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P Iversen

Publications and source records attributed to P Iversen.

At least 19 recordsLinked to original sources
PubMed2007

Peptide-based delivery of nucleic acids: design, mechanism of uptake and applications to splice-correcting oligonucleotides.

CPPs (cell-penetrating peptides) have given rise to much interest for the delivery of biomolecules such as peptides, proteins or ONs (oligonucleotides). CPPs and their conjugates were initially thought to translocate through the cell membrane by a non-endocytotic mechanism which has recently been re-evaluated. Basic-amino-acid-rich CPPs first interact with cell-surface proteoglycans before being internalized by endocytosis. Sequestration and degradation in endocytotic vesicles severely limits the cytoplasmic and nuclear delivery of the conjugated biomolecules. Accordingly, splicing correction by CPP-conjugated steric-block ON analogues is inefficient in the absence of endosomolytic agents. New arginine-rich CPPs allowing efficient splicing correction by conjugated PNAs (peptide nucleic acids) or PMO (phosphorodiamidate morpholino oligomer) steric blockers in the absence of endosomolytic agents have recently been defined in our group and are currently being characterized. They offer promising leads for the development of efficient cellular delivery vectors for therapeutic steric-block ON analogues.

Alternative Splicing↗
PubMed2005

Inhibition of infectious haematopoietic necrosis virus in cell cultures with peptide-conjugated morpholino oligomers.

Delivery of phosphorodiamidate morpholino oligomers (PMO) into fish cells in vitro and tissues in vivo was examined. Uptake was evaluated by fluorescence microscopy and flow cytometry after treating cultured cells or live rainbow trout with 3' fluorescein-tagged PMO. Arginine-rich peptide conjugated to the 5' end of the PMO markedly enhanced cellular uptake in culture by 8- to 20-fold compared with non-peptide-conjugated PMO as determined by flow cytometry. Enhanced uptake of PMO conjugated to peptide was also observed in tissues of fish treated by immersion. The efficacy of PMO as inhibitors of infectious haematopoietic necrosis virus (IHNV) replication was determined in vitro. Peptide-conjugated PMOs targeting sequences within the IHNV genomic RNA (negative polarity) or antigenomic RNA (positive polarity) significantly inhibited replication in a dose-dependent and sequence-specific manner. A PMO complementary to sequence near the 5' end of IHNV genomic RNA was the most effective, diminishing titre by 97%, as measured by plaque assay and Western blot. These data demonstrate that replication of a negative-stranded non-segmented RNA virus can be inhibited by antisense compounds that target positive polarity viral RNA, or by a compound that targets negative polarity viral RNA.

Animals↗
PubMed2003

The non-steroidal antiandrogen, bicalutamide ('Casodex'), may preserve bone mineral density as compared with castration: results of a preliminary study.

The impact of bicalutamide (Casodex) monotherapy on bone mineral density (BMD) was investigated in patients with locally advanced prostate cancer. BMD was assessed after treatment with bicalutamide 150 mg daily ( n=21) or by medical castration (goserelin acetate 3.6 mg every 28 days) ( n=8) for a median of 287 weeks. In 38% of castration compared with 17% of bicalutamide patients, femoral neck Z-scores were < or =-1 SD of the reference value (accepted as a two to three times increased risk of fracture) and T-scores were < or =-2.5 SD (World Health Organization definition of osteoporosis in white females). Total hip Z-scores were < or =-1 in 43% of castration patients and 13% of bicalutamide patients. In 38% of patients, lumbar spine BMD was affected by degenerative disease. These preliminary data suggest that there may be an advantage in terms of BMD in using bicalutamide monotherapy compared with castration; a benefit confirmed in a recent prospective randomised study.

Aged↗
PubMed2003

Immediate treatment with bicalutamide 150mg as adjuvant therapy significantly reduces the risk of PSA progression in early prostate cancer.

