Food is Medicine for HIV: Improved health and hospitalizations in the Changing Health through Food Support (CHEFS-HIV) pragmatic randomized trial.

BACKGROUND: Policy support for "Food is Medicine"-medically tailored meals or groceries to improve health-is rapidly growing. No randomized trials have heretofore investigated the benefits of medically tailored food programs for people living with HIV (PLHIV). METHODS: The CHEFS-HIV pragmatic randomized trial included PLHIV who were clients of Project Open Hand (POH), a San Francisco-based nonprofit food organization. The intervention arm (n = 93) received comprehensive medically tailored meals, groceries, and nutritional education. Control participants (n = 98) received less intensive (POH "standard of care") food services. Health, nutrition, and behavioral outcomes were assessed at baseline and 6 months later. Primary outcomes measured were viral non-suppression and health related quality of life. Mixed models estimated treatment effects as differences-in-differences between arms. RESULTS: The intervention arm had lower odds of hospitalization (odds ratio [OR] = 0.11), food insecurity (OR = 0.23), depressive symptoms (OR = 0.32), antiretroviral therapy adherence <90% (OR = 0.18), and unprotected sex (OR = 0.18), and less fatty food consumption (ß= -0.170 servings/day) over 6 months, compared to the control arm. There was no difference between study arms in viral non-suppression and health-related quality of life over 6 months. CONCLUSIONS: A "Food-is-Medicine" intervention reduced hospitalizations and improved mental and physical health among PLHIV, despite no impact on viral suppression. CLINICAL TRIALS REGISTRATION: NCT03191253.

Design of Y2 Receptor Selective and Proteolytically Stable PYY3-36 Analogues.

In recent years peptide YY (PYY) has attracted attention within the area of diabetes and obesity due to its involvement in food intake regulation and glucose homeostasis. It is well-known that PYY1-36 is rapidly cleaved by dipeptidyl peptidase-4 to the more Y2 receptor selective analogue PYY3-36, which is further cleaved to the inactive analogue PYY3-34. In order to improve the selectivity and proteolytic stability of the C-terminus, we synthesized several analogues incorporating N-methyl amino acids or ß-homo amino acids and other non-natural amino acids. These were tested against all four NPY receptors, and highly potent and Y2 receptor selective analogues were identified by combining a tryptophan residue in position 30 with either N-methyl or ß-homo arginine in position 35. We also identified an analogue with a MeGln34 substitution that surprisingly displayed high affinity toward all four receptors. In addition, these analogues displayed improved stability toward C-terminal proteolysis compared to native PYY3-36.

Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist.

Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies.

Short-stay unit hospitalisation vs. standard care outcomes in older internal medicine patients-a randomised clinical trial.

Background: the effect of hospitalisation in emergency department-based short-stay units (SSUs) has not been studied in older patients. We compared SSU hospitalisation with standard care at an Internal Medicine Department (IMD) in acutely admitted older internal medicine patients. Methods: pragmatic randomised clinical trial. We randomly assigned patients aged 75 years or older, acutely admitted for an internal medicine disease and assessed to be suitable for SSU hospitalisation to SSU hospitalisation or IMD hospitalisation. SSU hospitalisation was provided by a pragmatic 'fast-track' principle. The primary outcome was 90-day mortality. Secondary outcomes included adverse events, change in Lawton Instrumental Activities of Daily Living (IADL) score within 90 days from admission, in-hospital length of stay and unplanned readmissions within 30 days after discharge. Results: between January 2015 and October 2016, 430 participants were randomised (median age 84 years in both groups). Ninety-day mortality was 22(11%) in the SSU group and 32(15%) in the IMD group (odds ratio (OR) 0.66; 95% confidence interval (CI) 0.37-1.18; P = 0.16). When comparing the SSU group to the IMD group, 16(8%) vs. 45(21%) experienced at least one adverse event (OR 0.31; 95% CI 0.17-0.56; P < 0.001); 6(3%) vs. 35(20%) experienced a reduction in IADL score within 90 days from admission (P < 0.001); median in-hospital length of stay was 73 h [interquartile range, IQR 36-147] vs. 100 h [IQR 47-169], (P < 0.001), and 26(13%) vs. 58(29%) were readmitted (OR 0.37; 95% CI 0.22-0.61; P < 0.001). Conclusions: mortality at 90 days after admission was not significantly lower in the SSU group, but SSU hospitalisation was associated with a lower risk of adverse events, less functional decline, fewer readmissions and shorter hospital stay. Trial registration: NCT02395718.

