Exploring the Impact of Saccharin on Neovascular Age-Related Macular Degeneration: A Comprehensive Study in Patients and Mice.

Purpose: We aimed to determine the impact of artificial sweeteners (AS), especially saccharin, on the progression and treatment efficacy of patients with neovascular age-related macular degeneration (nAMD) under anti-vascular endothelial growth factor (anti-VEGF-A) treatment. Methods: In a cross-sectional study involving 46 patients with nAMD undergoing intravitreal anti-VEGF therapy, 6 AS metabolites were detected in peripheral blood using liquid chromatography - tandem mass spectrometry (LC-MS/MS). Disease features were statistically tested against these metabolite levels. Additionally, a murine choroidal neovascularization (CNV) model, induced by laser, was used to evaluate the effects of orally administered saccharin, assessing both imaging outcomes and gene expression patterns. Polymerase chain reaction (PCR) methods were used to evaluate functional expression of sweet taste receptors in a retinal pigment epithelium (RPE) cell line. Results: Saccharin levels in blood were significantly higher in patients with well-controlled CNV activity (P = 0.004) and those without subretinal hyper-reflective material (P = 0.015). In the murine model, saccharin-treated mice exhibited fewer leaking laser scars, lesser occurrence of bleeding, smaller fibrotic areas (P < 0.05), and a 40% decrease in mononuclear phagocyte accumulation (P = 0.06). Gene analysis indicated downregulation of inflammatory and VEGFR-1 response genes in the treated animals. Human RPE cells expressed taste receptor type 1 member 3 (TAS1R3) mRNA and reacted to saccharin stimulation with changes in mRNA expression. Conclusions: Saccharin appears to play a protective role in patients with nAMD undergoing intravitreal anti-VEGF treatment, aiding in better pathological lesion control and scar reduction. The murine study supports this observation, proposing saccharin's potential in mitigating pathological VEGFR-1-induced immune responses potentially via the RPE sensing saccharin in the blood stream.

[Possibilities of usage of modern herbal medicinal product in the treatment of patients with acute viral rhinosinusitis]. / Vozmozhnosti primeneniya sovremennogo rastitel'nogo lekarstvennogo preparata v lechenii patsientov s ostrym virusnym rinosinusitom.

INTRODUCTION: The issues of epidemiology, etiopathogenesis, diagnostics and clinic of acute catarrhal rhinosinusitis are considered, the possibility of using the herbal medicinal product Sinupret extract in the treatment of patients with acute viral rhinosinusitis is substantiated. OBJECTIVE: To evaluate the efficacy and safety of using the drug Sinupret extract in patients with acute viral rhinosinusitis. MATERIAL AND METHODS: A comparative study of the efficacy and safety of clinical use in patients of the drug Sinupret extract in patients with acute viral rhinosinusitis was carried out in comparison with symptomatic treatment. RESULTS AND DISCUSSION: After analyzing and processing the results obtained using statistical methods for the main group, a faster rate of decrease in the severity of complaints (data with the use of the MSS visual analogue scale), the severity of inflammation in the nasal cavity and nasopharynx, the amount of discharge from the nose and its viscosity were confirmed. Restoration of respiratory function according to rhinomanometry and mucociliary transport according to the results of the saccharin test also occurred more quickly in patients of the main group compared to the control group. The effectiveness of using Sinupret extract is also confirmed by the results of photoplethysmography. CONCLUSIONS: The use of the drug Sinupret extract not only contributes to a more rapid improvement in the general well-being of patients and a decrease in the severity of complaints, but also leads to an improvement in the objective picture of the disease (rhinoscopy, the results of anterior active rhinomanometry, saccharin test) compared with the control group, favorably affects the quality life of patients, causes a decrease in economic and social costs against the background of the development of acute viral rhinosinusitis.

Open-Label, Multicenter Study of Flecainide Acetate Oral Inhalation Solution for Acute Conversion of Recent-Onset, Symptomatic Atrial Fibrillation to Sinus Rhythm.

