Tenofovir Douche as HIV Preexposure Prophylaxis for Receptive Anal Intercourse: Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics (DREAM 01).

BACKGROUND: Despite highly effective HIV preexposure prophylaxis (PrEP) options, no options provide on-demand, nonsystemic, behaviorally congruent PrEP that many desire. A tenofovir-medicated rectal douche before receptive anal intercourse may provide this option. METHODS: Three tenofovir rectal douches-220 mg iso-osmolar product A, 660 mg iso-osmolar product B, and 660 mg hypo-osmolar product C-were studied in 21 HIV-negative men who have sex with men. We sampled blood and colorectal tissue to assess safety, acceptability, pharmacokinetics, and pharmacodynamics. RESULTS: The douches had high acceptability without toxicity. Median plasma tenofovir peak concentrations for all products were several-fold below trough concentrations associated with oral tenofovir disoproxil fumarate (TDF). Median colon tissue mucosal mononuclear cell (MMC) tenofovir-diphosphate concentrations exceeded target concentrations from 1 hour through 3 to 7 days after dosing. For 6-7 days after a single product C dose, MMC tenofovir-diphosphate exceeded concentrations expected with steady-state oral TDF 300 mg on-demand 2-1-1 dosing. Compared to predrug baseline, HIV replication after ex vivo colon tissue HIV challenge demonstrated a concentration-response relationship with 1.9 log10 maximal effect. CONCLUSIONS: All 3 tenofovir douches achieved tissue tenofovir-diphosphate concentrations and colorectal antiviral effect exceeding oral TDF and with lower systemic tenofovir. Tenofovir douches may provide a single-dose, on-demand, behaviorally congruent PrEP option, and warrant continued development. Clinical Trials Registration . NCT02750540.

Hypophosphatasia: presentation and response to asfotase alfa.

Hypophosphatasia (HPP) is a rare bone disease with limited scientific evidence on the tolerability and safety of its novel treatment, Asfotase Alfa (AA). We report 7 HPP patients' heterogenous presentations and the significant improvement in various clinical outcomes attained with AA shedding light on this highly effective and safe therapy. INTRODUCTION: Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder characterized by a deficiency in the tissue non-specific alkaline phosphatase (TNSALP) due to loss of function mutation in the ALPL gene. HPP is associated with impaired skeletal mineralization due to elevations in inorganic pyrophosphate and altered phosphate : pyrophosphate ratio. Asfotase alfa (AA) "enzyme replacement" was approved for treatment of HPP in 2015. We present 7 patients with HPP, 5 with pediatric-onset, and 2 with adult-onset, who have been treated with AA and describe the efficacy and safety in these patients. METHODS: 7 patients (4 females, 3 males) aged 19-68 years with HPP were included in this study. Diagnosis of HPP was confirmed by DNA analysis. AA was administered in doses of 6mg/kg/week with a mean follow-up of 6 months (SD= 5). RESULTS: Subjective improvement in muscle strength, muscle pain, walking ability, and walking distance with a reduction in the use of gait aids was seen "with AA in HPP patients." Muscle strength and pain improved by up to 70% from baseline as quantified subjectively by patients. Walking distance improved by up to 100%. Patients also reported improved cognition, mood, and energy levels, with up to 90% improvement in mood and 75% improvement in energy levels. 4 out of 6 patients first noted clinical signs of improvement after 3 months of being on therapy. 1 out of the 7 patients sustained a toe fracture 10 months from being on AA. AA was well-tolerated with injection site reactions being the most reported adverse effect. CONCLUSION: HPP treatment with AA in individuals with both pediatric and adult-onset forms resulted in significant subjective improvement in musculoskeletal and cognitive manifestations in addition to patients' quality of life. The drug was well tolerated in 6 patients. 1 patient discontinued therapy because of minor adverse effects with myalgias.

Ticagrelor inverse agonist activity at the P2Y12 receptor is non-reversible versus its endogenous agonist adenosine 5´-diphosphate.

