Pharmatest (Finland)

Background and ObjectivesAdditional risk minimization measures (aRMMs), such as direct healthcare professional communication (DHPC) and risk management plan (RMP) educational materials, are required for certain medicinal products to mitigate the risks associated with their use. This research aimed to assess healthcare professionals’ (HCPs) awareness and experiences of DHPC and RMP educational materials, identify the safety information most valued by HCPs, and determine ways to improve the processes and content of DHPCs and RMP educational materials.MethodsAn open, anonymous online questionnaire was created and made available to HCPs through their respective professional associations. The Chi-squared test for independence was the primary statistical analysis method used. Content analysis of the open-ended answers was conducted by two independent coders.ResultsA sample size of 185 HCPs (32 physicians, 50 nurses, 26 MSc pharmacists, and 77 BSc pharmacists) was achieved. HCPs showed limited familiarity with aRMMs, with 45% unsure whether they had received DHPCs, 41% uncertain whether they had used RMP educational materials, and 42% unaware where to check whether a product had RMP educational material. Overall, MSc pharmacists demonstrated the highest awareness of RMP educational materials and DHPCs. In addition, 54% of HCPs felt they received insufficient safety information, and 57% desired further training in pharmacovigilance (PhV).ConclusionsThis research reinforces and complements our previous findings on the need to enhance PhV awareness and expertise among HCPs, particularly in areas such as adverse drug reaction (ADR) reporting, additional monitoring, DHPCs, and RMP educational material. Future DHPCs and RMP educational materials should be made more distinguishable to effectively capture HCPs’ attention.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40290-025-00580-z.

Lacticaseibacillus paracasei Lpc-37 (Lpc-37) has previously shown to reduce perceived stress in healthy adults. The ChillEx study investigated whether Lpc-37 reduces stress in a model of chronic examination stress in healthy students. One hundred ninety university students (18–40 y) were randomized to take 1.56 × 1010 colony-forming units of Lpc-37 or placebo (1:1) each day for 10 weeks, in a triple-blind, parallel, multicenter clinical trial consisting of six visits: two screening visits, a baseline visit, and visits at 4, 8, and 10 weeks after baseline. The primary objective was to demonstrate that Lpc-37 reduces stress, as measured by the change in state anxiety from baseline to just before the first examination, after 8 weeks using the State Trait Anxiety Inventory (STAI-state). Secondary objectives aimed to demonstrate that Lpc-37 modulates psychological stress-induced symptoms and biomarkers related to mood and sleep. An exploratory analysis of fecal microbiota composition was also conducted. There was no difference between Lpc-37 and placebo groups in the change of STAI-state score (estimate 1.03; 95% confidence interval [CI]: -1.62, 3.67; p = 0.446). None of the secondary outcomes resulted in significant results when corrected for multiplicity, but exploratory results were notable. Results showed an improvement in sleep-disturbance scores (odds ratio 0.30; 95% CI: 0.11, 0.82; p = 0.020) and reduction in duration of sleep (odds ratio 3.52; 95% CI: 1.46, 8.54; p = 0.005) on the Pittsburgh Sleep Quality Index questionnaire after 8 weeks in the Lpc-37 group compared to placebo. A reduction in Bond Lader VAS-alertness was also demonstrated in the Lpc-37 group compared to placebo (estimate −3.97; 95% CI: -7.78, −0.15; p = 0.042) just prior to the examination. Analysis of fecal microbiota found no differences between study groups for alpha and beta diversity or microbiota abundance. Adverse events were similar between groups. Vital signs, safety-related laboratory measures, and gastrointestinal parameters were stable during the trial. In conclusion, probiotic Lpc-37 was safe but had no effect on stress, mood, or anxiety in healthy university students in this model of chronic academic stress. ClinicalTrials.gov: NCT04125810.

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor–bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease.

