2-period Crossover Research Articles

Abstract P4-12-11: Patient preference for subcutaneous trastuzumab via handheld syringe versus intravenous infusion in HER2-positive early breast cancer: Cohort 2 of the PrefHer study

Abstract Background In the HannaH study (NCT00950300), a 600 mg fixed dose of subcutaneous (SC) trastuzumab, administered via handheld syringe, was shown to have noninferior efficacy and comparable pharmacokinetic and safety profiles to the intravenous (IV) formulation for the (neo)adjuvant treatment of HER2-positive early breast cancer. Cohort 1 of the ongoing, randomized, multicenter, international, crossover PrefHer study (NCT01401166) showed that an overwhelming 92% of patients preferred SC trastuzumab via single-use injection device to conventional IV administration. The objective of the current analysis was to assess patient preferences for SC or IV trastuzumab in Cohort 2 of PrefHer, an independently assessed cohort in which SC trastuzumab was administered via handheld syringe. Methods After completing (neo)adjuvant chemotherapy, patients were randomized to receive 4 cycles of SC trastuzumab (fixed dose of 600 mg) followed by 4 cycles of IV trastuzumab (8 mg/kg→6 mg/kg) or the reverse sequence (the crossover period) as part of their adjuvant trastuzumab therapy. The primary endpoint was the proportion of patients indicating an overall preference for SC versus IV trastuzumab, assessed using a two-sided test against the null hypothesis of 65% preference for SC. Prior to randomization and again at the end of the crossover period, experienced interviewers conducted telephone interviews with patients. Information on factors potentially influencing preferences, including type of venous access device used and experiences during administration, was collected. After the crossover period, patients’ final preferences were elicited, along with reasons for these and the strength of them. Interviews were stringently quality-controlled to ensure impartial questioning. Four researchers independently coded from verbatim quotes the two primary reasons patients gave for their preferences. These were reconciled and grouped into ten categories for descriptive analyses. Adverse events (AEs) were assessed by standard methods. Results Two hundred and forty patients were enrolled: 231 received SC and IV trastuzumab and completed both patient interviews, and 239 received ≥1 dose of study drug. Baseline demographics/characteristics/treatment histories were generally balanced. SC trastuzumab was preferred by 199/231 patients (86%, 95% CI 81–90%; p<0.0001); 29 preferred IV (13%, 95% CI 9–18%), and 3 had no preference (1%, 95% CI 0–4%). Of the patients who preferred SC, overall preferences were “very strong” in 144/199 (72%), “fairly strong” in 36 (18%), and “not very strong” in 19 (10%). The two primary categories for SC preference were: i) time saving and ii) less pain/discomfort. AEs were reported in 77% of patients during the crossover period (69% mild, 36% moderate, 8% severe, 0% life-threatening/fatal, 1% serious). Overall safety was comparable with the known IV profile in early breast cancer. Summary As with Cohort 1, patients in Cohort 2 of the PrefHer study overwhelmingly preferred SC over IV trastuzumab delivery. The 4 cycles of SC trastuzumab and 4 of IV were well tolerated. SC trastuzumab is therefore an important option in the treatment of HER2-positive early breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-11.

Comparing Patient Preferences and Healthcare Provider Recommendations with the Pen Versus Vial-and-Syringe Insulin Delivery in Patients with Type 2 Diabetes

