Targeted Cyclo[8]pyrrole-Based NIR-II Photoacoustic Tomography Probe for Suppression of Orthotopic Pancreatic Tumor Growth and Intra-abdominal Metastases.

Pancreatic cancer is highly lethal. New diagnostic and treatment modalities are desperately needed. We report here that an expanded porphyrin, cyclo[8]pyrrole (CP), with a high extinction coefficient (89.16 L/g·cm) within the second near-infrared window (NIR-II), may be formulated with an αvß3-specific targeting peptide, cyclic-Arg-Gly-Asp (cRGD), to form cRGD-CP nanoparticles (cRGD-CPNPs) with promising NIR-II photothermal (PT) therapeutic and photoacoustic (PA) imaging properties. Studies with a ring-array PA tomography system, coupled with analysis of control nanoparticles lacking a targeting element (CPNPs), revealed that cRGD conjugation promoted the delivery of the NPs through abnormal vessels around the tumor to the solid tumor core. This proved true in both subcutaneous and orthotopic pancreatic tumor mice models, as confirmed by immunofluorescent studies. In combination with NIR-II laser photoirradiation, the cRGD-CPNPs provided near-baseline tumor growth inhibition through PTT both in vitro and in vivo. Notably, the combination of the present cRGD-CPNPs and photoirradiation was found to inhibit intra-abdominal metastases in an orthotopic pancreatic tumor mouse model. The cRGD-CPNPs also displayed good biosafety profiles, as inferred from PA tomography, blood analyses, and H&E staining. They thus appear promising for use in combined PA imaging and PT therapeutic treatment of pancreatic cancer.

Biomimetic platelet-camouflaged drug-loaded polypyrrole for the precise targeted antithrombotic therapy.

Lower extremity deep venous thrombosis (LEDVT) affects patient's quality of life for a long time, and even causes pulmonary embolism, which threatens human health. Current anticoagulant drugs in clinical treatment are hampered by the risk of bleeding due to poor targeting and low drug penetration. Here, we used platelet (PLT)-like biological targeting to enhance the delivery and accumulation of nanomedicines in thrombus and reduce the risk of bleeding. Meanwhile, the parallel strategy of "thrombus thermal ablation and anticoagulation" was applied to increase the permeability of drugs in thrombus and achieve the optimal antithrombotic effect. Polypyrrole (PPy) and rivaroxban (Riv, an anticoagulant drug) were co-assembled into platelet membrane-coated nanoparticles (NPs), PLT-PPy/Riv NPs, which actively targeted the thrombotic lesion at multiple targets in the platelet membrane and were thermally and drug-specific thrombolysed by 808 nm laser irradiation. The combination therapy resulted in up to 90% thrombolysis in a femoral vein thrombosis model compared to single phototherapy or drug therapy. The results showed that the nanoformulation provided a new direction for remote precise and controlled sustained thrombolysis, which was in line with the trend of nanomedicine towards clinical translation.

Novel Photodynamic/Photothermal Treatment of Fungal Keratitis Using Rose Bengal-Loaded Polypyrrole-Gold Nanoparticles in Wistar Albino Rats.

Purpose: Fungal keratitis is a potential corneal contagious disease mainly caused by yeast such as Candida albicans and filamentous fungi such as Aspergillus niger. The response of fungal keratitis to standard antifungals is limited by the poor bioavailability, the limited ocular penetration of antifungal drugs, and the development of microbial resistance. Photodynamic therapy using rose bengal (RB) as a photosensitizer was found to be effective in fungal keratitis management; however, the hydrophilicity of RB limits its corneal penetration. Polypyrrole-coated gold nanoparticles (AuPpy NP) were introduced as a nano-delivery system of RB with high loading capacity. It was proved that (RB-AuPpy NP) exhibited a combined photodynamic/photothermal effect. This study aims to use the combined photodynamic/photothermal effect of RB-AuPpy NP as a novel protocol for treating Fungal Keratitis in albino Wistar rats. Methods: The rats were infected by C. albicans and A. niger. Each infected group of rats was subdivided into groups treated by RB followed by radiation (photodynamic only), AuPpy NP followed by radiation (photothermal only), and RB-AuPpy NP followed by radiation (combined photodynamic/photothermal). Histopathological examination and slit lamp imaging were done to investigate the results. Results: The results revealed that 3 weeks post-treatment, the corneas treated by RB-AuPpy NP (combined photodynamic/photothermal effect) exhibited the best improvement compared to other groups. Conclusion: This protocol can be considered a promising one for Fungal Keratitis management that overcomes microbial resistance problems.

