Search

Robert L Hill,1,* John G Wilmot,1,* Beth A Belluscio,1 Kevin Cleary,2 David Lindisch,3 Robin Tucker,4 Emmanuel Wilson,2 Rajesh B Shukla11Meridian Medical Technologies Inc., Columbia, MD, 2Children’s National Medical Center, 3Washington DC VA Medical Center, 4Georgetown University Medical Center, Washington, DC, USA *These authors have contributed equally to this work Abstract: Parenteral routes of drug administration are often selected to optimize actual dose of drug delivered, assure high bioavailability, bypass first-pass metabolism or harsh gastrointestinal environments, as well as maximize the speed of onset. Intramuscular (IM) delivery can be preferred to intravenous delivery when initiating intravenous access is difficult or impossible. Drugs can be injected intramuscularly using a syringe or an automated delivery device (autoinjector). Investigation into the IM delivery dynamics of these methods may guide further improvements in the performance of injection technologies. Two porcine model studies were conducted to compare differences in dispersion of injectate volume for different methods of IM drug administration. The first study compared the differences in the degree of dispersion and uptake of injectate following the use of a manual syringe and an autoinjector. The second study compared the spatial spread of the injected formulation, or dispersion volume, and uptake of injectate following the use of five different autoinjectors (EpiPen® [0.3 mL], EpiPen® Jr [0.3 mL], Twinject® [0.15 mL, 0.3 mL], and Anapen® 300 [0.3 mL]) with varying needle length, needle gauge, and force applied to the plunger. In the first study, the autoinjector provided higher peak volumes of injectate, indicating a greater degree of dispersion, compared with manual syringe delivery. In the second study, EpiPen autoinjectors resulted in larger dispersion volumes and higher initial dispersion ratios, which decreased rapidly over time, suggesting a greater rate of uptake of injectate than the other autoinjectors. The differences in dispersion and uptake of injectate are likely the result of different functional characteristics of the delivery systems. Both studies demonstrate that the functional characteristics of the method for delivering IM injections impact the dispersion and uptake of the material injected, which could significantly affect the pharmacokinetics and, ultimately, the effectiveness of the drug. Keywords: anaphylaxis, autoinjector device, injector pen, intramuscular drug administration, dispersion volume

Micronutrient and protein malnutrition is recognized among the major global health issues. Genetic biofortification is a cost-effective and sustainable strategy to tackle malnutrition. Genomic regions governing grain iron concentration (GFeC), grain zinc concentration (GZnC), grain protein content (GPC), and thousand kernel weight (TKW) were investigated in a set of 163 recombinant inbred lines (RILs) derived from a cross between cultivated wheat variety WH542 and a synthetic derivative ( Triticum dicoccon PI94624/ Aegilops tauschii [409]//BCN). The RIL population was genotyped using 100 simple-sequence repeat (SSR) and 736 single nucleotide polymorphism (SNP) markers and phenotyped in six environments. The constructed genetic map had a total genetic length of 7,057 cM. A total of 21 novel quantitative trait loci (QTL) were identified in 13 chromosomes representing all three genomes of wheat. The trait-wise highest number of QTL was identified for GPC (10 QTL), followed by GZnC (six QTL), GFeC (three QTL), and TKW (two QTL). Four novel stable QTL ( QGFe.iari-7D.1, QGFe.iari-7D.2, QGPC.iari-7D.2 , and QTkw.iari-7D ) were identified in two or more environments. Two novel pleiotropic genomic regions falling between Xgwm350-AX-94958668 and Xwmc550-Xgwm350 in chromosome 7D harboring co-localized QTL governing two or more traits were also identified. The identified novel QTL, particularly stable and co-localized QTL, will be validated to estimate their effects on different genetic backgrounds for subsequent use in marker-assisted selection (MAS). Best QTL combinations were identified by the estimation of additive effects of the stable QTL for GFeC, GZnC, and GPC. A total of 11 RILs (eight for GZnC and three for GPC) having favorable QTL combinations identified in this study can be used as potential donors to develop bread wheat varieties with enhanced micronutrients and protein., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Krishnappa, Rathan, Sehgal, Ahlawat, Singh, Singh, Shukla, Jaiswal, Solanki, Singh and Singh.)