OBJECTIVE: To evaluate the effect of bicalutamide ('Casodex') 150mg (in addition to standard care), on the risk of prostate-specific antigen (PSA) progression, in patients with early prostate cancer. METHODS: The bicalutamide 150mg Early Prostate Cancer (EPC) programme is the largest clinical trial programme in the treatment of prostate cancer to date. This paper reports the PSA progression data from the EPC programme at a median of 3years' follow-up, for the overall study population, and across the radical prostatectomy and radiotherapy primary therapy strategies. PSA progression was predefined as the earliest occurrence of PSA doubling from baseline, objective progression, or death from any cause. RESULT: Overall, bicalutamide 150 mg in addition to standard care significantly reduced the risk of PSA progression by 59% compared with standard care alone (HR 0.41; 95% CI 0.38, 0.45; p<<0.0001). Significant reductions were observed following radical prostatectomy (51%; HR 0.49; 95% CI 0.43, 0.56; p<<0.0001) and radiotherapy (58%; HR 0.42; 95% CI 0.33, 0.53; p<<0.0001). Further exploration of the data by disease stage, nodal status, Gleason score and pre-treatment PSA level revealed significant reductions in the risk of PSA progression across most prognostic risk factor subgroups. CONCLUSIONS: Bicalutamide 150mg significantly reduces the risk of PSA progression, irrespective of whether patients received radical prostatectomy or radiotherapy as standard care. The EPC programme is ongoing and further progression and survival data are awaited.

Adult↗
PubMed2002

A randomised comparison of bicalutamide ('Casodex') 150 mg versus placebo as immediate therapy either alone or as adjuvant to standard care for early non-metastatic prostate cancer. First report from the Scandinavian Prostatic Cancer Group Study No. 6.

OBJECTIVES: To assess the efficacy and tolerability of bicalutamide 150 mg ('Casodex'(1)) as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with early (T1b-T4, any N, M0) prostate cancer. METHODS: This randomised, double-blind study was conducted in the Nordic countries as part of the 'Casodex' Early Prostate Cancer programme. Patients received bicalutamide 150 mg (n=607) or placebo (n=611) in addition to standard care. RESULTS: More than 80% of patients had not received therapy of primary curative intent. Median follow-up in both groups was 3 years. Median exposure to study treatment in the bicalutamide and standard care alone groups was 2.5 and 2.3 years, respectively. Bicalutamide reduced the risk of objective disease progression by 57% compared with standard care alone (HR 0.43; 95% CI 0.34, 0.55; p<<0.0001). Survival data were immature (11.4% deaths) with no difference between the two treatment groups. CONCLUSIONS: Bicalutamide 150 mg as immediate therapy, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with early prostate cancer. The trial is ongoing to assess whether the reduction in risk of objective progression translates into an overall survival benefit.

Aged↗
PubMed2002

Nicotinic receptor abnormalities in the cerebellar cortex in autism.

Autism is a common developmental disorder associated with structural and inferred neurochemical abnormalities of the brain. Cerebellar abnormalities frequently have been identified, based on neuroimaging or neuropathology. Recently, the cholinergic neurotransmitter system has been implicated on the basis of nicotinic receptor loss in the cerebral cortex. Cerebellar cholinergic activities were therefore investigated in autopsy tissue from a series of autistic individuals. The presynaptic cholinergic enzyme, choline acetyltransferase, together with nicotinic and muscarinic receptor subtypes were compared in the cerebellum from age-matched mentally retarded autistic (eight), normal control (10) and non-autistic mentally retarded individuals (11). The nicotinic receptor binding the agonist epibatidine (the high affinity receptor subtype, consisting primarily of alpha3 and alpha4, together with beta2 receptor subunits) was significantly reduced by 40-50% in the granule cell, Purkinje and molecular layers in the autistic compared with the normal group (P < 0.05). There was an opposite increase (3-fold) in the nicotinic receptor binding alpha-bungarotoxin (to the alpha7 subunit) which reached significance in the granule cell layer (P < 0.05). These receptor changes were paralleled by a significant reduction (P < 0.05) and non-significant increase, respectively, of alpha4 and alpha7 receptor subunit immunoreactivity measured using western blotting. Immunohistochemically loss of alpha(4 )reactivity was apparent from Purkinje and the other cell layers, with increased alpha7 reactivity in the granule cell layer. There were no significant changes in choline acetyltransferase activity, or in muscarinic M1 and M2 receptor subtypes in autism. In the non-autistic mentally retarded group, the only significant abnormality was a reduction in epibatidine binding in the granule cell and Purkinje layers. In two autistic cases examined histologically, Purkinje cell loss was observed in multiple lobules throughout the vermis and hemispheres. This was more severe in one case with epilepsy, which also showed vermis folial malformation. The case with less severe Purkinje cell loss also showed cerebellar white matter thinning and demyelination. These findings indicate a loss of the cerebellar nicotinic alpha4 receptor subunit in autism which may relate to the loss of Purkinje cells, and a compensatory increase in the alpha7 subunit. It remains to be determined how these receptor abnormalities are involved in neurodevelopment in autism and what is the relationship to mental function. Since nicotinic receptor agonists enhance attentional function and also induce an elevation in the high affinity receptor, nicotinic therapy in autism may be worth considering.

