The Combination of Aroxybutynin and Atomoxetine in the Treatment of Obstructive Sleep Apnea (MARIPOSA): A Randomized Controlled Trial.

Rationale: Obstructive sleep apnea (OSA) is a common sleep disorder for which the principal treatment option, continuous positive airway pressure, is often poorly tolerated. There is currently no approved pharmacotherapy for OSA. However, recent studies have demonstrated improvement in OSA with combined antimuscarinic and noradrenergic drugs. Objectives: The aim of this study was to evaluate the efficacy and safety of AD109, a combination of the novel antimuscarinic agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine, in the treatment of OSA. Methods: Phase II randomized, double-blind, placebo-controlled, parallel-group, 4-week trial comparing AD109 2.5/75 mg, AD109 5/75 mg, atomoxetine 75 mg alone, and placebo (www.clinicaltrials.gov identifier NCT05071612). Measurements and Main Results: Of 211 randomized patients, 181 were included in the prespecified efficacy analyses. Sleep was assessed by two baseline and two treatment polysomnograms. Apnea-hypopnea index with a 4% desaturation criterion (primary outcome) was reduced from a median (IQR) of 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 2.5/75 mg arm (-47.1%), from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the AD109 5/75 mg arm (-42.9%; both P < 0.0001 vs. placebo), and from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (-38.8%; P < 0.01 vs. placebo). Apnea-hypopnea index with a 4% desaturation criterion decreased from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) in the placebo arm. Subjectively, there was improvement in fatigue with AD109 2.5/75 mg (P < 0.05 vs. placebo and atomoxetine). Atomoxetine taken alone decreased total sleep time (P < 0.05 vs. AD109 and placebo). The most common adverse events were dry mouth, insomnia, and urinary hesitancy. Conclusions: AD109 showed clinically meaningful improvement in OSA, suggesting that further development of the compound is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT05071612).

PLGA-PEG-COOH nanoparticles are efficient systems for delivery of mefloquine to Echinococcus multilocularis metacestodes.

Alveolar echinococcosis (AE) is a severe disease caused by the infection with the larval stage of Echinococcus multilocularis, the metacestode. As there is no actual curative drug therapy, recommendations to manage AE patients are based on radical surgery and prophylactic administration of albendazole or mebendazole during 2 years to prevent relapses. There is an urgent need for new therapeutic strategies for the management of AE, as the drugs in use are only parasitostatic, and can induce toxicity. This study aimed at developing a drug delivery system for mefloquine, an antiparasitic compound which is highly active against E. multilocularis in vitro and in experimentally infected mice. We formulated mefloquine-loaded PLGA-PEG-COOH (poly-(lactic-co-glycolic acid)) nanoparticles that exhibit stable physical properties and mefloquine content. These nanoparticles crossed the outer acellular laminated layer of metacestodes in vitro and delivered their content to the inner germinal layer within less than 5 min. The in vitro anti-echinococcal activity of mefloquine was not altered during the formulation process. However, toxicity against hepatocytes was not reduced when compared to free mefloquine. Altogether, this study shows that mefloquine-loaded PLGA-PEG-COOH nanoparticles are promising candidates for drug delivery during AE treatment. However, strategies for direct parasite-specific targeting of these particles should be developed.

In Vivo Evaluation of Nose-to-Brain Delivery of Liposomal Donepezil, Memantine, and BACE-1 siRNA for Alzheimer's Disease Therapy.

Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a "triple-drug therapy" in treating Alzheimer's disease (AD). Female APP/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP/PS1 mice was evaluated by a Y-maze behavioral test. IN-administered formulations demonstrated better short-term memory recovery than oral administration. Triple-drug therapy induced short-term memory recovery and lowered beta-amyloid (Aß) 40 and 42 peptide levels and BACE-1 mRNA expression. Additionally, inflammatory cytokine mRNA expression was downregulated. This innovative approach opens new possibilities for Alzheimer's disease treatment and nose-to-brain delivery.