Seroprevalence against Rickettsia and Borrelia Species in Patients with Uveitis: A Prospective Survey.

Vector-borne diseases such as Lyme borreliosis and rickettsioses have been associated with ocular inflammation. Our aim was to study patients with diagnosed uveitis to evaluate serological signs of infection or exposure to these tick-borne agents. Forty-eight patients were prospectively examined with serology together with medical records and a questionnaire concerning previous exposure, diseases, and treatments. Seven patients (14.6%) showed seroconversion to Rickettsia spp. between acute and convalescent phase sera, which provides support for a positive Rickettsia diagnosis according to guidelines. The specificity was confirmed by Western blot. Additional 28 patients had stationary titres of which eight (16.6%) had 1 : 256 or higher titre in the first serum, and another 13 patients were seronegative. No epidemiological risk factor or marker could be identified. For Borrelia, only three patients showed moderate IgG titres. A control group of 100 blood donors, 60 patients with rheumatic disease, and 56 patients seeking medical care were tested of which 2.0-7.1% showed low anti-Rickettsia titres and 3.0-8.3% anti-Borrelia titres. The findings are indicative for an association between infection or exposure to Rickettsia spp. and uveitis with a seropositivity among patients with recurrent uveitis in concordance with the spread of rickettsial exposure in a tick-exposed population.

Admission of elderly medical patients to fast track or standard hospitalisation: protocol for a randomised trial.

INTRODUCTION: Emergency department-based short stay units (SSUs) are increasingly being introduced to provide accelerated care. The effects of treatment in SSUs for elderly medical patients are not well-studied. METHODS: The ELDER trial is a single-blinded, randomised parallel trial with 1:1 allocation between hospitalisation in an SSU (intervention) and the Department of Internal Medicine (standard care). The study is conducted at Holbaek Hospital, Denmark. Elderly patients are screened for inclusion if an emergency physician assesses that treatment in an SSU is possible. Eligible participants are patients aged ≥ 75 years needing in-hospital treatment of an acute medical problem and who are stable upon admission. The primary outcome is 90-day all-cause mortality. Secondary outcomes include: length of stay in hospital, incidence of complications during hospitalisation, rate of unplanned readmissions and change in instrumental activities of daily living. We aim at recruiting 430 patients based on an estimated effects size of reducing mortality by 10%. All outcome measures will be assessed in an intention-to-treat analysis. Recruitment started on 5 January 2015. By 16 October 2015, we have enrolled 203 patients. An interim safety analysis is scheduled. CONCLUSION: In the ELDER trial, we explore benefits and harms related to treatment in an SSU for elderly medical patients compared with standard hospitalisation. FUNDING: Region Zealand's Forskningsfond, the Tryg Foundation and University of Copenhagen. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02395718.

Comprehension deficits among older patients in a quick diagnostic unit.

BACKGROUND: Higher prevalence of multiple illnesses and cognitive impairment among older patients pose a risk of comprehension difficulties, potentially leading to medication errors. Therefore, the objective of this study was to investigate comprehension of discharge instructions among older patients admitted to a Quick Diagnostic Unit (QDU). METHODS: One hundred and two patients discharged from the QDU answered a questionnaire covering understanding of their hospitalization and discharge plan. Patients' ability to recall discharge instructions and awareness of comprehension deficits, ie, ability to identify the misconceived information, were evaluated by comparing the questionnaires with the discharge letters. The population was divided into an older group (age ≥65 years) and a younger group. RESULTS: The older group (n=40) was less able to recall correct medication instructions when compared to the younger group (54% versus 78%, respectively; P=0.02). In multiple logistic regression analysis, correct recall of medication instructions was 4.2 times higher for the younger group compared to the older group (odds ratio 4.2, 95% confidence interval 1.5-11.9, P=0.007) when adjusted for sex and education. The older patients were less aware of their own comprehension deficits, and in respect to medication instructions awareness decreased 6.1% for each additional year of age (odds ratio 0.939, 95% confidence interval 0.904-0.98, P=0.001) when adjusted for sex and education. CONCLUSION: Older patients were less able to recall correct medication instructions and less aware of their comprehension deficits after discharge from a QDU. The findings of the present study emphasize the importance of thorough communication and follow-up when treating older patients.

