API ionic liquids: probing the effect of counterion structure on physical form and lipid solubility

Lipid based formulations (LBFs) are extensively utilised as an enabling technology in drug delivery. The use of ionic liquids (ILs) or lipophilic salts (LS) in drug delivery has also garnered considerable interest due to unique solubility properties. Conversion of active pharmaceutical ingredients (API) to ILs by pairing with an appropriately lipophilic counterion has been shown to decrease melting point of the salt complex and improve solubility in LBFs. However, the relationship between the structure of the counterion, the physicochemical properties of the resulting salts and solubility in LBFs has not been systematically explored. This study investigates the relationship between alkyl sulfate counterion structure and melting temperature (T_m or T_g) in addition to LBF solubility, utilizing cinnarizine and lumefantrine as model weakly basic APIs. Three series of structurally diverse alkyl sulfate counterions were chosen to probe this relationship. Pairing cinnarizine and lumefantrine with a majority of these alkyl sulfate counterions resulted in a reduction in melting temperature and enhanced solubility in model medium chain and long chain LBFs. The chain length of the alkyl sulfate plays a crucial role in performance, and consistently branched alkyl sulfate counterions perform better than straight chain alkyl sulfate counterions, as predicted. Most interestingly, trends in counterion performance were found to be consistent across two APIs with disparate chemical structures. The findings from this study will facilitate the design of counterions which enhance solubility of ionisable drugs and unlock the potential to develop compounds previously restrained by poor solubility.

Structure/property relationship of API IL counterions and salt physicochemical properties are investigated, the results highlight the complex interplay involved.     

First impressions last… A survey of knowledge of first aid in burn-related injuries amongst hospital workers

Rationale

The administration of first aid in burns has been shown to have a significant influence on the ultimate severity of the burn. We wanted to assess in-hospital healthcare (HCW), and non-healthcare workers’ (nHCW) knowledge of first aid in burns.

Methods

A purpose-designed questionnaire, including information about previous attendance at a first aid course and four clinical scenarios of burns, was distributed to HCWs in the local hospitals and non-medical students in the Universities of Leeds and Sheffield.

Results

697 questionnaires were completed – 397 (57%) from HCW and 300 (43%) from nHCW. 59% of HCW had attended a first aid course, 68% of these courses included teaching on first aid in burns.HCW who had completed a first aid course generally did better than those who had not. Only 16% of HCW achieved correct answers in all questions compared to 30% nHCW.

Conclusions

We show that the knowledge of first aid in burns is relatively poor amongst HCW and that attendance at a burns first aid course improves knowledge (although perhaps not as much as one might hope). We recommend that the burns content of first aid courses be reviewed, and that there is a requirement for ALL hospital healthcare workers to undertake a first aid course, which includes appropriate burns first aid.     

Standardization of definitions in focal therapy of prostate cancer: report from a Delphi consensus project

Purpose

To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa).

Methods

A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated.

Results

Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text.

Conclusion

Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice.

     

Increased risk of strontium ranelate-related SJS/TEN is associated with HLA

Summary

Severe adverse drug reactions (ADR) of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) in some patients receiving strontium ranelate have been reported, but the risk factors are unclear. We show that HLA-A*33:03 and B*58:01 are significantly associated with patients who developed SJS/TEN; and provide the first evidence that genetic risk factors are involved in strontium ranelate-associated SJS/TEN.

Introduction

In this study, HLA as a genetic risk factor was assessed among osteoporotic patients prescribed with strontium ranelate that developed severe cutaneous adverse drug reactions (SCARs) compared with those who were tolerant.

Methods

Genomic DNA isolated from peripheral blood mononuclear cells (PBMCs) of patients was HLA typed using sequencing-based typing method to determine their HLA profiles.

Results

Osteoporotic patients who are currently on strontium ranelate were enrolled in the study (n?=?76). Tolerant controls were defined as patients who received strontium ranelate for a minimum of 3 months (range 3 months to 8 years) with no reports of any cutaneous reactions as these reactions usually occur within the first 12 weeks after starting treatment. Retrospective cases of SJS/TEN were also identified (n?=?5). The majority of the accrued samples were of Han Chinese descent: controls (n?=?72) and cases (n?=?4). All cases and controls were genotyped at four HLA genes, namely HLA-A, HLA-B, HLA-C, and HLA-DRB1. In comparing the samples of Han Chinese descent (72 controls and 4 cases), we found significant associations with HLA-A*33:03 (p?=?0.002) and HLA-B*58:01 (p?=?0.023). There was no significant association with any HLA-C or HLA-DRB1 alleles.

