Adequate Tolerability Research Articles

Pharmacological correction of immunological disorders in perimenopausal women with recurrent epithelial cervical dysplasia associated with human papillomavirus infection

Despite the successes achieved in implementing screening programs and treating diseases caused by human papillomavirus (HPV) infection, the frequency of cervical intraepithelial neoplasia (CIN) of moderate and high grades associated with high-risk human papillomavirus (HR-HPV) remains between 9% to 21%. Vaginal dysbiosis and the development of immunodeficient states due to persistent HR-HPV infection require effective immunomodulatory and antiviral therapy before cervical surgery in perimenopausal women with recurrent CIN II.The objective: to evaluate the effectiveness of antiviral and immunomodulatory therapy by determining the state of vaginal biocenosis, immunological status and papillomavirus load of the cervical mucosa before surgical treatment in perimenopausal women with recurrent CIN II.Materials and methods. A prospective study was conducted on 98 women aged 40 to 55 years old, including 60 patients with morphologically verified recurrent CIN II associated with high-risk HPV, forming the main group. The control group comprised 38 women with negative HPV test results and without significant gynecological or somatic pathology. In the main group, a complex consisting of a blend of plant extracts of sod pike grass (Deschampsia caespitosa), ground cinquefoil grass (Calamagrostis epigeios), and echinacea purpurea grass (Echinaceae purpureae) was administered orally.Vaginal microbiota was assessed using Hey-Іson criteria, and immunological status was examined in patients using solid-phase enzyme-linked immunosorbent assay to determine IgG, IgM, IgA antibodies in serum and cervical mucus, levels of interleukin-1β (IL-1β), interferons alpha (IFN-α), gamma (IFN-γ), tumor necrosis factor alpha (TNF-α). Additionally, the DNA of high-risk HPV in cervical mucosa was quantitatively assessed using real-time PCR. The investigations were conducted before and after the applied therapy.Results. The investigation of vaginal content revealed the presence of bacterial vaginosis in 65.0% of patients in the main group, the frequency of which decreased by 2 times after treatment, with the number of women with an intermediate type of vaginal content increasing by 2.8 times (51.7%) and those with normal microbiota increasing by 2.5 times. Disruptions in cellular and humoral immunity systems were identified. After treatment, there was an increase in viral load in the significant «threshold» category (3–5 lg) by 1.25 times and in the «above threshold for progression» category (>5 lg) by 2.3 times, reflecting natural HPV clearance. No direct correlation was found between viral load activity and the degree of CIN or positive morphological changes regarding regression of cervical intraepithelial lesions.Conclusions. The use of a complex containing a blend of plant extracts of sod pike grass (Deschampsia caespitosa), ground cinquefoil grass (Calamagrostis epigeios), and echinacea purpurea grass (Echinacea purpureae) improves the state of vaginal biocenosis, indicators of cellular and humoral immunity, and promotes HPV elimination, it has adequate safety and tolerability, which determines the feasibility of its use in the complex treatment of cervical intraepithelial neoplasia at the preparatory stage before surgery and in the postoperative period to prevent complications and relapses.

YL202/BNT326, a HER3-targeted ADC, in patients with locally advanced or metastatic non-small cell lung cancer and breast cancer: Preliminary results from a first-in-human phase I trial.

3034 Background: YL202/BNT326 is a novel ADC consisting of an anti-HER3 IgG1 monoclonal antibody linked to 8 molecules of YL0010014, a novel topoisomerase I inhibitor, via a tripeptide linker. We report preliminary safety and efficacy results from a phase I trial of YL202/BNT326. Methods: This multinational trial is recruiting patients (pts) with locally advanced/metastatic non-small cell lung cancer (NSCLC) with an EGFR-activating mutation who were previously treated with 3rd generation TKI and platinum-based chemotherapy, and pts with unresectable, locally advanced or metastatic, HR-positive and HER2-negative (IHC 0,1+,2+/ISH-) breast cancer (BC) who were previously treated with CDK4/6 inhibitor and at least one line of chemotherapy. YL202/BNT326 was given at 6 dose levels (DLs, Q3W, iv) in a BOIN dose escalation (D-ESC) scheme, followed by cohort backfill(BF) at selected doses. Primary endpoints are safety and tolerability (dose-limiting toxicities [DLTs] and adverse events [AEs]). Secondary endpoints include pharmacokinetics [PK] and efficacy per RECIST v1.1(ORR, DCR, BOR). Results: At data cutoff (4 Feb 2024), 52 pts were enrolled in D-ESC and BF (39 NSCLC, 13 BC). One DLT (grade 3 febrile neutropenia) occurred during D-ESC at the highest dose. Most common TRAEs (>20%, all grade / ≥ G3) were anemia (71%/20%), white blood cell count decreased (67%/31%), neutrophil count decreased (63%/29%), nausea (52%/0%), decreased appetite (42%/4%), lymphocyte count decreased (37%/23%), platelet count decreased (37%/10%), vomiting (37%/0%), dry mouth (25%/0%), fatigue (25%/0%), stomatitis (23%/2%), alopecia (21%/0%). Interstitial pneumonia occurred in 1 (2%) pt after COVID-19 infection. PK exposure was increased through dose escalation, with low systemic exposure of payload and no accumulation of YL202/BTN326 upon repeated administration. In 46 pts with at least 1 tumor assessment were evaluable for efficacy. Of the non-evaluable pts, 5 are on treatment pending first tumor assessment and 1 discontinued treatment prior to first assessment. In DL3 to DL5 dose range, ORR was 41.0% (95%CI, 25.6, 57.9), DCR was 94.9% (95%CI, 82.7, 99.4) across all tumor types; and the ORR in BC pts was 54.5% (95%CI, 23.4, 83.3), DCR was 100% (95%CI, 71.5, 100.0). Conclusions: YL202/BNT326 demonstrated encouraging efficacy in heavily pretreated locally advanced/ metastatic NSCLC and BC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05653752 . [Table: see text]

