Indomethacin distribution in acute pharmacological response among rats

A detailed examination of quantitative relationships of pharmacological action with plasma and tissue concentrations of indomethacin has been undertaken in the rat, after single oral administration of two sustained release preparations. In this study, drug was assayed by high performance liquid chromatography, whereas antiinflammatory response was assessed through the carrageenin-induced edema test. Significant linear correlations (p less than 0.001) were found between logarithmically transformed percent inhibition of edema and logarithmically transformed plasma, as well as tissue levels of indomethacin. However, the lack of significance for partial correlation regarding tissue concentration, contrary to plasma concentration, suggests that pharmacological response is more closely related to the latter, indicating that antidematous effect is mediated via the circulating drug rather than a local action in target tissues. This assumption is further discussed from the equivalence point of view. The relevance of this type of study in the case of topical administration of indomethacin is addressed as well. Taking into account the predictive value of the rat paw edema test for clinical efficacy, relationships similar to those observed are to be expected in man. The high correlation existing between plasma concentration of indomethacin and its pharmacological effect justifies the development and use of sustained release preparations in order to improve the outcome of treatment with this nonsteroidal antiinflammatory drug.     

An evaluation of CA 549, a circulating marker of breast cancer using a procedure for comparison with CA 15.3.

A serum assay of CA 549 (Hybri-BREScan CA 549 degrees, Hybritech), a new tumor marker, was performed in 129 patients with breast cancer and 35 healthy women, in parallel with CA 15.3 (ELSA-CA 15.3 degrees, CIS Biointernational). Comparing 95 women with primary breast carcinoma and 35 controls, Relative (or Receiver) Operating Characteristic (ROC) analysis revealed that the Area Under ROC Curve (AUC) of CA 15.3 was significantly higher than that of CA 549, indicating that, for our population, the first marker was more effective. Parallel and series analyses were also performed using ROC AUC and revealed that the combination of these two tests did not give more information than the CA 15.3 test alone; however, they did not in any way constitute diagnostic tools. In our experience, the best field of application for CA 549 seems to be the therapeutic monitoring and early detection of breast cancer recurrences. However, further investigations on a larger scale are necessary to assess more precisely the place of CA 549 in following the clinical course of breast cancer patients.     

Non-cerebellar visual afferents to the vestibular nuclei involving the prepositus hypoglossal complex: An autoradiographic study in the rat

Summary Radioactive amino-acids were injected into the nucleus reticularis tegmenti pontis (NRTP) and the pretectum (PT) in the rat. Beside the labeling of the several nuclei which are known to receive afferents of either the NRTP and/or the PT, monosynaptic projections from these two structures to the prepositus hypoglossal complex (PHN) were demonstrated. Pretectal visual inputs to the vestibular nuclei (VN) may thus be conveyed not only by the classical PT-inferior olive-cerebellar route, but also by two other non-cerebellar ones involving the strong efferent projections of the PHN onto the VN. These last two pathways are strong candidates to account for the residual visual sensitivity of VN neurons after cerebellectomy or inferior olive lesions.Supported by CNRS (A.T.P. 8115)     

Expression of ps2 and cathepsin-d in breast-cancer

Cytosolic levels of pS2 and Cathepsin D (Cath D) were compared in 145 primary breast cancer patients using the immunoradiometric (IRMA) assays ELSA-pS2-degrees and ELSA-Cath. D-degrees of Cis biointernational. The mean values were 20.04 +/- 41.75 ng pS2/mg of cytosol protein (cp) and 49.94 +/- 33.71 pmol Cath D/mg cp. The pS2 level was significantly associated with Estrogen Receptor (ER), Progesterone Receptor (PgR) and Cath D levels. Significant associations were also found between Log (pS2) or Log (Cath. D) and differentiation grade (SBR), between Log (pS2) and ER (+,-) or PgR (+,-), between Log (Cath. D) and PgR (+,-). No correlations were noted between Log (pS2) or Log (Cath D) and menopausal status, tumor size (T) and lymph node involvement (N), between pS2 and age, between Cath D and age, ER and PgR, between Log (Cath D) and ER (+,-). Contrary to Cath D, pS2 was strongly linked to steroid receptors.     

Perineal recurrence of prostate cancer along a brachytherapy needle track: A case report

Metastatic recurrence in an atypical site, such as the perineum, can occur after prostatectomy, cryotherapy, or brachytherapy, but is uncommon. To our knowledge, this is only the third case of perineal recurrence of prostatic cancer along a low dose rate brachytherapy needle track. A 64-year-old man was referred to an urologist with an increased PSA of 6.9 ng/mL in December 2008. There were no urinary symptoms. Prostatic biopsies revealed a Gleason 6 adenocarcinoma (3 + 3), and he was treated with low dose rate brachytherapy in May 2009. Sixty-seven seeds of iodine 125 were loaded under ultrasound control, and the PSA subsequently fell to a nadir of 1.19 ng/mL in November 2015. Eight years (May 2017) after the initial treatment, the PSA rose to 5.2 ng/mL. Pelvic MRI and choline PET revealed a nodule in the region of the left internal obturator muscle. Nodule biopsies confirmed prostatic origin. This perineal recurrence is thus most likely related to seeding of tumour cells along the track of a brachytherapy needle. To our knowledge, this is only the fourth case of perineal recurrence of prostatic cancer along a low-dose rate brachytherapy needle track. Perineal recurrence of prostatic cancer along a LDR brachytherapy needle track can occur. Improved imaging techniques may help to identify this type of recurrence earlier and optimise treatment.     

Antioxidant effects and anti-elastase activity of the calcium antagonist nicardipine on activated human and rabbit neutrophils--a potential antiatherosclerotic property of calcium antagonists?

