Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): A Novel Approach To Investigate the Wettability of Pharmaceutical Powder Blends.

The ability of broadband acoustic resonance dissolution spectroscopy (BARDS) to assess the wettability of powder blends is investigated. BARDS is a novel analytical technology developed on the basis of the change in acoustic phenomena observed when material is added into a solvent under resonance. Addition of solid material to the solvent results in the introduction of gas (air) into the solvent, changing the compressibility of the solvent system, and reducing the velocity of sound in the solvent. As a material is wetted and dissolved, the gas is released from the solvent and resonance frequency is altered. The main purpose of this work is to demonstrate the ability of BARDS to assess differences in the wetting behavior of tablet excipients (microcrystalline cellulose (MCC) and magnesium stearate (MgSt)) and a model drug (metoclopramide hydrochloride) as single component powders and multicomponent powder blends. BARDS acoustic responses showed a prolonged release of gas for the powdered blends with lubricant compared to unlubricated blends. As the elimination of gas from the solvent was assumed to follow first order elimination kinetics, a compressible gas elimination rate constant was calculated from the log plots of the gas volume profiles. The gas elimination rate constant was used as a parameter to compare the release of gas from the powder introduced to the solvent and hence the powder wetting behavior. A lower gas elimination rate constant was measured for lubricated blends compared to nonlubricated blends, suggesting the prolonged hydration of lubricated blends. Standard wetting techniques such as contact angle measurements and wetting time analysis were also used to analyze the blends and confirmed differences in wetting behavior determined by BARDS. The study results demonstrate the capability of BARDS as a rapid, analytical tool to determine the wetting behavior of the pharmaceutical powder blends and the potential of BARDS as a process analytical technology (PAT) tool.

Comparison of bovine tuberculosis recurrence in Irish herds between 1998 and 2008.

During the last several decades in Ireland, there has been substantial scientific progress in our understanding and related policy changes in the bovine tuberculosis (bTB) eradication programme. A range of performance measurements are routinely available, each highlighting a steadily improving situation in Ireland. However, recent research has highlighted an on-going problem of residual infection, contributing to recurrent breakdowns. In light of this general improvement, but also cognisant of residual infection, a critical evaluation of changes in effectiveness of managing recurrence is particularly valuable. Therefore, the objective of the study was to compare the herd-level risk of recurrence of bTB in Ireland between 1998 and 2008. A retrospective cohort study was carried out, using a Cox proportional-hazards model, to compare the risk of restriction recurrence in herds derestricted during 1998 and 2008. These herds were observed for up to 3 years from the end of the 'index restriction'. At the univariable level, 46.4% and 34.8% of study herds derestricted in 1998 and 2008, respectively, had a subsequent breakdown during the study period (χ(2)=70.6, P<0.001). In the multivariable analysis, there has been a significant reduction in bTB recurrence in Ireland, with 2008-derestricted herds being 0.74 times (95% confidence interval: 0.68-0.81) as likely to be restricted during the subsequent study period compared with 1998-derestricted herds. In the final Cox model, the rate of a future breakdown increased with increasing herd size, increasing number of standard reactors in the index restriction, increasing percentage of newly restricted herds within the District Electoral Division (DED) and if the herd had a previous bTB episode in the previous 5 years. The risk varied across herd type. The results from the current study provide further reassurance of an improved national situation, both in terms of limiting the establishment of new infection (bTB incidence) and in effectively clearing infection once detected (recurrence following derestriction). Recurrence of bTB requires effective implementation of multiple control strategies, focusing on identifying and removing residually infected cattle, and limiting environmental sources of infection, which in Ireland primarily relates to badgers.

Ketorolac therapy for the prevention of acute pseudophakic cystoid macular edema: a systematic review.