BACKGROUND: Oral and intravenous flecainide is recommended for cardioversion of atrial fibrillation. In this open-label, dose-escalation study, the feasibility of delivering flecainide via oral inhalation (flecainide acetate inhalation solution) for acute conversion was evaluated. We hypothesized that flecainide delivered by oral inhalation would quickly reach plasma concentrations sufficient to restore sinus rhythm in patients with recent-onset atrial fibrillation. METHODS: Patients (n=101) with symptomatic atrial fibrillation (for ≤48 hours) self administered flecainide acetate inhalation solution using a nebulizer (30 mg [n=10], 60 mg [n=22], 90 mg [n=21], 120 mg [n=19], and 120 mg in a formulation containing saccharin [n=29]). Electrocardiograms and flecainide plasma concentrations were obtained, cardiac rhythm using 4-hour Holter was monitored, and adverse events were recorded. RESULTS: Conversion rates increased with dose and with the maximum plasma concentrations of flecainide. At the highest dose, 48% of patients converted to sinus rhythm within 90 minutes from the start of inhalation. Among patients who achieved a maximum plasma concentration >200 ng/mL, the conversion rate within 90 minutes was 50%; for those who achieved a maximum plasma concentration <200 ng/mL, it was 24%. Conversion was rapid (median time to conversion of 8.1 minutes from the end of inhalation), and conversion led to symptom resolution in 86% of the responders. Adverse events were typically mild and transient and included: cough, throat pain, throat irritation; at the highest dose with the formulation containing saccharin, these adverse events were reported by 41%, 14%, and 3% of patients, respectively. Cardiac adverse events consistent with those observed with oral and intravenous flecainide were uncommon and included postconversion pauses (n=2), bradycardia (n=1), and atrial flutter with 1:1 atrioventricular conduction (n=1); none required treatment, and all resolved without sequelae. CONCLUSIONS: Administration of flecainide via oral inhalation was shown to be safe and to yield plasma concentrations of flecainide sufficient to restore sinus rhythm in patients with recent-onset atrial fibrillation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03539302.

Synthesis, hepatotoxic evaluation and antipyretic activity of nitrate ester analogs of the acetaminophen derivative SCP-1.

A series of nitrate ester analogues of the acetaminophen derivative SCP-1 were prepared by triflic acid catalyzed O-acylation of SCP-1 with chloroalkanoyl chlorides followed by nitration with silver nitrate. The chloroesters and corresponding nitrate esters were obtained in high yields. Preliminary hepatotoxicity studies revealed nitrate esters 5b (MD-38) and 5c (MD-39) to be well tolerated by human hepatocytes and had little effect on the three cytochrome P450 enzymes tested (CYP3A4, CYP2E1 and CYP2D6). In addition, the nitrate ester 5c (MD-39) exhibited antipyretic activity similar to acetaminophen.

Noncaloric Sweeteners in Children: A Controversial Theme.

Noncaloric sweeteners (NCS) are food additives used to provide sweetness without adding calories. Their consumption has become more widespread around the world in all age groups, including children. The aim of this study is to show the state of the art about the intake of noncaloric sweeteners in children, as well as their benefits and consumption risk. Scientific searchers were used (PUBMED, Scopus, and Scielo) to analyze articles that included keywords (noncaloric sweeteners/saccharin/cyclamate/acesulfame potassium/aspartame/sucralose/stevia/children) in English, Spanish, and Portuguese. Authors conclude that it is imperative that health professionals judiciously and individually evaluate the overall benefits and risks of NCS use in consumers before recommending their use. Different subgroups of the population incorporate products containing NCS in their diet with different objectives, which should be considered when recommending a diet plan for the consumer. In childhood, in earlier age groups, this type of additives should be used as a dietary alternative when other forms of prevention in obesity are not sufficient.

Mouth rinsing with a sweet solution increases energy expenditure and decreases appetite during 60 min of self-regulated walking exercise.

