Disulfiram-loaded immediate and extended release vaginal tablets for the localised treatment of cervical cancer

Objectives: To develop and manufacture both immediate and sustained release vaginal tablets containing the anticancer drug disulfiram, which has the potential to be used as a non-invasive treatment for cervical cancer. 
Methods: Disulfiram-loaded vaginal tablets were manufactured at pilot scale using the direct compression method. These tablets were tested in accordance with the European Pharmacopeia testing of solid dosage form guidelines. They were also tested using a biorelevant dissolution method as well as a dual-chambered release model designed to better mimic the dynamic nature of the vaginal vault.
Key findings: We have developed both immediate and sustained release vaginal tablets, which when manufactured at pilot scale are within the limits set by the European Pharmacopeia for the testing of solid dosage forms. Furthermore, these tablets are capable of releasing disulfiram in vitro using the dual-chambered release model at levels 25 000 times and 35 000 times greater than its IC50 concentration for the HeLa cervical cancer cell line. 
Conclusions: The successful pilot manufacture and testing of both the immediate and sustained release disulfiram-loaded vaginal tablets warrant further investigation, using an in-vivo model, to assess their potential for use as a non-invasive treatment option for cervical cancer.

Tissue healing of immediate implant placement in extraction sockets with titanium versus zirconium oxide implants : an experimental study in the beagle dog

Tese de doutoramento, Medicina Dentária (Periodontologia), Universidade de Lisboa, Faculdade de Medicina Dentária, 2016

The immediate and short-term chemosensory impacts of coffee and caffeine on cardiovascular activity

The immediate and short-term chemosensory impacts of coffee and caffeine on cardiovascular activity. Introduction: Caffeine is detected by 5 of the 25 gustatory bitter taste receptors (hTAS2Rs) as well as by intestinal STC-1 cell lines. Thus there is a possibility that caffeine may elicit reflex autonomic responses via chemosensory stimulation. Methods: The cardiovascular impacts of double-espresso coffee, regular (130 mg caffeine) and decaffeinated, and encapsulated caffeine (134 mg) were compared with a placebocontrol capsule. Measures of four post-ingestion phases were extracted from a continuous recording of cardiovascular parameters and contrasted with pre-ingestion measures. Participants (12 women) were seated in all but the last phase when they were standing. Results: Both coffees increased heart rate immediately after ingestion by decreasing both the diastolic interval and ejection time. The increases in heart rate following the ingestion of regular coffee extended for 30 min. Encapsulated caffeine decreased arterial compliance and increased diastolic pressure when present in the gut and later in the standing posture. Discussion: These divergent findings indicate that during ingestion the caffeine in coffee can elicit autonomic arousal via the chemosensory stimulation of the gustatory receptors which extends for at least 30 min. In contrast, encapsulated caffeine can stimulate gastrointestinal receptors and elicit vascular responses involving digestion. Conclusion: Research findings on caffeine are not directly applicable to coffee and vice versa. The increase of heart rate resulting from coffee drinking is a plausible pharmacological explanation for the observation that coffee increases risk for coronary heart disease in the hour after ingestion.

The immediate effects of atlanto-occipital joint manipulation and suboccipital muscle inhibition technique on active mouth opening and pressure pain sensitivity over latent myofascial trigger points in the masticatory muscles

DESIGN: A randomized controlled trial.OB JECTIVE: To investigate the immediate effects on pressure pain thresholds over latent trigger points (TrPs) in the masseter and temporalis muscles and active mouth opening following atlanto-occipital joint thrust manipulation or a soft tissue manual intervention targeted to the suboccipital muscles. BACKGROUND : Previous studies have described hypoalgesic effects of neck manipulative interventions over TrPs in the cervical musculature. There is a lack of studies analyzing these mechanisms over TrPs of muscles innervated by the trigeminal nerve. METHODS: One hundred twenty-two volunteers, 31 men and 91 women, between the ages of 18 and 30 years, with latent TrPs in the masseter muscle, were randomly divided into 3 groups: a manipulative group who received an atlanto-occipital joint thrust, a soft tissue group who received an inhibition technique over the suboccipital muscles, and a control group who did not receive an intervention. Pressure pain thresholds over latent TrPs in the masseter and temporalis muscles, and active mouth opening were assessed pretreatment and 2 minutes posttreatment by a blinded assessor. Mixed-model analyses of variance (ANOVA) were used to examine the effects of interventions on each outcome, with group as the between-subjects variable and time as the within-subjects variable. The primary analysis was the group-by-time interaction. RESULTS: The 2-by-3 mixed-model ANOVA revealed a significant group-by-time interaction for changes in pressure pain thresholds over masseter (P<.01) and temporalis (P =.003) muscle latent TrPs and also for active mouth opening (P<.001) in favor of the manipulative and soft tissue groups. Between-group effect sizes were small. CONCLUSIONS: The application of an atlanto-occipital thrust manipulation or soft tissue technique targeted to the suboccipital muscles led to an immediate increase in pressure pain thresholds over latent TrPs in the masseter and temporalis muscles and an increase in maximum active mouth opening. Nevertheless, the effects of both interventions were small and future studies are required to elucidate the clinical relevance of these changes. LEVEL OF EVIDENCE : Therapy, level 1b. J Orthop Sports Phys Ther 2010;40(5):310-317. doi:10.2519/jospt.2010.3257. KEYWORDSDS: cervical manipulation, muscle trigger points, neck, TMJ, upper cervical.