Overview of the Role of Pharmacological Management of Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) remains a prominent disease state characterized by the recurrent collapse of the upper airway while sleeping. To date, current treatment may include continuous positive airway pressure (CPAP), lifestyle changes, behavioral modification, mandibular advancement devices, and surgical treatment. However, due to the desire for a more convenient mode of management, pharmacological treatment has been thoroughly investigated as a means for a potential alternative in OSA treatment. OSA can be distinguished into various endotypic or phenotypic classes, allowing pharmacological treatment to better target the root cause or symptoms of OSA. Some medications available for use include antidepressants, CNS stimulants, nasal decongestants, carbonic anhydrase inhibitors, and potassium channel blockers. This review will cover the findings of currently available and future study medications that could potentially play a role in OSA therapy.

PEGylated AdipoRon derivatives improve glucose and lipid metabolism under insulinopenic and high-fat diet conditions.

The pleiotropic actions of adiponectin in improving cell survival and metabolism have motivated the development of small-molecule therapeutic agents for treating diabetes and lipotoxicity. AdipoRon is a synthetic agonist of the adiponectin receptors, yet is limited by its poor solubility and bioavailability. In this work, we expand on the protective effects of AdipoRon in pancreatic ß-cells and examine how structural modifications could affect the activity, pharmacokinetics, and bioavailability of this small molecule. We describe a series of AdipoRon analogs containing amphiphilic ethylene glycol (PEG) chains. Among these, AdipoRonPEG5 induced pleiotropic effects in mice under insulinopenic and high-fat diet (HFD) conditions. While both AdipoRon and AdipoRonPEG5 substantially attenuate palmitate-induced lipotoxicity in INS-1 cells, only AdipoRonPEG5 treatment is accompanied by a significant reduction in cytotoxic ceramides. In vivo, AdipoRonPEG5 can substantially reduce pancreatic, hepatic, and serum ceramide species, with a concomitant increase in the corresponding sphingoid bases and improves insulin sensitivity of mice under HFD feeding conditions. Furthermore, hyperglycemia in streptozotocin (STZ)-induced insulinopenic adiponectin-null mice is also attenuated upon AdipoRonPEG5 treatment. Our results suggest that AdipoRonPEG5 is more effective in reducing ceramides and dihydroceramides in the liver of HFD-fed mice than AdipoRon, consistent with its potent activity in activating ceramidase in vitro in INS-1 cells. Additionally, these results indicate that the beneficial effects of AdipoRonPEG5 can be partially attributed to improved pharmacokinetics as compared with AdipoRon, thus suggesting that further derivatization may improve affinity and tissue-specific targeting.

Dual antitubercular drug loaded liposomes for macrophage targeting: development, characterisation, ex vivo and in vivo assessment.

AIM: The present study was conducted to formulate and investigate liposomes for the dual drug delivery based on anti-tubercular drug(s) combination i.e. Isoniazid (INH) and Rifampicin (RIF). MATERIALS AND METHODS: Mannosylated and non mannosylated liposomes were prepared by lipid thin film hydration method, using DSPC: Chol at a molar ratio 6:4 while in case of mannosylated liposomes DSPC: Chol: Man-C4-Chol at a molar ratio 6.0:3.5:0.5 were used and extensively characterised. The particle size and zeta potential were recorded to be 1.29 ± 0.24 µm and -9.1 ± 0.11 mV. The drug entrapment (%) was recorded to be 84.7 ± 1.25% for Rifampicin and 31.8 ± 0.12% for Isoniazid. RESULTS: The antitubercular activity studied in Balb/C mice was maximum in the case of mannosylated liposomes. The biodistribution studies also revealed higher drug(s) concentration (accumulation) maintained over a protracted period. CONCLUSIONS: The liposomal preparations are passively as well as actively uptaken by the alveolar macrophages which are the cellular tropics of infection. The mannosylated liposomes appear to be a potential carrier for dual drug delivery and targeted antitubercular therapy.