Conclusions

This study reveals that the occurrence of SJS/TEN in Han Chinese patients receiving strontium ranelate is HLA associated. This has important clinical implications for understanding the underlying mechanisms for this ADR as well as evaluating the potential role of genetic pre-screening for osteoporotic patients who may be prescribed strontium ranelate.

     

Effect of post-retained composite restoration of MOD preparations on the fracture resistance of endodontically treated teeth

PURPOSE: The present study aimed to compare the fracture resistance and failure patterns of endodontically treated premolars with MOD preparations restored using different material combinations. The null hypothesis postulated that there was no association between the fracture resistance of endodontically treated premolars and the resin composite materials or the post-and-core system used to build up the restorations. MATERIALS AND METHODS: Eighty single-rooted maxillary premolars were used. After endodontic treatment and preparation of MOD preparations, 8 groups of 10 samples each were created, using the following material combinations: group 1 (control), flowable and microhybrid resin composites; group 2, flowable A; group 3, flowable B; group 4, microhybrid resin A; group 5, microhybrid resin B; group 6, flowable B + microhybrid resin B; group 7, flowable A + microhybrid resin A + post A; group 8, flowable B + microhybrid resin B + post B. Mechanical static fracture tests were performed loading the specimens till fracture. RESULTS: The mean failure loads (N) were 502 (control), 470 (group 7), 445 (group 8), 441 (group 6), 405 (group 5), 364 (group 4), 317 (group 2), and 302 (group 3). Statistically significant differences were found between groups 1 vs 2, 1 vs 3, and 3 vs 7 (p < 0.05). CONCLUSION: The fracture resistance of endodontically treated premolars with MOD preparations was enhanced by the use of the sandwich technique. The samples restored with posts predominantly showed restorable fractures, while teeth restored without posts mostly displayed unrestorable failures.     

Composite-to-composite microtensile bond strength in the repair of a microfilled hybrid resin: effect of surface treatment and oxygen inhibition

PURPOSE: To compare the 24-h microtensile bond strength of a microfilled hybrid composite to the same material after mechanical and/or chemical treatment and assess the effect of oxygen inhibition on the composite-composite bond. MATERIALS AND METHODS: Forty composite cylinders of Gradia Direct Anterior (GC) were prepared and stored 24 h prior to the following surface treatments: 50-microm aluminum oxide air abrasion and 37% phosphoric acid etching (group 1); hydrochloric acid and 6.9% hydrofluoric acid etching (group 2); diamond bur roughening and 37% phosphoric acid etching (group 3); diamond bur roughening (group 4). In all groups, Prime & Bond NT (Dentsply De Trey) was applied and light cured in air or under a nitrogen atmosphere, prior to layering a buildup of the repairing resin composite. Microtensile bond strength measurements were performed. Data were statistically analyzed with two-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: The curing atmosphere did not significantly influence the interfacial strength (p < 0.05). Surface treatment significantly affected the composite-composite bond (p > 0.05). Air abrasion, regardless of curing atmosphere, resulted in the strongest bond (p < 0.05). The other treatments were comparable. CONCLUSION: Air abrasion and the application of a bonding agent offer satisfactory bond strengths for composite repair. The oxygen inhibition layer on a light-cured adhesive is not crucial to the success of the 24-h composite-composite bond.     

Effects of a combined application of potassium oxalate gel/adhesive agent on dentin permeability in vitro

PURPOSE: To test the effects of sequential application of potassium oxalate gel/adhesive agent on in vitro dentin permeability. MATERIALS AND METHODS: Full crown preparations were made in extracted human molars to expose deep coronal dentin. The roots and pulp were removed and the resulting crown segments were connected to a special device (Flodec) to permit the measurement of the permeability of the specimens before and after treatments. Minimum and maximum permeability were recorded after smear layer and phosphoric acid treatment. A new smear layer was created and the permeability measured after the crowns were bonded with Single Bond (3M ESPE), One-Up Bond F (Tokuyama), and AdheSE (Ivoclar Vivadent), either according to manufacturer's instructions or after treating the acid-etched dentin with a 3 wt% potassium oxalate gel. The results were expressed as a percentage of maximum permeability values. Impressions and epoxy resin replicas from the crown segments were produced for SEM examination. RESULTS: None of the adhesives were able to eliminate the fluid flow through dentin. Two-way ANOVA revealed that the application of potassium oxalate prior to the bonding procedures was the most effective technique in reducingthe dentin permeability (p < 0.05), regardless of the adhesive used. SEM micrographs showed that transudation of dentinal fluid could be identified on the surfaces of all replicas. CONCLUSION: The use of potassium oxalate gel was effective in reducing the permeability of bonded dentin.