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Background: Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease., Methods: This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose-response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure-Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete., Findings: Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose-response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference -3·0 [95% CI -4·9 to -1·1]; p=0·0025 for 150 mg and -2·9 [-4·9 to -1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline -0·57 points [95% CI -1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period., Interpretation: The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials., Funding: Novartis Pharma., Competing Interests: Declaration of interests BAF received consulting fees from Novartis, Roche, BMS, Galapagos, Janssen, Servier, UCB, and Sanofi; and funding to his institution for collaborative research from Janssen, Celgene, Galapagos, and Servier. XM received consulting fees from BMS, Galapagos, GSK, Novartis, Pfizer, and Servier. AP received grants or research support from Novartis, Viela Bio, and Exosome Dx. TG-B received travel assistance from Novartis and has participated in the scientific advisory board of Novartis. W-FN provided consultation services for Novartis, AbbVie, BMS, Sanofi, Argenx, Janssen, Resolve Therapeutics, Bain Capitals, and UCB. SF reports consulting fees from AstraZeneca and Novartis; payment for sponsored talks or courses from AbbVie, Chugai, Galapagos, Novartis, and UCB; participation in the scientific advisory boards of AstraZeneca and Novartis; and a research grant from Novartis for their institution. GN received consulting fees from Novartis and Janssen; and participated in the scientific advisory boards of Novartis and Janssen. JH reported that his institution received research grants and study fees from Novartis, and he received honoraria for lectures from Lilly, MSD, AbbVie, Novartis, and Astro Pharma; travel support from Novartis; and participated in the scientific advisory boards of Lilly and Pfizer. SSM received consulting fees from Novartis, BMS, Otsuka, Visterra, Target RDW, Horizon, Kinksa, and iCell; and payment for educational content development. EA received grants from National Eye Institute, Novartis, Ocular Therapeutics, W.L. Gore & Associates, IRIS Registry Research Fund, and US Department of Defense; received speaker and consultation fees from Adelphi Values, Dompe, FirstString Medical Research, HanAll, Novalique, Regeneron Healthcare Solutions, Sinqi, Xequel, Kyria, and Hawkeye. MS, W-LL, CS, and WH are employees of Novartis and own stocks in Novartis. MM-P was an employee of Novartis at the time of the study and until the initial stages of the development of this manuscript and currently is an employee of Alcon. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Fatigue is a subjective, complex and multi-faceted phenomenon, commonly experienced as tiredness. However, pathological fatigue is a major debilitating symptom associated with overwhelming feelings of physical and mental exhaustion. It is a well-recognized manifestation in chronic inflammatory rheumatic diseases, such as Sjögren's Syndrome and Systemic Lupus Erythematosus and an important predictor of patient's health-related quality of life (HRQoL). Patient reported outcome questions are the key instruments to assess fatigue. To date, there is no consensus about reliable quantitative assessments of fatigue., Method: Observational data for a period of one month were collected from 296 participants in the United States. Data comprised continuous multimodal digital data from Fitbit, including heart rate, physical activity and sleep features, and app-based daily and weekly questions covering various HRQoL factors including pain, mood, general physical activity and fatigue. Descriptive statistics and hierarchical clustering of digital data were used to describe behavioural phenotypes. Gradient boosting classifiers were trained to classify participant-reported weekly fatigue and daily tiredness from multi-sensor and other participant-reported data, and extract a set of key predictive features., Results: Cluster analysis of Fitbit parameters highlighted multiple digital phenotypes, including sleep-affected, fatigued and healthy phenotypes. Features from participant-reported data and Fitbit data both contributed as key predictive features of weekly physical and mental fatigue and daily tiredness. Participant answers to pain and depressed mood-related daily questions contributed the most as top features for predicting physical and mental fatigue, respectively. To classify daily tiredness, participant answers to questions on pain, mood and ability to perform daily activities contributed the most. Features related to daily resting heart rate and step counts and bouts were overall the most important Fitbit features for the classification models., Conclusion: These results demonstrate that multimodal digital data can be used to quantitatively and more frequently augment pathological and non-pathological participant-reported fatigue., Competing Interests: CR and ED were employees of Novartis. DD, MS, and VD are employees of Novartis. NM is employee of Evidation Health, Inc., (© 2023 Rao, Di Lascio, Demanse, Marshall, Sopala and De Luca.)