Randomized All-Comers Evaluation of a Permanent Polymer Zotarolimus-Eluting Stent Versus a Polymer-Free Amphilimus-Eluting Stent.

BACKGROUND: Polymer-free amphilimus-eluting stents (PF-AES) represent a novel elution technology in the current era of drug-eluting stents. The clinical safety and efficacy of PF-AES as compared with latest-generation permanent-polymer zotarolimus-eluting stents (PP-ZES) have not yet been investigated in a large randomized trial. METHODS: In this physician-initiated, prospective, multicenter, randomized, noninferiority trial, an all-comers population requiring percutaneous coronary intervention was enrolled across 3 European sites. Randomization (1:1 ratio) to PP-ZES or PF-AES was performed after stratification for troponin status and diabetes mellitus. In both treatment arms, troponin-positive patients were planned for 12-month dual antiplatelet therapy, whereas troponin-negative patients were planned for 1-month dual antiplatelet therapy. Outcome assessors were blinded to the allocated treatment. The device-oriented primary end point of target-lesion failure was defined as cardiac death, target-vessel myocardial infarction, or target-lesion revascularization at 12-months as analyzed by modified intention-to-treat (80% power, and a 3.5% noninferiority margin). RESULTS: In total, 1502 patients were randomized and 1491 treated with the assigned stent and available for follow-up. The primary end point occurred in 42 (5.6%) of the 744 patients receiving PP-ZES versus 46 (6.2%) of the 747 patients receiving PF-AES. PF-AES were clinically noninferior to PP-ZES (risk difference, 0.5%; upper limit 1-sided 95% confidence interval, 2.6%; Pnoninferiority=0.0086). Cardiac death occurred in 10 (1.3%) versus 10 patients (1.3%; P value for difference, 1.00), target-vessel myocardial infarction occurred in 18 (2.4%) versus 17 patients (2.3%; P value for difference, 0.87), and target-lesion revascularization occurred in 22 (2.9%) versus 20 patients (2.6%; P value for difference, 0.75) for PF-AES as compared with PP-ZES. Overall, definite or probable stent thrombosis occurred in 1.0%. CONCLUSIONS: PF-AES were noninferior to PP-ZES regarding target-lesion failure at 12 months. Findings regarding the secondary end point and prespecified subgroups were generally consistent with that of the primary end point. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02328898.

Silibinin encapsulation in polymersome: A promising anticancer nanoparticle for inducing apoptosis and decreasing the expression level of miR-125b/miR-182 in human breast cancer cells.

Silibinin, a polyphenolic flavonolignan, is well-known as a safe therapeutic drug without any side effects in the treatment of many malignancies especially cancerous cells. In this study, to overcome problems such as low solubility of silibinin and to enhance its delivery to cancerous cells, we encapsulated silibinin in polymersome nanoparticles. Physicochemical measurements such as dynamic light scattering, transmission electron microscopy, scanning electron microscopy, and atomic force microscopy confirmed the proper encapsulation of silibinin in nanoparticles. Furthermore, antiproliferative and apoptotic activities of silibinin encapsulated in polymersome nanoparticles (SPNs) on MDA-MB-231 breast cancer cell line were validated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Annexin V/Propidium Iodide measurement, and cell cycle analysis. In addition, quantitative reverse transcription polymerase chain reaction analysis confirmed that SPNs can repress oncogenic microRNAs (miRNAs) such as miR-125b and miR-182, as well as antiapoptotic genes such as Bcl2. SPNs can also induce overexpression of proapoptotic target genes such as P53, CASP9, and BAX directly and/or indirectly (through regulation of miRNAs). Our results suggested that polymersomes can be used as stable carriers in nano-dimensions and SPNs can be considered as a promising pharmacological agent for cancer therapy.