9MW2821, a nectin-4 antibody-drug conjugate (ADC), in patients with advanced solid tumor: Results from a phase 1/2a study.

3013 Background: 9MW2821 is a monoclonal ADC that delivers monomethyl auristatin E to cells expressing Nectin-4. Nectin-4 is an adhesion molecule that highly expressed in variety of solid tumors, especially urothelial cancer (UC), cervical cancer (CC), esophageal cancer (EC) and breast cancer. Here we report the updated safety and efficacy data of 9MW2821. Methods: 9MW2821 was administered by intravenous infusion at doses of 0.33-1.5mg/kg on days 1, 8 and 15 of each 28-day cycle. The study included dose escalation, dose expansion and cohort expansion period which included UC, CC, EC, triple negative breast cancer (TNBC) and other Nectin-4 positive solid tumors that progressed after ≥1 systemic treatments (Tx). Primary objectives were assessment of safety and preliminary efficacy. Results: As of Jan 15, 2024, 260 patients (pts) were enrolled with doses ranging from 0.33 to 1.5mg/kg. Only 1 out of 6 pts in 1.5mg/kg group had dose limiting toxicity (grade 4 neutropenia lasted more than 5 days). The maximum tolerated dose was not reached up to 1.5mg/kg and the RP2D was selected as 1.25mg/kg for tolerance. 240 pts were enrolled at dose of 1.25mg/kg. The most common TRAEs of 1.25mg/kg dose group (≥20%, all grade/≥5%, ≥G3) were white blood cell (WBC) count decreased (50.8%, 23.3%), neutrophil count decreased (46.3%, 27.9%), anemia (43.8%, 8.3%), aspartate aminotransferase increased (42.1%, 2.9%), alanine aminotransferase increased (35.4%, 2.1%), asthenia (32.1%, 2.9%), rash (30.0%, 5.0%), decreased appetite (28.8%, 1.3%), nausea (26.7%, 0%), hyperglycemia (25.4%, 2.1%), platelet count decreased (24.2%, 4.6%), alopecia (24.2%, 0%), hypoaesthesia (22.5%, 1.7%), constipation (21.3%, 0%), vomiting (20.9%, 1.3%), hypertriglyceridemia (20.4%, 2.1%), gamma-glutamyltransferase increased (15.8%, 5.4%). Among 190 pts treated with 9MW2821 at 1.25mg/kg or above and reached tumor assessment, objective response rate (ORR) and disease control rate (DCR) was 35.3% and 78.4%, respectively. 37 UC pts, 45 CC pts, 27 EC pts and 16 TNBC pts were enrolled at 1.25mg/kg and evaluable for tumor assessment. Median prior lines of Tx were 2 (range, 1-4). All UC, 51% CC and 93% EC pts progressed after platinum-based chemotherapy and immune checkpoint inhibitors, respectively. Objective responses were also observed in pts with other solid tumor types. Conclusions: The data indicated encouraging efficacy of 9MW2821 in advanced UC, CC, EC and TNBC. 9MW2821 is the first Nectin-4 targeting ADC showed antitumor activity in patients with CC, EC and TNBC. The safety profile showed adequate tolerability. Clinical trial information: NCT05216965 . [Table: see text]

Abstract PS08-07: BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate, in patients with Locally Advanced or Metastatic Breast Cancer and other Solid Tumor: Results from a phase 1 study