The phase 3 PANORAMA-1 trial led to regulatory approvals of panobinostat (PAN) in combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of multiple myeloma after ≥2 prior regimens, including BTZ and an immunomodulatory drug. Patient-reported outcomes (PROs) were assessed in PANORAMA-1, with data available for 73 patients in the PAN + BTZ + DEX arm and 74 patients in the placebo (PBO) + BTZ + DEX arm. Per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), global health status/quality of life (QoL) scores initially declined with PAN + BTZ + DEX during the first 24 weeks before approaching baseline scores and remaining steady during the next 24 weeks, with no difference between arms at Week 48. The EORTC QLQ-Myeloma module (EORTC QLQ-MY20) demonstrated initial improvements and subsequent stabilization of disease symptom scores in both arms and initial worsening and subsequent improvement of side effects of treatment scores, with the initial worsening more pronounced and recovery less pronounced with PAN + BTZ + DEX. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scores remained relatively stable and similar between the arms. Overall, these PRO findings support the addition of PAN to the BTZ+DEX regimen as an efficacious treatment option, with limited symptomatology and impact on patients' QoL. The reported results are based on a descriptive analysis of the data. No formal statistical tests have been performed., (© 2018 John Wiley & Sons Ltd.)

Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes., (© 2017 John Wiley & Sons Ltd.)

Background: Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial., Methods: PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m 2 intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials.gov, NCT01023308., Findings: Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0-44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0-40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78-1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6-34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1-32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68-1·50)., Interpretation: The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this., Funding: Novartis Pharmaceuticals., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and ≥2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and ≥2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ≥2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01023308., (© 2016 by The American Society of Hematology.)

Background: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma., Methods: PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308., Findings: 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81-13·47) in the panobinostat group and 5·59 months (2·14-11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33-12·94] vs 8·08 months [7·56-9·23]; hazard ratio [HR] 0·63, 95% CI 0·52-0·76; p<0·0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33·64 months (95% CI 31·34-not estimable) for the panobinostat group and 30·39 months (26·87-not estimable) for the placebo group (HR 0·87, 95% CI 0·69-1·10; p=0·26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60·7%, 95% CI 55·7-65·6] for panobinostat vs 208 [54·6%, 49·4-59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2-32·4] vs 60 [15·7%, 12·2-19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76-14·92) in the panobinostat group and 10·87 months (9·23-11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41-1·64) in the panobinostat group and 2·00 months (1·61-2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%])., Interpretation: Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival., Funding: Novartis Pharmaceuticals., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Despite advancements, prognosis for patients with relapsed/refractory multiple myeloma (MM) is poor, and novel therapies are needed. Panobinostat is a potent deacetylase inhibitor that elicits synergistic effects on MM cells in combination with bortezomib. This phase Ib study sought to determine the maximum-tolerated dose (MTD) of panobinostat plus bortezomib in patients with relapsed or relapsed and refractory MM., Patients and Methods: In the dose-escalation phase (n = 47), panobinostat was administered orally thrice weekly every week in combination with bortezomib (21-day cycles). After MTD determination, patients were evaluated in an expansion phase (n = 15) that incorporated a 1-week treatment holiday of panobinostat, with dexamethasone added in cycle 2. Additional assessments included safety, pharmacokinetics, and efficacy per International Myeloma Working Group criteria., Results: The MTD was established at panobinostat 20 mg plus bortezomib 1.3 mg/m(2). Grade 3 or 4 adverse events (AEs) included thrombocytopenia (85.1%), neutropenia (63.8%), and asthenia (29.8%) in the escalation phase, and thrombocytopenia (66.7%), neutropenia (46.7%), and fatigue (20.0%) in the expansion phase. At MTD in the escalation phase, eight patients (47.1%) discontinued therapy as a result of AEs, whereas five patients (33.3%) discontinued treatment in the expansion phase. Expansion phase patients demonstrated greater median treatment duration. Overall response rate (ORR) was 73.3% in the expansion phase and 52.9% at the escalation phase MTD. Among bortezomib-refractory patients, the ORR was 26.3%, and 42.1% of patients had ≥ minimal response., Conclusion: The MTD of panobinostat plus bortezomib was determined and demonstrated activity in patients with relapsed or relapsed/refractory MM, including bortezomib-refractory patients. A phase II/III clinical trial program (Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma [PANORAMA]) has been initiated.