This study aimed to examine healthcare provider (HCP) recommendations and patient preferences for the insulin pen versus vial-and-syringe in patients with type 2 diabetes mellitus (T2DM) and to assess clinical end points and safety outcomes. Using a randomized, open-label, crossover design, in total, 405 insulin-naive adults with T2DM from 60 centers received basal insulin glargine in one of two device treatment sequences (2 weeks of pen followed by 2 weeks of vial-and-syringe, or vice versa). The primary end point, patient device preference, was evaluated at Week 4 (end of the crossover period) using the Insulin Injection Preference Questionnaire. Patient preference and HCP recommendation were assessed with one global item and three subscale items (blood glucose control, reluctance to use insulin, and long-term insulin use) using a 5-point scale ranging from 1=not preferred or not recommended to 5=preferred or recommended. Patients were then re-randomized to either pen or vial-and-syringe for further observation (6, 10, and 30 weeks) to evaluate clinical end points (glycosylated hemoglobin [A1C] and fasting blood glucose levels) and safety outcomes (hypoglycemia and adverse events). Patients reported a significant preference for pens over vial-and-syringe, and HCPs strongly recommended pens over vial-and-syringe (both P<0.001). Consistent response patterns were observed by HCPs and patients for the three subscale items. Fasting blood glucose, A1C levels, and the incidence of hypoglycemia were comparable in the two groups. Patients preferred pens over vial-and-syringe, with the pen device also recommended by HCPs, when initiating basal insulin treatment in insulin-naive patients with T2DM.

Experimental Study of Single-Phase and Two-Phase Water-in-Crude-Oil Dispersed Flow Wax Deposition in a Mini Pilot-Scale Flow Loop

Wax deposition tests under single-phase and two-phase dispersed water-in-oil at 16 and 35% water cut (WC) were conducted in a mini pilot-scale flow loop by using South Pelto crude oil. The initial inner wall temperature (Tw,ini) and the bulk fluid temperature (Tb) were controlled to be 85–87 °F and 105–107 °F, respectively, throughout the experimental program. The initial Reynolds number (Reini) of tests conducted in rectangular (TS1) and circular (TS2) test sections was in the range of 400–4300 and 1000–5300, respectively. A high temperature gas chromatograph with flame ionization detector (HTGC-FID) and a differential scanning calorimeter (DSC) were used to analyze wax deposits. The results revealed that the 16 and 35% water cut tests yielded deposits containing only a trace amount of water (less than 2% w/w). The crossover behavior of the thickness versus time trends for different flow conditions was observed. The initial thickness growth rate increases with the flow rate. After the crossover period e...

Gastric electrical stimulation with Enterra therapy improves symptoms of idiopathic gastroparesis.

BackgroundGastric electrical stimulation (GES) is a therapeutic option for intractable symptoms of gastroparesis (GP). Idiopathic GP (ID-GP) represents a subset of GP. AIMS: A prospective, multicenter, double-blinded, randomized, crossover study to evaluate the safety and efficacy of Enterra GES in the treatment of chronic vomiting in ID-GP.MethodsThirty-two ID-GP subjects (mean age 39; 81% F, mean 7.7 years of GP) were implanted with GES. The stimulator was turned ON for 1½ months followed by double-blind randomization to consecutive 3-month crossover periods with the device either ON or OFF. ON stimulation was followed in unblinded fashion for another 4.5 months. Twenty-five subjects completed the crossover phase and 21 finished 1 year of follow-up.Key ResultsDuring the unblinded ON period, there was a reduction in weekly vomiting frequency (WVF) from baseline (61.2%, P < 0.001). There was a non-significant reduction in WVF between ON vs OFF periods (the primary outcome) with median reduction of 17% (P > 0.10). Seventy-five percent of patients preferred the ON vs OFF period (P = 0.021). At 1 year, WVF remained decreased (median reduction = 87%, P < 0.001), accompanied by improvements in GP symptoms, gastric emptying and days of hospitalization (P < 0.05).Conclusions & Inferences(i) In this prospective study of Enterra GES for ID-GP, there was a reduction in vomiting during the initial ON period; (ii) The double-blind 3-month periods showed a non-significant reduction in vomiting in the ON vs OFF period, the primary outcome variable; (iii) At 12 months with ON stimulation, there was a sustained decrease in vomiting and days of hospitalizations.