BACKGROUND AND PURPOSE: Ticagrelor is labelled as a reversible, direct-acting platelet P2Y12 receptor (P2Y12 R) antagonist that is indicated clinically for the prevention of thrombotic events in patients with acute coronary syndrome (ACS). As with many antiplatelet drugs, ticagrelor therapy increases bleeding risk in patients, which may require platelet transfusion in emergency situations. The aim of this study was to further examine the reversibility of ticagrelor at the P2Y12 R. EXPERIMENTAL APPROACH: Studies were performed in human platelets, with P2Y12 R-stimulated GTPase activity and platelet aggregation assessed. Cell-based bioluminescence resonance energy transfer (BRET) assays were undertaken to assess G protein-subunit activation downstream of P2Y12 R activation. KEY RESULTS: Initial studies revealed that a range of P2Y12 R ligands, including ticagrelor, displayed inverse agonist activity at P2Y12 R. Only ticagrelor was resistant to washout and, in human platelet and cell-based assays, washing failed to reverse ticagrelor-dependent inhibition of ADP-stimulated P2Y12 R function. The P2Y12 R agonist 2MeSADP, which was also resistant to washout, was able to effectively compete with ticagrelor. In silico docking revealed that ticagrelor and 2MeSADP penetrated more deeply into the orthosteric binding pocket of the P2Y12 R than other P2Y12 R ligands. CONCLUSION AND IMPLICATIONS: Ticagrelor binding to P2Y12 R is prolonged and more akin to that of an irreversible antagonist, especially versus the endogenous P2Y12 R agonist ADP. This study highlights the potential clinical need for novel ticagrelor reversal strategies in patients with spontaneous major bleeding, and for bleeding associated with urgent invasive procedures.

Nucleoside Triphosphate Diphosphohydrolase 1 Exhibits Enzymatic Activity toward Tenofovir Diphosphate.

Tenofovir (TFV; prescribed as TFV disoproxil fumarate and TFV alafenamide prodrugs) is currently used for HIV prevention and treatment. TFV must be phosphorylated twice into TFV-diphosphate (TFV-DP) to become pharmacologically active. Previously, we reported heterogeneity in TFV-DP distribution in colorectal tissue (a putative site of HIV infection) sections collected from research participants receiving a TFV-containing enema. This observed heterogeneity is likely multifactorial. Of note, TFV-DP is structurally similar to ATP. It is known that nucleotidases such as nucleoside triphosphate diphosphohydrolases (NTPDases) dephosphorylate ATP. Thus, it was hypothesized that NTPDase-mediated dephosphorylation plays a role in regulating TFV-DP levels in colorectal tissue. To test this hypothesis, recombinant NTPDase proteins (NTPDase 1, 3, 4, 5, 6, and 8) were incubated, individually, with TFV-DP to determine their abilities to dephosphorylate TFV-DP in vitro. Following incubations, TFV-DP dephosphorylation was determined using both malachite green phosphate assays and ultrahigh-performance liquid chromatography tandem mass spectrometry. From these, NTPDase 1 exhibited the highest activity toward TFV-DP. Further, enzyme kinetic analysis revealed Michaelis-Menten kinetics for NTPDase 1-mediated TFV-DP dephosphorylation. Next, immunoblot analyses were conducted to confirm the expression of NTPDase 1 protein in human colorectal tissue. Liquid chromatography coupled to mass spectrometry proteomics analysis was used to measure the relative abundance of NTPDases in human colorectal tissue among healthy adult individuals (n = 4). These analyses confirmed the high abundance of NTPDase 1 in human colorectal tissue. Taken together, results suggest that NTPDase 1 may contribute to the regulation of TFV-DP levels. The above data provide important insights into the dephosphorylation of TFV-DP. SIGNIFICANCE STATEMENT: Nucleoside triphosphate diphosphohydrolases (NTPDases) that are involved in enzymatic ATP dephosphorylation may contribute to tenofovir-diphosphate (TFV-DP) dephosphorylation, leading to its inactivation. In this study, the NTPDases responsible for TFV-DP dephosphorylation in vitro and their expression in human colorectal tissue were investigated. Through this work, it was demonstrated that NTPDase 1 has the highest activity toward TFV-DP dephosphorylation, and it was abundant in human colorectal tissue. Importantly, these studies will increase our understanding of TFV-DP disposition.

Comparative Proteomic Analysis Identifies Key Metabolic Regulators of Gemcitabine Resistance in Pancreatic Cancer.