Discovery of bishomo(hetero)arylpiperazines as novel multifunctional ligands targeting dopamine D(3) and serotonin 5-HT(1A) and 5-HT(2A) receptors.

As a continuation of our efforts to develop innovative ligands for D(3), 5-HT(1A), and 5-HT(2A) receptors with low propensity to block hERG channels, we propose a series bishetero(homo)arylpiperazines 5a-m as novel and potent multifunctional ligands characterized by low occupancy at D(2) and 5-HT(2C) receptors.

Electrochemical oxidation of troglitazone: identification and characterization of the major reactive metabolite in liver microsomes.

Troglitazone (TGZ) was developed for the treatment of type 2 diabetes but was withdrawn from the market due to hepatotoxicity. The formation of reactive metabolites has been associated with the observed hepatotoxicity. Such reactive metabolites have been proposed to be formed via three different mechanisms. One of the proposed mechanisms involves the oxidation of the chromane moiety of TGZ to a reactive o-quinone methide. The two other mechanisms involve metabolic activation of the thiazolidinedione moiety of TGZ. In the present study, it is shown that electrochemical oxidations can be used to generate a reactive metabolite of TGZ, which can be trapped by GSH or N-acetylcysteine. From incubations of TGZ with rat and human liver microsomes in the presence of either GSH or N-acetylcysteine, it was shown that similar conjugates were formed in vitro as formed from electrochemical oxidations of TGZ. One- and two-dimensional NMR studies of the troglitazone- S-( N-acetyl)cysteine conjugate revealed that N-acetylcysteine was attached to a benzylic carbon in the chromane moiety, showing that the conjugate was formed via a reaction between the o-quinone methide of TGZ and N-acetylcysteine. From electrochemical oxidations of rosiglitazone, pioglitazone, and ciglitazone in the presence of GSH, no GSH conjugates could be identified. These three compounds all contain a thiazolidinedione moiety. In conclusion, it has been shown that the primary reactive metabolite of TGZ formed from electrochemical oxidation was the o-quinone methide, and this metabolite was similar to what was observed to be the primary reaction product in human and rat liver microsomes.

Metabolic activation of carboxylic acids.

BACKGROUND: Carboxylic acids constitute a large and heterogeneous class of both endogenous and xenobiotic compounds. A number of carboxylic acid drugs have been associated with adverse reactions, linked to the metabolic activation of the carboxylic acid moiety of the compounds, i.e., formation of acyl-glucuronides and acyl-CoA thioesters. OBJECTIVE: The objective is to give an overview of the current knowledge on metabolic activation of carboxylic acids and how such metabolites may play a role in adverse reactions and toxicity. METHODS: Literature concerning the formation and disposition of acyl glucuronides and acyl-CoA thioesters was searched. Also included were papers on the chemical reactivity of acyl glutathione-thioesters, and literature concerning possible links between metabolic activation of carboxylic acids and reported cellular and clinical effects. RESULTS/CONCLUSION: This review demonstrates that metabolites of carboxylic acid drugs must be considered chemically reactive, and that the current knowledge about metabolic activation of this compound class can be a good starting-point for further studies on the consequences of chemically reactive metabolites.

Bioactivation of diclofenac in vitro and in vivo: correlation to electrochemical studies.

