Long-Term Immunogenicity and Safety of a Homologous Third Dose Booster Vaccination with TURKOVAC: Phase 2 Clinical Study Findings with 32-Week Post-Booster Follow-Up.

Vaccine-induced immunity wanes over time and warrants booster doses. We investigated the long-term (32 weeks) immunogenicity and safety of a third, homologous, open-label booster dose of TURKOVAC, administered 12 weeks after completion of the primary series in a randomized, controlled, double-blind, phase 2 study. Forty-two participants included in the analysis were evaluated for neutralizing antibodies (NAbs) (with microneutralization (MNT50) and focus reduction (FRNT50) tests), SARS-CoV-2 S1 RBD (Spike S1 Receptor Binding Domain), and whole SARS-CoV-2 (with ELISA) IgGs on the day of booster injection and at weeks 1, 2, 4, 8, 16, 24, and 32 thereafter. Antibody titers increased significantly from week 1 and remained higher than the pre-booster titers until at least week 4 (week 8 for whole SARS-CoV-2) (p < 0.05 for all). Seroconversion (titers ≥ 4-fold compared with pre-immune status) persisted 16 weeks (MNT50: 6-fold; FRNT50: 5.4-fold) for NAbs and 32 weeks for S1 RBD (7.9-fold) and whole SARS-CoV-2 (9.4-fold) IgGs. Nine participants (20.9%) tested positive for SARS-CoV-2 RT-PCR between weeks 8 and 32 of booster vaccination; none of them were hospitalized or died. These findings suggest that boosting with TURKOVAC can provide effective protection against COVID-19 for at least 8 weeks and reduce the severity of the disease.

Bioequivalence Study of Capsules versus Film Tablets Containing Rivaroxaban in Healthy Caucasian Subjects under Fasting and Fed Conditions.

The bioequivalence (BE) of orally administered capsules versus film tablets containing 20  and 10 mg of rivaroxaban was assessed in 2 single-dose, open-label, randomized 2-way crossover trials with a washout period of at least 1 week. The study for the 10 mg strength was conducted under fasting conditions (n = 68) and the study for the 20 mg strength under fed conditions (n = 52). Blood samples were collected over a 36-hour period and concentrations were assayed using a liquid chromatography tandem mass spectrometry method. Pharmacokinetic (PK) evaluation was performed with the program Phoenix WinNonlin, for non-compartmental assessment of data. After administration of 10 mg rivaroxaban under fasting conditions, mean Area Under the time - concentration Curve until the last blood sampling point (AUCt ), Area Under the time - concentration Curve until infinity (AUC∞ ), and maximum plasma concentration (Cmax ) were comparable (972 ng/mL*h, 1048 ng/mL*h, and 111 ng/mL, respectively, for the test and 1013 ng/mL*h, 1070 ng/mL*h and 130 ng/mL, respectively, for the reference formulation). Mean AUCt , AUC∞ , and Cmax were also comparable under fed conditions after administration of 20 mg rivaroxaban (2145 ng/mL*h, 2198 ng/mL*h and 275 ng/mL, respectively, for the test and 1856 ng/mL*h, 1916 ng/mL*h and 240 ng/mL, respectively, for the reference formulation). The 90% confidence intervals for all PK parameters were within the acceptance range of 80%-125%, suggesting BE between the generic product and the innovator product in healthy Caucasian male subjects. A clinically relevant difference in the tolerability and safety of the treatments was not detected. Study results indicated that the capsule formulations were bioequivalent with the film tablet formulations.

Long-Term Results of Immunogenicity of Booster Vaccination against SARS-CoV-2 (Hybrid COV-RAPEL TR Study) in Turkiye: A Double-Blind, Randomized, Controlled, Multicenter Phase 2 Clinical Study.