Pancreatic adenocarcinoma (PDAC) is highly refractory to treatment. Standard-of-care gemcitabine (Gem) provides only modest survival benefits, and development of Gem resistance (GemR) compromises its efficacy. Highly GemR clones of Gem-sensitive MIAPaCa-2 cells were developed to investigate the molecular mechanisms of GemR and implemented global quantitative differential proteomics analysis with a comprehensive, reproducible ion-current-based MS1 workflow to quantify ∼6000 proteins in all samples. In GemR clone MIA-GR8, cellular metabolism, proliferation, migration, and 'drug response' mechanisms were the predominant biological processes altered, consistent with cell phenotypic alterations in cell cycle and motility. S100 calcium binding protein A4 was the most downregulated protein, as were proteins associated with glycolytic and oxidative energy production. Both responses would reduce tumor proliferation. Upregulation of mesenchymal markers was prominent, and cellular invasiveness increased. Key enzymes in Gem metabolism pathways were altered such that intracellular utilization of Gem would decrease. Ribonucleoside-diphosphate reductase large subunit was the most elevated Gem metabolizing protein, supporting its critical role in GemR. Lower Ribonucleoside-diphosphate reductase large subunit expression is associated with better clinical outcomes in PDAC, and its downregulation paralleled reduced MIAPaCa-2 proliferation and migration and increased Gem sensitivity. Temporal protein-level Gem responses of MIAPaCa-2 versus GemR cell lines (intrinsically GemR PANC-1 and acquired GemR MIA-GR8) implicate adaptive changes in cellular response systems for cell proliferation and drug transport and metabolism, which reduce cytotoxic Gem metabolites, in DNA repair, and additional responses, as key contributors to the complexity of GemR in PDAC. These findings additionally suggest targetable therapeutic vulnerabilities for GemR PDAC patients.

Reverse cardiac remodelling and dysfunction in A97S transthyretin cardiac amyloidosis after tafamidis treatment.

Transthyretin cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure, but it has received increasing attention due to the availability of treatment options. We present a case of hereditary transthyretin cardiomyopathy (A97S, an under-represented variant in current clinical studies) who presented with heart failure. Timely diagnosis and intervention with tafamidis demonstrated reversed cardiac remodelling via multiple imaging techniques (echocardiography, cardiac magnetic resonance imaging and technetium-99m pyrophosphate scintigraphy). The echocardiography and cardiac magnetic resonance imaging demonstrated improved global strain. Cardiac magnetic resonance imaging showed decreased extracellular volume. The technetium-99m pyrophosphate scintigraphy demonstrated decreased heart-to-contralateral ratio. This case highlights the potential reversible effect of tafamidis on A97S amyloidosis cardiomyopathy.

Continued attendance in a PrEP program despite low adherence and non-protective drug levels among adolescent girls and young women in Kenya: Results from a prospective cohort study.

BACKGROUND: In sub-Saharan Africa (SSA), adolescent girls and young women (AGYW) ages 15 to 24 years represent <10% of the population yet account for 1 in 5 new HIV infections. Although oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) can be highly effective, low persistence in PrEP programs and poor adherence have limited its ability to reduce HIV incidence among women. METHODS AND FINDINGS: A total of 336 AGYW participating in the PEPFAR-funded DREAMS PrEP program in western Kenya were enrolled into a study of PrEP use conducted between 6/2019 to 1/2020. AGYW, who used daily oral TDF/FTC, completed interviews and provided dried blood spots (DBS) for measurement of tenofovir-diphosphate (TFV-DP) concentrations at enrollment and 3 months later, and 176/302 (58.3%, 95% confidence interval [95% CI 52.3 to 63.8]) met our definition of PrEP persistence: having expressed intention to use PrEP and attended both the second interview and an interim refill visit. Among AGYW with DBS taken at the second interview, only 9/197 (4.6%, [95% CI 1.6 to 7.5]) had protective TFV-DP levels (≥700 fmol/punch) and 163/197 (82.7%, [95% CI 77.5 to 88]) had levels consistent with no recent PrEP use (<10 fmol/punch). Perception of being at moderate-to-high risk for HIV if not taking PrEP was associated with persistence (adjusted odds ratio, 10.17 [95% CI 5.14 to 20.13], p < 0.001) in a model accounting for county of residence and variables that had p-value <0.1 in unadjusted analysis (age, being in school, initiated PrEP 2 to 3 months before the first interview, still active in DREAMS, having children, having multiple sex partners, partner aware of PrEP use, partner very supportive of PrEP use, partner has other partners, AGYW believes that a partner puts her at risk, male condom use, injectable contraceptive use, and implant contraceptive use). Among AGYW who reported continuing PrEP, >90% indicated they were using PrEP to prevent HIV, although almost all had non-protective TFV-DP levels. Limitations included short study duration and inclusion of only DREAMS participants. CONCLUSIONS: Many AGYW persisted in the PrEP program without taking PrEP frequently enough to receive benefit. Notably, AGYW who persisted had a higher self-perceived risk of HIV infection. These AGYW may be optimal candidates for long-acting PrEP.