Evaluation of the Effects of Food on the Single‐Dose Pharmacokinetics of Trametinib, a First‐in‐Class MEK Inhibitor, in Patients with Cancer

The aim of this study was to estimate the effect of a high-fat, high-calorie meal on the single-dose pharmacokinetics (PK) of trametinib, a MEK inhibitor. The design of this 2 treatment, 2 period crossover, incomplete wash-out study was influenced by the subject population, long half-life and PK variability; 24 subjects were randomized to a single, oral 2 mg trametinib dose administered in a fed/fasted state, followed by 7 days of serial PK sampling. Period 2 PK parameters were adjusted based on residual Period 1 concentrations. Geometric least square mean ratios of fed:fasted were 0.30, 0.76, and 0.90 for corrected maximum concentration (C(max)), area under concentration-time curve from time 0 to last quantifiable sample (AUC(0-last)) and AUC from time 0 extrapolated to infinity (AUC(0-α)), respectively. Median half-life was 6.3 and 5.3 days for fed and fasted regimens, respectively. Uncorrected PK parameters were consistent with these results. Food delayed absorption and had a mean difference in time of maximum concentration (t(max)) of 3.9 hours. Both oral trametinib doses were well-tolerated. Single-dose trametinib administration with food decreased the rate and, to a lesser degree, the extent of absorption, supporting the recommendation to administer trametinib 1 hour before or 2 hours after a meal.

Comparison of Sleep Quality With Mechanical Versus Spontaneous Ventilation During Weaning of Critically Ill Tracheostomized Patients*

In mechanically ventilated patients under mechanical ventilation in the ICU, ventilatory mode or settings may influence sleep quality. The aim of this study was to evaluate the direct impact of mechanical ventilation per se on sleep quantity and quality in patients who were able to tolerate separation from mechanical ventilation over prolonged periods. Randomized crossover clinical trial in a medical ICU. Sixteen conscious patients, free of sedation and tracheostomized because of prolonged weaning from mechanical ventilation, were included in the study when able to tolerate at least 5 hours of spontaneous ventilation. Patients were randomized to receive either spontaneous ventilation or mechanical ventilation at low levels of pressure support for two crossover periods of 5-hour duration each, from 22:00 to 08:00. Polysomnography was performed throughout the study. Total sleep time was higher during mechanical ventilation than during spontaneous ventilation (183 min vs 132 min, p = 0.04). No significant differences between mechanical ventilation and spontaneous ventilation were observed in slow wave sleep time (45 min vs 28 min), rapid eye movement sleep time (11 min vs 3 min), or the fragmentation index (25 vs 23 arousals and awakenings per hr). In four patients, however, our analysis of patient-ventilator interaction suggested that the ventilatory settings were suboptimal and could have been improved to potentially improve sleep. In difficult-to-wean tracheostomized patients, sleep quality was similar with or without the ventilator. Sleep quantity was higher during mechanical ventilation. Reconnection to the ventilator during the night period may favor sleep efficiency in tracheostomized patients in prolonged weaning.

Alteration of fasting heat production during fescue toxicosis in Holstein steers

This study was designed to examine alteration of fasting heat production (FHP) during fescue toxicosis. Six ruminally cannulated Holstein steers (BW = 348 ± 13 kg) were BW-matched into pairs and used in a 2 period crossover design experiment. Each period consisted of 2 temperature segments, one each at 22 and 30°C. During each period, 1 steer per pair was ruminally dosed twice daily with 0.5 kg of ground endophyte-infected fescue seed (E+) and the other with ground endophyte-free fescue seed (E-) for 7 d. Steers on E- treatment were pair-fed to E+ steers offered alfalfa cubes at 1.5 × NEm. On d 8 of each segment, steers were moved to individual metabolism stalls fitted with indirect calorimetry head boxes. Ruminal contents were removed, weighed, and subsampled for DM determinations. The reticulorumen was washed and filled with a buffer (NaCl = 96; NaHCO3 = 24; KHCO3 = 30; K2HPO4 = 2; CaCl2 = 1.5; MgCl2 = 1.5 mmol·kg buffer(-1)) that was gassed with a 75% N2 and 25% CO2 mixture before rumen incubation. During buffer incubation, an E+ or E- fescue seed extract was added at 12 h intervals to maintain treatment presentation to the animal. After a 12-h wait, heart rate, O2 consumption, CO2 production, and urinary output were recorded for 16 h. There was no difference (P = 0.931) in DMI/kg(0.75) between endophyte treatments by design; however, intake decreased (P = 0.004) at 30°C. Increased temperature had no effect (P > 0.10) on other measurements and there were no significant interactions (P > 0.11) of temperature and endophyte treatment. Heart rate was unaffected by fescue treatment or environmental temperature. Percent DM of ruminal contents as well as total rumen DM/kg(0.75) was increased (P < 0.0001) in E+ steers. Respiratory quotient was elevated (P = 0.02) in E+ steers. Oxygen consumption decreased (P = 0.04) and CO2 production tended to be reduced (P = 0.07) during E+ treatment. Calculated FHP (kcal/kg BW(0.75)) was also less (P = 0.006) in steers receiving E+ treatment. These data suggest that consumption of endophyte-infected tall fescue by cattle results in a reduction in basal metabolic rate.

