Modulation of Arterial Stiffness Gradient by Acute Administration of Nitroglycerin

Background: Physiologically, the aorta is less stiff than peripheral conductive arteries, creating an arterial stiffness gradient, protecting microcirculation from high pulsatile pressure. However, the pharmacological manipulation of arterial stiffness gradient has not been thoroughly investigated. We hypothesized that acute administration of nitroglycerin (NTG) may alter the arterial stiffness gradient through a more significant effect on the regional stiffness of medium-sized muscular arteries, as measured by pulse wave velocity (PWV). The aim of this study was to examine the differential impact of NTG on regional stiffness, and arterial stiffness gradient as measured by the aortic-brachial PWV ratio (AB-PWV ratio) and aortic-femoral PWV ratio (AF-PWV ratio).Methods: In 93 subjects (age: 61 years, men: 67%, chronic kidney disease [CKD]: 41%), aortic, brachial, and femoral stiffnesses were determined by cf-PWV, carotid-radial (cr-PWV), and femoral-dorsalis pedis artery (fp-PWV) PWVs, respectively. The measurements were repeated 5 min after the sublingual administration of NTG (0.4 mg). The AB-PWV and AF-PWV ratios were obtained by dividing cf-PWV by cr-PWV or fp-PWV, respectively. The central pulse wave profile was determined by radial artery tonometry through the generalized transfer function.Results: At baseline, cf-PWV, cr-PWV, and fp-PWV were 12.12 ± 3.36, 9.51 ± 1.81, and 9.71 ± 1.89 m/s, respectively. After the administration of NTG, there was a significant reduction in cr-PWV of 0.86 ± 1.27 m/s (p < 0.001) and fp-PWV of 1.12 ± 1.74 m/s (p < 0.001), without any significant changes in cf-PWV (p = 0.928), leading to a significant increase in the AB-PWV ratio (1.30 ± 0.39 vs. 1.42 ± 0.46; p = 0.001) and AF-PWV ratio (1.38 ± 0.47 vs. 1.56 ± 0.53; p = 0.001). There was a significant correlation between changes in the AF-PWV ratio and changes in the timing of wave reflection (r = 0.289; p = 0.042) and the amplitude of the heart rate-adjusted augmented pressure (r = − 0.467; p < 0.001).Conclusion: This study shows that acute administration of NTG reduces PWV of muscular arteries (brachial and femoral) without modifying aortic PWV. This results in an unfavorable profile of AB-PWV and AF-PWV ratios, which could lead to higher pulse pressure transmission into the microcirculation.

DEVELOPMENT AND CHARACTERIZATION OF TACROLIMUS TABLET FORMULATIONS FOR SUBLINGUAL ADMINISTRATION

Objective: The study aimed to prepare and characterize inclusion complexes of tacrolimus with β-cyclodextrin to improve its solubility and to formulate them into sublingual fast disintegrating tablets with a view to bypass the first-pass metabolism. Methods: Tacrolimus: β-cyclodextrin inclusion complexes (1:1 and 1:2 molar proportions) were prepared using the kneading method. Their characterization was accomplished by determining the drug content, solubility, Attenuated Total Reflection-Infrared Spectroscopy (ATR-IR), Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), and powder X-Ray Diffraction analysis (pXRD). These were then formulated to fast disintegrating tablets and evaluated for precompression as well as post compressional characteristics. Results: SEM analysis showed the inclusion complexes as rough, non-porous, irregular surfaced aggregate particles. DSC and pXRD analyses confirm the crystallinity change and partial conversion to the amorphous form of the drug in the inclusion complexes. From the solubility studies, it was observed that both the inclusion complexes of 1:2 molar ratio (14.82±0.889 µg/ml) and 1:1 molar ratio (12.72±0.1004 µg/ml) improved the aqueous solubility to greater extents in comparison to that of the pure drug (3.05±0.121 µg/ml). All the tablet formulations showed good precompression and mechanical properties. The inclusion complex loaded tablets exhibited a superior drug release pattern when compared to tablets prepared with tacrolimus alone. The optimized formulation (TT3) showed an in vitro disintegration time of 34.33 s and a percent drug release of 97.87. Conclusion: The inclusion complex formulation combined with the sublingual route of administration can be expected to result in an improved bioavailability of tacrolimus by increasing its solubility and bypassing first-pass metabolism.