The influence of Cisplatin-based chemotherapy on the osseointegration of dental implants: An in vivo mechanical and histometrical study.

OBJECTIVES: To evaluate the effect of Cisplatin on bone repair and mineralization around implants and on the mechanical properties of bone tissue. MATERIALS AND METHODS: Forty-three Wistar rats were randomly divided into two groups: Cisplatin (CIS, medication) and control (CTL, placebo solution), administered once a week for 4 weeks. After 4 weeks, implants were installed in both tibiae metaphysis. After 30 and 60 days, the animals were sacrificed and their femurs and tibiae were removed. Femurs were subjected to mechanical tests and tibiae for removal torque, arrangement and distribution of collagen fibers, morphometrical analyses (bone tissue in contact with the implant surface [BIC] and areal fraction between implant threads occupied by bone tissue [BAFO]) and scanning electron microscopy to calcium and calcium/phosphorus analysis. Data were analyzed by ANOVA or MANOVA, and Tukey or Games-Howell post hoc tests, respectively (α = 0.05). RESULTS: The CTL specimens had significantly higher values (0.0001 ≤ p≤0.036) of strength (N), removal torque (N/cm2 ), %BIC, and %BAFO than CIS specimens, being their best results at day 60. No significant differences were found among the groups regarding the values of deformation, percentage of calcium, and calcium/phosphorus ratio. In CIS groups, there was a reduction in the organization of collagen at the bone/implant interface, resulting in a trabecular bone with thin trabeculae and birefringent collagen and irregular arrangement. CONCLUSIONS AND CLINICAL IMPLICATIONS: Cisplatin interfered negatively in the repair and mineralization around dental implants, as well as on the quality of the bone tissue, mainly in the period of 30 days after the implant placement.

Drug holiday patterns and bisphosphonate-related osteonecrosis of the jaw.

OBJECTIVES: There is limited evidence regarding the appropriate length of a bisphosphonate (BP) holiday to reduce the risk of osteonecrosis of the jaw (ONJ). In this cross-sectional study, we investigated the population-based patterns of the gaps between BP discontinuation and ONJ diagnosis. SUBJECTS AND METHODS: We used the claims database of the National Health Insurance Service in Korea. Among BP users between 2006 and 2015, incident ONJ cases during 2010-2015 with no history of ONJ in the last 4 years were identified. We assessed the time gap from the last BP administration to ONJ diagnosis. RESULTS: Among 1,569 incident ONJ cases, 836 (53.3%) occurred after BP discontinuation. The cumulative proportions of ONJ occurrence within 1 month, 3 months, 1 year, 2 years, and 3 years after discontinuation were 58.9%, 70.8%, 87.0%, 93.2%, and 96.1%, respectively. The length of drug holidays showed no significant difference between patients with or without comorbid cancer and diabetes mellitus (p-value, 0.12 and 0.52, respectively). However, the use of injectable BP formulations significantly affected ONJ incidence (p < 0.01). CONCLUSIONS: Most ONJ cases occurred within 3 years from BP suspension, with a higher prevalence among BP injection users with 1 year or lesser BP holiday.

Efficient Codelivery of Paclitaxel and Curcumin by Novel Bottlebrush Copolymer-based Micelles.

