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Biomedical subjects

P Iversen

Publications and source records attributed to P Iversen.

At least 73 records · Page 4Linked to original sources
PubMed1995

Cholesteryl-conjugated phosphorothioate oligodeoxynucleotides modulate CYP2B1 expression in vivo.

5' cholesteryl-conjugated phosphorothioate oligodeoxynucleotides with sequence complementary to the rat CYP2B1 mRNA were evaluated in adult male Sprague-Dawley rats for their pharmacokinetic properties, toxicity, and ability to modulate CYP2B1 expression in vivo. Following intraperitoneal administration of 35S-labelled oligodeoxynucleotides, volume of distribution for the phosphorothioate was 0.33 l/kg while the 5' cholesteryl-conjugate oligodeoxynucleotide was 0.12 l/kg. The elimination half-life was 23.2 and 55.4 hrs for cholesteryl-modified and unmodified oligodeoxynucleotides, respectively. Cholesteryl-conjugate oligodeoxynucleotide toxicity was detected at a dose of 1.0 mg/kg and consisted primarily of midzonal liver cell enlargement and increased total RNA. Hexobarbital sleep times, a measure of CYP2B1 enzyme activity in vivo, increased from 21.9 minutes in saline-treated animals to 29.5 minutes in cholesterol oligodeoxynucleotide-treated animals. A significant decrease in liver microsomal pentoxyresorufin O-dealkylase enzyme activity, a CYP2B1/2 specific assay, was observed but not a change in p-nitrophenol hydroxylase activity, a specific CYP2E1 assay. These data indicate that in vivo modulation of the CYP2B1 gene can be accomplished with synthetic phosphorothioate oligodeoxynucleotides in a sequence-specific manner. Further, cholesteryl conjugation to the 5' end of the oligodeoxynucleotide enhanced potency despite lesser bioavailability.

Animals↗
PubMed1995

Radical prostatectomy versus expectant treatment for early carcinoma of the prostate. Twenty-three year follow-up of a prospective randomized study.

In a study by the Veterans Administration Cooperative Urological Research Group (VACURG), 142 patients with localized prostate cancer, VACURG stage I and II, were randomized between radical prostatectomy plus placebo versus placebo alone as initial treatment. 111 patients were evaluable for treatment comparison. Median follow-up for survival is 23 years. The prognostic value of Gleason histologic grading was confirmed. A difference in overall survival in favor of radical prostatectomy was observed in stage I patients. However, after adjustment for imbalance in age distribution, no statistically significant differences in survival could be demonstrated in either stage or in both stages combined. The results are discussed considering the small sample size and the limited statistical power of the study.

Adenocarcinoma↗
PubMed1994

Suppression of Philadelphia1 leukemia cell growth in mice by BCR-ABL antisense oligodeoxynucleotide.

When injected into SCID mice, the Philadelphia chromosome-positive chronic myeloid leukemia-blast crisis cell line BV173 induces a disease process closely resembling that seen in leukemia patients. At 1 and 3 weeks after injection of 10(6) BV173 cells, CD10+ cells were detected in the bone marrow of the mice, leukemic colonies grew from bone marrow and spleen cell suspensions, and BCR-ABL transcripts were detectable in bone marrow, spleen, peripheral blood, liver, and lungs. Systemic treatment of the leukemic mice with a 26-mer BCR-ABL antisense oligodeoxynucleotide (1 mg/day for 9 days) induced disappearance of CD10+ and clonogenic leukemic cells and a marked decrease in BCR-ABL mRNA in mouse tissues. Untreated mice or mice treated with a BCR-ABL sense oligodeoxynucleotide or a 6-base-mismatched antisense oligodeoxynucleotide oligodeoxynucleotide were dead 8-13 weeks after leukemia cell injection; in marked contrast, mice treated with BCR-ABL antisense oligodeoxynucleotide died of leukemia 18-23 weeks after injection of leukemic cells. These findings provide evidence for the in vivo effectiveness of an anticancer therapy based on antisense oligodeoxynucleotides targeting a tumor-specific gene.

Animals↗
PubMed1994

Involvement of cytochrome P450 2E1-like isoform in the activation of N-nitrosobis(2-oxopropyl)amine in the rat nasal mucosa.