The immunogenicity of vaccines decreases over time, causing a need for booster doses. This study aimed to present the long-term (Day 84) immunogenicity results of the double-blind, randomized, controlled, phase II Hybrid COV-RAPEL TR Study (NCT04979949), in which the TURKOVAC or CoronaVac vaccines were used as a booster after the second dose of primary vaccination with CoronaVac. A total of 190 participants from the Hybrid COV-RAPEL TR Study, who had both Day 28 and Day 84 immunogenicity results, were included. The immunogenicity on Day 84, regarding the neutralizing antibody positivity (Wuhan and Delta variants) and anti-spike immunoglobulin (Ig) G (IgG) antibody positivity, was compared between TURKOVAC and CoronaVac vaccine arms according to sex and age groups. Overall, antibody positivity showed a slight decrease on Day 84 vs. Day 28, but was not different between TURKOVAC and CoronaVac arms either for sexes or for age groups. However, TURKOVAC produced better antibody response against the Delta variant than CoronaVac, while CoronaVac was superior over TURKOVAC regarding neutralizing antibody positivity in the 50-60 years age group, regardless of the variant. A single booster dose, after the completion of the primary vaccination, increases antibody positivity on Day 28 which persists until Day 84 with a slight decrease. However, an additional booster dose may be required thereafter, since the decrease in antibody titer may be faster over time.

Safety and Efficacy of a Novel Combination Cream (GN-037) in Healthy Volunteers and Patients with Plaque Psoriasis: A Phase 1 Trial.

INTRODUCTION: Psoriasis is a common skin disorder associated with physical and psychological burdens. Visible disfiguration can trigger a negative reaction which can cause much of the readily measurable psychological burden of the disease. Although many biological treatments provide some success in the initial clearance of lesions, there is a dispute about the long-term maintenance of the disease, as no current biological treatment has been shown to be curative. Topical therapies are still the most widely used agents as first-line and maintenance treatment for psoriasis. The present study aimed to investigate the safety, tolerability, and, to some extent, efficacy of GN-037 cream in patients with psoriasis and healthy volunteers. METHODS: A randomized, double-blind, single-center, placebo-controlled phase 1 clinical study was conducted to evaluate the safety, tolerability, and clinical efficacy of GN-037 cream topically applied twice daily for 2 weeks in healthy subjects (n = 12) and patients (n = 6) diagnosed with plaque-type psoriasis. Six healthy subjects received placebo. Patients with plaque psoriasis were evaluated by a dermatologist, and Physician Global Assessment (PGA) score was required to be ≥ 3 (moderate psoriasis) at screening. RESULTS: A total of 31 adverse events (AEs) occurred in 13 participants during the study: 9 AEs in healthy subjects receiving GN-037 cream, 3 AEs in healthy subjects receiving placebo, and 1 AE in one psoriatic patient. The most frequently reported AEs were reactions at the application site, including erythema, exfoliation, pruritus, and burning sensation. During the baseline evaluation, one patient had a PGA score of 3 (moderate) and five patients had a PGA score of 4 (severe). On day 14, in treatment, four patients experienced second grade and two patients third grade improvements compared with baseline, indicating a shift of patients from moderate and severe disease to mild disease and to almost clear (score 2 or 1). There were slight increases in plasma tumor necrosis factor (TNF)-α, interleukin-17 (IL-17) and interleukin-23 (IL-23) levels in both healthy volunteers and patients throughout the study, as compared with baseline. CONCLUSION: The results of this phase 1 trial conducted in 18 healthy volunteers and 6 patients with plaque psoriasis demonstrated a favorable safety and tolerability profile for GN-037; therefore, further clinical development of GN-037 in a phase 2 clinical trial has been initiated in patients with mild to moderate plaque psoriasis (NCT05706870). TRIAL REGISTRATION NUMBER: NCT05428202.

Safety and immunogenicity of an inactivated whole virion SARS-CoV-2 vaccine, TURKOVAC, in healthy adults: Interim results from randomised, double-blind, placebo-controlled phase 1 and 2 trials.

