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Papers by Titti Niskanen

$Research paper thumbnail of Data from A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma$

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics,... more Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients.Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses.Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505′s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 1...

BACKGROUND: TB-403 (RO 5323441), a humanised monoclonal antibody, is a novel antiangiogenesis age... more BACKGROUND: TB-403 (RO 5323441), a humanised monoclonal antibody, is a novel antiangiogenesis agent directed against placental growth factor. The safety, pharmacokinetics (PK), and antitumour activity of TB-403 were assessed in a phase I, dose-escalation study in patients with advanced solid tumours. METHODS: Patients in sequential dose groups received either weekly doses of 1.25, 5.0, or 10 mg kg À1 or doses of 20 or 30 mg kg À1 every third week. RESULTS: Twenty-three patients were enrolled and received TB-403. The most common adverse events (AEs) were fatigue, constipation, pyrexia, dyspnoea, and nausea. One serious AE, a lung embolus in a patient with non-small cell lung cancer treated with 10 mg kg À1 weekly, was deemed possibly related to TB-403. No dose-limiting toxicities were observed, and a maximum-tolerated dose was not reached. The PK parameters were dose linear and the terminal half-life values ranged from 9 to 14 days. Six patients exhibited stable disease for at least 8 weeks. Two patients, (oesophageal squamous cell carcinoma and pancreatic adenocarcinoma) both treated with 5 mg kg À1 weekly, remained stable for 12 months. CONCLUSION: TB-403 treatment in this patient population is well tolerated, with a safety profile distinct from that of vascular endothelial growth factor-axis inhibitors.

Anticorps anti-icam-1, utilisations et procédés

La presente invention concerne un anticorps ou un fragment de celui-ci de liaison a l'antigen... more La presente invention concerne un anticorps ou un fragment de celui-ci de liaison a l'antigene ayant une specificite de liaison a l'ICAM-1. L'invention concerne egalement l'utilisation de ceux-ci en medecine pour traiter les cancers, tels que le myelome multiple.

Ropivacaine and cellular functions : Towards an understanding of efficacy in ulcerative colitis

Beneficial effects of ropivacaine in rat experimental colitis

The Journal of pharmacology and experimental therapeutics, 1999

Ropivacaine, a new, long-acting local anesthetic agent, has been shown to have beneficial effects... more Ropivacaine, a new, long-acting local anesthetic agent, has been shown to have beneficial effects in the treatment of ulcerative colitis. Treatment with this drug results in prompt symptomatic relief. The aim of this study was to examine the effects of ropivacaine on mucosal healing and to investigate whether ropivacaine can restore the decreased colonic contractility seen in the diseased state. Colitis was induced in rats by a single intrarectal administration of trinitrobenzene sulfonic acid. Mucosal healing was assessed after 1 week of therapy. The effects on colonic contractility were examined either after 1 week of treatment or by application of the drugs to untreated, inflamed rat colon segments placed in organ baths. After the induction of colitis, daily intracolonic treatment with ropivacaine for 1 week reduced morphological damage and myeloperoxidase activity. One week of treatment also restored the contractile response to acetylcholine. By adding ropivacaine directly to un...

Ropivacaine inhibits serum-induced proliferation of colon adenocarcinoma cells in vitro

The Journal of pharmacology and experimental therapeutics, 1999

Ropivacaine, a new long-acting local anesthetic, is currently being investigated for the treatmen... more Ropivacaine, a new long-acting local anesthetic, is currently being investigated for the treatment of ulcerative colitis. In view of the increased incidence of dysplasia and neoplasia associated with ulcerative colitis, it is important that the medical treatment of these patients does not stimulate cell proliferation further. This study was performed to evaluate the effect of ropivacaine on the proliferation of human colon adenocarcinoma cells (HT-29 and Caco-2) in vitro. A serum-induced proliferation assay of human colon adenocarcinoma cells was used. Ropivacaine inhibited the growth of HT-29 and Caco-2 cells in a dose-dependent manner. Fifty percent inhibition of growth was found at a ropivacaine concentration of 250 microM when the HT-29 cells were cultured in 1% fetal calf serum and of 550 microM when the HT-29 cells were cultured in 10% serum. The effective concentrations are within the range of the therapeutic concentrations obtained in the colon of patients treated rectally w...