Carbohydrate mouth rinsing can improve endurance exercise performance and is most ergogenic when exercise is completed in the fasted state. This strategy may also be beneficial to increase exercise capacity and the energy deficit achieved during moderate-intensity exercise relevant to weight control when performed after an overnight fast. Eighteen healthy men (mean (SD); age, 23 (4) years; body mass index, 23.1 (2.4) kg·m-2) completed a familiarisation trial and 3 experimental trials. After an overnight fast, participants performed 60 min of treadmill walking at a speed that equated to a rating of perceived exertion of 13 ("fairly hard"). Participants manually adjusted the treadmill speed to maintain this exertion. Mouth rinses for the experimental trials contained either a 6.4% maltodextrin solution with sweetener (CHO), a taste-matched placebo (PLA), or water (WAT). Appetite ratings were collected using visual analogue scales and exercise energy expenditure and substrate oxidation were calculated from online gas analysis. Increased walking distance during CHO and PLA induced greater energy expenditure compared with WAT (mean difference (90% confidence interval); 79 (60) kJ, P = 0.035, d = 0.24; and 90 (63) kJ, P = 0.024, d = 0.27, respectively). Appetite area under the curve was lower in CHO and PLA than WAT (8 (6) mm, P = 0.042, d = 0.43; and 6 (8) mm, P = 0.201, d = 0.32, respectively). Carbohydrate oxidation was higher in CHO than PLA and WAT (7.3 (6.7) g, P = 0.078, d = 0.47; and 10.1 (6.5) g, P = 0.015, d = 0.81, respectively). This study provides novel evidence that mouth rinsing with a sweetened solution may promote a greater energy deficit during moderate-exertion walking exercise by increasing energy expenditure and decreasing appetite. A placebo effect may have contributed to these benefits.

Antineoplastic activity of the multitarget tyrosine kinase inhibitors CLM3 and CLM94 in medullary thyroid cancer in vitro.

BACKGROUND: We report the antineoplastic and anti-angiogenic activity of the pyrazolo[3,4-d]pyrimidine derivative CLM3 and the cyclic amide CLM94, both multiple tyrosine kinase inhibitors (TKIs), in human primary medullary thyroid cancer (P-MTC) cells, and in vitro in the medullary thyroid cancer (MTC) cell lines TT (harboring a RET C634W activating mutation) and MZ-CRC-1 (carrying the MEN2B RET mutation Met891Thr). METHODS: The antiproliferative and proapoptotic effects of CLM3 and CLM94 (1, 5, 10, 30, and 50 µmol/L) were tested in P-MTC cells obtained at operation, and in TT cells. In addition, the antiproliferative effects of CLM3 and CLM94 (0.005, 0.05, 0.5, and 5 µmol/L) were tested in TT and MZ-CRC-1 cells after 7 days of treatment to compare the results with those previously reported in the literature. RESULTS: CLM3 and CLM94 (30 or 50 µmol/L) inhibited (P < .01) the proliferation of the P-MTC cells, TT cells, and MZ-CRC-1 cells and increased the level of apoptosis in a dose-dependent manner at 10, 30, and 50 µmol/L (P < .001), while having no effect on migration or invasion. The inhibition of proliferation by CLM3 and CLM94 was similar among P-MTC cells with/without RET mutations, and similar effects were observed regarding the increased level of apoptosis. Furthermore, CLM3 and CLM94 significantly decreased vascular endothelial growth factor-A expression in TT cells. CONCLUSION: The antitumor activities of the multiple TKIs CLM3 and CLM94 were demonstrated in both primary MTC cultures as well as 2 established MTC cell lines in vitro, opening an avenue for future clinical evaluations.

Food restriction-induced hyperactivity: addiction or adaptation to famine?

Increased physical activity is present in 30-80% of anorexia nervosa patients. To explain the paradox of low food intake and excessive exercise in humans and other animals, it has been proposed that increased physical activity along with food restriction activates brain reward circuits and is addictive. Alternatively, the fleeing-famine hypothesis postulates that refusal of known scarce energy-low food sources and hyperactivity facilitate migration towards new habitats that potentially contain new energy-rich foodstuffs. The use of rewarding compounds that differ in energy density, such as the energy-free sweetener saccharin and the energy rich sucrose makes it possible to critically test the reward-addiction and fleeing-famine hypotheses. The aims of the present work were to study if sucrose and/or saccharin could attenuate food restriction-induced hyperactivity, weight loss, increased plasma corticosterone, and activation of brain structures involved in neuroendocrine control, energy balance, physical activity, and reward signaling in rats. Its major findings are that access to sucrose, but not to saccharin, attenuated food restriction-induced running wheel activity, weight loss, rises in plasma corticosterone, and expression of the cellular activation marker c-Fos in the paraventricular and arcuate hypothalamus and in the nucleus accumbens. These findings suggest that the energy-richness and easy availability of sucrose interrupted a fleeing-famine-like hyperactivity response. Since corticosterone mediates food restriction-induced wheel running (Duclos et al., 2009), we propose that the attenuating effect of sucrose consumption on plasma corticosterone plays a role in reduced wheel running and weight loss by lowering activation of the nucleus accumbens and arcuate hypothalamus in these animals.