105 Background: Radium-223 dichloride (Ra-223) is a targeted alpha therapy that binds to newly formed bone matrix in bone metastases and induces DNA double-strand breaks in cancer cells, osteoblasts and osteoclasts. It is used for treating men with castration-resistant prostate cancer (CRPC) and bone metastases. Enzalutamide (enza) is a second-generation androgen receptor inhibitor also used for treating the same patient population, and the combination of Ra-223 and enza is currently being investigated in clinical trials. We evaluated the antitumor efficacy of Ra-223 and enza in the LNCaP intratibial model mimicking prostate cancer metastasized to bone. Previously, additive or synergistic antitumor effects were not observed when Ra-223 was combined with abiraterone and prednisone in the LNCaP model (Suominen et al., AACR 2020). Methods: LNCaP prostate cancer cells were inoculated into the right tibia of male NOD.scid mice. The mice were randomized (n = 9/group) based on serum PSA and treated with vehicle, Ra-223 (330 kBq/kg, i.v., Q4W x 2), enza (30 mg/kg, p.o., QD) or with a combination treatment of Ra-223 and enza, for 28 days. Serum PSA levels were analyzed at the end of the study and compared to the pre-treatment levels. Serum bone formation and resorption biomarkers, PINP and CTX, respectively, were measured during the study. Tumor-induced abnormal bone area and Ra-223 uptake were determined by X-ray and gamma counter, respectively. The healthy tibiae were evaluated by microCT. Results: Combination treatment showed synergistic antitumor efficacy as observed by lower PSA levels when compared to the vehicle, Ra-223 or enza monotherapies (p = 0.04, p = 0.008 and p = 0.002, respectively). A statistical interaction between Ra-223 and enza treatments was found (p = 0.003), confirming the synergistic effect. In combination treatment, the serum PSA change relative to pre-treatment levels was 18% of the vehicle. Accordingly, a decreasing trend (p = 0.08) in tumor-induced abnormal bone changes was associated with the combination treatment in the tumor-bearing tibiae (46% of the vehicle), whereas no changes in total bone structure/quality were observed in the healthy tibiae. Compared to monotherapies, the combination treatment had the most prominent lowering effect on the bone metabolism biomarkers PINP and CTX during the study. Concurrent administration of enza with Ra-223 did not affect Ra-223 uptake in tumor-bearing tibiae. Conclusions: Compared to Ra-223 and enza monotherapies, the combination treatment demonstrated synergistic antitumor efficacy by decreasing PSA levels in the LNCaP intratibial model. Despite of prominent effects on tumor growth, the combination treatment was not observed to compromise bone health in the healthy tibiae. In conclusion, these preclinical results support the ongoing phase 3 trials PEACE III (NCT02194842) & ESCALATE (NCT04237584) of this combination.

Adjuvant imatinib is associated with improved recurrence-free survival (RFS) when administered after surgery to patients with operable gastrointestinal stromal tumor (GIST), but its influence on overall survival (OS) has remained uncertain. To evaluate the effect of adjuvant imatinib on OS of patients who have a high estimated risk for GIST recurrence after macroscopically complete surgery. In this open-label, randomized (1:1), multicenter phase 3 clinical trial conducted in Finland, Germany, Norway, and Sweden, 400 patients who had undergone macroscopically complete surgery for GIST with a high estimated risk for recurrence according to the modified National Institutes of Health Consensus Criteria were enrolled between February 2004 and September 2008. Data for this follow-up analysis were analyzed from September to November, 2019. Imatinib 400 mg/d administered orally for either 12 months or 36 months after surgery. The primary end point was RFS; the secondary objectives included OS and treatment safety. The intention-to-treat cohort consisted of 397 patients (12-month group, 199; 36-month group, 198; 201 men and 196 women; median [IQR] age, 62 (51-69) years and 60 (51-67) years, during a median follow-up time of 119 months after the date of randomization, 194 RFS events and 96 OS events were recorded in the intention-to-treat population. Five-year and 10-year RFS was 71.4% and 52.5%, respectively, in the 36-month group and 53.0% and 41.8% in the 12-month group (hazard ratio [HR], 0.66; 95% CI, 0.49-0.87; P = .003). In the 36-month group, 5-year OS and 10-year OS rates were 92.0% and 79.0%, respectively, and in the 12-month group 85.5% and 65.3% (HR, 0.55; 95% CI, 0.37-0.83; P = .004). The results were similar in the efficacy population, from which 15 patients who did not have GIST in central pathology review and 24 patients who had intra-abdominal metastases removed at surgery were excluded (36-month group, 10-year OS 81.6%; 12-month group, 66.8%; HR, 0.50; 95% CI, 0.32-0.80; P = .003). No new safety signals were detected. Three years of adjuvant imatinib is superior in efficacy compared with 1 year of imatinib. Approximately 50% of deaths may be avoided during the first 10 years of follow-up after surgery with longer adjuvant imatinib treatment. ClinicalTrials.gov Identifier: NCT00116935.

Introduction/BackgroundThe enzyme type 1 17β-hydroxysteroid dehydrogenase (HSD17B1), responsible for generating active 17β-estradiol (E2) from low-active estrone (E1), is over-expressed in endometrial cancer (EC) thus implicating an increased intra-tissue generation of E2 in this estrogen-dependent condition.In this study we explored the possibility of inhibiting HSD17B1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo and ex vivo models.MethodologyWe generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of HSD17B1 similar to human tissues. In these cells, HPLC analysis showed that HSD17B1 activity could be blocked by a specific HSD17B1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by HSD17B1 inhibition. In vivo, tumours grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by HSD17B1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using HSD17B1 negative cells (negative control).ResultsUsing a patient cohort of 52 primary ECs, we demonstrated the presence of HSD17B1 enzyme activity (ex vivo in tumour tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the HSDβB1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumour, we next demonstrated the mRNA expression of the potential drug target, HSD17B1, in metastatic lesions using a second cohort of 37 EC patients.ConclusionIn conclusion, HSD17B1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and HSD17B1 inhibitor development to make candidate compounds suitable for the first human studies are awaited.DisclosureNothing to disclose.