Abstract Background: BL-B01D1 is a first-in-class novel antibody drug conjugate (ADC) consisting of an EGFRxHER3 bispecific antibody bounded to a novel TOP-I inhibitor payload via a cleavable linker. We now present safety/efficacy data from a phase I study of BL-B01D1 in breast cancer. Methods: This study included patients (pts) with locally advanced or metastatic breast cancer (BC) and other solid tumors. BL-B01D1 was administered intravenously at doses of 2.5mg/kg Day 1 & Day 8 every 3 weeks (D1D8Q3W) or 5.0mg/kg Day 1 every 3 weeks (D1Q3W) during dose escalation (D-ESC, i3+3) based on the information obtained during the first-in-human study in solid tumors. A subset of pts will be enrolled in the dose-expansion (D-EXP) phase. Results: As of June 26, 2023, 42 pts were enrolled and received at least one dose (D-ESC, n=8; D-EXP, n=34) of BL-B01D1. Only one DLT of febrile neutropenia was observed at 5.0mg/kg D1 Q3W, maximum tolerated dose (MTD) has not been reached. D-EXP was conducted at 2.5mg/kg D1D8 Q3W. Forty-one pts with BC and 1 pt with non-small cell lung cancer (NSCLC) were enrolled in this study. The most common TRAEs ( >10%, all grade/≥ G3) were leukopenia (67%/24%), neutropenia (55%/33%), anemia (55%/26%), thrombocytopenia (60%/24%), nausea (38%/0%), vomiting (38%/0%), stomatitis (31%/2%), asthenia (29%/0%), hypokalemia (21%/5%), aspartate aminotransferase increased (19%/0), alanine aminotransferase increased (19%/0%), decreased appetite (19%/0%), hypertriglyceridemia (19%/0%), hyperglycemia (19%/0%), hyperglycemia (17%/0%), weight decreased (14%/0%), diarrhea (12%/0%), epistaxis (12%/0%), hypercholesterolemia (12%/0%). No ILD was observed. Twenty-four pts. were evaluable for efficacy (at least 1 tumor assessment). Updated information will be provided during the meeting. Conclusions: BL-B01D1 demonstrated encouraging efficacy in metastatic/locally advanced breast cancer that have failed standard of care, especially in pts with TNBC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05470348. Efficacy in Patients with Breast Cancer 1 Including pts whose PRs were not yet confirmed but still under treatment. Citation Format: Jiong Wu, Jian Zhang, Yiqun Du, Wen Zou, Muran Ding, Hui Yang, Sa Xiao, Hongwei Wang, Hai Zhu, Martin Olivo, Yi Zhu. BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate, in patients with Locally Advanced or Metastatic Breast Cancer and other Solid Tumor: Results from a phase 1 study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-07.

Abstract PO2-04-03: BL-M07D1, an antibody-drug conjugate directed to HER2 in patients with locally advanced or metastatic Breast Cancer with HER2-positive/low-expression and other solid tumors: Results from a first-in-human phase 1 study

Abstract Background: BL-M07D1 is an anti-HER2 antibody-drug conjugate (ADC) comprised of a humanized anti-HER2 antibody, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor (Ed-04). Methods: This study included subjects with locally advanced or metastatic HER2 expressing (positive/low) breast cancer (BC) and other solid tumors. BL-M07D1 would be administered at doses of 1.0mg/kg Day 1 & Day 8 every 3 weeks (D1D8 Q3W) or 2.6, 3.2, 3.8, 4.4, 5.0, 5.6, 6.2, 6.8 and 7.4 mg/kg Day 1 every 3 weeks (D1Q3W) during dose escalation (D-ESC). A subset of patients (pts) will be enrolled in the dose-expansion phase (D-EXP) at D1 Q3W regimens. Results: As of June 25, a total of 75 pts have been treated with at least one dose of BL-M07D1, with 22 pts in the D-ESC phase and 53 in the D-EXP phase. Among the 75 pts, 1 received 1.0 mg/kg D1D8Q3W and 74 were treated on the D1Q3W schedule. Dose-limiting toxicity (DLT) was observed at 6.2mg/kg (febrile neutropenia and G3 thrombocytopenia lasting >7 days in one patient). The maximum tolerated dose (MTD) has not been reached yet. D-EXP dose levels included 3.8, 4.4, 5.0 and 5.6mg/kg D1 Q3W. This study enrolled 62 patients with BC, 6 with gastric cancer, 4 with colorectal cancer and 3 with non-small cell lung cancer. The most common TEAEs ( >10%, all grade/≥G3) were leukopenia (79%/24%), neutropenia (69%/39%), anemia (63%/11%), nausea (47%/0%), thrombocytopenia (37%/9%), vomiting (37%/1%), decreased appetite (27%/0%), lymphopenia (24%/8%), alopecia (23%/0%), asthenia (19%/0), gamma-glutamyl transferase increased (17%/0%), aspartate aminotransferase increased (17%/0%), constipation (13%/0%), diarrhea (12%/0%), hypertriglyceridemia (12%/0%), urinary tract infection (11%/1%), COVID-19 (11%/0%), occult blood positive (11%/0%), pyrexia (11%/0%). No ILD was observed. Forty-five pts with BC were evaluated for efficacy (i.e., had at least one post-baseline tumor assessment). Updated efficacy and pharmacokinetic (PK) results will be presented at the meeting. Conclusions: BL-M07D1 demonstrated encouraging efficacy in heavily pretreated HER2 expressing cancers, especially in HER2+ BC. The safety profile showed adequate safety and tolerability. Clinical trial identification: NCT05461768. Efficacy in Patients with Breast Cancer a. 8/9 pts received prior HER2-ADC with microtubule inhibitor. 1/9 pts received prior HER2-ADC with TOPI inhibitor. b. 6 pts with tumor shrinkage are still on-going. c. All pts with tumor shrinkage are still on-going. Citation Format: Erwei Song, Herui Yao, Meili Sun, Hong Zong, Rongbo Lin, Wen Zou, Muran Ding, Jing Yu, Sa Xiao, Hongwei Wang, Hai Zhu, Martin Olivo, Yi Zhu. BL-M07D1, an antibody-drug conjugate directed to HER2 in patients with locally advanced or metastatic Breast Cancer with HER2-positive/low-expression and other solid tumors: Results from a first-in-human phase 1 study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-03.

Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin

Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period. Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed doseof 25mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466). Participants were randomized to immediate treatment (n=16) or delayed treatment (n= 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge's g effect size of 1.07 (p<0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline. PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity. This work was funded by Brain and Cognition Discovery Foundation(BCDF), Usona, and Braxia Scientific.

Pharmacokinetics and bioavailability of a new long-acting insulin analog in healthy Chinese volunteers: an open, randomized, single-dose, two-period and two-sequence cross-over study.

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T). Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate relative bioavailability. Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0-∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0-t and AUC0-∞ of T over R were 98.7% (90% CI: 92.7%-105.2%), 102.6% (90% CI: 100.0%-105.3%) and 102.8% (90% CI: 100.1%-105.5%). Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT05336071.

Triptan non-response in specialized headache care: cross-sectional data from the DMKG Headache Registry

BackgroundTriptans are effective for many migraine patients, but some do not experience adequate efficacy and tolerability. The European Headache Federation (EHF) has proposed that patients with lack of efficacy and/or tolerability of ≥ 2 triptans (‘triptan resistance’) could be considered eligible for treatment with the novel medications from the ditan and gepant groups. There is little data on the frequency of ‘triptan resistance’.MethodsWe used patient self-report data from the German Migraine and Headache Society (DMKG) Headache Registry to assess triptan response and triptan efficacy and/or tolerability failure.Results A total of 2284 adult migraine patients (females: 85.4%, age: 39.4 ± 12.8 years) were included. 42.5% (n = 970) had failed ≥ 1 triptan, 13.1% (n = 300) had failed ≥ 2 triptans (meeting the EHF definition of ‘triptan resistance’), and 3.9% (n = 88) had failed ≥ 3 triptans. Compared to triptan responders (current use, no failure, n = 597), triptan non-responders had significantly more severe migraine (higher frequency (p < 0.001), intensity (p < 0.05), and disability (p < 0.001)), that further increased with the level of triptan failure. Responders rates were highest for nasal and oral zolmitriptan, oral eletriptan and subcutaneous sumatriptan.ConclusionIn the present setting (specialized headache care in Germany), 13.1% of the patients had failed ≥ 2 triptans. Triptan failure was associated with increased migraine severity and disability, emphasizing the importance of establishing an effective and tolerable acute migraine medication. Acute treatment optimization might include switching to one of the triptans with the highest responder rates and/or to a different acute medication class.Trial registrationThe DMKG Headache Registry is registered with the German Clinical Trials Register (DRKS 00021081).

A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135–369 L/h with simnotrelvir alone, and decreased significantly to 19.5–29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.

Pharmacokinetic boosting of olaparib: A randomised, cross-over study (PROACTIVE-study)

BackgroundPharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose. MethodsThis cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC0–12 h) within no-effect boundaries. These boundaries were set at 0.57–1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets. ResultsOf 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC0–12 h was 1.45 (90% CI 1.27–1.65). No grade ≥3 adverse events were reported during the study. ConclusionsBoosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established.