Calcinosis in systemic sclerosis.

PURPOSE OF REVIEW: The aim of this study was to provide updated information on the prevalence, pathogenesis, diagnostics and therapeutics of calcinosis cutis associated with systemic sclerosis (SSc). RECENT FINDINGS: Observational studies show ethnic and geographical differences in the prevalence of calcinosis. In addition to clinical and serological associations, biochemical studies and in-vivo models have attempted to explain theories behind its pathogenesis, including prolonged state of inflammation, mechanical stress, hypoxia and dysregulation in bone and phosphate metabolism. Long-term use of proton pump inhibitors may increase the risk for calcinosis in SSc. Few single-centre observational studies have shown mild benefit with minocycline and topical sodium thiosulfate. SUMMARY: Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It affects up to 40% of SSc patients and causes significant morbidity. Long disease duration, features of vascular dysfunction and osteoporosis have been associated with calcinosis. Altered levels of inorganic pyrophosphate and fibroblast growth factor-23 have been implicated in dysregulated phosphate metabolism that may lead to calcinosis in SSc. Plain radiography can help with diagnosis and quantifying the calcinosis burden. Surgical treatment remains the most effective therapy when feasible. At present, no medical therapies have proven efficacy in large randomized controlled trials.

Evaluation of Treatment With Talazoparib and Avelumab in Patients With Recurrent Mismatch Repair Proficient Endometrial Cancer.

Importance: Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration-approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC. Objective: To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC. Design, Settings, and Participants: This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies. Interventions: Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects. Main Outcomes and Measures: Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity. Results: Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit. Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02912572.

Tenofovir-diphosphate in peripheral blood mononuclear cells during low, medium and high adherence to emtricitabine/ tenofovir alafenamide vs. emtricitabine/ tenofovir disoproxil fumarate.

OBJECTIVE: Tenofovir alafenamide (TAF) preferentially loads peripheral blood mononuclear cells (PBMCs), resulting in higher PBMC tenofovir-diphosphate (TFV-DP) vs. tenofovir disoproxil fumarate (TDF). No studies have yet compared TFV-DP in PBMC from lower than daily dosing between prodrugs, which has potential implications for event-driven preexposure prophylaxis and pharmacologic forgiveness. DESIGN: Two separate randomized, directly observed therapy (DOT) crossover studies (DOT-DBS and TAF-DBS) were conducted to mimic low, medium and high adherence. METHODS: HIV-negative adults were randomized to two 12-week DOT regimens of 33, 67 or 100% of daily dosing with emtricitabine (F)/TAF 200 mg/25 mg (TAF-DBS) or F/TDF 200 mg/300 mg (DOT-DBS), separated by a 12-week washout. PBMC steady-state concentrations (Css) of TFV-DP and FTC-TP were estimated using nonlinear mixed models and compared between F/TAF and F/TDF. RESULTS: Thirty-five participants contributed to 33% (n = 23), 67% (n = 23) and 100% (n = 23) of daily F/TAF regimens. Forty-four contributed to 33% (n = 15), 67% (n = 16) and 100% (n = 32) of daily F/TDF regimens. PBMC TFV-DP Css were 7.3 [95% confidence interval (95% CI): 6.4-8.2], 7.1 (5.9-8.2) and 6.7- (4.4-8.9) fold higher (P < 0.0001) following F/TAF vs. F/TDF; 593 vs. 81.7, 407 vs. 57.4, and 215 vs. 32.3 fmol/106 cells, respectively. TFV-DP was 2.6 (2.1-3.1) fold higher with 33% F/TAF vs. 100% F/TDF. Estimated half-lives (95% CI) of TFV-DP in PBMC were 2.9 (1.5-5.5) days for F/TAF and 2.1 (1.5-2.9) days for F/TDF. FTC-TP was similar in both studies (P = 0.119). CONCLUSION: F/TAF produced 6.7 to 7.3-fold higher TFV-DP in PBMC vs. F/TDF across adherence levels, supporting increased potency and pharmacologic forgiveness with F/TAF in the PBMC compartment.