Ropivacaine inhibits leukocyte rolling, adhesion and CD11b/CD18 expression

The Journal of pharmacology and experimental therapeutics, 1997

Ropivacaine, a new local anesthetic, is currently being investigated for the treatment of ulcerat... more Ropivacaine, a new local anesthetic, is currently being investigated for the treatment of ulcerative colitis, with promising results so far. The aim of this study was to examine anti-inflammatory properties of ropivacaine with regard to its effects on vascular permeability and inflammatory leukocyte behavior in vivo. The effects on leukocyte rolling, firm adhesion and vascular permeability were examined in the hamster cheek pouch microvasculature via intravital microscopy, and the effects on leukocyte adhesion molecules were examined in vitro by means of flow cytometry. In large venules, leukocyte adhesion induced by topical leukotriene B4 (LTB4) was almost completely inhibited during the combined application of ropivacaine and LTB4. The spontaneous rolling leukocyte flux was reduced by 72%, the rolling leukocyte fraction by 47% and the total leukocyte flux, which reflects blood flow, by 47%. In postcapillary venules, ropivacaine abolished rolling and LTB4-induced firm adhesion of l...

Local anaesthetics do not affect protein kinase C function in intact neuroblastoma cells

Life Sciences, 1993

The effects of local anaesthetics on protein kinase C function in vitro were examined in two mode... more The effects of local anaesthetics on protein kinase C function in vitro were examined in two model systems: differentiation in mouse Neuro-2a neuroblastoma cells and muscarine M1-receptor mediated phosphoinositide breakdown in human SK-N-MC neuroblastoma cells. Staurosporin, a protein kinase C inhibitor, induced marked neuritogenesis in Neuro-2a cells after incubation for 5 h, whereas no effect could be seen after exposure to the local anaesthetics ropivacaine, lidocaine or bupivacaine. In the other model, protein kinase C-mediated regulation of phospholipase C was demonstrated for SK-N-MC cells. Phorbol 12-myristate 13-acetate, a protein kinase C activator, produced a dose-dependent decrease in both basal and carbachol-stimulated phosphoinositide breakdown. Staurosporin blocked this phorbol ester-induced subsensitivity completely, while ropivacaine, lidocaine or bupivacaine did not, suggesting that no functional protein kinase C antagonism is mediated by local anaesthetics. The present study suggests that unlike the reported inhibiting effects of local anaesthetics on purified protein kinase C isoforms, no such modulation is found in intact neuroblastoma cells.

Inflammation Research, 1997

Objective: To examine the effects of ropivacaine, currently being investigated for treatment of u... more Objective: To examine the effects of ropivacaine, currently being investigated for treatment of ulcerative colitis, on the release of arachidonic acid metabolites. Material: Human granulocytes and endothelial cells. Treatment: Ropivacaine, lidocaine, hydrocortisone, 5-aminosalicylic acid or acetylsalicylic acid (10-1000 M). Methods: Leukotriene B 4 , 5-hydroxyeicosatetraenoic acid, 6-keto PGF 1a and 15-hydroxyeicosatetraenoic acid were measured using immuno assays. Wilcoxon signed rank test was used for statistical calculations. Results: Ropivacaine dose-dependently inhibited zymosaninduced release of leukotriene B 4 and 5-hydroxyeicosatetraenoic acid whereas the release after ionophore stimulation was not affected. Ropivacaine was more potent than 5aminosalicylic acid but less potent compared to hydrocortisone. Ropivacaine had only a weak inhibitory effect on the release of 15-hydroxyeicosatetraenoic acid from zymosanor ionophore-stimulated cells. In contrast to hydrocortisone and 5-aminosalicylic acid, ropivacaine only weakly affected the release of 6-keto PGF 1a after stimulation with thrombin. Conclusions: The inhibited release of 5-lipoxygenase products may account for some of the anti-inflammatory effects of ropivacaine seen in the treatment of ulcerative colitis.