Recent Advances of Diketopyrrolopyrrole Derivatives in Cancer Therapy and Imaging Applications.

Cancer is threatening the survival of human beings all over the world. Phototherapy (including photothermal therapy (PTT) and photodynamic therapy (PDT)) and bioimaging are important tools for imaging-mediated cancer theranostics. Diketopyrrolopyrrole (DPP) dyes have received more attention due to their high thermal and photochemical stability, efficient reactive oxygen species (ROS) generation and thermal effects, easy functionalization, and tunable photophysical properties. In this review, we outline the latest achievements of DPP derivatives in cancer therapy and imaging over the past three years. DPP-based conjugated polymers and small molecules for detection, bioimaging, PTT, photoacoustic imaging (PAI)-guided PTT, and PDT/PTT combination therapy are summarized. Their design principles and chemical structures are highlighted. The outlook, challenges, and future opportunities for the development of DPP derivatives are also presented, which will give a future perspective for cancer treatment.

A translational pharmacokinetic/pharmacodynamic approach supports optimal vonoprazan dosing for erosive oesophagitis and Helicobacter pylori infection.

BACKGROUND: Treatment of acid-related disorders relies on gastric acid suppression. The percentage of time intragastric pH is >4 (pH >4 holding time ratio [HTR]) is important for healing erosive oesophagitis; and the pH >6 HTR is critical for eradication of Helicobacter pylori infection, as bacterial replication is active and antibiotic effectiveness is optimised. Vonoprazan, a potassium-competitive acid blocker approved in the USA and other countries, suppresses gastric acid secretion in a predictable, rapid and consistent manner, extended over prolonged periods. AIM: To explore the relationship between vonoprazan exposure and pH HTR through a pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS: We pooled data from Phase 1 studies with intragastric pH measurements. Pharmacokinetic profiles were predicted for study participants using an existing population pharmacokinetic model. Pharmacokinetic and pharmacodynamic data were merged, and three direct-link PK/PD models were derived and used to simulate pH HTRs with between-participant variability for pH >4, >5 and >6, for vonoprazan doses of 20 mg once and twice daily. RESULTS: We used data from five Phase 1 studies to derive the PK/PD model. These included 245 participants (95.1% male, 50.6% Japanese and 49.4% non-Asian). Pre-dose, the mean pH >4 HTR was 6.4%, pH >5 3.2% and pH >6 1.2%. After 7 days of dosing, simulations predicted pH >4 HTRs of 89.7% and 98.1%, and pH >6 HTRs of 53.1% and 75.3%, for vonoprazan 20 mg once and twice daily, respectively. CONCLUSIONS: Vonoprazan 20 mg once- and twice-daily dosing demonstrated high, dose-dependent, 24-hour intragastric acid control in this PK/PD model, supporting clinical efficacy data in patients with acid-related disorders.

Immunogenic Cell Death Induction by Ionizing Radiation.

Immunogenic cell death (ICD) is a form of regulated cell death (RCD) induced by various stresses and produces antitumor immunity via damage-associated molecular patterns (DAMPs) release or exposure, mainly including high mobility group box 1 (HMGB1), calreticulin (CRT), adenosine triphosphate (ATP), and heat shock proteins (HSPs). Emerging evidence has suggested that ionizing radiation (IR) can induce ICD, and the dose, type, and fractionation of irradiation influence the induction of ICD. At present, IR-induced ICD is mainly verified in vitro in mice and there is few clinical evidence about it. To boost the induction of ICD by IR, some strategies have shown synergy with IR to enhance antitumor immune response, such as hyperthermia, nanoparticles, and chemotherapy. In this review, we focus on the molecular mechanisms of ICD, ICD-promoting factors associated with irradiation, the clinical evidence of ICD, and immunogenic forms of cell death. Finally, we summarize various methods of improving ICD induced by IR.