Measured comparison of contrast and crossover periods for passive millimeter-wave polarimetric imagery

Several targets are set-up outside and imaged by a passive millimeter-wave sensor over a 24 hour period. The sensor is capable of measuring two linear polarization states simultaneously and the contrasts of the targets are compared for the different polarizations. The choice of polarization is shown to have an impact on the contrast of different targets throughout the day. In an extreme case the contrast of a target experiences a crossover event and disappears for one polarization while it presents a strong contrast (9 K) with the other polarization. Experimental results are shown along with a simulation of the scene using a ray tracing program.

A Comparative Single Dose Bioequivalence Study of Extended Release Antihypertensive Drug Formulation among Healthy Human Volunteers

The objective of this study was to compare the in vivo characteristics of diltiazem extended release formulations for once daily, which were expected to be bioequivalent. Either two capsules of a test formulation or a 1 of the reference formulation, both containing 360 mg diltiazem were administered to healthy male volunteers after keeping fast of ten hour in a randomized, open label,three period crossover design. Plasma samples obtained over the subsequent period of 72 hours were analyzed using a validated LC-MS/MS method. Safety profile and tolerability of the study medications were assessed by analysis of adverse events obtained by vital sign measurements, electrocardiography, and clinical. The 90% CI for the log transformed data for Cmax, AUC0-t,AUC0-∞ for both the test product fell in the prescribed limits of bioequivalence for narrow therapeutics index drugs i.e. 80 to 120%. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in healthy, male volunteers under fasting.

The Safety and Efficacy of KAI-1678— An Inhibitor of Epsilon Protein Kinase C (εPKC)—Versus Lidocaine and Placebo for the Treatment of Postherpetic Neuralgia: A Crossover Study Design

Postherpetic neuralgia (PHN) occurs in approximately 10-20% of patients with herpes zoster, and the risk increases with age. In this clinical trial, we evaluated the analgesic properties of KAI-1678-an inhibitor of epsilon protein kinase C-in the treatment of neuropathic pain in patients with PHN. The study was a three-treatment period, double-blind, randomized, placebo and active comparator crossover trial evaluating subcutaneous infusions of KAI-1678 (25 mg), placebo, and lidocaine hydrochloride (700 mg; active comparator). A total of 17 men and 6 women (N = 23) were enrolled after fulfilling diagnosis of PHN with pain persisting for ≥3 months after a segmental herpes zoster eruption. Patients had to have a mean average pain score of ≥4 points on an 11-point numerical rating scale (NRS; ranging from 0 to 10) based on at least three daily entries prior to participation in the subsequent treatment period. Overall, administration of KAI-1678 was generally safe and well tolerated. However, compared with placebo, KAI-1678 did not improve clinical pain scores as recorded using the NRS (0-10). In contrast, subcutaneous infusions of lidocaine were associated with a significant reduction in pain intensity at the end of the infusion. We conclude that KAI-1678 is not efficacious as an acute analgesic for chronic neuropathic pain because of PHN. However, for the first time, the results demonstrate that subcutaneous infusions of lidocaine are effective in treating neuropathic pain. The results of lidocaine treatment also indicate that the crossover study design was adequate to detect a clinically meaningful response in this analgesia study.

