Nanoparticle-based oral formulation can surprise you with inferior in vivo absorption in humans.

Particle size reduction leads to an increase in the drug dissolution rate, which in turn can lead to a substantial increase in the bioavailability of a poorly soluble compound. To improve bioavailability, a practically insoluble investigational drug, ODM-106, was nanomilled and capsule formulations with three different drug amounts were prepared for the first-in-man study. Fast in vitro dissolution was achieved from all the capsules containing different amounts of drug nanoparticles but in the clinical study, surprisingly, low bioavailability was observed from the highest capsule strength (100 mg) in comparison to a lower strength (10 mg). In order to study further the discrepant in vitro-in vivo correlation (IVIVC), a discriminative dissolution method was developed. It was noticed that the degree of supersaturation increased significantly as the stabilizers' concentration within the dried nanoformulations was increased. Hypromellose provided a physical barrier between nanoparticles to prevent aggregation during drying. SLS on the other hand improved wettability and provided supersaturation. The drug load, nanoparticle/polymer/surfactant/filler ratios and selected drying step were discovered to be critical to the nanoformulations' performance. Aggregation of nanoparticles, in the absence of optimal stabilizer concentration, compromised dissolution due to decreased surface area. In conclusion, the early development of a discriminative dissolution method and cautious selection of the nanoparticle/polymer ratio before manufacturing clinical batches is recommended.

A prospective, double-blind, pilot, randomized, controlled trial of an "embodied" virtual reality intervention for adults with low back pain.

ABSTRACT: Adults with chronic low back pain, disability, moderate-to-severe pain, and high fear of movement and reinjury were recruited into a trial of a novel, automated, digital therapeutics, virtual reality, psychological intervention for pain (DTxP). We conducted a 3-arm, prospective, double-blind, pilot, randomized, controlled trial comparing DTxP with a sham placebo comparator and an open-label standard care. Participants were enrolled for 6 to 8 weeks, after which, the standard care control arm were rerandomized to receive either the DTxP or sham placebo. Forty-two participants completed assessments at baseline, immediately posttreatment (6-8 weeks), 9-week, and 5-month follow-up. We found that participants in the DTxP group reported greater reductions in fear of movement and better global impression of change when compared with sham placebo and standard care post treatment. No other group differences were noted at posttreatment or follow-up. When compared with baseline, participants in the DTxP group reported lower disability at 5-month follow-up, lower pain interference and fear of movement post treatment and follow-up, and lower pain intensity at posttreatment. The sham placebo group also reported lower disability and fear of movement at 5-month follow-up compared with baseline. Standard care did not report any significant changes. There were a number of adverse events, with one participant reporting a serious adverse event in the sham placebo, which was not related to treatment. No substantial changes in medications were noted, and participants in the DTxP group reported positive gaming experiences.

Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.

CONTEXT: Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α(2)-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort. OBJECTIVE: To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients' interaction with nursing care. DESIGN, SETTING, AND PATIENTS: Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251). INTERVENTIONS: Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials. MAIN OUTCOME MEASURES: For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients' ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223). RESULTS: Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients' interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001). CONCLUSIONS: Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00481312, NCT00479661.

Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation.

PURPOSE: To compare dexmedetomidine (DEX) with standard care (SC, either propofol or midazolam) for long-term sedation in terms of maintaining target sedation and length of intensive care unit (ICU) stay. METHODS: A pilot, phase III, double-blind multicenter study in randomized medical and surgical patients (n = 85) within the first 72 h of ICU stay with an expected ICU stay of >or=48 h and sedation need for >or=24 h after randomization. Patients were assigned to either DEX (

The safety and efficacy of zotepine in the treatment of schizophrenia: Results of a one-year naturalistic clinical trial.

INTRODUCTION AND METHOD: The safety and efficacy of zotepine,75 - 450 mg/day, were evaluated in an open multicentre one-year study in patients suffering from acute exacerbation of schizophrenia; total exposure amounted to 152.78 years. RESULTS: Mean BPRS total score was reduced from 51.7 at baseline to 40.8 at end-point (P<0.05). Similar significant reductions at all study time-points were recorded for BPRS total and subscores, CGI severity and improvement, BAS total scores and SANS total and global scores. Significant improvements in EPMS and AIMS were recorded from week 12 to end-point. Clinically significant improvements in acute symptoms, detected early in the study, were maintained to end-point. CONCLUSION: Zotepine was well tolerated: weight gain, reduced serum uric acid, raised liver enzymes and increased heart rate were associated with chronic zotepine treatment. Seven patients experienced seizures during the study, although concomitant medications and a known historical predisposition to seizure are factors likely to have contributed to these events. The improvements in negative symptoms and low propensity to cause further extrapyramidal side-effects support the importance of zotepine in maintenance treatment.

The efficacy of zotepine in treating acute negative symptoms of schizophrenia: The results of a meta-analysis.