To assess the effectiveness of ketorolac vs control for prevention of acute pseudophakic cystoid macular edema (CME). The following databases were searched: Medline (1950-June 11, 2011), The Cochrane Library (Issue 2, 2011), and the TRIP Database (up to 11 June 2011), using no language or other limits. Randomized controlled clinical trials (RCTs) were included that consisted of patients with acute pseudophakic cystoid macular edema, those comparing ketorolac with control, and those having at least a minimum follow-up of 28 days. In the four RCTs evaluating ketorolac vs control, treatment with ketorolac significantly reduced the risk of CME development at the end of treatment (≈ 4 weeks) compared to control (P=0.008; 95% confidence interval (0.03-0.58)). When analyzed individually, each individual study was statistically nonsignificant in its findings with the exception of one study. When the pooled relative risk was calculated, the large sample size of this systematic review led to overall statistical significance, which is attributable to the review's large sample size and not to the individual studies themselves. In this systematic review of four RCTs, two of which compared ketorolac with no treatment and two of which evaluated ketorolac vs placebo drops, treatment with ketorolac significantly reduced the risk of developing CME at the end of ≈ 4 weeks of treatment compared with controls. These results, however, should be interpreted with caution considering the paucity of large randomized clinical trials in the literature.

Primary intraocular lymphoma: another great masquerader.

PURPOSE: To describe diverse and atypical presentations of the most common masquerader in neoplastic masquerade syndromes. METHODS: Retrospective interventional case series. The authors identified three patients who presented with atypical and diagnostically challenging masquerading manifestations. These patients were eventually found to have primary intraocular lymphoma (PIOL). Their case histories, presenting signs and symptoms, diagnostic tests, and treatments are described. RESULTS: Patient 1 masqueraded as viral retinitis and branch retinal vein occlusion but was resistant to 5 weeks of oral and intravenous acyclovir. Patient 2 presented with choroidal infiltrates and vision loss. This patient had had breast carcinoma for the last 25 years and secondary metastasis was suspected. Patient 3 had chronic uveo-retinitis and a chronic Propionibacterium acnes infection was suspected. All three patients were diagnosed with PIOL. CONCLUSIONS: PIOL is an aggressive masquerader and not only presents clinical diagnostic difficulties but also requires expert tissue handling and analysis, so that early diagnosis can be made and therapy can be instituted.

The characteristic features of optical coherence tomography in posterior uveitis.

AIM: To describe the different retinal morphological characteristics that can present on optical coherence topography (OCT) in a spectrum of uveitic diseases. METHODS: We reviewed the literature and our own OCT image archive for characteristic features that may be suggestive of a particular disease process. RESULTS: OCT demonstrates a variety of characteristic morphological changes, some that may point towards a specific disease process. We describe the various forms of macular oedema found in uveitis as well as OCT features typically found in multifocal choroiditis, serpiginous chorioretinitis, toxoplasma chorioretinitis, Vogt-Koyanagi-Harada, sympathetic ophthalmia and the vitreomacular traction syndrome. CONCLUSION: Ophthalmologists should be aware of the variety of retinal morphological characteristics that can present on OCT in uveitic disease. Recognition may aid in the diagnostic process, which is complementary to conventional fundal photography and fluorescein angiography. This can facilitate earlier diagnosis and, more importantly, the initiation of specific treatment.

ANCA associated pauci-immune retinal vasculitis.

BACKGROUND: Antinuclear cytoplasmic antibodies (ANCA) are useful diagnostic serological markers for the most common forms of necrotising vasculitis. ANCA associated vasculitides represent distinctive clinicopathological categories--for example, Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and idiopathic necrotising crescentic glomerulonephritis, collectively known as the small vessel pauci-immune vasculitides. METHOD: Three cases of ANCA associated pauci-immune retinal vasculitis are described. Their systemic features are described and the clinical significance of ANCA as a diagnostic test in relation to retinal vasculitis discussed. RESULTS: These three cases represent a spectrum of clinical features associated with retinal vasculitis. Two cases have evolved into clinical recognisable entities as microscopic polyangiitis. Adherence to the international consensus statement on testing and reporting of ANCA is recommended and the authors speculate that the incidence of microscopic polyangiitis may be underestimated because of the under-recognition of systemic involvement in patients with retinal vasculitis. CONCLUSION: The receipt of a positive ANCA result should always raise the suspicion of a pauci-immune systemic vasculitis and prompt appropriate investigation. The authors emphasise the importance of the evaluation of systemic features in these patients with retinal vasculitis, enabling earlier recognition and thereby preventing significant morbidity and mortality.

A study to assess the effects of a new detergent-free, olive oil formulation dentifrice in vitro and in vivo.