BACKGROUND: Development of safe and effective vaccine options is crucial to the success of fight against COVID-19 pandemic. Herein, we report interim safety and immunogenicity findings of the phase 1&2 trials of ERUCoV-VAC, an inactivated whole virion SARS-CoV-2 vaccine. METHODS: Double-blind, randomised, single centre, phase 1 and 2 trials included SARS-CoV-2 seronegative healthy adults aged 18-55 years (18-64 in phase 2). All participants, except the first 4 in phase 1 who received ERUCoV-VAC 3 µg or 6 µg unblinded and monitored for 7 days for safety purposes, were assigned to receive two intramuscular doses of ERUCoV-VAC 3 µg or 6 µg (an inactivated vaccine containing alhydrogel as adjuvant) or placebo 21 days apart (28 days in phase 2) according to computer-generated randomisation schemes. Both trials are registered at ClinicalTrials.gov (phase 1, NCT04691947 and phase 2, NCT04824391). RESULTS: Forty-four participants (3 µg [n:17], 6 µg [n:17], placebo [n:10]) in phase 1 and 250 (3 µg [n:100], 6 µg [n:100], placebo [n:50]) in phase 2 received ≥1 dose. In phase 1 trial, 25 adverse events AEs (80 % mild) occured in 15 participants (34.1 %) until day 43. There was no dose-response relationship noted in safety events in ERUCoV-VAC recipients (p = 0.4905). Pain at injection site was the most common AE (9/44;20.5 %). Both doses of ERUCoV-VAC 3 µg and 6 µg groups were comparable in inducing SARS-CoV-2 wild-type neutralising antibody (MNT50): GMTs (95 %CI) were 8.3 (6.4-10.3) vs. 8.6 (7.0-10.2) at day 43 (p = 0.7357) and 9.7 (6.0-13.4) vs. 10.8 (8.8-12.8) at day 60 (p = 0.8644), respectively. FRNT50 confirmed MNT50 results: SARS-CoV-2 wild-type neutralising antibody GMTs (95 %CI) were 8.4 (6.3-10.5) vs. 9.0 (7.2-10.8) at day 43 (p = 0.5393) and 11.0 (7.0-14.9) vs. 12.3 (10.3-14.5) at day 60 (p = 0.8578). Neutralising antibody seroconversion rates (95 %CI) were 86.7 % (59.5-98.3) vs 94.1 % (71.3-99.8) at day 43 (p = 0.8727) and 92.8 % (66.1-99.8) vs. 100 % (79.4-100.0) at day 60 (p = 0.8873), in ERUCoV-VAC 3 µg and 6 µg groups, respectively. In phase 2 trial, 268 AEs, (67.2 % moderate in severity) occured in 153 (61.2 %) participants. The most common local and systemic AEs were pain at injection site (23 events in 21 [8.4 %] subjects) and headache (56 events in 47 [18.8 %] subjects), respectively. Pain at injection site was the only AE with a significantly higher frequency in the ERUCoV-VAC groups than in the placebo arm in the phase 2 study (p = 0.0322). ERUCoV-VAC groups were comparable in frequency of AEs (p = 0.4587). ERUCoV-VAC 3 µg and 6 µg groups were comparable neutralising antibody (MNT50): GMTs (95 %CI) were 30.0 (37.9-22.0) vs. 34.9 (47.6-22.1) at day 43 (p = 0.0666) and 34.2 (23.8-44.5) and 39.6 (22.7-58.0) at day 60, (p = 0.2166), respectively. FRNT50 confirmed MNT50 results: SARS-CoV-2 wildtype neutralising antibody GMTs were 28.9 (20.0-37.7) and 30.1 (18.5-41.6) at day 43 (p = 0.3366) and 34.2 (23.8-44.5) and 39.6 (22.7-58.0) at day 60 (p = 0.8777). Neutralising antibody seroconversion rates (95 %CI) were 95.7 % (91.4-99.8) vs. 98.9 % (96.9-100.0) at day 43 (p = 0.8710) and 96.6 % (92.8-100.0) vs 98.9 % (96.7-100.0) at day 60 (p = 0.9129) in ERUCoV-VAC 3 µg and 6 µg groups, respectively. CONCLUSIONS: Two-dose regimens of ERUCoV-VAC 3 µg and 6 µg 28 days both had an acceptable safety and tolerability profile and elicited comparable neutralising antibody responses and seroconversion rates exceeding 95 % at day 43 and 60 after the first vaccination. Data availability Data will be made available on request.

Efficacy, Immunogenicity, and Safety of the Two-Dose Schedules of TURKOVAC versus CoronaVac in Healthy Subjects: A Randomized, Observer-Blinded, Non-Inferiority Phase III Trial.