The novel self-assembling bottlebrush polyethylene glycol-polynorbornene-thiocresol block copolymers (PEG-PNB-TC) were synthesized by the ring opening metathesis polymerization (ROMP), followed by functionalization of the polymer backbone via the thio-bromo "click" postpolymerization strategy. The PEG-PNB-TC copolymers could easily self-assemble into the nanoscale core-shell polymeric micelles. The hydrophobic anticancer drugs, such as paclitaxel (PTX), could be loaded into their hydrophobic core to form a stable drug-loaded micelle with a superior drug loading capacity of up to ∼35% (w/w). The sustained drug release behavior of the PEG-PNB-TC micelles was observed under a simulated "sink condition". Compared with commercial PTX formulation (Taxol), the PTX-loaded PEG-PNB-TC micelles showed the enhanced in vitro cellular uptake and comparable cytotoxicity in the drug-sensitive cancer cells, while the copolymers were much safer than Cremophor EL, the surfactant used in Taxol. Furthermore, curcumin (CUR), a natural chemotherapy drug sensitizer, was successfully coloaded with PTX into the PEG-PNB-TC micelles. High drug loading capacity of the PEG-PNB-TC micelles allowed for easy adjustment of drug doses and the ratio of the coloaded drugs. The combination of PTX and CUR showed synergistic anticancer effect in both the drug mixture and drug coloaded micelles at high CUR/PTX ratio, while low CRU/PTX ratio only exhibited additive effects. The combinatorial effects remarkably circumvented the PTX resistance in the multidrug resistant (MDR) cancer cells. Due to the easy polymerization and functionalization, excellent self-assembly capability, high drug loading capability, and great stability, the PEG-PNB-TC copolymers might be a promising nanomaterial for delivery of the hydrophobic anticancer drugs, especially for combination drug therapy.

Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial.

BACKGROUND: Adjuvant treatment with interferon (IFN)-α-2a improved disease-free survival (DFS) and showed a trend for improving overall survival (OS) in melanoma. This trial was designed to examine whether PEG-IFN is superior to IFN with regard to distant metastasis-free survival (DMFS), DFS and OS. PATIENTS AND METHODS: In this multicenter, open-label, prospective randomized phase III trial, patients with resected cutaneous melanoma stage IIA(T3a)-IIIB (AJCC 2002) were randomized to receive PEG-IFN (180 µg subcutaneously 1×/week; 24 months) or IFN α-2a (3MIU subcutaneously 3×/week; 24 months). Randomization was stratified for stage, number of metastatic nodes, age and previous IFN treatment. The primary end point was DMFS; secondary end points were OS, DFS, quality of life (QoL) and tolerability. RESULTS: A total of 909 patients were enrolled (451 PEG-IFN versus 458 IFN). Neither 5-year DMFS [PEG-IFN 61.0% versus IFN 67.3%; hazard ratio (HR) 1.16, P = 0.21] nor 5-year OS (PEG-IFN 73.2% versus IFN 75.2%; HR 1.05, P = 0.70) nor 5-year DFS (PEG-IFN 57.3% versus IFN 60.9%; HR 1.09, P = 0.40) showed significant differences. Subgroup analyses in patients ± ulcerated primaries and of different tumor stages did not find differences in DMFS, OS or DFS between the treatment groups. One hundred and eighteen patients (26.2%) in the PEG-IFN and 61 patients (13.3%) in the IFN population did not receive the full dosage and length of treatment due to adverse events (P < 0.001). Leukopenia and elevation of liver enzymes were more common in the PEG-IFN arm (56% versus 23.5% LCP; 19.1% versus 9.4% AST; 33.0% versus 16.5% ALT). QoL was identical for nearly all domains. CONCLUSION: PEG-IFN did not improve the outcome over IFN. A higher percentage of patients under PEG-IFN discontinued treatment due to toxicity. CLINICAL TRIALSGOV IDENTIFIER: NCT00204529.

Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded with C6 Ceramide and Doxorubicin: In Vitro Evaluation on HeLa, A2780-ADR, and H69-AR Cells.