OBJECTIVE: To determine the effects of a detergent-free dentifrice containing olive oil using in vitro microbiological tests and an in vivo plaque re-growth model. METHOD: A total of 20 subjects took part in a double blind, single-centre, crossover study in which slurry rinses were the only form of plaque control over a 5-day period. Following a washout and prophylaxis the subjects used 2x daily rinses in the absence of all other plaque control methods. Subjects returned to the clinic on the afternoon of day 5 when plaque was disclosed and assessed by plaque index and area. A further 9-day washout was carried out and the rinse period repeated to ensure that each subject had used both experimental and control slurries. In vitro microbiological experiments were conducted to examine the effects of olive oil alone and in the new dentifrice on bacterial growth and adhesion. RESULTS: 20 subjects completed the trial. The olive oil product showed a significant inhibition of plaque re-growth (17.2%) compared with a fluoride-matched control using the Turesky index (p<0.0001) and also using the planimetric technique (22.0%) (p<0.0001). Significant decreases in bacterial growth and adhesion (measured as total viable count) were detected in the presence of olive oil and the new dentifrice. CONCLUSION: The results suggest that the experimental olive oil containing paste has potential value in the inhibition of plaque.

Fosfomycin therapy for multiresistant Pseudomonas aeruginosa in cystic fibrosis.

BACKGROUND: Increasing resistance to standard antibiotics has been demonstrated in CF patients colonised by Pseudomonas aeruginosa. The antibiotic Fosfomycin has a unique mode of action against this organism, and may protect against aminoglycoside mediated renal and ototoxic effects. However, there is little published experience of this drug in IV form, and it is not licensed for use in the UK. METHODS: In combination with other antibiotics, we used Fosfomycin to treat 30 pulmonary exacerbations in 15 adult CF patients colonised by P. aeruginosa, mainly multiresistant strains. All patients gave informed consent. We cultured sputum prior to treatment and measured spirometry, renal function, and symptoms before and after treatment, and recorded any side effects. RESULTS: One patient developed nausea and Fosfomycin treatment was withdrawn. The remaining patients showed clinical resolution of their chest exacerbations (mean FEV1% predicted: pre 41.1 vs. post 49.4, P<0.001). Although there was a statistical increase in plasma urea (pre 3.9 mmol/l vs. post 4.3, P<0.03), this was still within the normal range. Plasma creatinine was unchanged. CONCLUSIONS: This study shows that IV Fosfomycin is well tolerated by adult patients with CF and can be useful in the treatment of those colonised with multiresistant P. aeruginosa.

Spread of an epidemic Pseudomonas aeruginosa strain from a patient with cystic fibrosis (CF) to non-CF relatives.

Colonisation with Pseudomonas aeruginosa is common in adults with cystic fibrosis (CF) and there is increasing evidence that transmissible strains may cross colonise patients. However, transmission of these strains by social contact to healthy non-CF individuals has not been described. A case is presented where an adult CF patient colonised by an epidemic P aeruginosa strain infected her parents with subsequent morbidity.

Outcome of Burkholderia cepacia colonisation in an adult cystic fibrosis centre.

BACKGROUND: Colonisation with Burkholderia cepacia is a poor prognostic indicator in subjects with cystic fibrosis (CF), but outcome prediction is impossible since patients are colonised by different strains with differing pathogenicity. The clinical course of a large cohort of CF patients colonised with UK epidemic (ET12) B cepacia was followed for 5 years and compared with that of the remaining patients in the clinic. METHODS: Pulmonary function, nutritional state, and lung pathogen colonisation were recorded for 5 years before December 1997 or death for all 107 patients who had attended the Liverpool adult CF clinic since 1993. For each patient a time line from study entry to date of death or 1997 was constructed. In 1993 potential risk factors including age and sex were subjected to Cox proportional hazards analysis using the end point of mortality as the outcome variable. The analysis was supplemented by time varying covariables that described the change in FEV(1), BMI, and colonisation status across time, and the excess risk associated with B cepacia colonisation was calculated. Subsequently, in those patients who died between 1993 and 1997, predictive factors for death were compared within groups using complete 5 year data. RESULTS: Thirty seven patients had been colonised by epidemic B cepacia and these patients had four times the mortality of the remainder (p<0.01). In 1993 univariate predictors of mortality were age (alive 19.6 (0.64) v dead 23.8 (1.44); p<0.005) and baseline FEV(1) (alive 68.6 (2.5)% predicted v dead 43.2 (4.8)%; p<0.001) with a trend for BMI (p=0.07). However, following time varying covariate Cox proportional hazards analysis, only lower FEV(1) (hazards ratio 1.1, 95% confidence limits 1.06 to 1.14; p<0.001) and colonisation with B cepacia (hazards ratio 7.92, confidence limits 2.65 to 23.69; p<0.001) were identified as significant factors for death. Surviving B cepacia patients had similar initial lung function to the remaining surviving patients but had an accelerated loss of lung function over the study period (colonised -1.9% predicted per year v non-colonised -0.3% predicted per year; p<0.05). Deceased patients colonised with B cepacia had better spirometric results than the remaining deceased patients 5 years before death (p<0.05) but lost lung function at a greater rate than non-colonised patients (colonised -6.2% predicted per year v non-colonised -1.9% predicted per year; p<0.05). CONCLUSIONS: This study confirms the excess mortality associated with epidemic B cepacia colonisation and shows that those with poor spirometric values are at the greatest risk.