Effects of xylitol mouthrinse on Streptococcus mutans.

OBJECTIVES: This study aimed to measure the effect of xylitol mouthrinse on salivary Streptococcus mutans counts. METHODS: Subjects in the study group (n = 25) used xylitol mouthrinse for 4 weeks, while another group (n = 25) used saccharine mouthrinse. S. mutans were measured before and after intervention. RESULTS: At the baseline the mean S. mutans scores were 3.9 (SE = 0.03) and 3.9 (0.04) for the xylitol group and control group respectively, while the scores were 2.8 (0.13) and 3.9 (0.07) after the intervention. Significant reductions (p < 0.01) in the scores of S. mutans were found after the four week use of xylitol mouthrinse. CONCLUSIONS: Significant reductions in the scores of S. mutans were found after the four week use of 20% xylitol mouthrinse. The bacteriostatic effect of xylitol mouthrinse on S. mutans may be comparable to other xylitol products. Further studies are needed to confirm both the short and long term effects of xylitol mouthrinse.

CLM94, a novel cyclic amide with anti-VEGFR-2 and antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo.

CONTEXT AND OBJECTIVE: We have studied the antitumor activity of a novel cyclic amide, CLM94, with anti-vascular endothelial growth factor (VEGF) receptor-2 and antiangiogenic activity in primary anaplastic thyroid cancer (ATC) cells in vitro and in vivo. DESIGN AND MAIN OUTCOME MEASURES: CLM94 was tested: 1) in two human cell lines (HMVEC-d, dermal microvascular endothelial cells; and 8305C, undifferentiated thyroid cancer) at 0.001-100 µm; 2) in ATC cells at the concentrations of 10, 30, and 50 µm; and 3) in an ATC cell line (AF) in CD nu/nu mice. RESULTS: CLM94 significantly inhibited VEGF receptor-2 and epidermal growth factor receptor phosphorylation in HMVEC-d and proliferation in HMVEC-d and 8305C cells. A significant reduction of proliferation with CLM94 in ATC cells (P < 0.01, ANOVA) and a slight but significant reduction of proliferation with CLM94 30 and 50 µm in normal thyroid follicular cells (P < 0.01, ANOVA) were shown. CLM94 increased the percentage of apoptotic ATC cells dose-dependently (P < 0.001, ANOVA) and inhibited migration (P < 0.01) and invasion (P < 0.001). AF cell line was injected sc in CD nu/nu mice, and tumor masses became detectable 25 d afterward. CLM94 (40 mg/kg · d) significantly inhibited tumor growth (starting 10 d after the beginning of treatment). CLM94 significantly decreased the VEGF-A gene expression in the AF cell line and the VEGF-A protein and microvessel density in AF tumor tissues. CONCLUSIONS: The antitumor and antiangiogenic activity of a new "cyclic amide" compound, CLM94, is very promising in ATC, opening the way to a future clinical evaluation.

Allodynia and hyperalgesia suppression by a novel analgesic in experimental neuropathic pain.

SCP-1, n-[alpha-(benzisothiazol-3(2ho-ona,1-dioxide-2yl)-acetyl]-p-aminophenol (100 nmol), when intrathecally injected, suppressed tactile allodynia and thermal hyperalgesia in a rat neuropathic pain model. The tactile allodynia suppression lasted for at least 4h and SCP-M1 (100 nmol), the main metabolite of SCP-1, displayed similar suppression as SCP-1, but shorter latency, indicating SCP-M1 may be the bioactive component of SCP-1. Acetaminophen was less potent than SCP-1 and SCP-M1. To study mechanisms underlying SCP-1 action, we recorded voltage-gated Ca(2+) channel currents in acutely isolated dorsal root ganglion neurons using the whole-cell patch-clamp technique. SCP-1 and SCP-M1 inhibited non-L-type calcium channel currents up to 23.0+/-2.3% and 23.1+/-3.5%, respectively, at a depolarized pulse to -10 mV from a holding potential of -80 mV. Acetaminophen only induced 6.8+/-1.0% inhibition. The results suggest SCP-1 possesses anti-nociceptive activity in the rat model involving calcium channel blocking properties.