Особливості управління болем у вагітних та породіль

Purpose - to evaluate the efficacy and adverse side effects (if any) of intravenous infusion of 1000 mg paracetamol as a method of pain relief in labour during the active phase of labour and in the postoperative period after caesarean section. Materials and methods. 43 pregnant women in the first stage of labor with active labor were studied. The selection criteria were healthy low-risk first-term mothers; aged 18-35 years; with spontaneous onset of labor at 37-40 weeks of pregnancy; the first period of labor with the opening of the cervix by 3-5 cm; one live fruit; main presentation Infulgan inf. solution was chosen as a paracetamol preparation 10 mg/ml per 100 ml. Multimodal anesthesia with a combination of the drugs Infulgan (paracetamol) and Keydex (dexketoprofen) was performed for postoperative analgesia. The pain intensity indicator was determined using the visual analog scale (VAS) - a method of subjective pain assessment. The patient marked a point on a non-graduated ruler 10 cm long, which corresponds to the degree of severity of pain. During the dynamic evaluation of changes in pain intensity, they were considered objective and significant if the true VAS value differed from the previous one by more than 1.3 cm. The comparison group consisted of 20 pregnant women in the 1st stage of labor who did not receive anesthesia at their own request. Also, a study of the effectiveness of complex multimodal anesthesia (Infulgan (paracetamol) and Keydex (dexketoprofen)) was conducted in 5 (11.6%) women in labor after delivery by caesarean section. Results. The use of intravenous paracetamol injection for analgesia during labor is an effective analgesia. There was an initial but significant decrease in the VAS score 30 minutes after Infulgan administration and a statistically significant decrease in pain after 2, 3 and 4 hours compared with the VAS score before treatment. In the group of women who did not undergo analgesia, the intensity of the pain syndrome steadily increased. In the postoperative period, after caesarean section, women underwent combined analgesia with the use of Infulgan (paracetamol) drugs as the basic component of multimodal analgesia and Keydex (dexketoprofen) as a necessary step of multimodal analgesia. The above-mentioned combination of drugs allows for Step-Up analgesia - step-by-step pain therapy. Infulgan was administered in 1 vial (1000 mg) every 6 hours by intravenous injection, and Keydex - in 1 ampoule every 8 hours by intramuscular injection. The addition of Keydex (dexketoprofen) to the analgesia provided an adequate analgesic effect and did not require the administration of opioid analgesics in the postoperative period. Conclusions. Intravenous paracetamol is an effective non-opioid drug for the relief of labor pain without any significant side effects for mother and fetus. The absence of any maternal side effects (sedation, respiratory depression, delayed gastric emptying, nausea and vomiting) or neonatal side effects (respiratory depression and decreased Apgar scores) associated with opioids allows us to recommend Infulgan for the relief of labor pain. The step-by-step Step-Up pain therapy in the postoperative period allows you to reduce the doses of each of the analgesics and reduce the frequency and side effects of the drugs. The use of Infulgan and Keydex as a method of pain management by means of Step-Up analgesia in the postoperative period in parturient women showed high efficiency, adequate tolerability and patient’s satisfaction. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Low Doses of Melatonin to Improve Sleep in Children with ADHD: An Open-Label Trial.

Only a few studies assessing the sleep effects of low doses of melatonin (aMT) have been performed in the past, most of them in adults, and only one in subjects with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to provide evidence of the changes induced by aMT doses as low as 1 mg in the sleep pattern of pediatric patients with ADHD under treatment with methylphenidate (MPH). Children and adolescents (7-15 years) with ADHD who were receiving extended-release MPH were recruited. A seven-week sleep diary was collected prior to starting a four-week treatment with 1 mg of aMT (30 min before bedtime). Seven-day actigraphic assessments of sleep were performed before and after treatment. Twenty-seven patients (17 males, 62.96%) participated in the study, who had been receiving MPH for 1.57 (1.11) months. A significant increase in sleep duration (TST) was observed after one month of treatment (463 (49) min to 485 (41) min; p < 0.040), with nonsignificant improvements in sleep-onset latency (SOL), nocturnal awakenings, or sleep efficiency. Only minor adverse effects were reported. Low doses of melatonin (1 mg) are able to increase TST in children and adolescents with ADHD receiving treatment with psychostimulants, with an adequate tolerability profile. Further placebo-controlled trials adjusting the time of aMT administration to the individual circadian profile should explore the effects of low doses of this hormone to shorten SOL in this population of patients.

BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study.

3001 Background: BL-B01D1 is a first-in-class novel ADC consisting of an EGFRxHER3 bispecific antibody linked to a novel TOP-I inhibitor payload via a cleavable linker. We now present safety/efficacy results from a FIH phase I study of BL-B01D1. Methods: This study included patients (pts) with locally advanced or metastatic solid tumors. For dose escalation (D-ESC, i3+3), BL-B01D1 was administered intravenously at doses of 0.27, 1.5, 3.0 mg/kg QW, 2.5, 3.0, 3.5mg/kg D1D8 Q3W or 4.5, 5.0, 6.0 mg/kg D1 Q3W. A subset of pts were enrolled into dose-expansion (D-EXP) at Q3W regimens. Results: As of Dec 31, 2022, 150 pts were enrolled and received at least one dose (D-ESC, n=25; D-EXP, n=125). DLTs were neutropenia, febrile neutropenia and thrombocytopenia at 3.0mg/kg QW and 3.5mg/kg D1D8 Q3W. The MTDs were determined to be 3.0mg/kg D1D8 Q3W and 6.0mg/kg D1 Q3W. D-EXP was carried out at 2.5, 3.0mg/kg D1D8 Q3W and 4.5, 5.0, 6.0 mg/kg D1 Q3W. 144 pts were enrolled across all Q3W dose levels (D-ESC and D-EXP), including 89 NSCLC, 7 SCLC, 27 nasopharyngeal cancer (NPC), 19 HNSCC and 2 others. Most common TRAEs (&gt;10%, all grade / ≥ G3) were leukopenia (60%/30%), neutropenia (51%/34%), anemia (45%/15%), thrombocytopenia (44%/19%), alopecia (30%/0%), nausea (29%/&lt;1%), vomiting (28%/0%), asthenia (21%/&lt;1%), decreased appetite (22%/&lt;1%), asthenia (21%/&lt;1%), hypophagia (16%/0%), diarrhoea (15%/2%), mouth ulceration (15%/&lt;1%), rash (13%/0%). No ILD was observed. 122 pts were evaluable for efficacy (at least 1 tumor assessment). PK and other details will be updated in the meeting. Conclusions: BL-B01D1 demonstrated encouraging efficacy in heavily pretreated metastatic/locally advanced solid tumors, especially in pts with EGFRm NSCLC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05194982 . [Table: see text]