Background: The pharmaceutical market offers a wide range of inhalant drug products applied on the skin that contain essential oils and/or their isolated compounds, i.e. terpenes. Because there are few data concerning the skin penetration of terpenes, especially from complex carriers, the goal of this study was to determine the ex vivo skin absorption kinetics of chosen terpenes, namely eucalyptol, menthol, camphor, alpha-pinene, and beta-pinene, from the product Vicks VapoRub., Material/methods: Human cadaver skin was placed in a flow-through diffusion chamber and the product was applied for 15, 30, and 60 min. After the application time the skin was separated into layers using a tape-stripping technique: three fractions of stratum corneum and epidermis with dermis, and terpenes amounts in the samples were determined by gas-chromatography., Results: The investigated terpenes showed different absorption characteristics related to their physicochemical properties and did not permeate through the skin into the acceptor fluid. Eucalyptol had the largest total accumulation in the stratum corneum and in the epidermis with dermis, while alpha-pinene penetrated into the skin in the smallest amount., Conclusions: The short time in which saturation of the stratum corneum with the terpenes occurred and the high accumulation of most of the investigated terpenes in the skin layers proved that these compounds easily penetrate and permeate the stratum corneum and that in vivo they may easily penetrate into the blood circulation.

The aim of the present study was to characterize neuroprotective activity of NS- 7, a mixed voltage-gated sodium and calcium channel blocker in a model of transient focal ischaemia in rats. Ischaemia was induced by a 75 min reversible occlusion of middle cerebral artery (MCAo) using a nylon filament. NS-7 (0.5 mg/kg i.v.) or 0.9% NaCl (1 ml/kg i.v.) were infused over 3 min. starting 30 min after the MCAo. Infarct analysis was performed 72 h after ischaemia. Application of NS- 7 produced significant protection seen in neurological tests and diminished brain damage by 37% in total infarct (17.7+/- 3.0% vs. 27.9 +/- 3.2% control; [p < 0.01]; t-test), 47.8% in cortical infarct size by (8.5 +/- 2.4% vs. 16.2 +/- 2.4% control; [p < 0.01]), and by 21.5% in striatal infarction (9.2 +/- 0.8% vs. 11.7 +/- 0.9% control; [p < 0.05]). The results indicate that NS- 7 has potential for neuroprotection against transient ischaemic insult.

The objective of the present study was to characterise the neuroprotective activity of the novel glycineB site NMDA (N-methyl-D-aspartate) receptor antagonist MRZ 2/576 (8-chloro-4-hydroxy-l-oxo- 1,2-dihydropyridazino[4,5-b]quinolin-5-oxide choline salt, CAS 202807-80-5) in a rodent model of focal cerebral ischaemia. Since the solubility of MRZ 2/576 at a physiological pH, is minimal and adequate concentrations can be achieved only at relatively high basic pH the in vivo use of the substance is substantially limited. Therefore, a special nanoparticle formulation was developed to provide means for lengthy i.v. administration of experimentally relevant doses within the physiological range of pH. Focal ischaemia of 75 min duration was induced in rats by a reversible occlusion of the middle cerebral artery (MCAo). MRZ 2/576 (18 mg/kg over 10 min followed by 18 mg/kg/h over 6 h) or placebo treatment was initiated immediately after onset of MCAo. Neurological deficit was evaluated daily for 3 consecutive days and then brain infarct analysis was performed. MRZ 2/576 significantly improved the neurological score at 24 h and 72 h post stroke (p < 0.05 vs. placebo). It also produced a 53.0% reduction of total infarct size, 60.4% of cortical and 42.3% of striatal infarction (p < 0.05 vs. placebo). Temporary drug-induced hypothermia and ataxia were observed during infusions. This leads to the conclusion that prolonged administration of the glycineB site antagonist MRZ 2/576 in form of the nanoparticle suspension ameliorates ischaemic damage induced by the transient MCAo in rats. The results suggest that nanoparticles hold promise as an effective strategy e.g. for substances with physico-chemical characteristics that otherwise would preclude them from pre-clinical development and/or clinical application.

The effect of low power laser light upon the haematopoietic system of rats and also upon the basic haematological parameters was studied. A HeliumNeon continuous emission laser (632.8 nm; max. power 5 mW) and a Galium arsenide semiconductor pulse laser (904 nm; power 80 mW; pulse duration 200 ns) were used as light sources. Intact skin on the hind legs of rats was exposed, over a section of the femur. Peripheral blood analysis carried out before and after the experiments. These indicated that AsGa laser light induced a decrease in bone marrow mastocytes and peripheral blood basophils with an increase in the number of eosinophils. An increase in mitotic activity in the bone marrow was observed in the exposed groups of animals. No significant changes in Hb, Ht, erythrocyte or reticulocyte levels in the peripheral blood were noted, nor was there an increase in megakaryocyte emperipolesis.