Current research in cancer therapy is beginning to shift toward the use of combinational drug treatment regimens. However, the efficient delivery of drug combinations is governed by a number of complex factors in the clinical setting. Therefore, the ability to synchronize the pharmacokinetics of the individual therapeutic agents present in combination not only to allow for simultaneous tumor accumulation but also to allow for a synergistic relationship at the intracellular level could prove to be advantageous. In this work, we report the development of a novel folic acid-targeted liposomal formulation simultaneously co-loaded with C6 ceramide and doxorubicin [FA-(C6+Dox)-LP]. In vitro cytotoxicity assays showed that the FA-(C6+Dox)-LP was able to significantly reduce the IC50 of Dox when compared to that after the treatment with the doxorubicin-loaded liposomes (Dox-LP) as well as the untargeted drug co-loaded (C6+Dox)-LP on HeLa, A2780-ADR, and H69-AR cells. The analysis of the cell cycle distribution showed that while the C6 liposomes (C6-LP) did not cause cell cycle arrest, all the Dox-containing liposomes mediated cell cycle arrest in HeLa cells in the G2 phase at Dox concentrations of 0.3 and 1 µM and in the S phase at the higher concentrations. It was also found that this arrest in the S phase precedes the progression of the cells to apoptosis. The targeted FA-(C6+Dox)-LP were able to significantly enhance the induction of apoptotic events in HeLa cell monolayers as compared to the other treatment groups. Next, using time-lapse phase holographic imaging microscopy, it was found that upon treatment with the FA-(C6+Dox)-LP, the HeLa cells underwent rapid progression to apoptosis after 21 h as evidenced by a drastic drop in the average area of the cells after loss of cell membrane integrity. Finally, upon evaluation in a HeLa spheroid cell model, treatment with the FA-(C6+Dox)-LP showed significantly higher levels of cell death compared to those with C6-LP and Dox-LP. Overall, this study clearly shows that the co-delivery of C6 ceramide and Dox using a liposomal platform significantly correlates with an antiproliferative effect due to cell cycle regulation and subsequent induction of apoptosis and thus warrants its further evaluation in preclinical animal models.

Bisphosphonates, healthcare professionals and oral health.

OBJECTIVE: General medical and dental practitioner and pharmacists all encounter patients on bisphosphonates and as such require adequate knowledge regarding osteonecrosis of the jaw, a potential complication associated with its use. The cross-sectional study investigated perceived implications of and attitudes towards bisphosphonate use in oral health among general medical and dental practitioners and pharmacists. MATERIALS AND METHODS: Medical and dental practitioners and pharmacists registered in Victoria, Australia, completed an online survey (SurveyMonkey©). Data analysis consisted of chi-square tests with significance as p < 0.05. RESULTS: One hundred and thirty six doctors (general medical practitioners, GMPs), 283 dentists (GDPs) and 26 pharmacists (PHs) participated. 70, 38 and 80%, respectively, reviewed patients prescribed bisphosphonates (BPs). GMPs (88%), GDPs (76%) and PHs (85%) were aware of osteonecrosis of the jaws (ONJ). GMPs (76%) and PHs (100%) advised patients to inform dentists. GMPs (45%) referred patients for dental assessments prior to commencing BPs with 71.9% of GDPs received such referrals. In terms of available information on oral health and BPs, GMPs (56%), GDPs (50%) and PH (53.8%) were either unsure any existed or reported receiving sufficient information. CONCLUSIONS: Discrepancies exist amongst different healthcare professionals in terms of BP use and oral health, and common consensus guidelines are warranted.

Changes in antimicrobial susceptibility profile and prevalence of quinolone low-sensitive strains in subgingival plaque from acute periodontal lesions after systemic administration of sitafloxacin.