Popped eye (blunt trauma leading to penetrating eye injury and lens displacement in the pseudophakic eye).

Blunt trauma to the eye of patients with an artificial intraocular lens may cause globe rupture with all the accompanying sequelae. It must be recognised promptly and dealt with appropriately before urgent referral to ophthalmology.

Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: results from a multicenter, randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Benzydamine was evaluated in patients with head and neck carcinoma for treatment of radiation-induced oral mucositis, a frequent complication of radiation therapy (RT) for which there is no predictable therapy or preventive treatment currently available. METHODS: The safety and efficacy of 0.15% benzydamine oral rinse in preventing or decreasing erythema, ulceration, and pain associated with oral mucositis during RT were evaluated in a randomized, placebo-controlled trial conducted in patients with head and neck carcinoma. Subjects were to rinse with 15 mL for 2 minutes, 4-8 times daily before and during RT, and for 2 weeks after completion of RT; study evaluations were conducted before RT and routinely thereafter up to 3 weeks after RT. RESULTS: During conventional RT, regimens up to cumulative doses of 5000 centigrays (cGy) benzydamine (n = 69) significantly (P = 0.006) reduced erythema and ulceration by approximately 30% compared with the placebo (n = 76); greater than 33% of benzydamine subjects remained ulcer free compared with 18% of placebo subjects (P = 0.037), and benzydamine significantly delayed the use of systemic analgesics compared with placebo (P < 0.05). Benzydamine was not effective in subjects (n = 20) receiving accelerated RT doses (> or = 220 cGy/day). The incidence of adverse events between treatment groups was comparable without significant differences. Early discontinuation because of adverse events occurred in 6% of benzydamine subjects and 5% of placebo subjects, and there was 1 death (related to the primary diagnosis) in a placebo subject. CONCLUSIONS: Benzydamine oral rinse was effective, safe, and well tolerated for prophylactic treatment of radiation-induced oral mucositis.

Interaction of barbiturate analogs with the Torpedo californica nicotinic acetylcholine receptor ion channel.

Barbiturate-induced anesthesia is a complex mechanism that probably involves several ligand-gated ion channel superfamilies. One of these superfamilies includes the archetypical nicotinic acetylcholine receptor (nAChR), in which barbiturates act as noncompetitive antagonists. In this regard, we used the Torpedo californica nAChR and a series of barbiturate analogs to characterize the barbiturate binding site(s) on this superfamily member. [(14)C]Amobarbital binds to one high-affinity (K(d) = 3.7 microM) and several (approximately 11) low-affinity (K(d) = 930 microM) sites on the resting and desensitized nAChRs, respectively. Characteristics of the barbiturate binding site on the resting nAChR include: (1) a tight structure-activity relationship. For example, the barbiturate isobarbital [5-ethyl-5'-(2-methylbutyl) barbituric acid] is >10-fold less potent than its formula isomer amobarbital [5-ethyl-5'-(3-methylbutyl) barbituric acid] in inhibiting [(14)C]amobarbital binding. (2) A binding locus within the pore of the nAChR ion channel. Each of the barbiturate analogs inhibited the binding of [(3)H]tetracaine or photoincorporation of 3-trifluoromethyl-3-(m-[(125)I]iodophenyl) diazirine in a mutually exclusive manner. (3) Stereoselective binding. The R(+)-enantiomers of isobarbital and pentobarbital are approximately 2-fold more potent in inhibiting 3-trifluoromethyl-3-(m-[(125)I]iodophenyl) diazirine photoincorporation than the S(-)-enantiomers. Finally, molecular modeling suggests that within the channel, the pyrimidine ring of the barbiturate is located just above the highly conserved leucine ring (M2--9; e.g., delta Leu-265), whereas the 5' side chain projects downward, and depending upon its conformation, introduces steric hindrance to binding because of the restriction in the lumen of the channel introduced by the leucine side chains.