Adult↗
PubMed2001

[Radical prostatectomy. The first 50 consecutive patients undergoing surgery at Rigshospitalet].

INTRODUCTION: Radical prostatectomy has not been performed in Denmark until recently. In this paper, we report the results of the first patients undergoing a radical retropubic prostatectomy at Rigshospitalet. MATERIAL AND METHODS: Fifty consecutive patients, aged 47-68, median 59 years underwent radical prostatectomy. Ninety percent of the patients received three months of neoadjuvant endocrine therapy. RESULTS: Histopathology showed that 78% had organ-confined disease. During a median follow-up of 370 days, 11 patients (22%) developed biochemical failure, defined as a PSA value above 0.1 ng/ml. Although the number of patients is small and the follow-up limited, we confirmed correlations between preoperative characteristics and the risk of extraprostatic extension at tumour and biochemical progression. Surgery was performed without major complications. Erectile dysfunction was reported by 88%, whereas complete urinary continence was achieved in 90% of the patients.

Aged↗
PubMed2001

[Morbidity among patients with clinically localized prostatic cancer. A registry-based case-control study].

INTRODUCTION: Until recently, expectant management of localised prostate cancer was the routine strategy in Denmark. MATERIAL AND METHODS: In a historical, prospective, case-control study, morbidity in 4744 patients, aged 74 years or younger, with newly diagnosed clinically localised prostate cancer, was compared to that in an age-matched background population. RESULTS: Patients with clinically localised prostate cancer were found to have significant excess morbidity compared to the background population. Patients were admitted 6.7 times more often than the controls in the year prostate cancer was diagnosed and 2.7 times more often in the nine years following the diagnosis. When adjusted for prostate cancer-related admissions, morbidity approximates unity. Costs associated with the hospital care of patients with prostate cancer significantly exceeded the costs in the control group. DISCUSSION: The study demonstrates that patients with newly diagnosed, clinically localised prostate cancer have a significant morbidity associated to their primary malignancy. Further, these patients were found to have a significant excess morbidity compared to age-matched controls. The possibility of reducing morbidity and associated costs is discussed.

Aged↗
PubMed2001

Autonomic responses of autistic children to people and objects.

Several recent lines of inquiry have pointed to the amygdala as a potential lesion site in autism. Because one function of the amygdala may be to produce autonomic arousal at the sight of a significant face, we compared the responses of autistic children to their mothers' face and to a plain paper cup. Unlike normals, the autistic children as a whole did not show a larger response to the person than to the cup. We also monitored sympathetic activity in autistic children as they engaged in a wide range of everyday behaviours. The children tended to use self-stimulation activities in order to calm hyper-responsive activity of the sympathetic ('fight or flight') branch of the autonomic nervous system. A small percentage of our autistic subjects had hyporesponsive sympathetic activity, with essentially no electrodermal responses except to self-injurious behaviour. We sketch a hypothesis about autism according to which autistic children use overt behaviour in order to control a malfunctioning autonomic nervous system and suggest that they have learned to avoid using certain processing areas in the temporal lobes.