[Effect of saccharol glycosides on energy metabolism in animals with abnormal carbohydrate tolerance]. / Vliianie glikozidov sakharola na énergeticheskii obmen u zhivotnykh s narushennoi tolerantnostíu k uglevodam.

A trial has been performed of a new sweetening agent saccharol, glycosides complex, on energy metabolism in rats with experimental alloxan diabetes. Elevated glucose level observed in rats with insulin insufficiency was associated with hexokinase activity inhibition and changes in the activity of the enzymes involved in glucose-6-phosphate transformation: enhanced activity of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase against inhibition of phosphoglucomutase activity. Introduction of saccharose aggravated the above shifts in the rat liver, whereas saccharol possesses a protective action on hexokinase hepatic reaction and enzymes of glucose-6-phosphate conversion, reduced blood glucose. Positive changes induced by saccharol on energy metabolism in animals with insulin insufficiency can be attributed to the effect of saccharol glycosides.

Efficacy of sweeteners and sugar substitutes in caries prevention.

The caries-preventive efficacy of sweeteners and sugar substitutes is not clearly established on an epidemiological scale. A review of cariogenicity assessments in vitro and in vivo as well as of human clinical caries trials, however, clearly demonstrates that the replacement of sugar by such products has a caries-preventive effect. The clinical relevance of some bacteriostatic and/or cariostatic properties ascribed to saccharin, aspartame, and xylitol remains to be corroborated.

Effect of the novel synthetic protease inhibitor furoyl saccharin on elastase-induced emphysema in rabbits and hamsters.

Furoyl saccharin, a novel heterocyclic acylating agent which has been previously found to possess a potent inhibitory capacity in vitro for elastase and other serine proteases, has been investigated in vivo in two acute animal models of emphysema. In hamsters, intratracheal (i.tr.) administration of 0.1 mg porcine pancreatic elastase resulted seven days later, in a 42% increase of the mean linear intercept (Lm). Addition of 0.3 mg to 0.3 mg furoyl saccharin to elastase exhibited a partial, not dose-related, but statistically significant inhibition of the increase of LM. Addition of 1 mg furoyl saccharin (equivalent to a dose of 12.5 mg/kg) completely abolished the increase in Lm. In the rabbit i.tr. instillation of 3.7 mg porcine pancreatic elastase induced within seven days, a 48% increase of the Lm, a 27% decrease of the internal surface area (ISA) of the lungs and a 33% decrease of the ISA corrected to an arbitrary total lung volume of 70 ml (ISA70). Furoyl saccharin given i.tr. 15 min prior to elastase at the doses 3, 10 and 20 mg prevented significantly in a dose-related manner, the changes in Lm, ISA and ISA70. The highest furoyl saccharin dose (equivalent to a dose of 10.8 mg/kg) completely protected against the emphysematous lesion. Additionally furoyl saccharin (20 mg i.tr.) prevented in the rabbit model the depletion in lung insoluble elastin and the increase in salt soluble collagen induced by the elastase administration. These results show that furoyl saccharin also in vivo has a marked antielastase activity.

The effect of furoyl saccharin, a novel non-peptidic acylating protease inhibitor, on experimental emphysema in the hamster.

Furoyl saccharin was evaluated for its ability to prevent the development of emphysematous lesions produced in hamsters by the exposure to aerosolized papain (3% for 3 h). Pretreatment with intratracheal furoyl saccharin (at the doses of 0.3, 1, 3 mg) reduced the appearance of papain-induced emphysema as evaluated by both physiologic (static compliance) and histologic (mean linear intercept and internal surface area of the lungs) methods. Inhibition was dose-related with maximal reduction of changes in static compliance (74%), mean linear intercept (84%) and internal surface area (65%) observed after a dose of 3 mg. This is the first time that a non-peptide acylating inhibitor of serine proteases is reported to be affective in preventing the development of experimental emphysema.