Respiratory Syncytial Virus (RSV) causes lower respiratory tract infections that can be severe and sometimes fatal. The risk for severe RSV infection is highest in infants and older adults. A safe ...and effective RSV vaccine for older adults represents a serious unmet medical need due to higher morbidity and mortality in this age group. In this randomized, partially double-blind, placebo-controlled, phase 1 dose-escalation study, we evaluated the safety, tolerability and immunogenicity of an investigational messenger ribonucleic acid (mRNA) vaccine encoding the RSV fusion protein (F) stabilized in the prefusion conformation. The study was conducted in healthy younger adults (ages ≥18 and ≤49 years) and healthy older adults (ages ≥60 and ≤79 years). Participants received mRNA-1777 (V171) or placebo as a single intramuscular dose. For each dose level, three sentinel participants were administered open-label mRNA-1777 (V171). Seventy-two younger adults were randomized and administered 25, 100, or 200 µg mRNA-1777 (V171) or placebo, and 107 older adults were randomized and administered 25, 100, 200 or 300 µg mRNA-1777 (V171) or placebo. Primary objectives were safety and tolerability and secondary objectives included humoral and cell-mediated immunogenicity. All dose levels of mRNA-1777 (V171) were generally well tolerated and no serious adverse events related to the vaccine were reported. Immunization with mRNA-1777 (V171) elicited a humoral immune response as measured by increases in RSV neutralizing antibody titers, serum antibody titers to RSV prefusion F protein, D25 competing antibody titers to RSV prefusion F protein, and cell-mediated immune responses to RSV-F peptides.
SPR741 is a novel polymyxin B derivative, with minimal intrinsic antibacterial activity and reduced nonclinical nephrotoxicity compared to levels with polymyxin B, that interacts with the outer ...membrane of Gram-negative bacteria, enhancing penetration of coadministered antibiotics. The safety, tolerability, and pharmacokinetics (PK) of SPR741 were evaluated in two studies, after single and multiple intravenous (i.v.) doses in healthy adult subjects and after coadministration with partner antibiotics. In the single and multiple ascending-dose study, SPR741 or placebo was administered as a 1-h infusion at single doses of 5 to 800 mg and in multiple doses of 50 to 600 mg every 8 h (q8h) for 14 days. In the drug-drug interaction study, a single 400-mg i.v. dose of SPR741 was administered alone and in combination with piperacillin-tazobactam, ceftazidime, and aztreonam. PK parameters for SPR741 and partner antibiotics were determined using noncompartmental analysis. After single doses, a dose-linear and proportional increase in mean maximum concentration in plasma (
) and area under the concentration-time curve (AUC) was observed. At doses of 100 to 800 mg, >50% of the dose was excreted in the urine in the first 4 h postdose. After multiple doses, the mean half-life was 2.2 h on day 1 and up to 14.0 h on day 14, with no evidence of accumulation after 14 days of dosing up to 400 mg. The PK profile of SPR741 and partner antibiotics was unchanged with coadministration. SPR741 was generally well tolerated at doses up to 1,800 mg/day. These data support further clinical development of SPR741 for treating serious infections due to resistant bacteria. (These studies have been registered at ClinicalTrials.gov under identifiers NCT03022175 and NCT03376529.).
BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) and ulcerative colitis (UC) that targets the lanthionine synthetase C-like 2 (LANCL2) pathway and ...immunometabolic mechanisms. Oral BT-11 was assessed for safety, tolerability, and pharmacokinetics (PK) in normal healthy volunteers (n = 70) in a randomized, double-blind, placebo-controlled trial. Subjects (n = 70) were randomly assigned to one of five single ascending dose cohorts (up to 100 mg/kg, p.o.) and three multiple ascending dose cohorts up to 100 mg/kg daily (QD) for seven days, orally. Safety and tolerability were assessed by adverse event (AE) reporting, vital signs, electrocardiogram, hematology, and clinical chemistry. BT-11 did not increase total or gastrointestinal AE rates, as compared with placebo, and no serious adverse events were observed. Oral BT-11 dosing does not result in any clinically significant findings by biochemistry, coagulation, electrocardiogram, hematology, or urinalysis as compared with placebo. Mean fecal concentrations of BT-11 increased linearly with increasing oral doses, with 2.39 mg/g at 7.7 mg/kg on day 7 of the multiple ascending dose (MAD). Analysis of plasma pharmacokinetics indicates that maximum systemic concentrations are approximately 1/6000th of observed concentrations in feces and the distal gastrointestinal tract. Fecal calprotectin levels were lower in BT-11 treated groups as compared to placebo. BT-11 significantly decreases interferon gamma positive (IFNγ+) and tumor necrosis factor alpha positive (TNFα+) cluster of differentiation 4 positive (CD4+) T cells and increases forkhead box P3 positive (FOXP3+) CD4+ T cells in colonic lamina propria mononuclear cells from patients with CD and patients with UC at concentrations of 0.01 µM when treated ex vivo. BT-11 treatment is well-tolerated with no dose-limiting toxicities up to daily oral doses of 100 mg/kg (16 tablets); whereas the efficacious dose is a single tablet (8 mg/kg). Phase II studies in CD and UC patients are ongoing.
•This was a first in human Phase 1, randomized, double blind, placebo controlled study in 60 healthy adults of 18 to 45 years of age in Australia to assess safety and immunogenicity of SII Dengue ...vaccine.•SII Dengue vaccine was safe and well tolerated with no causally related serious adverse event reported in the study.•More than 69% participants had tetravalent and >15% participants had trivalent seroconversion.•These data support further development of this vaccine in Phase 2/3 clinical trials to assess efficacy, immunogenicity and safety in larger target population.
Dengue fever is an important public health problem, especially in Asia and South America. A tetravalent live attenuated dengue vaccine was manufactured in India after receipt of vaccine strains from NIAID, NIH, USA.
This was a Phase 1, double-blind, randomized, placebo-controlled study performed in 60 healthy adults of 18 to 45 years. Participants were randomized 2:1 to receive a single subcutaneous injection of either a tetravalent live attenuated dengue vaccine or placebo. Safety was assessed by unsolicited adverse events (AEs) and solicited reactions through 21 days after vaccination and serious adverse events (SAEs) through the entire study period of 180 days. Dengue viremia was assessed at baseline and on day 8, 10 and 12 post-vaccination using a plaque assay. Immunogenicity was assessed using the plaque reduction neutralization test (PRNT) assay using vaccine virus serotypes (DENV 1, DENV 2, DENV 3 and DENV 4) at baseline and on 56-, 84- and 180-days post-vaccination. PRNT assay using wild type DENV 1, DENV 2, DENV 3 and DENV 4 were done on day 1 and day 85 for a subset of 31 participants.
60 participants were randomized to receive dengue vaccine (n=40) or placebo (n=20). 23 participants (59%) showed DENV vaccine viremia post- vaccination for any of the four serotypes with majority on day 9 and day 11. At baseline, all participants were naïve by dengue PRNT50 for all four serotypes in both the study groups except for four in the dengue vaccine group and two in the placebo group. On day 57, the GMTs of neutralizing antibodies ranged from 66.76 (95% CI 36.63, 121.69) to 293.84 (95% CI 192.25, 449.11) for all four serotypes in the dengue vaccine group. On day 181 though the titers declined, they still remained much higher than the baseline. The titers in the placebo group did not change after vaccination. Seroconversion through day 85 ranged from 79.5% for DENV 1 to 100% for DENV2 while in the placebo group, no participant showed seroconversion through day 85. Similar trends were noted when PRNT was done using wild DENV serotypes in both vaccine and placebo groups.
Among solicited reactions, injection site erythema, rash, headache, fatigue, myalgia and arthralgia were reported more frequently in the vaccine group than placebo group. All solicited reactions were of grade 1 or grade 2 severity and completely resolved. One unrelated serious adverse event was reported in the vaccine group.
A single dose of dengue vaccine was safe and well tolerated in adults. The vaccine was highly immunogenic with trivalent or tetravalent seroconversion and seropositivity in most of the participants.
Background
Warfarin is underutilised in frail older people because of the fear of bleeding complications. Drug interactions are an independent bleeding risk factor. However, the extent to which ...potential drug interactions are taken into account at warfarin therapy initiation in frail patients is not known.