Adolescent↗
PubMed2001

A genomewide screen for autism susceptibility loci.

We report the analysis of 335 microsatellite markers genotyped in 110 multiplex families with autism. All families include at least two "affected" siblings, at least one of whom has autism; the remaining affected sibs carry diagnoses of either Asperger syndrome or pervasive developmental disorder. Affected sib-pair analysis yielded multipoint maximum LOD scores (MLS) that reach the accepted threshold for suggestive linkage on chromosomes 5, X, and 19. Nominal evidence for linkage (point-wise P<.05) was obtained on chromosomes 2, 3, 4, 8, 10, 11, 12, 15, 16, 18, and 20, and secondary loci were found on chromosomes 5 and 19. Analysis of families sharing alleles at the putative X chromosomal linked locus and one or more other putative linked loci produced an MLS of 3.56 for the DXS470-D19S174 marker combination. In an effort to increase power to detect linkage, scan statistics were used to evaluate the significance of peak LOD scores based on statistical evidence at adjacent marker loci. This analysis yielded impressive evidence for linkage to autism and autism-spectrum disorders with significant genomewide P values <.05 for markers on chromosomes 5 and 8 and with suggestive linkage evidence for a marker on chromosome 19.

Asperger Syndrome↗
PubMed2001

Local delivery of c-myc neutrally charged antisense oligonucleotides with transport catheter inhibits myointimal hyperplasia and positively affects vascular remodeling in the rabbit balloon injury model.

Myointimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA) is a key component of the process of restenosis. The c-myc is a critical cell-cycle division protein involved in the formation of neointima. We evaluated the long-term impact of local delivery of c-myc neutrally charged antisense oligonucleotides (Resten-NG) on myointimal hyperplasia after PTCA in a rabbit model. PTCA was performed in the iliac arteries of 25 New Zealand white rabbits, using a Transport catheter at 8 atm for 30 sec, three times; 500 microg Resten-NG (n = 11) or saline (n = 14) was delivered to the PTCA site at 2 atm with the outer balloon for 2 min. The diet was supplemented with 0.25% cholesterol for 10 days before and 60 days after PTCA. Angiography was performed at harvest, and vessels were fixed in formalin, processed, and stained with hematoxylin and eosin (H&E) and Movat. Quantitative angiography showed that local delivery of antisense c-myc at PTCA reduced late luminal loss from 1.8 +/- 0.30 mm in control animals to 0.90 +/- 0.30 mm in the treatment group (P = 0.001). Histological analysis by planimetry showed that intimal areas were 1.67 +/- 0.44 mm(2) and 0.82 +/- 0.32 mm(2) in the control and antisense delivery groups, respectively (P < 0.05). We conclude that local delivery of Resten-NG inhibited myointimal hyperplasia after PTCA in cholesterol-fed rabbits for up to 60 days.

Angioplasty, Balloon, Coronary↗
PubMed2001

Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer.

Nonsteroidal antiandrogens are generally used in conjunction with castration as combined androgen blockade. However, the changing profile of patients with prostate cancer has made monotherapy with a nonsteroidal antiandrogen an attractive alternative therapeutic approach, offering potential quality-of-life benefits over conventional treatment modalities. Of available antiandrogens, monotherapy with bicalutamide has been most extensively evaluated. Combined data from 2 studies at a median follow-up time of 6.3 years revealed no statistically significant difference in overall survival between bicalutamide 150-mg monotherapy and castration in patients with nonmetastatic locally advanced disease. In patients with metastatic disease, there was a statistically significant difference (6 weeks) in overall survival in favor of castration. Bicalutamide monotherapy is associated with significant quality-of-life benefits (sexual interest and physical capacity), with preliminary data suggesting that the risk of osteoporosis may also be reduced by bicalutamide 150-mg monotherapy compared with castration. In general, bicalutamide is well tolerated, with a predictable adverse-effect profile. Breast pain (40%) and gynecomastia (49%) are the most common adverse events seen during monotherapy with this drug. In summary, the availability of bicalutamide 150-mg monotherapy broadens treatment options for men with locally advanced prostate cancer, offering a viable and attractive alternative to castration in this patient population. Ongoing studies will determine the role of bicalutamide in the treatment of localized disease.

