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Biomedical subjects

P Neven

Publications and source records attributed to P Neven.

At least 55 records · Page 3Linked to original sources
PubMed1997

Study of the influence of both cyclodextrins and L-lysine on the aqueous solubility of nimesulide; isolation and characterization of nimesulide-L-lysine-cyclodextrin complexes.

Nimesulide is a nonsteroidal antiinflammatory drug that exhibits a very poor water solubility (0.01 mg.mL-1). A nimesulide-beta-cyclodextrin complex prepared according to patent application WO 94/ 02177 has an aqueous solubility of approximately 16 mg.mL-1 of nimesulide. A nimesulide-L-lysine salt has also been prepared and increases the aqueous solubility of nimesulide to approximately 5.0-7.5 mg.mL-1. The purpose of the present study was to investigate the interaction of both cyclodextrins and L-lysine on the aqueous solubility of nimesulide. Nimesulide-L-lysine-beta- or gamma-cyclodextrin complexes were prepared by spray-drying. The inclusion of the nimesulide-L-lysine salt into the cyclodextrin cavity was confirmed by differential scanning calorimetry and proton nuclear magnetic resonance spectroscopy. These complexes offered remarkable aqueous solubility. The incorporation of nimesulide in a nimesulide-L-lysine-beta-cyclodextrin complex increased its water solubility by a factor of 10 at pH 1.5 (0.050 mg.mL-1 for the complex versus 0.005 mg.mL-1 for nimesulide), 160 at pH 6.8 (2.373 mg.mL-1 for the complex versus 0.015 mg.mL-1 for nimesulide), and 3600 in purified water (36.400 mg.mL-1 for the complex versus 0.01 mg.mL-1 for nimesulide).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Synthesis and biological evaluation of new 3-aralkylamino-2-aryl-2H-1, 2,4-pyridothiadiazine 1,1-dioxides as potential CCK-receptor ligands.

A series of 2-aralkyl-4H-pyridothiadiazine 1,1-dioxides and 3-aralkylamino-2-aryl-2H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides structurally related to quinazolinone CCK receptor antagonists were synthesized and evaluated as CCK-A and CCK-B receptor ligands. The compounds were effective as cholecystokinin-ligands in the micromolar range of concentration, c.f. the cholecystokinin receptor antagonists asperlicin, lorglumide or benzotript, and were thus less potent than the best quinazolinones previously reported. Although the compounds were unsuitable for drug use, the work contributed to our understanding of the chemistry of unusual 2,3-disubstituted pyridothiadiazinedioxides.

Binding, Competitive↗
PubMed1996

Lack of genotoxicity of tamoxifen in human endometrium.

The potential for the anti-breast cancer drug tamoxifen [(Z)-1-[4-[2-( dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-butene] to induce genotoxic damage (DNA adducts) in the human endometrium was investigated in vivo and in vitro. Endometria from hysterectomy patients who were not on tamoxifen were sectioned and maintained in short-term organ culture. The cultures were treated with either solvent vehicle (DMSO), tamoxifen, alpha-hydroxytamoxifen [(E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-buten-3- ol; the major DNA-reactive metabolite in the rat], or benzo(a)pyrene. DNA was isolated and analyzed by 32P postlabeling. Chromatography on polyethyleneimine-cellulose TLC plates revealed DNA adducts in endometria treated with alpha-hydroxytamoxifen identical to those seen previously in the rat liver. However, no adducts were seen from treatment with tamoxifen itself. The viability of the enzyme-metabolizing systems of the endometrial samples was demonstrated by the detection of expected DNA adducts induced by benzo(a)pyrene. Examination by liquid chromatography-mass spectrometry of the explant culture media from endometria treated with tamoxifen revealed the presence of the alpha-hydroxy metabolite in a dose-dependent manner, although apparently at levels insufficient to produce detectable DNA adducts. Endometrial DNA obtained from 18 patients undergoing daily treatment with 10-40 mg tamoxifen for 3 months-9 years was also analyzed. No evidence for any DNA adducts induced by tamoxifen was found in any of the patients examined. These data suggest that the genotoxic events observed with tamoxifen in the rat may not apply to the human endometrium.

Adult↗
PubMed1996

A realistic clinical perspective of tamoxifen and endometrial carcinogenesis.

Tamoxifen has been the endocrine treatment of choice for all stages of breast cancer for nearly a decade. Millions of women are currently receiving tamoxifen worldwide, while large-scale randomised trials have been launched aiming to investigate the drug's merit as a preventive agent. However, there are now concerns about tamoxifen's potential carcinogenicity. The goal of this review is to address these concerns, re-evaluate the available data from laboratory biological models and those from clinical reports and put the whole issue into perspective. Our focus is the association between tamoxifen and the increased frequency of endometrial tumours, while key issues, such as the role of duration of tamoxifen therapy, are also addressed. Finally, we discuss the various monitoring strategies for early detection of endometrial lesions and pertinent problems most likely to be encountered by clinicians taking care of patients who are receiving tamoxifen.

Animals↗
PubMed1995

Measurement of urinary beta core fragment of human chorionic gonadotrophin in women with vulvovaginal malignancy and its prognostic significance.