Phase 1b/2 study of abemaciclib combined with chemoimmunotherapy in pediatric and young adult patients with relapsed/refractory neuroblastoma (JPCS Part C).

TPS10068 Background: Survival for high-risk neuroblastoma (NBL) remains poor with over 50% of patients experiencing disease relapse. The addition of dinutuximab (DIN) and granulocyte macrophage colony-stimulating factor (GM-CSF) to irinotecan (IRN) and temozolomide (TMZ) in patients with first relapse achieved an overall response rate of 42% in the study ANBL12211 and is now standard of care. However, there remains a significant unmet need to improve outcomes for children with relapsed/refractory NBL. Deregulation of the Cyclin D/cyclin-dependent kinase (CDK) 4 &amp; 6 pathway has been observed in NBL, rendering CDK4 &amp; 6 inhibition logical to explore. Abemaciclib is an orally administered, selective CDK4 &amp; 6 inhibitor approved to treat breast cancer. JPCS (NCT04238819) is designed to assess the pharmacokinetics, safety, and tolerability of abemaciclib added to standard treatment regimens for relapsed/refractory pediatric solid tumors. Part A defined the recommended phase 2 dose (RP2D) of abemaciclib in combination with IRN and TMZ. In Part C, the addition of DIN + GM-CSF to the JPCS Part A regimen will be evaluated. The co-primary objectives of Part C are to determine the RP2D and to estimate the anti-tumor activity of abemaciclib added to the ANBL1221 chemoimmunotherapy backbone in patients with first relapse/refractory NBL. Methods: JPCS Part C is a two-stage, non-randomized, open-label, Phase 1b/2 study for patients &lt; 21 years of age with first relapse/refractory NBL. Stage 1 aims to identify the maximum tolerated dose (MTD) of abemaciclib at a starting dose of 55 mg/m2 combined with DIN, GM-CSF, IRN and TMZ using a 3+3 design. One dose de-escalation (30 mg/m2) will be possible if the starting dose is not tolerated. Further tolerability and initial anti-tumor activity will be evaluated in an expansion cohort at the MTD. Up to 11 evaluable patients will enroll in Stage 1 at the MTD; the MTD will be declared the RP2D if adequate safety and tolerability are observed and ≥6 patients achieve minimal response or better per International Neuroblastoma Response Criteria (INRC). Following determination of the RP2D, Stage 2 will enroll 35 patients. If ≥26 of 46 total patients achieve an INRC minimum response or better, further investigation of this regimen could be warranted. As of 31 Jan 2023, Part C is open for enrollment at one site (US) and additional sites are being evaluated.

Prospective study of the modified Atkins diet in adult drug-resistant epilepsy: effectiveness, tolerability, and adherence

IntroductionDrug-resistant epilepsy presents high worldwide prevalence and is difficult to control despite the wide variety of available antiepileptic drugs (AED). The modified Atkins diet (MAD) is an additional treatment alternative. Several studies have addressed the use of the ketogenic diet and MAD in children with drug-resistant epilepsy, but insufficient research has been conducted into adults with the same condition. ObjectiveTo evaluate the effectiveness and tolerability of, and adherence to, the MAD in adults with drug-resistant epilepsy. Material and methodsWe conducted a 6-month pre-post prospective study at a reference hospital. Patients were prescribed the MAD with limited carbohydrate intake and unlimited fat intake. We conducted clinical and electroencephalographic follow-up according to the relevant guidelines, and assessed adverse effects changes in laboratory findings, and adherence. ResultsThirty-two patients with drug-resistant epilepsy were included in the study. Patients’ mean age was 30 years, mean disease progression time was 22 years, and all patients had focal or multifocal epilepsy. Thirty-four percent of patients presented > 50% decreases in overall seizure frequency (P = .001); seizure control was greater in the first month and subsequently declined. These patients presented weight loss (RR: 7.2; 95% CI, 1.3–39.5; P = .02), good to fair adherence only in the first and third months (RR: 9.4; 95% CI, 0.9–93.6; P = .04 and RR: 0.4; 95% CI, 0.30−0.69; P = .02, respectively). Tolerability data showed that the MAD is safe: adverse effects were minor and short-lived in most cases, with the exception of mild to moderate hyperlipidaemia in one-third of patients. The adherence rate was 50% at the end of the study. ConclusionsIn adults with drug-resistant focal epilepsy, the MAD showed adequate tolerability and moderate but decreasing effectiveness and adherence, probably due to a preference for a carbohydrate-based diet.