Androgen Antagonists↗
PubMed2001

Inhibition of carotid artery neointimal formation with intravenous microbubbles.

Because therapeutic gene products such as synthetic antisense oligodeoxynucleotides (ODN) bind to albumin-coated microbubbles, we sought to determine whether IV perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles could target their delivery to the carotid artery following balloon injury. In 5 pigs, the concentration of ODN taken up within the carotid vascular wall was found to be significantly increased when the IV antisense (ODN) was administered bound to PESDA (ODN-PESDA), and while transcutaneous low-frequency (20 kHz) ultrasound was applied over the carotid artery. Based on these results, a chronic model was then developed, in which 21 pigs received either IV ODN-PESDA, ODN alone, or control, following carotid balloon injury. At 30 days following balloon injury, percent area stenosis was only 8 +/- 2% in the ODN-PESDA groups compared to 19 +/- 8% and 28 +/- 3% in the other groups (p < 0.01). IV PESDA may be a method of noninvasively targeting the delivery of therapeutic genes.

Animals↗
PubMed2001

The bicalutamide Early Prostate Cancer Program. Demography.

BACKGROUND: The optimal treatment for early prostate cancer has yet to be established. A well-tolerated hormonal therapy such as bicalutamide could be a useful treatment option in this setting, either as adjuvant or immediate therapy. A major collaborative clinical trials program was set up to investigate bicalutamide as a treatment option for local prostate cancer (localized or locally advanced disease). METHODS: The bicalutamide Early Prostate Cancer program comprises three randomized, double-blind, placebo-controlled trials of similar design that are being conducted in distinct geographical areas (North America; Australia, Europe, Israel, South Africa and Mexico; and Scandinavia). Men with T1b-4N0-1M0 (TNM 1997) prostate cancer have been randomized on a 1:1 basis to receive bicalutamide 150 mg daily or placebo. Recruitment to the program closed in July 1998, and follow-up is ongoing. Study endpoints include time to clinical progression, overall survival and tolerability. RESULTS: 8113 men aged 38 to 93 years (mean 66.9) were randomized over a 3-year period. 67.4% of the enrolled patients had localized disease (T1-2) and 66.4% had a Gleason score </=6 at study entry, while the majority of patients had node-negative (N0) disease; only 3.1% in two of the studies and none in the third study had confirmed N+ disease. Overall, 71.8% of the patients received therapy of primary curative intent within 16 weeks of randomization; the remainder received watchful waiting as their primary approach. Across the program, the two randomized groups are well balanced. CONCLUSION: This is the largest randomized clinical trial program to date in local prostate cancer and is expected to provide critical information on the role of bicalutamide as an addition to standard care for patients with local prostate cancer who have received a therapy of curative intent or are candidates for watchful waiting.

Journal Article↗
PubMed2001

Is there a role for antiandrogen monotherapy in patients with metastatic prostate cancer?

Castration is the most widely used form of androgen ablation employed in the treatment of metastatic (M1) prostate cancer. Non-steroidal antiandrogen monotherapy is a potential alternative treatment option for men for whom castration is unacceptable or not indicated. Of the three non-steroidal antiandrogens, bicalutamide ('Casodex'), flutamide and nilutamide, only bicalutamide has been compared with castration in large, controlled, randomised, Phase III trials in M1 patients. A post-hoc analysis of these studies indicated that bicalutamide 150 mg/day monotherapy may be of benefit to M1 patients with a prostate specific antigen (PSA) level </=400 ng/ml. Significant advantages for M1 patients treated with bicalutamide were observed in subjective response rate, maintenance of sexual interest and physical capacity. Patients with a higher disease burden (PSA >400 ng/ml) may decide that quality of life and symptomatic benefits outweigh the slight survival disadvantage seen in clinical trials and opt for bicalutamide monotherapy as an alternative to castration.Prostate Cancer and Prostatic Diseases (2001) 4, 196-203.

Journal Article↗