Adherence to event-driven HIV PrEP among men who have sex with men in Amsterdam, the Netherlands: analysis based on online diary data, 3-monthly questionnaires and intracellular TFV-DP.

INTRODUCTION: Event-driven pre-exposure prophylaxis (edPrEP) with oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) is highly effective for preventing HIV acquisition in men who have sex with men (MSM) and is preferred over daily PrEP by some MSM. However, it is largely unknown how well MSM adhere to edPrEP. We then aimed to assess PrEP protection during CAS among MSM using edPrEP and participating in the Amsterdam PrEP demonstration project (AMPrEP). METHODS: We analysed data from participants enrolled in AMPrEP who were taking edPrEP. We measured adherence through (1) a mobile application in which sexual behaviour and PrEP-use were recorded daily, (2) three-monthly self-completed questionnaires and (3) dried blood spot (DBS) samples collected around six, twelve and twenty-four months after PrEP initiation. We assessed the proportion of days with condomless anal sex (CAS) acts that were protected by PrEP, per partner type (i.e. steady partners, known casual partners, unknown casual partners), and the proportion of three-month periods during which PrEP was correctly used. Intracellular TFV-diphosphate (TFV-DP) concentrations were determined from DBS. Good adherence was defined as at least one tablet before and one tablet within 48 hours after a CAS act. RESULTS: Between 11 September 2015 and 6 October 2019, 182 of 376 MSM (48.4%) used edPrEP for at least one three-month period. Of the 8224 CAS days that were reported in the app during edPrEP-use, we observed good protection for most CAS days involving steady partners (n = 1625/2455, 66.9%), known casual partners (n = 3216/3472, 92.6%) and unknown casual partners (n = 2074/2297, 90.3%). Men reported consistently correct PrEP-use in 851 (81.4%) of the 1046 three-month periods of edPrEP-use. The median TFV-DP concentration was 591 fmol/sample (interquartile range = 270 to 896). CONCLUSIONS: Adherence to edPrEP was high as determined from the online app and questionnaire. DBS measurements were consistent with two to three tablets per week on average.

Pyrophosphate therapy prevents trauma-induced calcification in the mouse model of neurogenic heterotopic ossification.

Trauma-induced calcification is the pathological consequence of complex injuries which often affect the central nervous system and other parts of the body simultaneously. We demonstrated by an animal model recapitulating the calcification of the above condition that adrenaline transmits the stress signal of brain injury to the calcifying tissues. We have also found that although the level of plasma pyrophosphate, the endogenous inhibitor of calcification, was normal in calcifying animals, it could not counteract the acute calcification. However, externally added pyrophosphate inhibited calcification even when it was administered after the complex injuries. Our finding suggests a potentially powerful clinical intervention of calcification triggered by polytrauma injuries which has no effective treatment.

Treatment of iron deficiency anemia with liposomal iron in inflammatory bowel disease: efficacy and impact on quality of life.

Background Anemia is a clinical condition frequently seen in patients with inflammatory bowel disease, which is responsible for a significant loss of quality of life. Objective To assess the efficacy and safety of using oral liposomal iron to treat iron deficiency anemia in inflammatory bowel disease patients, as well as assess the impact of this treatment on psychometric scores. Methods Patients with inactive/mildly active inflammatory bowel disease were screened for anemia in this interventional pilot study conducted from November 2016 to March 2018. Patients with mild anemia were treated with oral liposomal iron for 8 weeks. Main outcome measure The primary endpoint of the study was the response to liposomal oral iron therapy. Treatment response was defined as patients who achieved a hemoglobin increase of ≥ 1 g/dL and/or hemoglobin normalization by the 8th week of treatment. Results Out of 200 screened patients, 40 (20%) had anemia. Of the 21 patients who completed treatment, 13 (62%) responded to oral liposomal iron replacement therapy (mean increases of hemoglobin from 11.4 to 12.6 g/dL). The transferrin saturation index increased by an average of 10.2 (p = 0.006) and the quality of life by 26.3 (p < 0.0001). There was also a mean reduction of 9.2 in the perception of fatigue (p < 0.0001). Conclusion Treatment with oral liposomal iron is effective in improving mild iron deficiency anemia and quality of life, as well as in decreasing fatigue in patients with inactive or mildly active inflammatory bowel disease.