A near-isogenic line (NIL) of the Indian wheat variety HD2733, carrying an introgressed Lr24/Sr24 genomic region was used for studying the effect of this introgression on quality traits. Data on the grain yield and 21 quality traits were recorded in this NIL and its recurrent parent (RP), both of which were grown in a randomized block design for two consecutive years. The statistical analysis revealed that grain yield was on par between the NIL and the RP. The NIL and its RP were both hard grained but the NIL showed a grain hardness index reduced by 9.7%. However, quality traits such as grain weight, protein content, sedimentation value, gluten traits, and solvent retention capacity were significantly higher in the NIL. The NIL also showed an increase in dough stability , a lower degree of softening and a higher farinograph quality number. These results indicated that the NIL could be utilized for hard grain, high protein and strong gluten-based products. An overall improvement in the quality of the NIL over its recurrent parent and without any yield penalty suggests that the Lr24/Sr24 genomic region could be gainfully utilized in wheat breeding for improving the industrial quality of wheat without jeopardising grain yield. The authors suggest that the improved quality of the NIL may be due to the genomic segment carried along with the Lr24/Sr24 genes., Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-021-02679-x., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest in the publication, (© King Abdulaziz City for Science and Technology 2021.)

Grain softness has been a major trait of interest in wheat because of its role in producing flour suitable for making high-quality biscuits, cookies, cakes and some other products. In the present study, marker-assisted backcross breeding scheme was deployed to develop advanced wheat lines with soft grains. The Australian soft-grained variety Barham was used as the donor parent to transfer the puroindoline grain softness gene Pina - D1a to the Indian variety, DBW14, which is hard grained and has PinaD1bPinbD1a genes. Foreground selection with allele-specific PCR-based primer for Pina - D1a (positive selection) was used to identify heterozygous BC 1 F 1 plants. Background selection with 173 polymorphic SSR primers covering all the 21 chromosomes was also carried out, in the foreground-selected BC 1 F 1 plants. BC 1 F 2 plants were selected by ascertaining the presence of Pina - D1a (positive selection) and absence of Pina - D1b (negative selection). Using the approach of positive, negative and background selection with molecular markers, 15 BC 1 F 2 and 31 BC 2 F 1 plants were finally selected. The 15 BC 1 F 2 plants were selfed and the 31 BC 2 F 1 plants were further backcrossed and selfed to raise BC 3 F 1 and BC 2 F 2 progenies, respectively. A part of the BC 2 F 2 seed of each of the 31 plants was analyzed for grain hardness index (GHI) with single-kernel characterization system. The GHI varied from 12.1 to 37.1 in the seeds borne on the 31 BC 2 F 1 plants. The reasons for this variation and further course of action are discussed., Competing Interests: Compliance with ethical standardsThe authors declare that they have no conflict of interest in the publication.

Genomic regions responsible for accumulation of grain iron concentration (Fe), grain zinc concentration (Zn), grain protein content (PC) and thousand kernel weight (TKW) were investigated in 286 recombinant inbred lines (RILs) derived from a cross between an old Indian wheat variety WH542 and a synthetic derivative (Triticum dicoccon PI94624/Aegilops squarrosa [409]//BCN). RILs were grown in six environments and evaluated for Fe, Zn, PC, and TKW. The population showed the continuous distribution for all the four traits, that for pooled Fe and PC was near normal, whereas, for pooled Zn, RILs exhibited positively skewed distribution. A genetic map spanning 2155.3cM was constructed using microsatellite markers covering the 21 chromosomes and used for QTL analysis. 16 quantitative trait loci (QTL) were identified in this study. Four QTLs (QGFe.iari-2A, QGFe.iari-5A, QGFe.iari-7A and QGFe.iari-7B) for Fe, five QTLs (QGZn.iari-2A, QGZn.iari-4A, QGZn.iari-5A, QGZn.iari-7A and QGZn.iari-7B) for Zn, two QTLs (QGpc.iari-2A and QGpc.iari-3A) for PC, and five QTLs (QTkw.iari-1A, QTkw.iari-2A, QTkw.iari-2B, QTkw.iari-5B and QTkw.iari-7A) for TKW were identified. The QTLs together explained 20.0%, 32.0%, 24.1% and 32.3% phenotypic variation, respectively, for Fe, Zn, PC and TKW. QGpc.iari-2A was consistently expressed in all the six environments, whereas, QGFe.iari-7B and QGZn.iari-2A were identified in two environments each apart from pooled mean. QTkw.iari-2A and QTkw.iari-7A, respectively, were identified in four and three environments apart from pooled mean. A common region in the interval of Xgwm359-Xwmc407 on chromosome 2A was associated with Fe, Zn, and PC. One more QTL for TKW was identified on chromosome 2A but in a different chromosomal region (Xgwm382-Xgwm359). Two more regions on 5A (Xgwm126-Xgwm595) and 7A (Xbarc49-Xwmc525) were found to be associated with both Fe and Zn. A QTL for TKW was identified (Xwmc525-Xbarc222) in a different chromosomal region on the same chromosome (7A). This reflects at least a partly common genetic basis for the four traits. It is concluded that fine mapping of the regions of the three chromosomes of A genome involved in determining the accumulation of Fe, Zn, PC, and TKW in this mapping population may be rewarding.