Safety of opicapone after 5 years of post-marketing experience worldwide (P14-11.013)

<h3>Objective:</h3> Review the safety data of opicapone (OPC) after five years of marketing experience worldwide. <h3>Background:</h3> OPC is a once-daily catechol-O-methyltransferase (COMT) inhibitor proven to be effective in PD patients with motor fluctuations. OPC marketing authorisation was first granted on 24 June 2016 (EU). It was launched in October 2016 and is currently marketed in over 18 countries worldwide (including the US since September 2020). <h3>Design/Methods:</h3> Patient exposure to marketed OPC was estimated based on worldwide ex-factory sales cumulatively until 30 September 2021 (assuming the ex-factory amounts delivered were entirely dispensed and administered, and were used at the dosage of 1 hard capsule/day). From the first marketing authorisation until 30 September 2021, safety data was pooled and analysed from global post-marketing sources, including spontaneous, health authorities, literature reports, and non-interventional studies. Cumulative summary tabulations of adverse events arranged by primary System Organ Class (SOC) and preferred terms within each SOC were retrieved and sorted. <h3>Results:</h3> The estimated patient exposure was 1 413 624 patient-months during the period, corresponding to 117 802 patient-years. In the 5-year period, 4035 events were reported, 545 (13.5%) serious and 3490 (86.5%) non-serious. This corresponds to an incidence of 34.3 reports per 1000 patient-years. The 5 SOCs with the highest number of events were “Nervous system disorders”, “General disorders and administration site conditions”, “Psychiatric disorders”, “Gastrointestinal disorders” and “Surgical and medical procedures”. The 10 most frequently reported adverse events were “Dyskinesia”, “Muscle rigidity”, “Hallucination”, “Bradykinesia”, “Constipation”, “Tremor”, “Gait disturbance”, “Freezing phenomenon”, “Sleep disorder” and “Reduced facial expression”. <h3>Conclusions:</h3> Safety reports during 5 years of post-marketing experience with OPC were uncommon, and mostly refer to non-serious adverse events. Motor-symptoms of PD were among the most frequently reported adverse events. No new relevant safety concern was identified. OPC continues to have an adequate safety and tolerability profile with a favourable benefit-risk ratio. <b>Disclosure:</b> Mr. Guedes has received personal compensation for serving as an employee of BIAL - Portela &amp; C.ª, S.A.. Joana Graça has received personal compensation for serving as an employee of BIAL - Portela &amp; C.ª, S.A.. Ms. Sampaio has nothing to disclose. Mariana Vieira has received personal compensation for serving as an employee of Bial - Portela &amp; Cª, S.A.. Francisco Rocha has received personal compensation for serving as an employee of BIAL - Portela. Helena Gama has received personal compensation for serving as an employee of Bial-Portela &amp; Cª S.A..

Observation study of using a small dose of rituximab treatment for thyroid-associated ophthalmopathy in seven Chinese patients: One pilot study.

To report the efficacy, long-term safety, and tolerability of using a small dose (125 mg/m2 weekly for 4 weeks) of rituximab to treat Chinese patients with thyroid-associated ophthalmopathy (TAO). Seven patients with active moderate-to-severe TAO were prospectively recruited in this study. A small dose of rituximab (125mg/m2 body surface area) was given weekly with a duration of four weeks. Thyroid function, thyrotropin receptor antibody (TRAb), B cell and T cell subsets, ophthalmological examination, magnetic resonance imaging derived parameters, and adverse reactions were recorded at each visit. Seven patients were followed for an average of 224 weeks. B-cell depletion was observed in all patients following rituximab infusion. The clinical activity score (CAS) decreased from 4.86 ± 0.69 to 3.00 ± 0.82 at 5 weeks after treatment (P = 0.033) and remained significantly lower than baseline values at the end of follow-up (P = 0.001). Compared to baseline values, significant decreases in exophthalmos of the right eye, the thickness of extraocular muscles with maximum signal intensity, and the highest signal intensity ratio (SIR) of extraocular muscle to ipsilateral temporal muscle values were observed at the last follow-up (all P < 0.05). Disease progressions or recurrences were not observed during follow-up. Only mild fatigue was observed after the first infusion as a side effect (n = 1). Small dose of rituximab may be a promising option with adequate safety, tolerability, and long-term efficacy for patients with active moderate-to-severe TAO.

