Rizatriptan (MAXALT) for the Acute Treatment of Migraine and Migraine Recurrence. A Placebo-Controlled, Outpatient Study

Rizatriptan is a novel 5-HT_1B/1D agonist which is rapidly absorbed after oral administration. The efficacy and tolerability of oral rizatriptan (5 mg and 10 mg) were examined in this multicenter, double-blind, outpatient study of 1473 migraineurs which featured randomized, placebo-controlled treatment of migraine recurrences. On experiencing moderate or severe migraine headaches, patients rated headache severity prior to dosing and at 30-minute intervals for 2 hours after dosing. Onset of effect was seen as early as 30 minutes after dosing with rizatriptan 10 mg. At 2 hours postdose, the percentage of patients with pain relief was significantly higher after rizatriptan 5 mg (62%) or 10 mg (71%) compared with placebo (35%). Complete relief was also significantly higher after rizatriptan 5 mg (33%) and 10 mg (42%) compared with placebo (10%). In patients experiencing headache recurrence after initial benefit, further relief was obtained in 71% with rizatriptan 5 mg (placebo 54%) and in 82% with rizatriptan 10 mg (placebo 44%). Complete relief of recurrent headache was obtained in 36% with rizatriptan 5 mg, 49% with rizatriptan 10 mg, and 15% with placebo ( P <0.05). The most common drug-related adverse experiences were dizziness, somnolence, asthenia/fatigue, and nausea (the incidences of which were low and dose related). There was no increase in the incidence of adverse experiences after use of up to three doses of rizatriptan within 24 hours. We conclude that both doses of rizatriptan are effective and well tolerated in the acute treatment of migraine and migraine recurrence, with the l0-mg dose preferred as it is more effective with a faster onset of action.     

Measurement of faecal immunoglobulin a levels in young children

A nephelometric immunoassay was developed to quantify immunoglobulin A (IgA) in children's stools. This method enables IgA in faecal protein extracts to be measured over a large range of concentrations (1.61-51.50 mg/L) with good accuracy (linear recovery in dilution-overloading assay) and precision (within- and between-run coefficients of variation (CVs) of 1-6%). An excellent recovery (105%) was obtained in stool samples overloaded by purified colostral IgA, demonstrating that the method used for faecal IgA extraction is adapted, not to induce significant IgA degradation, and probably allow a complete extraction of IgA. The amount of faecal IgA, as determined in stool samples from 125 children (6-24 months old), was an average of 14 mg per 100 g of stools (about 10% of the total protein stool content), with large individual variation (3-30 mg per 100 g of stools). No correlation was observed between faecal IgA amounts and the children's age or sex. Such an immunoassay could enable exhaustive noninvasive investigations of the maturation of the intestinal immune system, as well as accurate studies of the effect of oral dietary supplementation on IgA regulation.     

Quantitative imaging of the structure and function of the heart, lungs, and circulation

A 28-x-ray-source, cylindrical-scanning, transaxial tomographic x-ray-imaging system is in the process of being fabricated. This system will scan synchronously up to 250 parallel transverse cross sections of the human body over an axial range of 25 cm within 0.01 second at a maximum rate of 60 scans per second. The system will provide numerous variations of scanning configurations to permit quantitative assessment of the relative importance of transverse section thickness, image contrast, spatial and temporal resolution, and related computerized algorithms and display techniques. Synchronous imaging at high temporal resolution of a three-dimensional volume--for example, the heart--eliminates the need for successive periods of breath-holding and gated imaging techniques and is essential for quantitation of cardiovascular and pulmonary function and structure in intact animals or humans. Initial clinical applications are expected to be in the early detection of lung cancer and the diagnosis of the nature and degree of congenital and acquired cardiovascular disabilities.     

Use of bispectral electroencephalogram monitoring to assess neurologic status in unsedated, critically ill patients

