveal differences between neuroblastic and Schwannian stromal cells

Neuroblastic tumours are a group of paediatric cancers with marked morphological heterogeneity. Neuroblastoma (Schwannian stroma-poor) (NB-SP) is composed of undifferentiated neuroblasts. Ganglioneuroblastoma intermixed (Schwannian stroma-rich) (GNBi-SR) is predominantly composed of Schwannian stromal (SS) and neuroblastic (Nb) cells. There are contrasting reports suggesting that SS cells are non-neoplastic. In the present study, laser capture microdissection (LCM) was employed to isolate SS and Nb cells. Chromosome 1p36 deletion and MYCN gene amplification were found to be associated in two out of seven NB-SPs, whereas no abnormalities were observed in five GNBi-SRs. In some cases, loss of heterozygosity (LOH) at 1p36 loci was detected in Nb cells but not in the bulk tumour by LCM; furthermore, LOH was also identified in both SS and tumour tissue of a GNBi-SR. DNA gain and loss studied by comparative genomic hybridization were observed at several chromosome regions in NB-SP but in few regions of GNBi-SR. Finally, gene expression profiles studied using an oligo-microarray technique displayed two distinct signatures: in the first, 32 genes were expressed in NB-SP and in the second, 14 genes were expressed in GNBi-SR. The results show that NB-SP is composed of different morphologically indistinguishable malignant cell clones harbouring cryptic mutations that are detectable only after LCM. The degree of DNA imbalance is higher in NB-SP than in GNBi-SR. However, when the analysis of chromosome 1p36 is performed at the level of microdissection, LOH is also observed in SS cells. These data provide supportive evidence that SS cells have a less aggressive phenotype and play a role in tumour maturation.     

The role of ITPA and ribavirin transporter genes polymorphisms in prediction of ribavirin‐induced anaemia in chronic hepatitis C Egyptian patients

Few data are available concerning the roles of polymorphisms of inosine triphosphatase (ITPA) gene and ribavirin (RBV) transporter genes in the prediction of RBV‐induced anaemia among Egyptians with chronic hepatitis C (CHC). Genotyping of three ITPA gene variants and two variants of RBV transporter genes has been performed in 123 patients under pegylated interferon‐α/ribavirin treatment. The baseline haemoglobin and ITPA rs1127354 CA/AA have been found as predictors of anaemia at 4, 8 and 12 weeks of RBV therapy. In addition, ITPA rs7270101 AC/CC and age predicted anaemia after 12 weeks of therapy. In conclusion, the ITPA variant rs1127354C>A significantly predict RBV‐induced anaemia during the first 3 months of treatment and it is recommended to be assessed before RBV administration.     

Blood Brain Barrier Impairment in HIV-Positive Naïve and Effectively Treated Patients: Immune Activation Versus Astrocytosis

Blood brain barrier (BBB) damage is a common feature in central nervous system infections by HIV and it may persist despite effective antiretroviral therapy. Astrocyte involvement has not been studied in this setting. Patients were enrolled in an ongoing prospective study and subjects with central nervous system-affecting disorders were excluded. Patients were divided into two groups: treated subjects with cerebrospinal fluid (CSF) HIV RNA <50 copies/mL (CSF-controllers) and in late-presenters CD4+ T lymphocytes <100/uL. CSF biomarkers of neuronal or astrocyte damage were measured and compared to CSF serum-to-albumin ratio. 134 patients were included; 67 subjects in each group (50 %) with similar demographic characteristics (with the exception of older age in CSF controllers). CD4 (cells/uL), plasma and CSF HIV RNA (Log₁₀ copies/mL) were 43 (20-96), 5.6 (5.2-6) and 3.9 (3.2-4.7) in LPs and 439 (245-615), <1.69 (9 patients <2.6) and <1.69 in CSFc. BBB impairment was observed in 17 late-presenters (25.4 %) and in 9 CSF-controllers (13.4 %). CSF biomarkers were similar but for higher CSF neopterin values in late-presenters (2.3 vs. 0.6 ng/mL, p?<?0.001). CSARs were associated with CSF neopterin (rho?=?0.31, p?=?0.03) and HIV RNA (rho?=?0.24, p?=?0.05) in late-presenters and with CSF tau (rho?=?0.51, p?<?0.001), p-tau (rho?=?0.47, p?<?0.001) and S100beta (rho?=?0.33, p?=?0.009) in CSF-controllers. In HAART-treated subjects with suppressed CSF HIV RNA, BBB altered permeability was associated with markers of neuronal damage and astrocytosis. Additional treatment targeting astrocytosis and/or viral protein production might be needed in order to reduce HIV effects in the central nervous system.     

Growth standards for infants and children: a cross-sectional study.

Measurements of height and weight were collected on 1,233 Black and white infants and children attending a Child Health Clinic in Washtenaw County, Michigan. Polynomial curves were fitted to each race and sex group and, from these, estimates were made of the 3rd, 50th, and 97th percentiles for height and weight. Blacks tended to be lighter and shorter than whites in early infancy. In the second year of life, Blacks tended to exceed whites in height and weight achievement. For infants and children in the 97th percentile this change in status occurred earlier. The differences in weight and height achievement were statistically significant in the two race groups, but not between sexes. The percentile estimates differed significantly from the percentiles of local as well as the "Iowa," "Harvard," and "Tanner" (United Kingdom) standards. Differences in the racial and environmental background of the clinic population and the samples used in the development of the national standards probably accounts for the variations in the percentile estimates. It is concluded that race- and sex-specific standards are required before growth achievements in infants and children can be properly evaluated.     

Pancytopenia with mixed cryoglobulinemia: Evidence for anti-precursor cell activity of cryoglobulin—Effects of plasmapheresis

The efficacy of plasmapheresis in a patient with mixed cryoglobulinemia and pancytopenia is shown. The cryoglobulin was shown to have precursor cell suppressing activity and its depletion by plasmapheresis resulted in improvement of blood counts. Indications, limitations and guidelines for plasmapheresis in various diseases are discussed.     

Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome

BACKGROUND: To investigate the effectiveness and safety of pioglitazone (45 mg/day) on clinical and endocrine-metabolic features of polycystic ovary syndrome (PCOS), we studied 18 obese PCOS patients, classified as normoinsulinaemic (N-PCOS, n = 6) and hyperinsulinaemic (H-PCOS, n = 12) according to their insulin secretion. METHODS: Evaluation of clinical signs, hormonal and lipid profile assays, oral glucose tolerance tests and euglycaemic hyperinsulinaemic clamps were performed at baseline and after 2 (visit 2), 4 (visit 3) and 6 (visit 4) months of treatment. RESULTS: Body weight, body fat distribution and blood pressure remained stable throughout the treatment; hirsutism and acne significantly improved (P < 0.001 for visits 3 and 4 versus baseline) in both groups. A restoration of menstrual cyclicity was observed at visit 4 in 83% (P < 0.001) of H-PCOS and in 33% of N-PCOS. A decrease in LH, LH/FSH ratio, androstenedione and 17-hydroxy-progesterone was observed in both groups, attaining statistical significance in H-PCOS. A significant amelioration of insulin secretion, sensitivity and clearance was obtained in H-PCOS. A trend towards improvement was observed in lipid assessment of both groups. Therapy was well-tolerated. CONCLUSIONS: Present data suggest that there is a selective effect, partially independent of insulin secretion, of pioglitazone on the clinical and hormonal disturbances of PCOS.