Abstract 016: Effect of Dietary Carbohydrate (Amount and Type) on Risk Factors for Cardiovascular Disease and Diabetes: The OmniCarb Trial

Background: Foods that have similar carbohydrate content can differ in the amount they raise blood glucose. The effects of this property, called the glycemic index (GI), on risk factors for cardiovascular disease and diabetes, are not well understood, especially in the context of a healthful dietary pattern that itself improves risk factors. Aims: To study the effects of the amount of dietary carbohydrate (40% vs 58% energy) and GI (40% vs 65% on the glucose scale) on insulin sensitivity (determined by glucose and insulin levels during a 2 hour oral glucose tolerance test), systolic blood pressure (SBP), and fasting lipids (LDL-C, HDL-C, and TG) in non-diabetic, overweight adults with SBP 120 - 159 mmHg. Methods: We randomized 163 adults, mean age 53 y, in a 4 period crossover feeding study. The 4 diets, each studied for 5 weeks, were (1) higher-carbohydrate, higher-GI; (2) higher-carbohydrate, lower-GI; (3) lower-carbohydrate, higher-GI; and (4) lower-carbohydrate, lower-GI. All diets were based on a healthful DASH-type dietary pattern. At the end of each feeding period in a subsample of participants (N=51-57) we obtained hourly blood samples for glucose, insulin, and TG over 12 hours while participants ate the day’s meals in the research facility. Results: The four study diets did not significantly differentially affect insulin sensitivity, LDL-C, or SBP. The lower-carbohydrate or lower-GI diets increased HDL-C by about 4% (with between diet P-values &lt;0.016) and lowered TG by 20% (P&lt;0.031, compared to the higher-carbohydrate, higher-GI diet. Most of these effects were accounted for by lower amount of carbohydrate rather than lower GI. Similarly, the lower carbohydrate or lower GI diets lowered 12-hour blood glucose by an average of 20% (P&lt;0.031) compared to the higher carbohydrate, higher GI diet. The lower-carbohydrate, lower-GI diet reduced 12-hour serum insulin levels the most by 17% (P=0.032). Compared to levels measured when the participants were eating their own diets, all study diets lowered SBP by an average of 9 mm (7%) and LDL-C by 13 mg/dL (9%). Conclusions: In the context of healthful dietary patterns, varying the amount of carbohydrate or its GI in non-diabetic overweight adults does not affect fasting insulin sensitivity, SBP or LDL-C over 5 weeks. HDL-C and triglycerides improved on the lower carbohydrate diets but were not affected by GI. However, postprandial glycemia is reduced either by lowering GI or amount of carbohydrate, and hyperinsulinemia is reduced by the combination of low GI and low carbohydrate. We speculate that consistent associations in populations of reduced CVD event rates with lower intakes of carbohydrate and GI, if causal, result more from reduced postprandial glycemia and hyperinsulinemia than from lower BP and improved lipid risk factors.

Amino acids and energy utilization in zero-tannin faba bean and co-fermented wheat and corn dried distillers grains with solubles fed to growing pigs1