Human papillomavirus in pterygium.

AIM: To determine the prevalence and significance of human papillomaviral types in conjunctival pterygia. METHODS: Polymerase chain reaction technology was used to identify the presence of human papillomavirus (HPV) in 10 formalin fixed paraffin embedded pterygia samples. 10 conjunctival papillomas were used as positive controls. 20 conjunctival samples, 10 with primary acquired melanosis and 10 with malignant melanoma, were used as negative controls. Sample subgroups were of equal sex, race, and age distribution to eliminate bias. All samples were further analysed (for 21 HPV types) using dot-blot hybridisation techniques. RESULTS: HPV was identified in 90% of the conjunctival papillomas, 50% of the pterygia samples, but no HPV was detected in the negative control group. Two pterygia showed type 6, two type 11, and one type 16. These three HPV types were also detected in papillomas. CONCLUSION: These results suggest that HPV may be involved in the pathogenesis of pterygia and that broadly the same HPV types are found in pterygia and in papillomas. Persistent conjunctival HPV may possibly play a part in the recurrence of pterygia post excision but further larger studies are required to elucidate this hypothesis.

Interactions between 3-(Trifluoromethyl)-3-(m-[(125)I]iodophenyl)diazirine and tetracaine, phencyclidine, or histrionicotoxin in the Torpedo series nicotinic acetylcholine receptor ion channel.

3-(Trifluoromethyl)-3-(m-[(125)I]iodophenyl)diazirine ([(125)I]TID) and [(3)H]tetracaine, an aromatic amine, are noncompetitive antagonists (NCAs) of the Torpedo species nicotinic acetylcholine receptor (nAChR), which have been shown by photoaffinity labeling to bind to a common site in the ion channel in the closed state. Although tetracaine and TID bind to the same site, the amine NCAs phencyclidine (PCP) and histrionicotoxin (HTX), which are also believed to bind within the ion channel, interact competitively with tetracaine but allosterically with TID. To better characterize drug interactions within the nAChR ion channel in the closed state, we identified the amino acids photoaffinity labeled by [(125)I]TID in the presence of tetracaine, PCP, or HTX. In the absence of other drugs, [(125)I]TID reacts with alphaLeu-251 (alphaM2-9) and alphaVal-255 (alphaM2-13) and the homologous residues in each of the other subunits. None of the NCAs shifted the sites of [(125)I]TID labeling to other residues within the ion channel. Tetracaine inhibited [(125)I]TID labeling of M2-9 and M2-13 without changing the relative(125)I incorporation at these positions, whereas PCP and HTX each altered the pattern of [(125)I]TID incorporation at M2-9 and M2-13. These results indicate that tetracaine and TID bind in a mutually exclusive manner to a common site in the closed channel that is spatially separated from the binding sites for PCP and HTX.

Pharmacological characterization of interactions of RO 25-6981 with the NR2B (epsilon2) subunit.

We used ligand binding to ascertain whether the pharmacological actions of RO 25-6981 [(R:(*), S:(*))-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidinepropanol] match those of other NR2B (epsilon2) subunit specific agents. RO 25-6981 inhibited binding of 125I-MK801 [iodo-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine maleate] to receptors made from NR1a/epsilon2 but not NR1a/epsilon1. Increasing the concentration of spermidine did not change the efficacy of RO 25-6981 and minimally changed the IC(50) value. Chimeric epsilon1/epsilon2 receptors demonstrated that the structural determinants for high affinity actions of RO 25-6981 were contained completely within the first 464 amino acids, but no receptor retained wildtype features when the size of the epsilon2 component was decreased further. Epsilon1Q336R receptors were more inhibited by ifenprodil and RO 25-9681 than wildtype epsilon1 receptors in ligand binding assays but not in functional assays. Selected mutations of epsilon2E200 and epsilon2E201 also decreased the sensitivity of receptors to ifenprodil and RO 25-6981. These results suggest that RO 25-6981 shares structural determinants with ifenprodil and other modulators in the NR2B subunit.