INTRODUCTION: Zotepine is a unique antipsychotic drug, having effects which are both antiserotonergic and antidopaminergic that may make it more effective in the treatment of negative symptoms of schizophrenia than more conventional agents. METHOD: A meta-analysis was performed on the effect of zotepine on the negative symptoms in seven double-blind studies, as measured by the SANS scale. RESULTS: Of the trials selected for this meta-analysis, one showed significant improvement in acute negative symptoms in favour of zotepine. Negative symptoms measured in the other trials showed trends in favour of zotepine, except for one study where the trend was in favour of perazine. The meta-analysis showed zotepine to be significantly better then either placebo or conventional antipsychotic comparators using the standardized treatment difference methodology, and it confirmed the results from a previous study using patients with predominantly negative symptoms. CONCLUSION: Zotepine may have a place in the treatment of this group of patients where conventional antipsychotic drugs have had little effect. ( Int J Psych Clin Pract 2000; 4: 209 - 214).

A fast and inexpensive method for isolation of high-quality RNA from eimerian oocysts.

An inexpensive and simple method using acid-phenol was developed for the isolation of total RNA from eimerian oocysts. This procedure provides a pure preparation of undegraded RNA in high yield and can be completed in under 2 h.

Stimulation of mitotic recombination upon transcription from the yeast GAL1 promoter but not from other RNA polymerase I, II and III promoters.

Homologous recombination in Saccharomyces cerevisiae and other organisms can be stimulated by transcription. Consistent with this, we find that recombination of a chromosomal ade1 allele with a plasmid-borne ADE1 ORF under the control of the GAL1 promoter increased from 6.1x10(-6) to 1.7x10(-4) when transcription of the plasmid locus was induced by growing the cells in the presence of galactose. Recombination could also be stimulated by over-expressing the Gal4 transcription factor in the presence of the GAL1-ADE1 plasmid, while culturing the cells in dextrose medium. However, when transcription of the same ORF was driven from the highly active promoters of the rDNA (RNA polymerase I), and ADH1 (RNA polymerase II) genes, only background levels of recombination (5-10x10(-6)) were observed, irrespective of the carbon source. Recombination was found to involve integration of the whole plasmid and to depend on RAD51, RAD52 and RAD54. The results indicate that increased accessibility of transcriptionally active chromatin is not sufficient to cause increased rates of this kind of reciprocal exchange.

Cell cycle arrest promotes trans-hammerhead ribozyme action in yeast.

A hammerhead ribozyme designed to cleave the yeast ADE1 mRNA has been expressed in yeast under the control of a galactose-inducible promoter. RNA prepared from the galactose-induced yeast cultures possesses an activity that cleaves ADE1 mRNA in vitro. However, in spite of high expression levels of the ribozyme, no cleavage activity could be demonstrated in vivo. On the other hand, when the yeast cells expressing hammerhead RNA were treated with the alpha-factor mating pheromone, the level of ADE1 mRNA was reduced by 50%. Similar reductions were observed when this strain was cultured in the presence of lithium acetate or in nitrogen-free medium. Moreover, control experiments in which disabled hammerhead genes were expressed showed no such reductions. Extension of the length of the flanking recognition arms of the ribozyme from a total of 10 to 16 or 24 nucleotides diminished the inhibitory effect of the ribozyme. These data suggest that ribozymes are able to cleave a trans-RNA target in yeast.

A hammerhead ribozyme inhibits ADE1 gene expression in yeast.

To study factors that affect in vivo ribozyme (Rz) activity, a model system has been devised in Saccharomyces cerevisiae based on the inhibition of ADE1 gene expression. This gene was chosen because Rz action can be evaluated visually by the Red phenotype produced when the activity of the gene product is inhibited. Different plasmid constructs allowed the expression of the Rz either in cis or in trans with respect to ADE1. Rz-related inhibition of ADE1 expression was correlated with a Red phenotype and a diminution of ADE1 mRNA levels only when the Rz gene was linked 5' to ADE1. The presence of the expected 3' cleavage fragment was demonstrated using a technique combining RNA ligation and PCR. This yeast system and detection technique are suited to the investigation of general factors affecting Rz-catalyzed inhibition of gene expression under in vivo conditions.

Relationship between hypoglycaemic response and plasma concentrations of BTS 67 582 in healthy volunteers.

The relationships between blood glucose, plasma insulin and plasma BTS 67 582 concentrations were studied in a randomised, placebo-controlled, four-way crossover study involving 16 healthy male volunteers aged between 19 and 43 years. Single oral doses of 125, 250 and 500 mg BTS 67 582 were studied. Fasting blood samples were taken pre-dose and half-hourly for 8 h post-dose. Mean peak plasma concentrations of BTS 67 582 were 518, 1076 and 2435 ng ml-1 for doses of 125, 250 and 500 mg, respectively. Mean maximum reductions in blood glucose were 1.13, 1.59 and 1.78 mmol l-1, and mean maximum increases in plasma insulin were 26, 14 and 21 muu ml-1 for the three doses, respectively. Changes in incremental area under the curve (AUC) of blood glucose were correlated with changes in plasma BTS 67 582 AUC. The maximum reduction in blood glucose was correlated with the peak plasma BTS 67 582 concentration. No correlations between plasma insulin and plasma BTS 67 582 concentrations were observed. Anticlockwise hysteresis was evident in concentration-effect curves, but less evident following subtraction of placebo data, and was mainly due to an underlying downward trend in fasted blood glucose levels with time evident under placebo treatment. This suggests that hypoglycaemic effects were related to systemic BTS 67 582 concentrations, suggesting that active metabolites of the drug do not make a major contribution to acute hypoglycaemic effects. A log-linear model described the relationship between blood glucose and plasma BTS 67 582 concentrations for 14 of the 16 volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the metabolic effects of flosequinan and propranolol in patients with non-insulin-dependent diabetes mellitus.