Objective: Part 1 of this phase III study was a randomized, double-blind, parallel-group, placebo-controlled, multicenter study of caregiver administered diazepam auto-injector (AI) in subjects with acute repetitive seizures (ARS) and demonstrated that diazepam AI was well-tolerated and significantly more effective than placebo AI in delaying the time to next seizure or rescue. Part 2 of this study, presented herein, was an open-label continuation to assess the long-term safety and effectiveness of diazepam AI for the treatment of ARS., Methods: Of the 234 subjects randomized in part 1, 161 continued into part 2 and were provided open-label diazepam AI. Effectiveness measures were time to next seizure or rescue, number of subsequent rescues by type (rescue medication, emergency room visit, or other medical care), and number of subsequent seizures during the 12-h follow-up period. Safety data (adverse events and respirations <8/min) were also collected., Results: During the open-label part 2 study, 129 subjects were administered a total of 1,380 diazepam AI treatments (median 4.5; range 1-118), of which 1,071 (77.6%) were effective with no subsequent seizure or rescue during the 12-h follow-up period. Median number of subsequent seizures experienced by subjects was one (range 0-20). Of the 1,380 administrations, 79 (5.7%) required use of rescue medication, 18 (1.3%) required a visit to an emergency room, and 6 (0.4%) required other rescue medical care. In most (75%) of subjects with treatment-emergent adverse events (TEAEs), TEAEs were mild or moderate in severity. Commonly reported treatment-related TEAEs were injection-site pain (10.9%), injection-site hemorrhage (7%), and injection-site bruising (6.3%). Although three subjects met the predefined respiratory rate threshold, none were considered clinically significant or reported as AEs., Significance: Long-term treatment with diazepam AI administered by trained caregivers in an outpatient setting to treat ARS is a safe and effective option. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Purpose: A diazepam auto‐injector (AI) has been developed for intramuscular administration to treat acute repetitive seizures (ARS). The objective of this study was to evaluate the efficacy and safety of the diazepam AI when administered by caregivers to control an episode of ARS (ClinicalTrials.gov identifier NCT00319501)., Methods: In this phase III, randomized, double‐blind, parallel‐group, placebo‐controlled, multicenter study, subjects with epilepsy on a stable antiepileptic drug regimen who required intermittent medical intervention to control ARS were randomized 1:1 to the placebo AI or the diazepam AI group. Subjects were stratified according to age (2–5, 6–11, ≥12 years). Dose (5, 10, 15, or 20 mg) was based on age and weight. A single dose of study medication was dispensed to be administered by caregivers in an outpatient setting when required. The primary end point was time to next seizure or rescue from 15 min to 12 h postdose. Secondary end points included rescue medication use, number of seizures postdose, caregiver and physician treatment assessments, and safety measures., Key Findings: Of 234 subjects randomized, 81/110 in the placebo AI group and 82/124 in the diazepam AI group were included in the intent‐to‐treat analysis. Baseline characteristics were similar for both groups. Time to next seizure or rescue was significantly longer in the diazepam AI group compared with the placebo AI group, with a hazard ratio of 0.55 (95% confidence interval [CI] 0.34–0.88; p = 0.012) for diazepam AI versus placebo AI, adjusted for age group. The 25th percentile for time to the next seizure or rescue was 1.18 h (95% CI 0.38–2.03) for placebo AI and 2.70 h (95% CI 0.48–11.42) for diazepam AI; the median was 5.9 h for placebo AI and was inestimable for diazepam AI due to the low number of events experienced by subjects in that group. The proportion of subjects using rescue medication postdose was 30% (24/81) placebo AI versus 17% (14/82) diazepam AI (p = 0.066). An event (seizure or rescue) occurred in 55.6% of subjects in the placebo AI group and 35.4% in the diazepam AI group. The number of seizures experienced during the 12‐h postdose period was significantly lower for diazepam AI (median 0.0) compared with placebo AI (median 1.0; p = 0.010). Treatment‐emergent adverse events (TEAEs) were reported in 44% (35/79) of subjects in the placebo AI group and 42% (34/81) in the diazepam AI group. The most common TEAEs reported were injection site pain (15% placebo AI, 17% diazepam AI) and injection site hemorrhage (6% placebo AI, 5% diazepam AI)., Significance: The diazepam AI was significantly more effective than placebo AI at delaying the next seizure or rescue. Secondary efficacy end points were generally supportive of the primary outcome. Diazepam AI administered by trained caregivers was effective for the treatment of ARS and was well tolerated, with a safety profile similar to placebo., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Compound A, a novel disubstituted pyrrolidine acid, is a member of a new class of agents that are potentially useful for the treatment of diabetes and dyslipidemia. The absolute configuration of this compound was determined by using vibrational circular dichroism (VCD). The results are in agreement with the assignments based on both X-ray analysis and the stereo-selective chemical synthesis. During VCD analysis, the solution conformation for a portion of compound A in CDCl(3) was also established. The compound is found to associate as an H-bonded carboxylic acid "dimer" in CDCl(3) solution, and VCD calculations on a model dimer fragment were required to establish the absolute configuration.