Frequency and Predictors of Tenofovir-diphosphate Detection Among Young Kenyan Women in a Real-world Pre-exposure Prophylaxis Implementation Program.

In a pre-exposure prophylaxis program for Kenyan women, we detected tenofovir-diphosphate in 61% (125/201) of randomly selected dried blood spots collected at the first follow-up visit. Tenofovir-diphosphate was detected more frequently among women who had partners living with human immunodeficiency virus, who were not pregnant, and who were ≥24 years.

Oral Supplementation with Sucrosomial Ferric Pyrophosphate Plus L-Ascorbic Acid to Ameliorate the Martial Status: A Randomized Controlled Trial.

Altered martial indices before orthopedic surgery are associated with higher rates of complications and greatly affect the patient's functional ability. Oral supplements can optimize the preoperative martial status, with clinical efficacy and the patient's tolerability being highly dependent on the pharmaceutical formula. Patients undergoing elective hip/knee arthroplasty were randomized to be supplemented with a 30-day oral therapy of sucrosomial ferric pyrophosphate plus L-ascorbic acid. The tolerability was 2.7% among treated patients. Adjustments for confounding factors, such as iron absorption influencers, showed a relevant response limited to older patients (≥ 65 years old), whose uncharacterized Hb loss was averted upon treatment with iron formula. Older patients with no support lost -2.8 ± 5.1%, while the intervention group gained +0.7 ± 4.6% of circulating hemoglobin from baseline (p = 0.019). Gastrointestinal diseases, medications, and possible dietary factors could affect the efficacy of iron supplements. Future opportunities may consider to couple ferric pyrophosphate with other nutrients, to pay attention in avoiding absorption disruptors, or to implement interventions to obtain an earlier martial status optimization at the population level.

High Bioavailability from Ferric Pyrophosphate-Fortified Bouillon Cubes in Meals is Not Increased by Sodium Pyrophosphate: a Stable Iron Isotope Study in Young Nigerian Women.

BACKGROUND: It is challenging to find an iron compound that combines good bioavailability with minimal sensory changes when added to seasonings or condiments. Ferric pyrophosphate (FePP) is currently used to fortify bouillon cubes, but its bioavailability is generally low. Previously, the addition of a stabilizer, sodium pyrophosphate (NaPP), improved iron bioavailability from a bouillon drink. OBJECTIVE: We assessed whether there is a dose-response effect of added NaPP on iron bioavailability from local meals prepared with intrinsically labeled FePP-fortified bouillon cubes in young Nigerian women using iron stable isotope techniques. METHODS: In a double-blind, randomized, cross-over trial, women (n = 24; aged 18-40 y; mean BMI 20.5 kg/m2) consumed a Nigerian breakfast and lunch for 5 d prepared with bouillon cubes containing 2.5 mg 57Fe (as FePP) and 3 different molar ratios of NaPP: 57Fe (0:1, 3:1, and 6:1). Iron bioavailability was assessed by measuring 57Fe incorporation into erythrocytes 16 d after each 5 d NaPP: 57Fe feeding period. Data were analyzed using a linear regression model of log iron absorption on NaPP ratio, with body weight and baseline body iron stores as covariates and subject as a random intercept. RESULTS: Of the women included, 46% were anemic and 26% were iron deficient. Iron bioavailability was 10.8, 9.8, and 11.0% for the 0:1, 3:1, and 6:1 NaPP:57Fe treatments, respectively. There was no dose-response effect of an increasing NaPP:57Fe ratio (ß ± SE: 0.003 ± 0.028, P = 0.45). CONCLUSIONS: In this study, the addition of NaPP did not increase iron bioavailability from FePP-fortified bouillon cubes. However, iron bioavailability from the Nigerian meals prepared with FePP-fortified bouillon cubes was higher than expected. These results are encouraging for the potential of bouillon cubes as a fortification vehicle. Further studies are needed to assess the effect of FePP-fortified bouillon cubes on improving iron status in low-income populations. This trial was registered at clinicaltrials.gov as NCT02815449.

Glucocorticoid-induced osteoporosis: 2019 concise clinical review.