The effects of steady-state flosequinan, a new peripheral vasodilator, and propranolol on glucose tolerance and plasma lipids in 22 non-insulin-dependent diabetics were investigated in a randomized double-blind placebo-controlled, three-way crossover trial. Flosequinan produced no impairment of glucose tolerance compared with placebo. Propranolol produced significant increases in fasting plasma glucose (P less than 0.01) and increases in the area under the glucose tolerance curve (P less than 0.05) compared to placebo. No significant effects on cholesterol levels were seen on either treatment but triglyceride levels were significantly elevated on propranolol compared with placebo (P less than 0.01). These data suggest that flosequinan, used in therapeutic dosage, has no adverse metabolic effects on the non-insulin-dependent diabetic and this may be an advantage for a drug used in the treatment of hypertension or congestive heart failure.

A preliminary study of the effects of flosequinan on psychomotor function in healthy volunteers.

The central nervous system effects of flosequinan (100 mg), a chemically novel quinolone vasodilator, were assessed by a double-blind crossover comparison with placebo and diazepam (10 mg) in 12 healthy volunteers. After five practice sessions on a battery of automated psychomotor tests, assessments of psychomotor function and mood ratings were made on each volunteer at baseline and 1, 3, 6 and 24 h after dosing. Compared with placebo, diazepam (10 mg), the verum control, significantly (p less than 0.05) reduced subjective alertness, impaired critical flicker fusion threshold at 1 and 3 h, digit symbol substitution at 6 h, overall total choice reaction time and overall rate on two of five finger tapping tests. Flosequinan (100 mg), however, was indistinguishable from placebo in all tests with two contrasting exceptions: improved alternate right and left finger tapping (mean 5.1/s) compared to either diazepam (4.7/s) or placebo (4.8/s) (p less than 0.05), and impaired digit symbol substitution at 6 h (45.7/min) in comparison with placebo (50.7/min) (p less than 0.01). Ten volunteers reported 12 adverse effects after flosequinan treatment (10 of which were headaches), two reported drowsiness after diazepam and one reported headache after placebo. It was concluded that flosequinan has no central nervous system depressant effects despite the occurrence of headache in 10 volunteers.

Characterization of a chemically synthesized RNA having the sequence of the yeast initiator tRNA(Met).

A 75-unit long oligoribonucleotide corresponding to the sequence of the Saccharomyces cerevisiae initiator tRNA was synthesized chemically. The crude RNA was purified, and the sequence was verified by RNA sequencing techniques. A particularly useful purification step involved hydrophobic chromatography on BND-cellulose. The purified RNA could be aminoacylated to 28% of a bona fide initiator tRNA(Met) sample and threonylated to 76% of the level observed with native tRNA(fMet) from E. coli.

A comparison of the effects of flosequinan, a new vasodilator, and propranolol on sub-maximal exercise in healthy volunteers.

1. The effects of steady state flosequinan, a new vasodilator, and propranolol, on glucose mobilisation, lipolysis and plasma potassium concentration during sub-maximal exercise testing were investigated in a double-blind, randomised, three-way crossover study in 12 healthy volunteers. 2. Plasma glucose, potassium and free fatty acid concentration during and after exercise on flosequinan were similar to those on placebo. Exercise heart rates were 7% (+9.2 beats min-1) higher on flosequinan compared with placebo (P less than 0.05). During exercise on propranolol plasma glucose concentrations were comparable with those on placebo but plasma potassium concentrations were higher (mean increase 0.26 mmol l-1, P less than 0.01) whereas free fatty acid concentrations were lower (mean decrease 0.10 mmol 1-1, P less than 0.01). As expected the heart rate on exercise was 25% less (-35 beats min-1) on propranolol (P less than 0.05). 3. These data suggest that, in contrast to propranolol, flosequinan does not adversely affect the mobilisation of the two major sources of energy during sub-maximal exercise.

The effects of flosequinan and nifedipine on glucose tolerance in healthy volunteers.

The influence of flosequinan and nifedipine on glucose tolerance has been investigated in a placebo-controlled four-way crossover study in 12 healthy volunteers. There was no statistical difference between the glucose tolerance curves after placebo, a single dose of flosequinan, chronic treatment with flosequinan or nifedipine at steady state. Headache was more frequent in volunteers on flosequinan than after either nifedipine or placebo.