Objective
The objective of this study was to investigate the use of potentially interacting drugs increasing the bleeding risk before and after warfarin initiation in frail and non-frail patients.
Methods
We conducted an observational study including inpatients aged ≥ 60 years initiated on warfarin in a tertiary hospital in Adelaide, South Australia. Frailty status was assessed with the Reported Edmonton Frail Scale. Medication charts were reviewed before and after warfarin initiation.
Results
In total, 151 patients (102 non-frail and 49 frail) were included. Before warfarin initiation, the use of clopidogrel and acetaminophen was more common in frail patients compared with non-frail patients (25.5% vs 10.2%,
p
= 0.0135, 63.8% vs 35.7%
p
= 0.0014, respectively). The use of non-steroidal anti-inflammatory drugs, 9.2% in non-frail patients and 6.4% in frail patients before warfarin initiation, was completely stopped after warfarin initiation in both groups. The use of antiplatelet drugs decreased from 56.1% in non-frail patients and 66.0 % in frail patients to 12.2% and 14.9%, respectively. Instead, the use of drugs affecting the metabolism of warfarin or vitamin K increased in both groups. No statistically significant difference was seen in the exposure to interacting drugs between study groups after warfarin initiation. Acetaminophen, senna glycosides and cytochrome P450 2C9 inhibiting drugs were the most common interacting drugs at discharge used in 49.0%, 18.4% and 20.4% of non-frail patients and 53.2%, 29.8% and 19.1% of frail patients, respectively.
Conclusions
The overall frequency of potential drug interactions was moderate and frail patients were not exposed to warfarin drug interactions more often than non-frail patients. Further studies in larger study populations are required to verify these results.
Although there remains some significant controversy regarding the use and benefits of coumarin (5,6-benzo-alpha pyrone), it would seem that targeted appropriate and monitored use of the drug does ...have a significant role in the treatment of lymphedemas. The particular benefits are its cost and ease of administration. Given today's demands for high level investigative clinical trials, it would be virtually impossible to conduct a study large enough to make any significant conclusions about hepatotoxic effects. However, it seems without doubt that the majority of studies conducted thus far suggest that coumarin (and other benzopyrones, i.e., the ruto-sides, which do not have hepatotoxic effects and which are often discussed in aggregate with coumarin) is effective in treating lymphedema, particularly when used in conjunction with complex physical therapy. The use of pharmacogenomics could significantly lower the risk of coumarin-associated hepatotoxicity, by targeting the use of coumarin to those with functional CYP2A6. Further research in this area will be required to re-evaluate the cost- benefit ratio and to determine the potential for the reintroduction of coumarin as a potent treatment for lymphedema. The perceived negative image of coumarin should not be allowed to carry across to the other benzopyrones, as they still confer a significant benefit in the management of lymphedemas.
Residents of aged care facilities use increasingly complex medication regimens. Reducing unnecessary medication regimen complexity (eg, by consolidating the number of administration times or using ...alternative formulations) may benefit residents and staff.
To develop and validate an implicit tool to facilitate medication regimen simplification in aged care facilities.
A purposively selected multidisciplinary expert panel used modified nominal group technique to identify and prioritize factors important in determining whether a medication regimen can be simplified. The five prioritized factors were formulated as questions, pilot-tested using non-identifiable medication charts and refined by panel members. The final tool was validated by two clinical pharmacists who independently applied the tool to a random sample of 50 residents of aged care facilities to identify opportunities for medication regimen simplification. Inter-rater agreement was calculated using Cohen's kappa.
The Medication Regimen Simplification Guide for Residential Aged CarE (MRS GRACE) was developed as an implicit tool comprising of five questions about 1) the resident; 2) regulatory and safety requirements; 3) drug interactions; 4) formulation; and 5) facility and follow-up considerations. Using MRS GRACE, two pharmacists independently simplified medication regimens for 29/50 and 30/50 residents (Cohen's kappa=0.38, 95% CI 0.12-0.64), respectively. Simplification was possible for all residents with five or more administration times. Changing an administration time comprised 75% of the two pharmacists' recommendations.
Using MRS GRACE, two clinical pharmacists independently simplified over half of residents' medication regimens with fair agreement. MRS GRACE is a promising new tool to guide medication regimen simplification in aged care.
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