We present the interim results of the efficacy, immunogenicity, and safety of the two-dose schedules of TURKOVAC versus CoronaVac. This was a randomized, observer-blinded, non-inferiority trial (NCT04942405). Volunteers were 18-55 years old and randomized at a 1:1 ratio to receive either TURKOVAC or CoronaVac at Day 0 and Day 28, both of which are 3 µg/0.5 mL of inactivated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) adsorbed to aluminum hydroxide. The primary efficacy outcome was the prevention of polymerase chain reaction (PCR)-confirmed symptomatic coronavirus disease 2019 (COVID-19) at least 14 days after the second dose in the modified per-protocol (mPP) group. Safety analyses were performed in the modified intention-to-treat (mITT) group. Between 22 June 2021 and 7 January 2022, 1290 participants were randomized. The mITT group consisted of 915 participants, and the mPP group consisted of 732 participants. During a median follow-up of 90 (IQR 86-90) days, the relative risk reduction with TURKOVAC compared to CoronaVac was 41.03% (95% CI 12.95-60.06) for preventing PCR-confirmed symptomatic COVID-19. The incidences of adverse events (AEs) overall were 58.8% in TURKOVAC and 49.7% in CoronaVac arms (p = 0.006), with no fatalities or grade four AEs. TURKOVAC was non-inferior to CoronaVac in terms of efficacy and demonstrated a good safety and tolerability profile.

Safety and immunogenicity of inactive vaccines as booster doses for COVID-19 in Türkiye: A randomized trial.

Protective neutralizing antibody titers reduce in time after COVID-19 vaccinations, as in individuals who have had COVID-19. This study aimed to evaluate the safety and immunogenicity of CoronaVac and TURKOVAC vaccines used as a booster dose after CoronaVac primary vaccination. This double-blind, randomized, controlled, phase II, multicenter study included healthy male and female adults (18-60 years) who were vaccinated with two doses of CoronaVac vaccine and did not exceed the duration of at least 90 days and a maximum of 270 days from the second dose of vaccination. Among 236 eligible volunteers, 222 were recruited for randomization between July 12, 2021 and September 10, 2021; 108 and 114 were randomized to the TURKOVAC and CoronaVac arms, respectively. The primary endpoint was adverse events (AEs) (ClinicalTrials.gov; Identifier: NCT04979949). On day 28, at the neutralizing antibody threshold of 1/6, the positivity rate reached 100% from 46.2% to 98.2% from 52.6% in the TURKOVAC and CoronaVac arms, respectively, against the Wuhan variant and the positivity rate reached 80.6% from 8.7% in the TURKOVAC arm vs. 71.9% from 14.0% in the CoronaVac arm against the Delta variant. IgG spike antibody positivity rate increased from 57.3% to 98.1% and from 57.9% to 97.4% in the TURKOVAC and CoronaVac arms, respectively. The TURKOVAC and CoronaVac arms were comparable regarding the frequency of overall AEs. Both vaccines administered as booster yielded higher antibody titers with acceptable safety profiles.

What is the context? The timing of the primary and booster doses for each vaccine differs.We aimed to evaluate the safety and immunogenicity of CoronaVac and TURKOVAC vaccines used as homologous booster dose after CoronaVac primary vaccination.What is new? The neutralizing antibody titers against the Wuhan variant decreased below 1/6- the seropositivity threshold value- in more than 55% of the participants 4 months after administration of two doses of CoronaVac vaccine.Immunogenicity was re-stimulated and the neutralizing antibody titers increased rapidly and markedly with the administration of the CoronaVac or TURKOVAC as a booster dose 4 months after the second dose.While the increase in neutralizing antibodies against the Wuhan variant was similar with both CoronaVac and TURKOVAC, more antibodies developed against the Delta variant with TURKOVAC.What is the impact? With the Hybrid COV-RAPEL TR study, after the primary vaccination consisting of two doses of inactivated vaccine, antibody titers decreased in the long term; however, higher antibody titers are achieved than the primary vaccination after the booster dose administered after 4­6 month interval.Booster application with TURKOVAC provides antibodies at least as much as the CoronaVac booster dose, with an acceptable safety profile.

Indomethacin prevents TGF-ß-induced epithelial-to-mesenchymal transition in pancreatic cancer cells; evidence by Raman spectroscopy.