Agents and Actions, 1993

Local anaesthetics are known to affect a variety of cell functions, many of which are involved in... more Local anaesthetics are known to affect a variety of cell functions, many of which are involved in the inflammatory response. Local anaesthetics have also been shown to influence cell proliferation. The aim of this study was to examine the effect of two local anaesthetics (ropivacaine and lidocaine) on cell proliferation of cultured human fibroblasts, vascular endothelial cells and epithelial cells, i.e. keratinocytes, as earlier studies have not included primary human cell types. Significant inhibition of fibroblast proliferation was observed with concentrations of 50 gM ropivacaine or 100 gM lidocaine in 1% newborn calf serum and 500 gM ropivacaine or lidocaine in 10% newborn calf serum. The proliferation of endothelial cells was significantly inhibited by 1 mM ropivacaine in 5% human serum and 500 gM ropivacaine or 100 gM lidocaine in 40% human serum. Significant inhibition was not obtained with lidocaine when these cells were cultured in 5% HS. Significant inhibition of keratinocytes was obtained with 100 gM ropivacaine and 500 gM lidocaine. The effective concentrations are within the range of therapeutical concentrations in vivo and there seems to be a general correlation between the local anaesthetic potency and the inhibiting effect on cell proliferation. This suggest a mechanism by which local anaesthetics may exhibit anti-hyperproliferative effects in clinical situations.

European Journal of Nutrition

The original version of this article unfortunately contained a mistake. A number in Table 6 has b... more The original version of this article unfortunately contained a mistake. A number in Table 6 has been corrected.

$Research paper thumbnail of A Phase I Dose-Escalation Study of Antibody BI-505 inRelapsed / RefractoryMultipleMyeloma$

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics,... more Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses. Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-5050s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at ...

The effect of Lactiplantibacillus plantarum 299v together with a low dose of iron on iron status in healthy pregnant women: A randomized clinical trial

Acta Obstetricia et Gynecologica Scandinavica

Iron deficiency during pregnancy is a global health problem and is associated with adverse pregna... more Iron deficiency during pregnancy is a global health problem and is associated with adverse pregnancy outcomes. The aim of this randomized, double‐blind, placebo‐controlled study was to evaluate the effect of Lactiplantibacillus plantarum 299v (Lp299v, 1010 colony forming units), 4.2 mg iron, 12 mg ascorbic acid and 30 µg folic acid (Lp) on iron status in healthy, non‐anemic, pregnant Swedish women.

The Journal of Nutrition

Background Viral infections of the upper airways are the most common cause for absence from work ... more Background Viral infections of the upper airways are the most common cause for absence from work or school, and there is evidence for probiotic efficacy in reducing the incidence and severity of these infections. Objectives We aimed to confirm the previously reported beneficial effects of Lactiplantibacillus plantarum HEAL9 and Lacticaseibacillus paracasei 8700:2 against community-acquired common colds and identify a possible mechanism of action. Methods In a double-blind study, healthy adults (18–70 years of age) with at least 4 colds during the last 12 months before recruitment were randomly allocated to consume either probiotics (n = 448; total daily dose of 109 CFU with the 2 strains equally represented) or placebo (n = 450) once daily for 12 weeks. Recruitment took place from October to February during 2013–2016 (over 3 cold seasons). The probiotic impact on the severity of the colds (Wisconsin Upper Respiratory Symptom Survey−21) was the primary endpoint, whereas secondary end...