High Body Mass Index Is Correlated with the Success of Vonoprazan-Based Second-Line Therapy for Helicobacter Pylori Infection.

Eradication of Helicobacter pylori (Hp) is necessary for preventing peptic ulcers and stomach cancer. The potassium-competitive acid blocker vonoprazan is a gastric acid secretion inhibitor that improves the success rate of Hp eradication through its immediate and persistent inhibition of acid excretion. In Japan, first-line treatment involves a regimen in which vonoprazan is combined with amoxicillin and clarithromycin, while second-line treatment involves vonoprazan combined with amoxicillin and metronidazole. However, in contrast to the vonoprazan-based first-line therapy, no studies have investigated the factors influencing the success of vonoprazan-based second-line therapy. In this study, we therefore aimed to investigate factors related to the success of vonoprazan-based second-line therapy. We analyzed the association between the success of Hp eradication and patient factors including metronidazole/amoxicillin minimal inhibitory concentrations (MICs). MICs were measured using the Hp isolated from each patient. A receiver operating characteristic (ROC) analysis was conducted to examine continuous variables and eradication success. We reviewed the records of 33 patients (age: 34-79 years, male/female: 22/11, and body mass index (BMI): 16.1-28.8 kg/m2) who underwent vonoprazan-based second-line therapy after failure of first-line therapy at seven Japanese facilities between October 2018 and June 2019. The eradication success rate was 81.8% (27/33). ROC analysis revealed an area under the curve and BMI cutoff value of 0.796 and 23.8 kg/m2, respectively. The eradication success rate was higher in patients with high BMI than in those with low BMI (p = 0.007). Our findings indicate that higher BMI is correlated with the success of vonoprazan-based second-line therapy.

Dual-Targeting Glycol Chitosan/Heparin-Decorated Polypyrrole Nanoparticle for Augmented Photothermal Thrombolytic Therapy.

Near-infrared (NIR)-light-modulated photothermal thrombolysis has been investigated to overcome the hemorrhage danger posed by clinical clot-busting substances. A long-standing issue in thrombosis fibrinolytics is the lack of lesion-specific therapy, which should not be ignored. Herein, a novel thrombolysis therapy using photothermal disintegration of a fibrin clot was explored through dual-targeting glycol chitosan/heparin-decorated polypyrrole nanoparticles (GCS-PPY-H NPs) to enhance thrombus delivery and thrombolytic therapeutic efficacy. GCS-PPY-H NPs can target acidic/P-selectin high-expression inflammatory endothelial cells/thrombus sites for initiating lesion-site-specific thrombolysis by hyperthermia using NIR irradiation. A significant fibrin clot-clearance rate was achieved with thrombolysis using dual-targeting/modality photothermal clot disintegration in vivo. The molecular level mechanisms of the developed nanoformulations and interface properties were determined using multiple surface specific analytical techniques, such as particle size distribution, zeta potential, electron microscopy, Fourier-transform infrared spectroscopy (FTIR), wavelength absorbance, photothermal, immunofluorescence, and histology. Owing to the augmented thrombus delivery of GCS-PPY-H NPs and swift treatment time, dual-targeting photothermal clot disintegration as a systematic treatment using GCS-PPY-H NPs can be effectively applied in thrombolysis. This novel approach possesses a promising future for thrombolytic treatment.

Financial Implications of Avapritinib for Treatment of Unresectable Gastrointestinal Stromal Tumors in Patients With a PDGFRA Exon 18 Variant or After 3 Previous Therapies in a Hypothetical US Health Plan.