This study aimed to assess changes in antimicrobial susceptibilities of subgingival bacteria in acute periodontal lesions following systemic administration of a new-generation fluoroquinolone, sitafloxacin and to monitor the occurrence and fate of quinolone low-sensitive strains. Patients with acute phase of chronic periodontitis were subjected to microbiological assessment of their subgingival plaque samples at baseline (A1). Sitafloxacin was then administered systemically (100 mg/day for 5 days). The microbiological examinations were repeated one week after administration (A2). Susceptibilities of clinical isolates from acute sites to various antimicrobials were determined using broth and agar dilution methods. At A2, subgingival bacteria with low sensitivity to levofloxacin were identified in four patients, and they were subjected to a follow-up microbiological examination at on the average 12 months after sitafloxacin administration (A3). The patients received initial and supportive periodontal therapy during the period A2 to A3. From the examined subgingival sites, 8 and 19 clinical isolates were obtained at A2 and A3, respectively. Some Streptococcus strains isolated at A2 were found to be resistant to levofloxacin (MIC 16-64 µg/ml), azithromycin (MIC 2->128 µg/ml) or clarithromycin (MIC 1->32 µg/ml). At A3, isolated streptococci were highly susceptible to levofloxacin (MIC 0.5-2 µg/ml), while those resistant to azithromycin or clarithromycin were still isolated. It is suggested that the presence of the quinolone low-sensitive strains in initially acute lesions after sitafloxacin administration was transient, and they do not persist in the subgingival milieu during the periodontal therapy.

Effects of systemic administration of sitafloxacin on subgingival microflora and antimicrobial susceptibility profile in acute periodontal lesions.

The aim of this study was to assess the effect(s) of systemic administration of sitafloxacin on subgingival microbial profiles of acute periodontal lesions. Antimicrobial susceptibility of clinical isolates was also investigated. Patients with acute phases of chronic periodontitis were subjected to clinical examination and microbiological assessment of their subgingival plaque samples by culture technique. Sitafloxacin was then administered (100 mg/day for 5 days) systemically. The clinical and microbiological examinations were repeated 6-8 days after administration. Susceptibilities of clinical isolates to various antimicrobials were determined using the broth and agar dilution methods. From the sampled sites in 30 participants, a total of 355 clinical isolates (34 different bacterial species) were isolated and identified. Parvimonas micra, Prevotella intermedia and Streptococcus mitis were the most prevalent cultivable bacteria in acute sites. Systemic administration of sitafloxacin yielded a significant improvement in clinical and microbiological parameters. Among the antimicrobials tested, sitafloxacin was the most potent against the clinical isolates with an MIC90 of 0.12 µg/ml at baseline. After administration, most clinical isolates were still highly susceptible to sitafloxacin although some increase in MICs was observed. The results suggest that systemic administration of sitafloxacin is effective against subgingival bacteria isolated from acute periodontal lesions.

Heme oxygenase-1: potential therapeutic targets for periodontitis.

Periodontitis is one of the most prevalent inflammatory disease worldwide, which affects 11% of the global population and is a major cause of tooth loss. Recently, oxidative stress (OS) has been found to be the pivital pathophysiological mechanism of periodontitis, and overactivated OS will lead to inflammation, apoptosis, pyroptosis and alveolar bone resorption. Interestingly, heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme degradation, can exert antioxidant activites through its products-carbon monoxide (CO), Fe2+, biliverdin and bilirubin in the inflammatory microenvironment, thus exhibiting anti-inflammatory, anti-apoptotic, anti-pyroptosis and bone homeostasis-regulating properties. In this review, particular focus is given to the role of HO-1 in periodontitis, including the spatial-temporal expression in periodental tissues and pathophysiological mechanisms of HO-1 in periodontitis, as well as the current therapeutic applications of HO-1 targeted drugs for periodontitis. This review aims to elucidate the potential applications of various HO-1 targeted drug therapy in the management of periodontitis, investigate the influence of diverse functional groups on HO-1 and periodontitis, and pave the way for the development of a new generation of therapeutics that will benefit patients suffering from periodontitis.

Chitosan-based intelligent polymeric networks for site-specific colon medication delivery: A comprehensive study on controlled release of diloxanide furoate and network formation dynamics.