Comparison of human gut microbial profiles of matched faecal and biopsy samples from healthy individuals using culture dependent and independent methods

Access Microbiology

Faecal samples have often been used to characterise the gut microbiota in health and disease. The... more Faecal samples have often been used to characterise the gut microbiota in health and disease. There is significant debate whether faecal bacterial communities accurately reflect the mucosa associated bacterial populations, which are considered critical in the aetiopathogenesis of several gastrointestinal diseases. We simultaneously assessed faecal and mucosal microbiota from healthy volunteers to unravel the degree of concordance between the two profiles. Paired fresh rectal biopsies and faecal samples were obtained from ten healthy volunteers and processed under stringent anaerobic conditions. Composition and diversity of the microbiota were studied using next generation sequencing targeting the 16S ribosomal nucleic acid (rRNA) gene and culturomics. Bacterial richness and diversity were comparable between mucosal and faecal samples with no significant statistical differences. The relative abundance of Oxalobacteraceae, Propionibacteriaceae, Campylobacteraceae and Corynebacteriacea...

European Journal of Nutrition

Background The combination of Lactobacillus plantarum HEAL9 and Lactobacillus paracasei 8700:2 (c... more Background The combination of Lactobacillus plantarum HEAL9 and Lactobacillus paracasei 8700:2 (commercially available as Probi Defendum®) has previously been reported to reduce the incidence, duration and severity of naturally acquired common colds in adults. The aim of the present study was to evaluate the impact of Probi Defendum® on aspects of common cold in healthy children 1–6 years of age attending day care. Methods A total of 131 children, out of the planned 320, were recruited into the study during 1 common cold season and randomised to consume once daily either 109 CFU (colony forming units) of the probiotic product or placebo. Due to unforeseen reasons, the recruitment of more children did not continue beyond the first cold season. Results There were 106 children that completed the study out of the 131 randomised. Daily consumption of the probiotic product for a period of 3 months significantly reduced the severity of the symptom “nasal congestion/runny nose” with a mean ...

Probiotic treatment using a mix of three Lactobacillus strains for lumbar spine bone loss in postmenopausal women: a randomised, double-blind, placebo-controlled, multicentre trial

The Lancet Rheumatology

Summary Background Postmenopausal bone loss in the spine is associated with an increased risk of ... more Summary Background Postmenopausal bone loss in the spine is associated with an increased risk of vertebral fractures. Certain probiotic treatment protects rodents from ovariectomy-induced bone loss. The aim of the present study was to determine if treatment with a combination of three bacterial strains protects against the rapid spine bone loss occurring in healthy early postmenopausal women. Methods This randomised, double-blind, placebo-controlled, multicentre trial was done at four study centres in Sweden. Early postmenopausal women were randomly assigned in a 1:1 ratio to receive probiotic treatment consisting of three Lactobacillus strains (Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312, and Lactobacillus plantarum DSM 15313; 1 x 1010 colony-forming units per capsule) or placebo once daily for 12 months. The primary outcome was the percentage change from baseline in lumbar spine bone mineral density (LS-BMD) at 12 months. The primary analysis was done in all participants with BMD measurements available both at baseline and at 12 months. Analyses of adverse events and safety included all participants who had taken at least one capsule of placebo or Lactobacillus. This trial is registered with ClinicalTrials.gov , NCT02722980 , and is completed. Findings Between April 18 and Nov 11, 2016, 249 participants were randomly assigned to receive probiotic product or placebo, and 234 (94%) completed the analyses required for the primary outcome. Lactobacillus treatment reduced the LS-BMD loss compared with placebo (mean difference 0·71%, 95% CI 0·06 to 1·35). The LS-BMD loss was significant in the placebo group (–0·72%, −1·22 to −0·22), whereas no bone loss was observed in the Lactobacillus-treated group (–0·01%, −0·50 to 0·48). The adverse events were similar between the two groups. Interpretation Probiotic treatment using a mix of three Lactobacillus strains protects against lumbar spine bone loss in healthy postmenopausal women. Funding Probi.