Sublingual Immunization with Chimeric C1q/CD40 Ligand/HIV Virus-like Particles Induces Strong Mucosal Immune Responses against HIV

Development of a vaccine that can elicit robust HIV specific antibody responses in the mucosal compartments is desired for effective prevention of HIV via sexual transmission. However, the current mucosal vaccines have either poor immunogenicity when administered orally or invite safety concerns when administered intranasally. Sublingual immunization has received more attention in recent years based on its efficiency in inducing systemic and mucosal immune responses in both mucosal and extra-mucosal tissues. To facilitate the transport of the immunogen across the sub-mucosal epithelial barrier, we found that CD91, the receptor of C1q, is prevalently expressed in the sublingual mucosal lining, and thus, a modified chimeric C1q surface conjugated CD40L/HIV VLP was generated. The ability of this chimeric C1q/CD40L/HIV VLP to bind, cross the epithelial layer, access and activate the sub-mucosal layer dendritic cells (DCs), and ultimately induce enhanced mucosal and systemic immune responses against HIV is evaluated in this study. We found that C1q/CD40L/HIV VLPs have enhanced binding, increased transport across the epithelial layer, and upregulate DC activation markers as compared to CD40L/HIV VLPs alone. Mice immunized with C1q/ CD40L/HIV VLPs by sublingual administration showed higher levels of IgA salivary antibodies against both HIV Gag and Env than mice immunized with CD40L/HIV VLPs. Moreover, sublingual immunization with C1q/CD40L/HIV VLPs induced more Env- and Gag-specific IFN-γ producing T cells than the CD40L/HIV VLPs group. Interestingly, C1q/CD40L/HIV VLP immunization can also induce more mucosal homing T cells than that in CD40L/HIV VLP group. Our data suggest that incorporation of C1q to CD40L/HIV VLPs is a promising novel strategy and that the sublingual immunization can be a favorite immunization route for HIV mucosal vaccines.

Efficacy of Sublingual Administration Misoprostol 600 mcg Versus 800 mcg for Induced Abortion in Women with Early Pregnancy Loss: A Randomized Controlled Trial

Objective: To compare the complete abortion rate, the induction-to-abortion time, and side effects between 600 mcg and 800 mcg misoprostol sublingually. Materials and Methods: Total, of 108 pregnant women with gestational age less than 12 weeks with early pregnancy loss from March 2020 to February 2021 at the Department of Obstetrics and Gynecology, Queen Savang Vadhana Memorial Hospital, were included. For group 1 (n=54), 600 mcg misoprostol was administrated sublingually. For group 2 (n=54), 800 mcg misoprostol was administrated sublingually. If the abortion did not occur, the repeated misoprostol in the same dose would be administrated sublingually every 6 hours for a maximum of three doses. Results: There was no significant difference in the complete abortion rate between the two groups (55.6% in the 600 mcg misoprostol group, 64.7% in the 800 mcg misoprostol group, p=0.339, and 95% CI 0.082 to 1.862). The induction-to-abortion time was 9.5 hours (IQR 6.75 to 48.00) in the 600 mcg misoprostol group and 10 hours (IQR 6.00 to 60.00) in the 800 mcg misoprostol group. The side effects of both groups were similar, included abdominal pain, diarrhea, nausea and vomiting, fever, heavy bleeding, and headache. Conclusion: The efficacy of the 600 mcg misoprostol was noninferior to 800 mcg misoprostol. The adverse effects were similar in both groups. Mean induction-to-abortion time was also similar in both groups. Keywords: Early pregnancy loss; Misoprostol; Medical abortion

Vascular Endothelial Function Assessed by Flow-Mediated Vasodilatation in Young Adults Born Very Preterm or With Extremely Low Birthweight: A Regional Cohort Study

Background: Preterm birth and low birthweight have been associated with increased risk of cardiovascular disease in young adults. Endothelial dysfunction is established as an early marker for development of atherosclerotic cardiovascular disease. Previous studies of endothelial function in young adults born very preterm or with extremely low birthweight have, however, shown diverging results.Objective: We aimed to evaluate the risk of cardiovascular disease as measured by vascular endothelial function in young adults born very preterm (<29 weeks of gestation) or with extremely low birthweight (<1,000 g), compared with term-born controls.Methods: This study included 50 young adults born very preterm or with extremely low birthweight and 49 term-born controls born in Norway in the periods 1982–1985, 1991–1992, and 1999–2000 at mean age 28 (±6) years. The endothelial function was assessed by ultrasound measured flow-mediated dilatation (FMD) of the right brachial artery. The arterial diameter was measured at baseline, after release of 5 min of occlusion, and after sublingual administration of nitroglycerine. FMD was reported as absolute and percentage diameter change from baseline and relative to nitroglycerine-induced dilatation.Results: The participants were mainly normal weight non-smokers, without hypertension, diabetes, or established cardiovascular disease. The cases and controls had mean blood pressure 112/71 (SD 12/9) and 112/69 (SD 11/8) mmHg, body mass index 24.0 (SD 4.2) and 24.4 (SD 4.5) kg/m2, and HbA1c 32.7 (SD 2.5) and 33.0 (SD 2.6) mmol/mol, respectively. For both groups, 4 (8%) were smokers. Mean FMD for the adults born very preterm or with extremely low birthweight was 0.17 mm (95% CI 0.14, 0.21) vs. 0.24 mm (95% CI 0.20, 0.28) for the controls (p = 0.01), corresponding to a percentage increase of 5.4% (95% CI 4.2, 6.6) and 7.6% (95% CI 6.2, 8.9), respectively (p = 0.02). The FMD relative to maximal nitroglycerine-induced dilatation was 20% and 31%, respectively (p = 0.001).Conclusions: Young adults born very preterm or with extremely low birthweight have significantly lower FMD compared with the term-born controls suggesting an increased risk of cardiovascular disease.