Induction of tumours in the nasal olfactory region of MRC rats by N-nitrosobis(2-oxopropyl)amine (BOP) is inhibited by orchiectomy and restored by testosterone. These results suggest the involvement of a sex-specific enzyme in BOP bioactivation in rat nasal mucosa. The present study was undertaken to identify this enzyme. Enzyme-linked immunosorbent assay (ELISA) and the metabolism of known substrates (p-nitrophenol) pointed to a microsomal cytochrome P450 (P450) 2E1-like isoform as a candidate enzyme. A correlation was found between the enzyme activity in nasal mucosal microsomes and serum testosterone levels. Four times more activity was detected in the nasal mucosa than in the liver of male rats. Vanillin inhibited the activity of the nasal mucosal enzyme to a greater extent than that of the liver enzyme. The overall results suggest that a nasal mucosal P450 2E1-like isoform is involved in BOP metabolism.

Animals↗
PubMed1994

Working capacity and expression of myosin heavy chain isoforms in skeletal muscle of chronic alcoholic men without liver disease after 1 day and 4 weeks of alcohol abstinence.

1. The aim of this study was to examine the effect of chronic alcohol ingestion on working capacity and on the expression of myosin heavy chain isoforms in fibre types of human skeletal muscle. 2. Six alcoholic men having drunk more than 240 g of alcohol/day for more than 10 years underwent a test for working capacity and a muscle biopsy on the first day of alcohol abstinence (test 1) and again after 4 weeks of abstinence (test 2). The biopsies were analysed using histochemical, immunochemical and gel-electrophoretic techniques, and the results were compared with those from eight age-matched non-alcoholic control subjects. 3. The area of type IIB muscle fibres was decreased by 33% in the alcoholic patients compared with normal control subjects at both test 1 and test 2. The area of type IIA fibres was lower (13%) in alcoholic patients at test 1 than in the control group, and increased to the normal level at test 2. 4. The relative proportion of fibres expressing only myosin heavy chain type IIB isoforms was one-third of normal in the alcoholic patients at both tests 1 and 2. The relative proportion of fibres expressing only myosin heavy chain type IIA isoforms was the same in alcoholic patients at test 1 and in normal control subjects, but increased by 25% between test 1 and 2 in the alcoholic group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Update of monotherapy trials with the new anti-androgen, Casodex (ICI 176,334). International Casodex Investigators.

Casodex (ICI 176,334) is a non-steroidal anti-androgen, which has a half-life compatible with once-daily oral dosing. In an open, phase II study on 267 patients given Casodex, 50 mg/day, an overall objective response (i.e. partial regression) was seen in 55.5% of patients (146 of 263) with a further 15.6% (41 of 263) having stable disease. Two of three randomized, phase III studies conducted with Casodex, 50 mg/day, showed it to be inferior to castration (either medical or surgical) on time to treatment failure and time to progression. A subsequent overview analysis of survival from these three studies showed a statistically significant difference in favour of castration. Prostate specific antigen (PSA) at 3 months correlated well with clinical outcome in the phase III studies of Casodex, 50 mg/day; a greater fall in PSA at 3 months was observed with Casodex, 100 and 150 mg/day, in an open dose-ranging study. As no significant tolerability issues were reported, further investigation of Casodex at these higher doses is in progress. All studies in which Casodex has been investigated have shown it to be a well-tolerated anti-androgen with a good side-effect profile compared with those reported for other available non-steroidal anti-androgens.

Aged↗
PubMed1994

Serum testosterone as a prognostic factor in patients with advanced prostatic carcinoma.

In 245 patients with previously untreated advanced carcinoma of the prostate, serum concentrations of testosterone have been measured before androgen deprivation therapy, and patients were divided in quartiles according to their serum concentration. Pretreatment level of serum testosterone was confirmed as having significant prognostic value on progression-free, overall, and cancer-specific survival, and the hazard ratios of lower quartiles compared to the upper quartile for these endpoints were 2.3, 2.1, and 2.0, respectively. However, correlations with symptomatology and other pretreatment parameters suggest that low serum testosterone merely is a consequence of the advanced malignancy rather than a causative factor in the pathogenesis of prostatic cancer.

Aged↗
PubMed1993

Comparability of prostate trials.

The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type of antiandrogen (flutamide, Anandron, or cyproterone acetate) added to castration. This paper reviews the different types of heterogeneity that might exist among trials that are involved in the overview: study design, randomization procedure, treatment evaluation, statistical evaluation, and data maturity. In order to overcome these various types of heterogeneity and to compare like with like, the treatment comparison should be stratified a posteriori by question (i.e., type of castration or type of anti-androgen studied) and by study. In this way, one may draw valid conclusions. Of course, those trials with a larger number of patients and a longer follow-up will contribute more to the overview's results.