ANTI-ICAM-1 Antibody, Uses and Methods

Abstract A111: A phase I, dose escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with solid tumors

Molecular Cancer Therapeutics, 2009

Rationale and Objectives: TB‐403 is a humanised recombinant immunoglobulin G isotype 1 monoclonal... more Rationale and Objectives: TB‐403 is a humanised recombinant immunoglobulin G isotype 1 monoclonal antibody expressed in Chinese hamster ovary cells and directed to the receptor‐binding site of placental growth factor (PlGF). The antibody is highly specific and does not cross‐react with vascular endothelial growth factor A (VEGFA). PlGF levels are low in normal tissues, but up‐regulated in several pathological conditions, including several types of cancer. TB‐403 has been shown to significantly inhibit tumor growth in xenograft tumor models. The primary objective of the phase 1 study was to determine the maximum tolerated dose (if Methods: In this multi‐center study, cohorts of 3 patients were treated with 8 weekly doses of 1.25, 5, or 10 mg/kg or 3 doses of 20 and 30 mg/kg once every three weeks (q3w). Six additional patients were treated with 30 mg/kg q3W. Patients showing objective tumor response or stable disease (SD) after 8 weeks were offered extended therapy. Main eligible criteria were: solid tumor with no other treatment options, ECOG performance status 0–1, normal organ function, and no prior anticancer therapy within 30 days (bevacizumab within 60 days). Results: A total of 23 patients were accrued. No DLT, changes in ECG, laboratory findings or urine analysis were seen, except for one patient with an unrelated biliary stenoses. Of related or possibly related grade III or IV adverse events only one episode of pulmonary embolism, one case of dyspnoea and a case of dry skin were observed. Related or possibly related grade I and II adverse events included skin rash (1 patient), fatigue (5 patients), fever (1 patient), diarrhoea (1 patient), and hypertension (1 patient). No objective responses according to RECIST criteria were observed but five patients had SD ≥ 8 weeks, including 2 patients (pancreatic adenocarcinoma and esophageal squamous carcinoma) treated with weekly 5 mg/kg TB‐403 with SD > 10 months. Conclusion: TB‐403 was well tolerated. MTD was not established due to lack of dose‐limiting toxicity up to a dose of 10 mg/kg weekly and 30 mg/kg q3w. Prolonged SD (> 10 months) was seen in two patients treated with 5 mg/kg weekly TB‐403. Pharmacokinetic and molecular pharmacodynamic data will be presented. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A111.

Clinical Therapeutics, 2011

Background: TB-403 (RO5323441) is a humanized monoclonal antibody directed against placental grow... more Background: TB-403 (RO5323441) is a humanized monoclonal antibody directed against placental growth factor (PlGF). Preclinical studies have demonstrated that targeting PlGF can result in significant inhibition of tumor growth and metastasis. Objectives: The purpose of this study was to assess the safety profile, tolerability, and pharmacokinetics of TB-403, developed for the treatment of solid tumors. Methods: Healthy male subjects were exposed to a single intravenous infusion of TB-403 or placebo. Blood samples for hematology, clinical chemistry, coagulation factors, and urinalysis were collected; vital signs and ECGs were recorded; and serial blood samples were drawn for pharmacokinetic and immunogenicity measurements and circulating levels of pharmacodynamics markers PlGF and (VEGF) vascular endothelial growth factor. Sixteen subjects received either placebo or TB-403 at doses ranging from 0.3 to 5.0 mg/kg. Results: Mild (grade 1 or 2) nasopharyngitis, headache, neck pain, and joint pain were the most frequently reported adverse events (AEs). There were no serious AEs in the study, and none of the AEs led to withdrawal. None of the safety laboratory assessments was considered clinically significant, and none was reported as an AE. There were no apparent differences in terms of safety profiles among the 3 dose levels of active treatment compared with placebo. Clearance, volume of distribution, and terminal t ½ (mean values) for TB-403 in all 3 cohorts were in the range of 4.2 to 4.9 (mL/d/kg), 56 to 79 (mL/ kg), and 8 to 13 (days), respectively. Conclusion: The highest dose of TB-403 (5.0 mg/kg) was well tolerated in this study of a single intravenous infusion to healthy males. This result allowed a higher starting dose level in a subsequent Phase I study in cancer patients, the patient population for which this antibody is developed.