BMS-188184, an anthracene derivative, has been found to form at least two complexes with beta-cyclodextrin. The association/dissociation kinetics of the two complexes were extremely slow, with one complex requiring approximately 24 h, and the other complex requiring more than 8 weeks, to reach equilibrium. The stability constants of the two complexes were estimated at approximately 11,000 and 39,000 M(-1) under nonequilibrium conditions. The slow rates of dissociation allowed the complexes and the unbound BMS-188184 to be separated using high-performance liquid chromatography. Exact mass liquid chromatography/mass spectrometry, tandem mass spectrometry, and nuclear magnetic resonance techniques were used to characterize the stoichiometry of both complexes as 1:1. Because of the ability of the complexes to survive high-performance liquid chromatography analysis, their slow reaction rates, and 1:1 stoichiometry, the complexes were tentatively characterized as [2]-rotaxanes. The available data suggest that the two complexes are conformational isomers., (Copyright 2004 Wiley-Liss, Inc.)

The longitudinal electronic state lifetime of the paramagnetic Gd metal within a macrocyclic ligand core can be increased by designing ligand frames that alter the vibronic interactions between the ligating atoms and the metal. We conducted the first pulsed EPR studies that demonstrated the increase in the longitudinal state lifetimes of the electronic subsystem at cryogenic temperatures. We also designed a simple sucrose/ water model that significantly increases the rotational correlation time in solution of the Gd chelate. This model system enables relaxivity studies at ambient temperatures that more readily interrogate exchange and electronic contributions to the inner-sphere relaxivity by effectively removing the rotational correlation time contribution. These results combined with water residence (Q) measurements suggest that rigidification of the macrocyclic core or that of the pendant arms increases the longitudinal electronic state lifetime of the paramagnetic Gd metal. This increased lifetime possibly contributes to the improved relaxivity for the rigid Gd chelates observed in the sucrose/ water model studies.

A retrospective study of 46 patients who presented with proved testicular torsion over five years at two Dublin hospitals showed that in 40 cases torsion had occurred when the temperature was under 2 degrees C; the incidence of torsion was higher during the cold months of the year. Both of these findings were statistically significant. These and other results suggest that the ambient temperature may have some role in the incidence and aetiology of testicular torsion.