Diclofenac is widely used in the treatment of, for example, arthritis and muscle pain. The use of diclofenac has been associated with hepatotoxicity, which has been linked to the formation of reactive metabolites. Diclofenac can be metabolized to 4'-OH- and 5-OH-diclofenac, both of which are able to form quinone imines capable of reacting with, for example, GSH and nucleophilic groups in proteins. Electrochemistry has been shown to be a suitable tool for mimicking some types of oxidative drug metabolism and for studying the formation of reactive metabolites. In these studies, the electrochemical oxidation of diclofenac to a +16 Da metabolite was shown to be identical to a synthetic standard of 5-OH-diclofenac. Furthermore, two different experimental designs were investigated with respect to the electrochemical oxidation of 4'-OH- and 5-OH-diclofenac. In the first approach, the oxidized sample was collected in an aqueous solution of GSH, whereas in the other approach, GSH was added to the sample before the oxidation was performed. From these electrochemical oxidations, a range of GSH conjugates of 4'-OH- and 5-OH-diclofenac were observed and characterized by MS/MS. This allowed the development of sensitive LC-MS methods in order to detect the GSH conjugates from in vivo (rat bile) and in vitro (human liver microsomes (HLM), rat liver microsomes (RLM), and rat hepatocytes) samples. A wide range of mono-, di-, and triglutathionyl conjugates were detected in the in vitro and in vivo samples. It was also observed that 5-OH-diclofenac formed GSH conjugates with RLM and HLM without addition of NADPH, whereas GSH conjugate formation of 4'-OH-diclofenac was NADPH-dependent. This indicated that 5-OH-diclofenac was prone to auto-oxidation. The oxidation potentials of the two hydroxy metabolites were determined by cyclic voltammetry. A difference of 69 mV was observed between the two oxidation potentials, which in part may explain the extent of auto-oxidation for 5-OH-diclofenac. In conclusion, it was shown that electrochemical oxidation was capable of mimicking the metabolic hydroxylation of diclofenac to 5-OH-diclofenac. Furthermore, electrochemical oxidation was used to generate a range of GSH conjugates of 4'-OH- and 5-OH-diclofenac and a number of these conjugates were also detected in metabolism studies with microsomes (HLM/RLM) and freshly isolated rat hepatocytes, and in vivo in rat bile.

Development and evaluation of an electrochemical method for studying reactive phase-I metabolites: correlation to in vitro drug metabolism.

A reactive metabolite may react covalently with proteins or DNA to form adducts that ultimately may lead to a toxic response. Reactive metabolites can be formed via, for example, cytochrome P450-mediated phase 1 reactions, and in this study, we report the development and evaluation of an electrochemical method for generating reactive metabolites. Paracetamol was used as a test compound to develop the method. The stability of the electrochemically generated N-acetyl-p-benzoquinoneimine (NAPQI) from paracetamol was investigated at 37 degrees C at pH 5.0, 7.4, and 9.0. The highest stability of NAPQI was observed at pH 7.4. The reaction rate between NAPQI and glutathione (GSH) was studied with cyclic voltammetry. NAPQI reacted quantitatively with GSH within 130 ms. The reactivity of NAPQI toward other nucleophiles was investigated, and for the reaction with N-acetyltyrosine, a time-dependent formation of a conjugate with N-acetyltyrosine was observed from 0 to 4 min. The applicability of the method was evaluated with compounds that were able to form quinone imines (amodiaquine), quinones (3-tert-butyl-4-hydroxyanisole and p-cresol), imine methides (3-methylindole; trimethoprim), quinone methides (3,5-di-tert-butyl-4-hydroxytoluene), and nitrenium ions (clozapine). The compounds were oxidized in an analytical electrochemical cell, and the formed reactive metabolites were trapped with GSH. The samples were then analyzed by LC-MS and LC-MS/MS. For comparison, all compounds were incubated with GSH in rat and human liver microsomes, and the formation of GSH conjugates was compared with that observed by electrochemical oxidation. Furthermore, the electrochemical method was used to synthesize a GSH conjugate of clozapine, which made it possible to obtain structural information by NMR. In summary, a high degree of similarity was observed between the conjugates identified from electrochemical oxidation and GSH conjugates identified from incubation with liver microsomes. In conclusion, we have developed a method that is useful for studies on reactive metabolites and furthermore can be scaled up for the synthesis of GSH conjugates for NMR.