OBJECTIVE: To test whether spectral indices derived from the electroencephalogram (EEG), and especially the bispectral index (BIS), can be used as measures of neurologic status in unsedated, critically ill patients. DESIGN: Prospective, observational study. SETTING: Medical intensive care unit (ICU) of a university-affiliated teaching hospital. PATIENTS: Thirty-one awake, unsedated critically ill adults were assessed in 108 separate sessions. MEASUREMENTS AND MAIN RESULTS: In each session, severity of illness was assessed by the Acute Physiology and Chronic Health Evaluation (APACHE III). The APACHE III Acute Physiology Score was used to quantify the degree of physiologic derangement. Neurologic function was assessed using the APACHE III Neurologic Score, the Glasgow Coma Scale, the Reaction Level Scale, and the Modified Ramsay Sedation Scale. All indices were plotted against various spectral parameters of the EEG, including BIS, an empirical index of EEG activity that is scaled from 0 to 100. BIS was significantly (p <.05) correlated with neurologic score regardless of scoring system used and was more strongly correlated than any other EEG spectral parameter. Better neurologic function was associated with higher values of BIS. In multivariate analysis, the combination of BIS and relative power in the theta band of the EEG accounted for 38% of the variability in the Glasgow Coma Scale. CONCLUSIONS: BIS provides a reliable index of neurologic status in awake, unsedated, critically ill patients. Further research is needed to determine whether the effects of neurologic status and pharmacologic sedation upon EEG are additive, whether BIS can be used to assess pharmacologic sedation in the critically ill patient population, and whether such objective measures of neurologic status have prognostic value.     

Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings

BACKGROUND AND OBJECTIVE: Mexiletine and propafenone are often used concomitantly and are metabolized by the same cytochrome P450 isozymes, namely CYP2D6, CYP1A2, and probably CYP3A4. Our objective was to study the potential pharmacokinetic and electrophysiological interactions between mexiletine and propafenone. METHODS: Fifteen healthy volunteers, 8 extensive metabolizers and 7 poor metabolizers of CYP2D6, received oral doses of mexiletine 100 mg two times daily from day 1 to day 8 and oral doses of propafenone 150 mg two times daily from day 5 to day 12. Interdose studies were performed at steady-state on mexiletine alone (day 4), mexiletine plus propafenone (day 8), and propafenone alone (day 12). RESULTS: In subjects in the extensive metabolizer group, coadministration of propafenone decreased oral clearances of R-(-)-mexiletine (from 41+/-11 L/h to 28+/-7 L/h) and S-(+)-mexiletine (from 43+/-15 L/h to 29+/-11 L/h) to an extent such that these values were no longer different between the extensive and the poor metabolizer groups. Propafenone coadministration also decreased partial metabolic clearances of mexiletine to hydroxymethylmexiletine, p-hydroxymexiletine, and m-hydroxymexiletine in extensive metabolizers by 71%, 67%, and 73%, respectively. In contrast, propafenone did not alter the kinetics of mexiletine enantiomers in subjects in the poor metabolizer group except for a slight decrease in the formation of hydroxymethylmexiletine. Pharmacokinetic parameters of propafenone were not changed during concomitant administration of mexiletine in subjects of either phenotype. Finally, electrocardiographic parameters (QRS duration, QTc, RR, and PR intervals) were not modified during the combined administration of the drugs. CONCLUSION: Propafenone is a potent CYP2D6 inhibitor that may cause an increase in plasma concentrations of coadministered CYP2D6 substrates.     

IGF1R signalling in testicular germ cell tumour cells impacts on cell survival and acquired cisplatin resistance

Testicular germ cell tumours (TGCTs) are the most frequent malignancy and cause of death from solid tumours in the 20‐ to 40‐year age group. Although most cases show sensitivity to cis‐platinum‐based chemotherapy, this is associated with long‐term toxicities and chemo‐resistance. Roles for receptor tyrosine kinases other than KIT are largely unknown in TGCT. We therefore conducted a phosphoproteomic screen and identified the insulin growth factor receptor‐1 (IGF1R) as both highly expressed and activated in TGCT cell lines representing the nonseminomatous subtype. IGF1R was also frequently expressed in tumour samples from patients with nonseminomas. Functional analysis of cell line models showed that long‐term shRNA‐mediated IGF1R silencing leads to apoptosis and complete ablation of nonseminoma cells with active IGF1R signalling. Cell lines with high levels of IGF1R activity also showed reduced AKT signalling in response to decreased IGF1R expression as well as sensitivity to the small‐molecule IGF1R inhibitor NVP‐AEW541. These results were in contrast to those in the seminoma cell line TCAM2 that lacked IGF1R signalling via AKT and was one of the two cell lines least sensitive to the IGF1R inhibitor. The dependence on IGF1R activity in the majority of nonseminomas parallels the known role of IGF signalling in the proliferation, migration, and survival of primordial germ cells, the putative cell of origin for TGCT. Upregulation of IGF1R expression and signalling was also found to contribute to acquired cisplatin resistance in an in vitro nonseminoma model, providing a rationale for targeting IGF1R in cisplatin‐resistant disease. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Dystrophin expression in muscle following gene transfer with a fully deleted ("gutted") adenovirus is markedly improved by trans-acting adenoviral gene products