Acute effects of sublingual nitroglycerin on cardiovagal and sympathetic baroreflex sensitivity

The effects of nitroglycerin (glyceryl trinitrate, GTN) on baroreflex sensitivity (BRS) are incompletely understood. Moreover, there are no reports evaluating the acute responses in both the sympathetic BRS (SBRS) and the cardiovagal BRS (CBRS) to the administration of sublingual GTN. We hypothesized that sublingual GTN modulates both CBRS and SBRS. In 10 healthy subjects, beat-to-beat heart rate (HR), blood pressure (BP) and muscle sympathetic nerve activity (MSNA) were recorded before and for 10 min after sublingual administration of GTN 0.4 mg. SBRS was evaluated from the relationship between spontaneous variations in diastolic BP and MSNA. CBRS was assessed with the sequence technique. These variables were assessed during baseline, during min 3rd - 6th (Post A) and 7th -10th min (Post B) after GTN administration. Two min after GTN administration, MSNA increased significantly and remained significantly elevated during recording. Compared to baseline, CBRS decreased significantly (Post A: 12.9 ± 1.6 to 7.1 ± 1.0 ms/mmHg, P < 0.05), while SBRS increased significantly (Post A: 0.8 ± 0.2 to 1.5 ± 0.2 units･beat-1･mmHg-1, P < 0.05) with an upward shift of the operating point. There were no differences in these variables between Post A and B. A clinical dose of GTN increased MSNA rapidly through effects on both CBRS and SBRS. These effects should be kept in mind when nitrates are used to clinically treat chest pain and acute coronary syndromes and used as vasodilators in experimental settings.

Treating Insomnia Symptoms with Medicinal Cannabis: A Randomized, Cross-Over Trial of the Efficacy of a Cannabinoid Medicine Compared with Placebo

Study Objectives This randomized, double-blind, placebo-controlled, cross-over study was conducted to evaluate the safety and efficacy of two-weeks of nightly sublingual cannabinoid extract (ZTL-101) in treating chronic insomnia (symptoms ≥three months). Methods Co-primary study endpoints were safety of the medication based on adverse event reporting and global insomnia symptoms (Insomnia Severity Index; ISI). Secondary endpoints included: self-reported (sleep diary), actigraphy-derived and polysomnography measurements of sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), sleep efficiency (SE); and self-reported assessments of sleep quality (sSQ) and feeling rested upon waking. Adjusted mean differences between placebo and ZTL-101 were calculated. Results Twenty-three of 24 randomized participants (n=20 female, mean age 53±9years) completed the protocol. No serious adverse events were reported. Forty mild, non-serious, adverse events were reported (36 during ZTL-101) with all but one resolving overnight or soon after waking. Compared to placebo, ZTL-101 decreased ISI (-5.07units [95%CI: -7.28 to -2.86]; p=0.0001) and self-reported SOL (-8.45mins [95%CI: -16.33 to -0.57]; p=0.04) and increased self-reported TST (64.6mins [95%CI: 41.70 to 87.46]; p&lt;.0001), sSQ, (0.74units [95%CI: 0.51 to 0.97]; p&lt;0.0001) and feeling of being rested on waking (0.51units [95%CI: 0.24 to 0.78]; p=0.0007). ZTL-101 also decreased actigraphy-derived WASO (-10.2mins [95%CI: -16.2 to -4.2]; p=0.002), and increased actigraphy-derived TST (33.4mins [95%CI: 23.07 to 43.76]; p&lt;0.001) and SE (2.9% [95%CI: 2.0 to 3.8]; p=0.005). Conclusion Two-weeks of nightly sublingual administration of a cannabinoid extract (ZTL-101) is well tolerated and improves insomnia symptoms and sleep quality in individuals with chronic insomnia symptoms.

Anticancer Effects of Sublingual Type I IFN in Combination with Chemotherapy in Implantable and Spontaneous Tumor Models

Salivary gland tumors are a heterogeneous group of neoplasms representing less than 10% of all head and neck tumors. Among salivary gland tumors, salivary duct carcinoma (SDC) is a rare, but highly aggressive malignant tumor resembling ductal breast carcinoma. Sublingual treatments are promising for SDC due to the induction of both local and systemic biological effects and to reduced systemic toxicity compared to other administration routes. In the present study, we first established that the sublingual administration of type I IFN (IFN-I) is safe and feasible, and exerts antitumor effects both as monotherapy and in combination with chemotherapy in transplantable tumor models, i.e., B16-OVA melanoma and EG.7-OVA lymphoma. Subsequently, we proved that sublingual IFN-I in combination with cyclophosphamide (CTX) induces a long-lasting reduction of tumor mass in NeuT transgenic mice that spontaneously develop SDC. Most importantly, tumor shrinkage in NeuT transgenic micewas accompanied by the emergence of tumor-specific cellular immune responses both in the blood and in the tumor tissue. Altogether, these results provide evidence that sublingual IFN holds promise in combination with chemotherapy for the treatment of cancer.