Oral medications are prone to gastric degradation and enzymatic inactivation, diminishing their efficacy. This study investigates a solution by developing intelligent polymeric networks, incorporating chitosan, methacrylic acid, N, N, methylene bisacrylamide, and montmorillonite clay, to enable the controlled release of Diloxanide Furoate (DF), an anti-protozoal drug. Employing a swelling-assisted diffusion technique, drug loading percentages varied from 63.96 % to 76.82 % among different formulations. Increased chitosan and methacrylic acid content enhanced drug loading, while N, N, methylene bisacrylamide and montmorillonite clay demonstrated an inverse relationship affecting diffusion and swelling. Equilibrium swelling studies unveiled formulation-dependent behaviors, with chitosan reducing swelling and methacrylic acid promoting it. Higher N, N, methylene bisacrylamide concentrations decreased swelling, indicating a denser cross-linked structure, while montmorillonite clay reduced hydrophilicity and swelling capacity. Further analyses confirmed successful gel formation, particularly in formulations with higher chitosan, methacrylic acid, and N, N, methylene bisacrylamide content, while montmorillonite clay limited gel fraction due to restricted polymer chain mobility. Techniques such as Fourier transform infrared spectroscopy, Differential scanning calorimetry, and thermal gravimetric analyses supported network development, enhancing thermal stability and cross-linking density. This research underscores the flexibility of polymeric networks for precise drug delivery, offering potential advancements in targeted therapies for various medical conditions.

Current Treatment Methods for Charcot-Marie-Tooth Diseases.

Charcot-Marie-Tooth (CMT) disease, the most common inherited neuromuscular disorder, exhibits a wide phenotypic range, genetic heterogeneity, and a variable disease course. The diverse molecular genetic mechanisms of CMT were discovered over the past three decades with the development of molecular biology and gene sequencing technologies. These methods have brought new options for CMT reclassification and led to an exciting era of treatment target discovery for this incurable disease. Currently, there are no approved disease management methods that can fully cure patients with CMT, and rehabilitation, orthotics, and surgery are the only available treatments to ameliorate symptoms. Considerable research attention has been given to disease-modifying therapies, including gene silencing, gene addition, and gene editing, but most treatments that reach clinical trials are drug treatments, while currently, only gene therapies for CMT2S have reached the clinical trial stage. In this review, we highlight the pathogenic mechanisms and therapeutic investigations of different subtypes of CMT, and promising therapeutic approaches are also discussed.

Association of the severity and progression rate of periodontitis with systemic medication intake.

Background/purpose: Information on the systemic medication profiles of patients with periodontitis is limited. Therefore, this retrospective cross-sectional study aimed to analyze the relationship between the severity and rate of progression of periodontitis and systemic medication intake using a database of patients who attended the Clinic of Periodontics of the Faculty of Dentistry of the University of Costa Rica. Methods: Electronic health records of patients diagnosed with periodontitis based on the Classification of Periodontal and Peri-Implant Diseases and Conditions (2017) were evaluated. Individuals were further categorized based on the severity (stage) and rate of progression (grade). Data extracted from the patient records included age, sex, and self-reported medication intake. Results: In total, 930 records were included. Most of the studied population was middle-aged (36-64 years old); 43.01% were male, and 56.99% were female. Four hundred and fifty-seven patients (49.14%) reported taking at least one systemic medication for a chronic condition. Regarding the periodontal treatment phase, 62.37% underwent steps 1-3, and 37.63% underwent step 4. The most common systemic medications taken were for cardiovascular diseases (42.28%), followed by medications for diabetes (14.46%) and neurologic disorders (14.46%). Most patients (59.35%) were diagnosed with Stage III periodontitis. Grade B (48.28%) was the most prevalent. Calcium channel blockers demonstrated a disease severity-dependent association with the periodontal stage (p = 0.021). In addition, systemic medications for diabetes mellitus were associated with periodontal disease severity and rate of progression (all Ps < 0.05). Conclusions: This study provides indirect evidence of the association between systemic diseases and periodontitis. The positive association between medications used to treat diabetes and the severity and rate of progression of periodontitis may be due to the underlying disease rather than the medications per se.