Activated neutrophils which produce certain proteases, such as elastase and reactive oxygen species (ROS) are involved in oxidative stress and inflammation. In the present study, we have shown that nicardipine, a calcium channel blocker, affects the release of elastase and superoxide anion radicals (O₂ ^–) in vitro during human and rabbit neutrophil respiratory bursts. The drug inhibited the release of elastase and O₂ ^– by fMLP (N-formyl-methionylleucin-phenylalaninin), calcium ionophore (A23187) and PMA (phorbol-myristate-acetate)-stimulated human and rabbit neutrophils. Besides the release of elastase, strongly inhibited in the fMLP and A23187 stimulated systems, nicardipine affected elastase and O₂ ^– in a dose-dependent manner. The corresponding 50% inhibitory concentration (IC₅₀) of nicardipine for elastase, released in PMA-stimulated human and rabbit neutrophils, was 15.95 ± 0.17 M and 18.06 ± 0.08 M, respectively, whereas for O₂ ^–, the IC₅₀ of nicardipine in PMA, fMLP and A23187-stimulated human and rabbit neutrophils was 55.41 ± 0.09 M and 58.43 ± 0.03 M, 45.21 ± 0.13 M and 37.19 ± 0.53 M, 33.54 ± 0.09 M and 30.54 ± 0.29, respectively. The mechanisms underlying the inhibition of elastase and superoxide anion radicals by nicardipine appear related to an inhibiting effect on the mobilisation of cytosolic calcium and on activation of protein kinase C (PKC). These antioxidant and anti-elastasic activities contribute to the properties of nicardipine, as positive side effects of its antihypertensive activity and may be useful to prevent inflammatory disorders (tissue damage, oxidative injury) involved in the pathogenesis of hypertension.     

Cytomegalovirus infection in transplant recipients resolves when circulating gammadelta T lymphocytes expand, suggesting a protective antiviral role

gammadelta T cells undergo massive expansion in the peripheral blood of renal transplant recipients who are infected with cytomegalovirus (CMV). In a 3-year prospective study, the relationship between the evolution of CMV infection and the kinetics of gammadelta T cell amplification was followed for 10 months after transplantation. Patients with late gammadelta T cell expansion (>/=45 days) had significantly longer (P<.0001) and higher (P<.0003) pp65 antigenemia and more-symptomatic CMV disease than did patients with early expansion. Analysis of data for each patient showed that gammadelta T cell expansion is concomitant with the resolution of CMV infection and disease, regardless of the CMV serologic status of donor and recipient before transplantation. These observations point to gammadelta T cell percentage determination as a new, rapid, and reliable prognosis factor to predict the resolution of CMV infection and strongly suggest that gammadelta T cells play a protective role against CMV infection.     

In vitro study of frog (Rana ridibunda Pallas) neurointermediate lobe secretion by use of a simplified perifusion system. IV. Interaction between dopamine and thyrotropin-releasing hormone on alpha-melanocyte-stimulating hormone secretion

The interaction between dopamine and TRH on alpha-melanocyte-stimulating hormone (MSH) release from the intermediate lobe of amphibian pituitary has been studied in vitro using the perifusion model. Dopamine (10(-10) to 10(-6) M) was responsible for a dose-related inhibition of alpha-MSH secretion. The inhibitory effect of dopamine (10(-8) and 3.16 X 10(-8) M) was completely abolished in the presence of haloperidol (10(-5) and 10(-6) M, respectively). It has been previously established that, in amphibians, TRH stimulated alpha-MSH release in vitro and that the action of TRH was not mediated via an inhibition of the release of endogenous dopamine (M. C. Tonon, P. Leroux, M. E. Stoeckel, S. Jégou, G. Pelletier, and H. Vaudry, 1986, Endocrinology 112, 133-141). In the present study we demonstrate that TRH (10(-7) M) reverses the inhibitory effect of dopamine (for concentrations ranging from 3.16 X 10(-8) to 10(-6) M) on alpha-MSH secretion and that the effects of TRH and dopamine are additive. Thus, these results indicate that the intracellular events associated with TRH-induced stimulation and dopamine-induced inhibition of alpha-MSH release are not linked together.     

IGHV gene mutational status and LPL/ADAM29 gene expression as clinical outcome predictors in CLL patients in remission following treatment with oral fludarabine plus cyclophosphamide

Several prognostic factors can predict the rapid progression in chronic lymphocytic leukaemia (CLL), including IGHV mutational status, cytogenetic abnormalities and, more recently, LPL/ADAM29 expression. In contrast, few studies have been devoted to the influence of these factors on clinical outcome in responding patients after therapy. We here propose to analyse the impact of IGHV gene status, LPL and ADAM29 gene expression on disease-free survival (DFS) and overall survival (OS) in 41 stage B or C CLL patients in remission after oral fludarabine plus cyclophosphamide. The median follow-up was of 64 (16–74) months. Sequencing of IGHV showed mutated (M) VH genes in 16 of 41 cases and unmutated (UM) in 25 cases. Analysis of LPL and ADAM29 expression in 35 of 41 cases showed overexpression of ADAM29 in 17 cases (14 M and three UM) and LPL in 18 cases (all UM). Patients expressing UM IGHV and LPL had shorter DFS and OS when compared to patients expressing M IGHV and/or ADAM29. Furthermore, blood minimal residual disease (MRD) evaluation using four-colour flow cytometry was performed in 33 out the 41 patients. We showed that patients who achieved phenotypic remission displayed longer DFS than those with MRD⁺. Our results support the use of LPL and ADAM29 gene expression associated to IGHV mutational status for predicting the clinical outcome of patients treated by oral fludarabine + cyclophosphamide and could be considered for treatment strategies.