Importance: With the approval of avapritinib for adults with unresectable or metastatic gastrointestinal stromal tumors (GISTs) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 variant, including PDGFRA D842V variants, and National Comprehensive Cancer Network guideline recommendations as an option for patients with GIST after third-line treatment, it is important to estimate the potential financial implications of avapritinib on a payer's budget. Objective: To estimate the budget impact associated with the introduction of avapritinib to a formulary for metastatic or unresectable GISTs in patients with a PDGFRA exon 18 variant or after 3 or more previous treatments from the perspective of a US health plan. Design, Setting, and Participants: For this economic evaluation, a 3-year budget impact model was developed in March 2020, incorporating costs for drug acquisition, testing, monitoring, adverse events, and postprogression treatment. The model assumed that avapritinib introduction would be associated with increased PDGFRA testing rates from the current 49% to 69%. The health plan population was assumed to be mixed 69% commercial, 22% Medicare, and 9% Medicaid. Base case assumptions included a GIST incidence rate of 9.6 diagnoses per million people, a metastatic PDGFRA exon 18 mutation rate of 1.9%, and progression rate from first-line to fourth-line treatment of 17%. Exposures: The model compared scenarios with and without avapritinib in a formulary. Main Outcomes and Measures: Annual, total, and per member per month (PMPM) budget impact. Results: In a hypothetical 1-million member plan, fewer than 0.1 new patients with a PDGFRA exon 18 variant per year and 1.2 patients receiving fourth-line therapy per year were eligible for treatment. With avapritinib available, the total increase in costs in year 3 for all eligible adult patients with a PDGFRA exon 18 variant was $46 875, or $0.004 PMPM. For patients undergoing fourth-line treatment, the total increase in costs in year 3 was $69 182, or $0.006 PMPM. The combined total budget impact in year 3 was $115 604, or $0.010 PMPM, including an offset of $3607 in postprogression costs avoided or delayed. The higher rates of molecular testing resulted in a minimal incremental testing cost of $453 in year 3. Conclusions and Relevance: These results suggest that adoption of avapritinib as a treatment option would have a minimal budget impact to a hypothetical US health plan. This would be primarily attributable to the small eligible patient population and cost offsets from reduced or delayed postprogression costs.

[Updates and interpretations of the NCCN Clinical Practice Guidelines (2019 6th version) on gastrointestinal stromal tumor].

The diagnosis and treatment of gastrointestinal stromal tumor (GIST) is getting more and more standardized. In the last two decades, due to the elucidation of molecular mechanism of tumorigenesis, as well as the effectiveness of tyrosine kinase inhibitors, GIST has become well-known as one of the most classical models of targeted therapy on solid tumors in the precision medicine era. The National Comprehensive Cancer Network (NCCN) issued the latest version of clinical practice guideline on soft tissue sarcoma in February 2020. Compared with previous versions, the new version of the guideline highlighted the treatment recommendations of avapritinib, which further promoted the precise targeted treatment of GIST.

Partial repigmentation of vitiligo with tofacitinib, without exposure to ultraviolet radiation

Abstract Vitiligo is a disease that causes macules and achromic and/or hypochromic patches, which can affect from small areas to the entire tegument. Treatment options are few and are generally ineffective. Recently, some case reports have appeared which show positive results with the use of Janus kinase inhibitors associated with phototherapy. This report details the case of a patient with rheumatoid arthritis associated with vitiligo in treatment for two years, whose condition partially improved initially after eight months of oral tofacitinib at a dose of 5 mg twice a day, without exposure to ultraviolet radiation and with continuous improvement during these two years of treatment.

A 12 week, randomized, double-blind, placebo-controlled clinical trial for the evaluation of the efficacy and safety of HT083 on mild osteoarthritis.