Pancreatic ductal adenocarcinoma (PDAC) has a very low survival rate due to the late detection and poor response to chemotherapy. Epithelial-to-mesenchymal transition (EMT) is considered an important step in tumor progression with regard to invasion and metastasis, and Transforming Growth Factor-beta (TGF-ß) signaling has been shown to play an important role in EMT. Therefore, we aimed to investigate whether indomethacin, an anti-inflammatory and analgesic drug, has any effect on TGF-ß-induced EMT in pancreatic cancer cell line and analyze the changes in their molecular structures by Raman spectroscopy and other molecular techniques. Indomethacin treated Panc-1 cells were analyzed with Raman spectroscopy, quantitative polymerase chain reaction and immunofluorescence techniques after the induction of EMT with TGF-ß. The exposure of Panc-1 cells to TGF-ß resulted in characteristic morphological alterations of EMT, and indomethacin inhibits TGF-ß-induced EMT through up-regulation of E-cadherin and down-regulation of N-cadherin and Snail expressions. Raman spectroscopy supported by principal component analysis (PCA) confirmed the effects of both TGF-ß and indomethacin. Raman spectra were further analyzed using the PCA-assisted vector machine algorithm and it was seen that the data could be classified with 97.6% accuracy. Our results suggest that indomethacin may have a significant effect on PDAC metastasis, and Raman spectroscopy was able to probe EMT-related changes and the efficacy of indomethacin in a short time and without the need for specific reagents compared to other molecular techniques.

Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice.

OBJECTIVES: Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. METHODS: In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 µg/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 µg/kg), intraperitoneally, 30 min before hot plate or holed open field tests. RESULTS: In the hot plate test in mice, co-administration of 15 µg/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. CONCLUSION: We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans.

Mirtazapine does not affect pentylenetetrazole- and maximal electroconvulsive shock-induced seizures in mice.

Mirtazapine is an antidepressant exhibiting both noradrenergic and serotonergic activity. We have investigated the effects of mirtazapine on pentylenetetrazole (PTZ)- and maximal electroconvulsive shock (MES)-induced seizures in mice. Mirtazapine (1.25-20mg/kg) or saline was administered, and locomotor activity was evaluated for 30 min. One hour after administration of mirtazapine (1.25-5mg/kg) or saline, PTZ (80 mg/kg) was injected intraperitoneally into the mice. Immediately afterward, times of onset of the first myoclonic jerk (FMJ), generalized clonic seizures (GCS), and tonic extension (TE) were recorded. In the MES groups, we used the MES protocol to induce convulsions characterized by tonic hindlimb extension. Similarly, 1h after mirtazapine or saline administration, an electroshock was evoked by ear-clip electrodes to induce convulsion. Mirtazapine, at 10 and 20 mg/kg, depressed locomotor activity. Doses of 1.25-5mg/kg had no significant effect on the time of onset of FMJ, GCS, or TE induced by PTZ; on the duration of GCS and TE; or on the latency to reinstatement of the righting reflex after MES administration. Our results suggest that mirtazapine neither aggravates nor alleviates PTZ- or MES-induced seizures in mice.

Comparing the relaxing effects of desflurane and sevoflurane on oxytocin-induced contractions of isolated myometrium in both pregnant and nonpregnant rats.

In this study, the effects of 2 volatile anesthetics, desflurane and sevoflurane, on oxytocin-induced contractions of isolated myometrium in pregnant and nonpregnant rats were compared. Twenty pregnant and 20 nonpregnant Wistar albino rats were studied at 19 to 20 days' gestation (term, 22 days). A total of 40 myometrial strips were obtained from pregnant and nonpregnant rats, and each of these was randomly assigned to 1 of 4 groups (n=10, each group). After spontaneous myometrial contractions were induced in the De Jalon solution, the effects of 0.5, 1, and 2 minimum alveolar anesthetic concentrations (MAC) of desflurane or sevoflurane, in the absence and presence of oxytocin (2 x 10(-9) M), were investigated. Oxytocin significantly increased the amplitude and duration of spontaneous contractions in longitudinal myometrial strips (P<.05), but not the frequency. Both agents (except for 0.5 MAC in the nonpregnant group) inhibited the duration, amplitude, and frequency of induced contractions in a dose-dependent manner. The inhibitory potencies of desflurane and sevoflurane were similar. It was found that isolated strips of pregnant rat myometrium were more sensitive to the inhibitory effects of both agents than were the nonpregnant rat myometrial strips.