Glucocorticoids remain widely used for many medical conditions, and fractures are the most serious common adverse event related to long-term glucocorticoid use. Glucocorticoid-induced osteoporosis (GIOP) develops in a time- and dose-dependent manner, but even at low doses, an increased risk of fragility fracture may be observed even within the first month of treatment. GIOP is mediated by multiple pathophysiologic mechanisms resulting in an inhibition of bone formation and an increase in bone resorption. The clinical assessment of GIOP has potential pitfalls since dual-energy X-ray absorptiometry (DXA) may underestimate the risk of fracture in patients treated with glucocorticoids. Many national organizations have developed guidelines for assessing fracture risk and treating patients with, or at risk for, GIOP. These groups advocate both antiresorptive agents and bone-forming agents based predominately on their efficacy in improving bone mineral density. Oral bisphosphonates are generally the first-line therapy for GIOP in most patients due to their proven efficacy, good safety, and low cost. For those patients at greater risk of fracture, teriparatide should be considered earlier, based on its ability to significantly reduce vertebral fractures when compared with alendronate. GIOP remains a major public health concern that is at least partially preventable with current and potential future therapeutic options.

Adherence to osteoporosis therapy after an upper extremity fracture: a pre-specified substudy of the C-STOP randomized controlled trial.

Despite their proven efficacy for secondary fracture prevention, long-term adherence with oral bisphosphonates is poor. INTRODUCTION: To compare the effectiveness of two interventions on long-term oral bisphosphonate adherence after an upper extremity fragility fracture. METHODS: Community-dwelling participants 50 years or older with upper extremity fragility fractures not previously treated with bisphosphonates were randomized to either a multi-faceted patient and physician educational intervention (the active control arm) vs. a nurse-led case manager (the study arm). Primary outcome was adherence (taking > 80% of prescribed doses) with prescribed oral bisphosphonates at 12 months postfracture between groups; secondary outcomes included rates of primary non-adherence and 24-month adherence. We also compared quality of life between adherent and non-adherent patients. RESULTS: By 12 months, adherence with the initially prescribed bisphosphonate was similar (p = 0.96) in both groups: 38/48 (79.2%) in the educational intervention group vs. 66/83 (79.5%) in the case manager arm. By 24 months, adherence rates were 67% (32/48) in the educational intervention group vs. 53% (43/81) in case managed patients (p = 0.13). Primary non-adherence was 6% (11 patients) in the educational intervention group and 12% (21 patients) in the case managed group (p = 0.07). Prior family history of osteoporosis (aOR 2.1, 95% CI 1.0 to 4.4) and being satisfied with current medical care (aOR 2.3, 95% CI 1.1 to 4.8) were associated with better adherence while lower income (aOR 0.2, 95% CI 0.1 to 0.6, for patients with income < $30,000 per annum) was associated with poorer rates of adherence. There were no differences in health-related quality of life scores at baseline or during follow-up between patients who were adherent and those who were not. CONCLUSION: While both interventions achieved higher oral bisphosphonate adherence compared to previously reported adherence rates in the general population, primary non-adherence and long-term adherence to bisphosphonates were similar in both arms. Adherence was influenced by family history of osteoporosis, satisfaction with current medical care, and income. TRIAL REGISTRATION: ClinicalTrials.gov : NCT01401556.

Sucrosomial® Iron Supplementation in Mice: Effects on Blood Parameters, Hepcidin, and Inflammation.

Sucrosomial® Iron is a recently developed formulation to treat iron deficiency based on ferric pyrophosphate covered by a matrix of phospholipids plus sucrose esters of fatty acids. Previous data indicated that Sucrosomial® Iron is efficiently absorbed by iron-deficient subjects, even at low dosage, and without side effects. Its structural properties may suggest that it is absorbed by an intestinal pathway which is different to the one used by ionic iron. Although, studies in vitro showed that Sucrosomial® Iron is readily absorbed, no animal models have been established to study this important aspect. To this aim, we induced iron deficient anemia in mice by feeding them with a low-iron diet, and then we treated them with either Sucrosomial® Iron or sulfate iron by gavage for up to two weeks. Both iron formulations corrected anemia and restored iron stores in a two-week period, but with different kinetics. Ferrous Sulfate was more efficient during the first week and Sucrosomial® Iron in the second week. Of note, when given at the same concentrations, Ferrous Sulfate induced the expression of hepcidin and four different inflammatory markers (Socs3, Saa1, IL6 and CRP), while Sucrosomial® Iron did not. We conclude that anemic mice are interesting models to study the absorption of oral iron, and that Sucrosomial® Iron is to be preferred over Ferrous Sulfate because of similar absorption but without inducing an inflammatory response.