Rhopressa Clinical Use: A Case Series

Purpose. The aim of this paper is to discuss and highlight via case reports the effective use of Rhopressa in three individual cases of Primary Open-Angle Glaucoma (POAG) treated at a glaucoma clinic in Philadelphia, PA, USA. The cases display the clinical use of netarsudil and reviews therapeutic approach- es to combating the side effects of conjunctival hyperemia associated with netarsudil. Material and Methods. A systematized PubMed literature search based on the terms “Rhopressa”, “netarsudil”, “ROCK inhibition” was conducted. Six eyes of three adult patients were monitored for three months after beginning treatment with Rhopressa (0.02 % netasurdil ophthalmic solution, Aerie Pharmaceuticals Inc, Durham, NC, 2018). Results. In all three cases, an efficacious response was achieved with all three patients obtaining an intraocular pressure of 13 mmHg or lower. In two out of three cases the patients were taking three or more medications prior to the addition of Rhopressa (0.02 % netasurdil ophthalmic solution, Aerie Pharmaceuticals Inc, Durham, NC, 2018). Two eyes out of six possessed a stage of severe glaucoma and two out of six eyes previously underwent multiple surgical glaucoma interventions. Conclusion. A desirable intraocular pressure reduction was found in all six eyes out of three patients with an accept- able tolerability of use of the medication. Rhopressa (0.02 % netasurdil ophthalmic solution, Aerie Pharmaceuticals Inc, Durham, NC, 2018) is a viable and effective adjunct therapy for the treatment of open-angle glaucoma with adequate patient tolerability. Keywords Primary Open Angel Glaucoma (POAG), glaucoma treatment, intraocular pressure, Rhopressa

Tolerability and Reactogenicity Profile of mRNA SARS-Cov-2 Vaccines from a Mass Vaccination Campaign in a Tertiary Hospital: Between-Vaccine and Between-Population Prospective Observational Study (VigilVacCOVID Study).

BackgroundThe comparative safety profile of SARS-Cov2 vaccines requires further characterization in real-world settings.ObjectivesThe aim of the VigilVacCOVID study was to assess the short-term safety of BNT162b2 and mRNA-1273 during the vaccination campaign of healthcare professionals (HCPs) and solid-organ transplant recipients (SOTRs) at a hospital clinic.MethodsWe conducted an observational, prospective, single-center, post-authorization study to characterize short-term adverse reactions (ARs) after vaccination. The primary endpoint was to assess between-vaccine differences (HCPs receiving BNT162b2 or mRNA-1273) and between-population differences (HCPs and SOTRs, both receiving mRNA-1273) in the risk of any ARs. Propensity score and covariate-adjusted multivariate models were used. The key secondary endpoint was to provide a descriptive assessment of the frequencies and intensity distribution of ARs.ResultsWe included 5088 HCPs and 1289 patients. mRNA-1273 showed greater reactogenicity than BNT162b2, with an odds ratio (OR) for any AR of 3.04 (95% confidence interval (CI) 2.48–3.73; p value: < 0.001) and a higher frequency and intensity of reported ARs. Compared with HCPs vaccinated with mRNA-1273, SOTRs showed a lower risk of ARs (OR = 0.36; 95% CI 0.25–0.50), with fewer and less severe ARs. Age, sex, and previous SARS-CoV-2 infection were statistically significant covariates for the risk of any AR. A history of drug allergy was significant in the comparison between vaccines (BNT162b2 vs. mRNA-1273), but not in that between SOTRs and HCPs.ConclusionsOur study shows that mRNA-1273 had greater reactogenicity than BNT162b2. Overall, both vaccines had an adequate tolerability profile. mRNA-1273 vaccination caused fewer ARs with milder severity in SOTRs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40259-022-00543-9.

A rational pharmacovigilance safety appraisal of topical pefloxacin 0.3% ophthalmological drops in bacterial conjunctivitis, in global multi-centre tertiary care hospitals

Background: Pefloxacin is a newer broad-spectrum bactericidal fluoroquinolone antibiotic, with superior antibacterial activity in vivo against pathogenic ocular gram-negative and anaerobic microorganisms and better pharmacokinetic properties. The objective of this clinical research study was the rational pharmacovigilance safety appraisal of topical pefloxacin 0.3% ophthalmological drops in bacterial conjunctivitis, in global multi-centre tertiary care hospitals.Methods: The 43 bacterial conjunctivitis patients were prescribed topical pefloxacin 0.3% ophthalmological drops, 2 drops in each eye after every 3 hours for 2 days, and 2 drops in each eye after every 6 hours for next 5 days. The pharmacovigilance safety appraisal was performed by monitoring the occurrence of adverse drug reactions, like, transient ocular burning or discomfort, ocular irritation, redness, stinging, pruritis, photophobia, ocular watering and dryness, and recording in Adverse Event Case Report Forms, on days 0, 3, 5, 7, 10, 15, 30, and on further follow-ups.Results: In this study, the safety assessment showed that only 1 patient had ocular discomfort in the eye. The occurrence of adverse effects was statistically non-significant. Thus, 0.3% pefloxacin ophthalmological drops treatment was safe and tolerable, among all 43 patients.Conclusions: Therefore, pefloxacin is a safe ocular antibiotic for treating bacterial conjunctivitis, with adequate drug tolerability exhibited by the patients.