Tumours of the vulva and vagina are rare and there are relatively few studies of circulating markers in these conditions. The urinary measurement of the core fragment of the beta-subunit of hCG has been proposed as a useful tumour marker in non-trophoblastic gynaecological malignancies. This study describe the measurement of urinary beta-core in 50 patients with vulvovaginal malignancy. In contrast to other studies corrections were made for both the effect of urine concentration and the age of the patient. Each patient was followed up for at least 24 months, and at this time their status was correlated with their initial level of urinary beta-core. The sensitivity of beta-core was only 38%, but of those patients with elevated levels 90% had died within 24 months, while only 32% of those with normal levels had died. For both patients at initial presentation and those with recurrent disease, there was a highly significant difference in the survival curve between those with elevated beta-core levels and those with normal levels. This is similar to findings in cervical carcinoma, and suggests that for lower genital tract cancer the measurement of urinary beta-core may be valuable as a prognostic indicator, allowing a more informed approach to treatment and follow-up.

Adult↗
PubMed1994

The prognostic significance of urinary beta core fragment in premenopausal women with carcinoma of the cervix.

The mortality of premenopausal women with cervical carcinoma has increased in recent decades despite attempts to provide screening. The urinary concentration of the beta core fragment of hCG has been proposed as a sensitive marker in gynecological malignancies, although most studies have not corrected for urine concentration. We measured the urinary concentration of beta core and creatinine in 61 women who developed cervical cancer premenopausally and expressed the concentration of beta core per millimole of creatinine using the 90th percentile of a control group as a cutoff level. While correcting for urinary concentration results in a reduction in sensitivity of the test (67 to 51%), there is improved correlation with prognosis in that after 18 months 81% of women positive for beta core had died, while 80% of women negative for beta core were still alive. Of those initially presenting and dying there was an increase with increasing stage of disease. For patients with initial presentation disease, 11 (79%) of the 14 patients with elevated levels had died compared with 1 of 21 (5%) who were negative for beta core. Urinary beta core fragment may have a major role as a prognostic indicator in cervical carcinoma rather than as a screening or diagnostic marker and enables identification of patients at higher risk of an aggressive disease.

Biomarkers, Tumor↗
PubMed1993

Urinary chorionic gonadotropin subunits and beta-core in nonpregnant women. A study of benign and malignant gynecologic disorders.

BACKGROUND: The presence of urinary excretion products of human chorionic gonadotropin (hCG) has been proposed as a tumor marker. To ascertain the clinical value in gynecologic cancers, the authors studied 612 nonpregnant women. METHODS: Three different assays in four clinical groups were compared: no disease, benign disease, malignant disease, and complete remission of previously treated malignant disease. The assays were for the urinary beta-core, "total" beta-hCG, and free alpha-subunit. RESULTS: Measurement of the alpha-subunit was of no obvious clinical value. In some patients with benign disease, hCG metabolites were elevated. In the 141 patients with active gynecologic malignancy the sensitivity of the total beta-hCG assay was 47% and that of the beta-core assay was 36%. The specificities were 80.3% and 90.4%, respectively. Advanced cancers generally had higher levels of total beta-hCG and beta-core. Squamous cell and poorly differentiated cervical tumors had higher levels of total beta-hCG than did adenocarcinomas and well-differentiated cervical tumors. Invasive, serous, endometrioid, and germ cell ovarian tumors had higher total beta-hCG, beta-core, and alpha-subunit levels than did borderline, mucinous, and clear cell ovarian tumors. Six of 16 patients with disease in complete remission had elevated levels. CONCLUSION: The excretion of hCG and its metabolic fragments is a common event in gynecologic cancer, but sensitivity and specificity are low, and there is little consistent relationship between tumor stage and histologic type.

Adenocarcinoma↗
PubMed1993

Reconstruction of the abdominal wall with a latissimus dorsi musculocutaneous flap: a case of a massive abdominal wall metastasis from a cervical cancer requiring palliative resection.

A 49-year-old woman presented with a huge abdominal mass. At laparotomy, a 36-cm diameter semisolid, semicystic mass from the abdominal wall was removed. The peritoneal defect was covered by a mesh and a free latissimus dorsi myocutaneous flap. Histology showed a poorly differentiated squamous cell carcinoma consistent with metastatic tumor from a cervical primary. Surgery has a finite palliative role to extirpate a tumor mass of this size if reconstruction and some form of closure can be achieved.

Abdominal Muscles↗
PubMed1993

The measurement of urinary beta core fragment in conjunction with serum CA125 does not aid the differentiation of malignant from benign pelvic masses.

The urinary concentration of the renal metabolite of the beta subunit of human chorionic gonadotropin (beta core) has been proposed as a tumor marker in certain nontrophoblastic malignancies including those of the female genital tract. A previous study investigated the use of urinary beta core in conjunction with serum CA125 in distinguishing malignant from benign pelvic masses and showed that the combined test improved the overall sensitivity to 88%; this was greater than that for either test alone. However, the cutoff levels used to distinguish normal from abnormal were approximately six times greater than those generally used for CA125 and four to five times lower than those used for beta core in our laboratory. Furthermore there was no recognition of the possible difference in normal levels of beta core between pre- and postmenopausal women. We have examined a similar group of cases using our cutoff levels for urinary beta core of 0.36 ng/ml in premenopausal women and 0.48 ng/ml in postmenopausal women and 35 u/ml for CA125. We show that measurement of CA125 is substantially more sensitive that that of beta core and that the combination of beta core with CA125 does not improve the overall sensitivity of the test. However, there was a small improvement in positive predictive value if both tests were positive (97.5%) and of specificity when one or the other test was negative (98.5%).

Adult↗