Abstract Metastatic breast cancer (MBC) is the most advanced stage of breast cancer, diagnosed as stage IV. Typically, MBC metastases occur in the bones, liver, brain, and lungs. Bone metastases cause significant morbidity and mortality in late-stage breast cancer patients. At present, there is no efficient curative or preventive treatment for bone metastases. Therefore, establishment and validation of well characterized in vivo models of breast cancer bone metastasis is of utmost importance. The aim of this study was to validate an intracardiac model of bone MBC utilizing GFP tagged triple negative (estrogen receptor; ER, progesterone receptor; PR and human epidermal growth factor receptor 2; HER2 negative) human breast cancer cells, which could be used to study efficacy of new potential treatments. Female athymic nude mice (Hsd: Athymic Nude-Foxn1nu) were used in this study. Bone seeking MDA-MB-231(SA)-GFP human breast cancer cells were inoculated into the left cardiac ventricle of 4-6 weeks old female mice. Allocation to treatment groups (n=15) was performed by stratification procedure based on animal weight prior to the beginning of the study. To validate the model, the current standard-of-care (SOC) treatment (Paclitaxel) was administered between study days 13-17 at the therapeutic dose. Serum bone biomarker TRACP5b was measured before cancer cell inoculation and at sacrifice. Planar X-ray of hind limbs and ex vivo fluorescence imaging of the whole body were performed at sacrifice. The observed tumor take rate was 100%. 33% of mice in the vehicle group were cachectic, but mice treated with SOC exhibited only mild and temporary weight loss. Tumors were observed mainly in skeletal sites but also in soft tissues. The SOC treatment decreased both total and skeletal tumor burden. Based on X-ray images, tumor induced osteolytic bone lesions were smaller in the SOC treated group compared to vehicle though no differences were observed in total bone lesion area. Serum TRACP5b was increased in the vehicle group as a result of osteolytic lesions, and decreased with the SOC treatment. In conclusion, an intracardiac model of MBC was successfully validated with the SOC treatment paclitaxel that efficiently inhibited disease progression. Therefore, this intracardiac model provides a promising tool for testing new treatments against bone and soft tissue MBC in vivo. Citation Format: Justyna Zdrojewska, Mari I. Suominen, Katja M. Fagerlund, Jussi M. Halleen, Jenni Bernoulli, Johann Zimmermann. Validation of a preclinical model for bone metastatic triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2007.

SummaryBackgroundMedetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral α2‐adrenoceptors. Vatinoxan, a peripheral α2‐antagonist, has been shown experimentally to alleviate the adverse effects of some α2‐agonists in horses. However, vatinoxan has not been investigated during constant‐rate infusion (CRI) of medetomidine in standing horses.ObjectivesTo evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine.Study designExperimental, randomised, blinded, cross‐over study.MethodsSix healthy horses were given medetomidine hydrochloride, 7 μg/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 μg/kg i.v., followed by CRI of medetomidine at 3.5 μg/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t‐tests as appropriate.ResultsInitially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared with MED+V. For example at 10 min HR (mean ± s.d.) was 26 ± 2 and 31 ± 5 beats/minute (P = 0.04) and MAP 129 ± 15 and 103 ± 13 mmHg (P<0.001) respectively. At 10 min, cardiac index was lower (P = 0.02) and systemic vascular resistance higher (P = 0.001) with MED than with MED+V. Borborygmi were reduced after MED; this effect was attenuated by vatinoxan (P<0.001). All horses were sedated with medetomidine, but the mean sedation scores were reduced with MED+V until 20 min (6.8 ± 0.8 and 4.5 ± 1.5 with MED and MED+V, respectively, at 10 min, P = 0.001). Plasma concentration of dexmedetomidine was significantly lower in the presence of vatinoxan (P = 0.01).Main limitationsExperimental study with healthy, unstimulated animals.ConclusionsVatinoxan administered i.v. with a loading dose of medetomidine improved cardiovascular function and gastrointestinal motility during medetomidine CRI in healthy horses. Sedation was slightly yet significantly reduced during the first 20 min..The Summary is available in Portuguese – see Supporting Information