BACKGROUND: The increasing prevalence of osteoarthritis among the old population worldwide is a great concern. Two of the biggest complaints of OA patients are joint pain and inflammation. Currently, people are relying on non-steroidal anti-inflammatory drugs (NSAIDs) and steroids to control pain and inflammation. However, long-term use of these pharmaceutical drugs has negative health consequences in the elderly, including gastro-intestinal, respiratory, and renal diseases. Natural products are receiving more attention than ever as alternative treatments against OA for their efficacies and safety. The root of Paeonia lactiflora Pal and the gum resin of Commiphora myrrha have been used as analgesics and anti-inflammatory agents since ancient time. A new herbal formula composed of P. lactiflora root and C. myrrha gum resin extracts, known as HT083, has shown promising antinociceptive and anti-inflammatory effects in a rodent model of OA. We design this study to investigate the safety and the efficacy of HT083 to prevent OA in patients with mild OA. METHODS: This is a randomized, double-blind, and placebo-controlled study. A total of 100 eligible participants will be divided into two groups and will be given HT083 and a placebo for 12 weeks in 1:1 ratio. Treatment results will be assessed using a visual analog scale (VAS), Korean-Short Form health survey-36 score (SF-36), personal evaluation, and laboratory analysis. DISCUSSION: This trial is expected to provide clinical evidence on the effectiveness and the safety of HT083 as a natural treatment for mild OA. TRIAL REGISTRATION: Korean Clinical Research Information Service (CRIS) number KCT0004925 Registered on 2020.04.16.

Synergistic reduction in albuminuria in type 2 diabetic mice by esaxerenone (CS-3150), a novel nonsteroidal selective mineralocorticoid receptor blocker, combined with an angiotensin II receptor blocker.

Esaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin-angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 8-hydroxy-2'-deoxyguanosine (8-OHdG), were measured, along with systolic blood pressure (SBP), fasting blood glucose, and serum K+ levels. Prior to the initiation of drug administration, KK-Ay mice showed higher blood glucose, insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic control, indicating the development of diabetic renal injury. Combined treatment with esaxerenone and olmesartan significantly reduced the change in UACR from baseline compared with the change associated with vehicle at week 8 (-1.750 vs. 0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from baseline compared with the change associated with vehicle at week 8 (P < 0.002). The combination treatment also reduced urinary excretion of podocalyxin and MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K+ levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy in KK-Ay mice without affecting SBP, suggesting that the renoprotective effects of esaxerenone could be exerted independently of its antihypertensive effect.

Update on quinolone-containing rescue therapies for Helicobacter pylori infection.

Third generation of quinolones, such as levofloxacin and moxifloxacin, -containing regimens are often used in second-line or rescue treatment of Helicobacter pylori infection. However, the increasing antibiotic resistance to quinolones affects the efficacies of quinolones-containing therapies in recent years. Therefore, there is a need to enhance the effectiveness of quinolones-containing therapies. Sitafloxacin, a fourth-generation quinolone, and vonoprazan, a novel potassium-competitive acid blocker, are now available as more effective treatment options. The aim of this paper is to summarize the current evidence of quinolone-containing therapies in rescue treatments, and to discuss the importance of drug sensitivity tests or analysis of gyrA mutation before treatments.

Partial repigmentation of vitiligo with tofacitinib, without exposure to ultraviolet radiation.

Vitiligo is a disease that causes macules and achromic and/or hypochromic patches, which can affect from small areas to the entire tegument. Treatment options are few and are generally ineffective. Recently, some case reports have appeared which show positive results with the use of Janus kinase inhibitors associated with phototherapy. This report details the case of a patient with rheumatoid arthritis associated with vitiligo in treatment for two years, whose condition partially improved initially after eight months of oral tofacitinib at a dose of 5mg twice a day, without exposure to ultraviolet radiation and with continuous improvement during these two years of treatment.

Precisely Tuning Photothermal and Photodynamic Effects of Polymeric Nanoparticles by Controlled Copolymerization.

Cancer possesses normoxic and hypoxia microenvironments with different levels of oxygen, needing different efficacies of photothermal and photodynamic therapies. It is important to precisely tune the photothermal and photodynamic effects of phototherapy nano-agents for efficient cancer treatment. Now, a series of copolymeric nanoparticles (PPy-Te NPs) were synthesized in situ by controlled oxidative copolymerization with different ratios of pyrrole to tellurophene by FeCl3 . The photothermal and photodynamic effects of semiconducting nano-agents under the first near-infrared (NIR) irradiation were precisely and systematically tuned upon simply varying the molar ratio of the pyrrole to tellurophene. The PPy-Te NPs were used for cancer treatment in mice, exhibiting excellent biocompatibility and therapeutic effect. This work presents a simple method to tune photothermal and photodynamic therapies effect in semiconducting nano-agents for cancer treatment.