Immediate effects of hip mobilization with movement in patients with hip osteoarthritis: A randomised controlled trial

Background Mobilization with movement (MWM) has been shown to reduce pain, increase range of motion (ROM) and physical function in a range of different musculoskeletal disorders. Despite this evidence, there is a lack of studies evaluating the effects of MWM for hip osteoarthritis (OA). Objectives To determine the immediate effects of MWM on pain, ROM and functional performance in patients with hip OA. Design Randomized controlled trial with immediate follow-up. Method Forty consenting patients (mean age 78 ± 6 years; 54% female) satisfied the eligibility criteria. All participants completed the study. Two forms of MWM techniques (n = 20) or a simulated MWM (sham) (n = 20) were applied. Primary outcomes: pain recorded by numerical rating scale (NRS). Secondary outcomes: hip flexion and internal rotation ROM, and physical performance (timed up and go, sit to stand, and 40 m self placed walk test) were assessed before and after the intervention. Results For the MWM group, pain decreased by 2 points on the NRS, hip flexion increased by 12.2°, internal rotation by 4.4°, and functional tests were also improved with clinically relevant effects following the MWM. There were no significant changes in the sham group for any outcome variable. Conclusions Pain, hip flexion ROM and physical performance immediately improved after the application of MWM in elderly patients suffering hip OA. The observed immediate changes were of clinical relevance. Future studies are required to determine the long-term effects of this intervention.

The Falls of Niagara : being a complete guide to all the points of interest around and in the immediate neighbourhood of the great cataract with views taken from sketches by Washington Friend, and from photographs. --

Includes index.

Immediate and enduring effects of corticosterone administration during adolescence and adulthood on anxiety and depressive behavior in male rats

Previous research has shown that the stress hormone corticosterone can increase depressive and anxiety-like behavior in rats as well as dampen the HPA response to a novel stressor (Kalynchuk et aI., 2004; Johnson et aI., 2006). Several studies have also shown that adolescence is a period of increased sensitivity to the negative effects of stressors (reviewed in McCormick et aI., 2010), which are often the result of exposure to corticosterone, and yet there is no research to date examining the effects of corticosterone administration during adolescence. The purpose of these experiments is to determine both the immediate and enduring effects of prolonged exposure to corticosterone in adolescence and adulthood on anxiety-like behavior, depressive behavior, and the HPA response. In Experiment 1 adolescent and adult rats were administered an injection of 40 mg/kg of corticosterone or vehicle daily for 16 days. Ha l f of the rats were then tested on the elevated plus maze (EPM) one day after their last injection, and the following day were tested on the forced swim test (FST). After the FST, which is a stressor, blood samples were collected at three time points, and the plasma concentrations of corticosterone were determined using a radioimmunoassay. The remaining rats were left undisturbed for three weeks, and then underwent the same testing as the first group. Corticosterone treatment had little effect on anxiety-like and depressive behavior, but it did alter the HPA response to the FST. In those rats tested soon after the period of injections, corticosterone dampened the HPA response as compared to vehicle treated rats in both adolescent and adult treated rats. For the adolescent treated rats that were tested several weeks later, corticosterone treatment increased HPA response as compared to the vehicle treated rats, but the same was not true for the adult treated rats. I t was hypothesized that the lack of behavioral effects of the corticosterone treatment may be the result of the vehicle injections inducing a stress response and thereby both groups would have similarly altered behavior. In Experiment 2 rats were administered corticosterone dissolved in their drinking water with 2.5% ethanol, or jus t the 2.5% ethanol or plain water, to determine the effects of corticosterone treatment without a stressor present. The regular drinking water was replaced with treated water for 16 days either during adulthood or adolescence, and as before, rats were either tested in the FST one day after the water was removed or three weeks later. Again there was no effect of treatment on depressive behavior. Similar to what was observed in Experiment 1, corticosterone treatment dampened the HPA response to a stressor for the rats tested soon after the treatment period. However, in Experiment 2 there was no effect of treatment on HPA response in those rats tested several weeks after they were treated. These results indicate that corticosterone can have a lasting effect on the HPA when administered in adolescence by injections but not in drinking water, which is likely because of the different schedules of exposure and rates of absorption between the two administration methods.

Message from the President of the United States, Recommending an Immediate Declaration of War Against Great Britain (1812)

"June 1st, 1812. Referred to the Committee on Foreign Relations. June 3d, 1812. Bill reported, declaring war ..."

Immediate recall by aphasic, deaf and normally hearing children for visual forms presented simultaneously or sequentially in tim

This paper discusses a study to investigate immediate recall of visual stimuli presented simultaneously or sequentially in time.

Modeling distributions of immediate memory effects: No strategies needed?

Many models of immediate memory predict the presence or absence of various effects, but none have been tested to see whether they predict an appropriate distribution of effect sizes. The authors show that the feature model (J. S. Nairne, 1990) produces appropriate distributions of effect sizes for both the phonological confusion effect and the word-length effect. The model produces the appropriate number of reversals, when participants are more accurate with similar items or long items, and also correctly predicts that participants performing less well overall demonstrate smaller and less reliable phonological similarity and word-length effects and are more likely to show reversals. These patterns appear within the model without the need to assume a change in encoding or rehearsal strategy or the deployment of a different storage buffer. The implications of these results and the wider applicability of the distributionmodeling approach are discussed.

Input and output modality effects in immediate serial recall

In immediate recall tasks, visual recency is substantially enhanced when output interference is low (Cowan, Saults, Elliott, & Moreno, 2002; Craik, 1969) whereas auditory recency remains high even under conditions of high output interference. Ibis auditory advantage has been interpreted in terms of auditory resistance to output interference (e.g., Neath & Surprenant, 2003). In this study the auditory-visual difference at low output interference re-emerged when ceiling effects were accounted for, but only with spoken output. With written responding the auditory advantage remained significantly larger with high than with low output interference. These new data suggest that both superior auditory encoding and modality-specific output interference contribute to the classic auditory-visual modality effect.