Androgen Antagonists↗
PubMed1993

Long-term results of Danish Prostatic Cancer Group trial 86. Goserelin acetate plus flutamide versus orchiectomy in advanced prostate cancer.

In a multicenter trial conducted by the Danish Prostatic Cancer Group, 264 patients with advanced prostate cancer were randomized either to undergo bilateral orchiectomy or to receive combination treatment with goserelin acetate and flutamide. This report is an update of that study, covering a median follow-up for survival of 57 months. Of 262 patients who were evaluated, 208 have died. As noted in earlier analyses of this study, no differences in time to progression and cause-specific and overall survival could be identified between the two treatment groups. In conclusion, the combination of goserelin and flutamide was not clinically superior to bilateral orchiectomy in the treatment of advanced prostate cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

An FPLC method for determination of calpains and calpastatin in porcine m longissimus dorsi.

Using a rapid FPLC procedure for the separation of calpain I, calpain II and the inhibitor calpastatin from pork meat, results of proteolytic and inhibitory activity were obtained. Duplicate measurements showed variation coefficients less than 0.13. Compared to others we found lower calpain I activity 1 h post-mortem. Three groups of pigs were randomly selected. One group was exposed to work immediately before slaughter, another group was exposed to work but allowed 30 min rest before slaughter, while the third group was a control group. Samples were taken from m longissimus dorsi 1 h and 6 h post-mortem. Work had no influence on the calpain/calpastatin activity, but a significant decrease in the calpain and calpastatin activity 6 h post-mortem was found. It should be noted that the results are preliminary and are part of an ongoing study. The method described allows separation of three extracts per instrument per day followed by activity determinations of calpains and calpastatin by the casein assay.

Animals↗
PubMed1993

Extraperitoneal pelvioscopy in staging of bladder carcinoma and detection of pelvic lymph node metastasis.

This study was carried out to examine the efficacy of extraperitoneal pelvioscopy in detecting pelvic metastasis in patients scheduled to undergo radical cystectomy without preoperative chemo- or radiotherapy. The results of pelvioscopy were compared with those obtained by laparotomy. 54 consecutive patients underwent pelvioscopy without complications. Three were technically insufficient. Lymphatic tissue was biopsied in 29 (54%). Pelvioscopy demonstrated tumor dissemination in 5 patients (9.3%): 2 had pT4b tumor, 2 pelvic nodal metastases and 1 both. The remaining 49 patients with benign pelvioscopy were scheduled for laparotomy but 7 patients did not undergo the procedure: 3 had extrapelvic metastasis, 1 bronchial carcinoma, 1 aortic aneurysm, 1 refused surgery and 1 had pulmonary insufficiency. Accordingly, 42 patients underwent open exploration which demonstrated pelvic metastasis in 11: 9 had nodal metastasis, 1 a pT4b tumor and 1 both. Consequently the sensitivity of pelvioscopy in detecting pelvic metastasis was calculated at only 31%. This result indicates that extraperitoneal pelvioscopy should be considered a screening procedure rather than an accurate staging procedure for pelvic metastasis.

Adult↗
PubMed1992

Local staging of prostate cancer with transrectal ultrasound: a literature review.

A literature review was undertaken to investigate whether transrectal ultrasound can predict the local stage of prostate cancer. Twelve papers were found which correlated ultrasound findings with surgical findings and another paper reported on strategic staging biopsies guided by transrectal ultrasound. Eleven of these papers reported on ultrasound findings in patients in whom digital rectal examination had defined localized disease. One paper compared ultrasound findings and digital rectal findings. One paper indicated that transrectal ultrasound, though not suited to patients with clinically localized disease defined by digital rectal examination, may be superior as the initial staging tool. We conclude that transrectal ultrasound has too low a specificity to upgrade the diagnostic results of digital rectal examination, but that it may be more useful as the primary staging tool and for guidance in strategic staging biopsies.

Humans↗
PubMed1991

Screening for prostatic cancer. Investigational models.

Prostatic cancer has a long natural history and a significant preclinical period, during which the disease is detectable. Thus, this common malignancy in males fulfills some of the most important criteria for initiating screening programs. However, the still enigmatic epidemiology also includes features of the disease, which make the possible gain from screening programs questionable. Thus, before embarking on expensive community or national screening programs, the beneficial effect of such an effort on morbidity and mortality must be demonstrated in large-scale trials comparing a screened population with non-screened controls. In this paper, some of the problems associated with such studies are addressed.

Humans↗