Tofacitinib cream plus narrowband ultraviolet B phototherapy for segmental vitiligo in a child.

Segmental vitiligo often presents in childhood and tends to be more recalcitrant to therapy than generalized vitiligo. Recently, Janus kinase inhibitors have emerged as a promising treatment option, with some reports suggesting that concomitant ultraviolet light exposure may enhance therapeutic response. Here, we present a child with segmental vitiligo who responded rapidly and completely to treatment with tofacitinib cream plus phototherapy.

Effect of probiotics during vonoprazan-containing triple therapy on gut microbiota in Helicobacter pylori infection: A randomized controlled trial.

BACKGROUND: Probiotics are beneficial to patients with Helicobacter pylori infections by modulating the gut microbiota. Biofermin-R (BFR) is a multiple antibiotic-resistant lactic acid bacteria preparation of Enterococcus faecium 129 BIO 3B-R and is effective in normalizing the gut microbiota when used in combination with antibiotics. This study aimed to determine the effect of BFR in combination with vonoprazan (VPZ)-based therapy on gut microbiota. METHODS: Patients with positive urinary anti-H pylori antibody test (primary test) and fecal H pylori antigen test (secondary test) were examined. Patients in group 1 (BFR- ) received VPZ (20 mg twice daily), amoxicillin (750 mg twice daily), and clarithromycin (400 mg twice daily) for 7 days. Patients in group 2 (BFR+ ) received BFR (3 tablets/day) for 7 days, in addition to the aforementioned treatments. Following treatment, the relative abundance, α-diversity, and ß-diversity of gut microbiota were assessed. RESULTS: Supplementation with BFR prevented the decrease in a-diversity after eradication therapy (Day 7). ß-diversity was similar between groups. The incidence rate of diarrhea was non-significantly higher in the BFR- than in the BFR+ group (73.1% vs 56.5%; P = .361). Stool consistency was comparable in the BFR+ group on Days 7 and 1 (3.86 ± 0.95 vs 3.86 ± 1.46; P = .415). CONCLUSION: Biofermin-R combined with VPZ-based therapy resulted in higher microbial α-strain diversity and suppressed stool softening during H pylori eradication therapy.

Therapeutic lifestyle change intervention improved metabolic syndrome criteria and is complementary to amlodipine/atorvastatin.

AIMS: To examine whether addition of amlodipine (5 mg)/atorvastatin (10 mg) A/A to Therapeutic Lifestyle change intervention (TLC) would beneficially modulate Metabolic Syndrome (MetS) and oxidized low-density lipoprotein (Ox-LDL) levels. METHODS: Patients with MetS (n = 53) were randomized to TLC + placebo or TLC + A/A for 12 months. Anthropometric measurements, blood pressure (BP), lipid profile, plasma Ox-LDL, and area under the curve of free fatty acid (AUCFFA) during oral glucose tolerance test, a marker of adipose tissue health, were assessed before and after the intervention. RESULTS: Twenty-six patients completed the study with an overall improvement of MetS (p = 0.02). TLC + placebo was beneficial in reversing MetS comparable to TLC + A/A (54% vs. 39%; p = 0.08). Both treatments decreased systolic BP (p ≤ 0.01). TLC + A/A also decreased diastolic BP and triglyceride levels. The changes in Ox-LDL levels directly correlated with changes in weight in the TLC-placebo group (r = 0.64; p = 0.04). AUCFFA determined the loss of fat mass (r = 0.472, p = 0.03). CONCLUSIONS: 1) Addition of A/A has the advantage of improving the lipid profile and BP; but TLC alone was comparable to TLC + A/A in improving MetS; 2) weight change determines the TLC-associated change in Ox-LDL levels; and 3) AT metabolic health is a significant predictor of TLC-associated loss of body fat mass.