Helper-dependent adenoviruses (HDAd) are Ad vectors lacking all or most viral genes. They hold great promise for gene therapy of diseases such as Duchenne muscular dystrophy (DMD), because they are less immunogenic than E1/E3-deleted Ad (first-generation Ad or FGAd) and can carry the full-length (Fl) dystrophin (dys) cDNA (12 kb). We have compared the transgene expression of a HDAd (HDAdCMVDysFl) and a FGAd (FGAdCMV-dys) in cell culture (HeLa, C2C12 myotubes) and in the muscle of mdx mice (the mouse model for DMD). Both vectors encoded dystrophin regulated by the same cytomegalovirus (CMV) promoter. We demonstrate that the amount of dystrophin expressed was significantly higher after gene transfer with FGAdCMV-dys compared to HDAdCMVDysFl both in vitro and in vivo. However, gene transfer with HDAdCMVDysFl in the presence of a FGAd resulted in a significant increase of dystrophin expression indicating that gene products synthesized by the FGAd increase, in trans, the amount of dystrophin produced. This enhancement occurred in cell culture and after gene transfer in the muscle of mdx mice and dystrophic golden retriever (GRMD) dogs, another animal model for DMD. The E4 region of Ad is required for the enhancement, because no increase of dystrophin expression from HDAdCMVDysFl was observed in the presence of an E1/E4-deleted Ad in vitro and in vivo. The characterization of these enhancing gene products followed by their inclusion into an HDAd may be required to produce sufficient dystrophin to mitigate the pathology of DMD by HDAd-mediated gene transfer.     

Potential clinical use of butyric acid derivatives to induce antigen-specific T cell inactivation

Compounds with the capacity to induce antigen-specific unresponsiveness in CD4(+) T cells can in some clinical situations be more beneficial than general immune suppressants. Newly synthesized ester, ester/amide, and amide derivatives of butyrate with the capacity to induce antigen-specific T cell unresponsiveness in vivo and in vitro were tested here. The ester and ester/amide derivatives of butyrate were shown to block proliferation by interleukin-2-stimulated murine Th1 cells in vitro. A 3-day treatment with these same two derivatives also suppressed a primary antibody response to a thymus-dependent antigen in mice. In addition, even a single injection of the ester derivative of n-butyrate 2-(4-morpholinyl)ethyl butyrate hydrochloride (MEB) on day 2 or 3 after immunization suppressed the generation of memory T cells capable of proliferating to antigen or of promoting a secondary antigen-specific antibody response. MEB also induced antigen-specific unresponsiveness in antigen-activated, but not resting or interleukin-2-activated, T cells in vitro. DNA analysis showed that regardless of when MEB was added to the cultures, it induced the eventual G(1) sequestration of essentially all activated Th1 cells. Because G(1) blockade is associated with Th1 cell anergy, this finding suggests that MEB has the potential to induce anergy in already-activated CD4(+) T cells. Taken together, the results presented here establish MEB as a novel means of inducing anergy in CD4(+) T cells both in vitro and in vivo and underscore the likelihood that MEB and/or other butyrate derivatives can be used as immunotherapeutic reagents.     

Achieving a sustained reduction in benzodiazepine use through implementation of an area-wide multi-strategic approach

OBJECTIVE: This study aimed to evaluate the impact, in a regional setting, of a multi-strategic partnership approach for reducing benzodiazepine use in the management of insomnia, as recommended in Australia's National Policy on Quality Use of Medicines. METHOD: The setting was a rural region of South Australia, covering approximately 2000 km2, with a population of over 20 000. The study involved participatory action research, with qualitative and quantitative evaluations. The intervention involved a multi-strategic approach, including provision of treatment guidelines, provision of consumer information, a local media campaign and education and training of health professionals. The quantitative evaluation involved a single region before/after study with 2 years of follow-up using pharmacy-based dispensing data for benzodiazepines and antidepressants, gathered for the months of November to April in 1998/99 ('before' period) through to 2000/01 ('after' period). The data were analysed using non-parametric statistics. RESULTS: There was a 19% reduction in benzodiazepine dispensing 2 years after the intervention compared with a 6% reduction nationally. Dispensing of antidepressants increased by 33%, compared with a 28% increase nationally. CONCLUSION: It was concluded that the multi-strategic approach to the management of sleep disorders proved successful in promoting the use of non-drug alternatives, achieving sustained reduction in benzodiazepine consumption in a rural community, without therapeutic substitution of antidepressants. IMPLICATIONS: The study demonstrated that a sustainable reduction in prescribing of benzodiazepines can be achieved through the implementation of a multi-strategic approach involving local consumers, health professionals, a Division of General Practice, a government department, aged-care facilities and the local media.