Application of alternative feedstuffs in swine diets will be dependent on characterization of their nutritive value. In 2 experiments, we determined the AA and energy utilization of Manitoba-grown zero-tannin faba beans (ZTFB) and co-fermented wheat and corn dried distillers grains with solubles (wcDDGS). Corn dried distillers grains with solubles (cDDGS) was also included for comparison. In Exp. 1, 6 ileal cannulated barrows (29.3 ± 1.3 kg) were fed 3 diets in a replicated 3 × 3 Latin square design to determine the apparent (AID) and standardized (SID) ileal digestibility of AA. The 3 diets contained ZTFB, wcDDGS, or cDDGS as the sole source of AA. The SID of N and AA were calculated using published values for ileal endogenous N and AA losses from our laboratory. In Exp. 2, 12 intact barrows (22.5 ± 1.1 kg) were fed 4 diets in a two 15-d period crossover design to determine DE and ME contents of the test ingredients by difference method. The diets were a basal corn-based diet or the basal diet with corn replaced by 46% ZTFB, wcDDGS, or cDDGS. The concentrations (DM basis) of GE (kcal/kg), CP (%), and Lys (%) in ZTFB were 4,144, 27, and 1.6, respectively, and corresponding values for wcDDGS were 5,112, 31, and 0.8. The ZTFB had greater (P < 0.05) SID of Lys (87%) compared with wcDDGS (72%) and cDDGS (68%); as a result, the SID content (g/kg DM) of Lys in ZTFB (13.5) was greater (P < 0.05) than that of either wcDGGS (6.03) or cDDGS (6.68). The dried distillers grains with solubles (DDGS) samples had greater (P < 0.05) SID and contents of sulfur AA (Met and Cys) compared with ZTFB. The ME content (kcal/kg DM) of ZTFB (3,548) was less (P < 0.05) than that of cDDGS (3,851) whereas the ME content of wcDDGS (3,669) was similar to that of ZTFB or cDDGS. The results showed that ZTFB has greater digestible Lys whereas wcDDGS has greater digestible sulfur AA but both ingredients have comparable ME content. Therefore, a blend of these 2 ingredients can serve as an excellent source of AA and energy for swine.

Pharmacodynamics, pharmacokinetics and safety of GSK2190915, a novel oral anti‐inflammatory 5‐lipoxygenase‐activating protein inhibitor

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5-lipoxygenase-activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations. Western European subjects received single (50-1000 mg) or multiple (10-450 mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10-200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B₄ and leukotriene E₄, respectively, as pharmacodynamic markers of drug activity. There was no clear difference in adverse events between placebo and active drug-treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose-related manner and mean half-life values ranged from 16-34 h. Dose-dependent inhibition of blood leukotriene B₄ production was observed and near complete inhibition of urinary leukotriene E₄ excretion was shown at all doses except the lowest dose. The EC₅₀ values for inhibition of LTB₄ were 85 nM and 89 nM in the Western European and Japanese studies, respectively. GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E₄ at 24 h post-dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB₄.

In vivo determination of rumen undegradable protein of dried distillers grains with solubles and evaluation of duodenal microbial crude protein flow

The objectives of this trial were to determine the rumen undegradable protein (RUP) of dried distillers grains with solubles (DDGS), to compare the estimates of duodenal bacterial CP (BCP) flow using diaminopumelic acid (DAPA) or DNA as bacterial markers, and to estimate duodenal protozoal CP (PCP) and yeast CP (YCP) flow when DDGS are fed. Three crossbred steers fitted with ruminal and double L-shaped duodenal cannulae (average BW 780 ± 137 kg) were used in a 3 treatment, 6 period crossover design. Animals were housed in individual free stalls and fed twice daily at 0700 and 1900 h. Diets (DM basis) were 1) CONTROL, which is 0% DDGS but with 19.5% corn bran, 20% sorghum silage, 60% brome hay, 0.5% trace minerals, and 0.25% urea, 2) LOW DDGS, which is inclusion of 9.75% DDGS replacing equal percentage of corn bran, and 3) HIGH DDGS, which is inclusion of 19.5% DDGS completely replacing corn bran. Duodenal BCP flow was estimated using DAPA and DNA as bacterial markers. In addition, duodenal PCP and YCP flow were estimated using DNA markers. The value of DDGS RUP as a percent of CP was determined to be 63.0 ± 0.64%. Estimates of duodenal BCP flow using DAPA were 473, 393, and 357 ± 78 g/d (P = 0.09) for CONTROL, LOW DDGS, and HIGH DDGS, respectively. Estimates of duodenal BCP flow using DNA were 479, 397, and 368 ± 74 g/d (P = 0.14), respectively. Average BCP flow across treatments was unaffected (P = 0.71) by marker type and were 404 and 417 ± 83 g/d for DAPA and DNA markers, respectively. Estimates of duodenal PCP flow were 82, 80, and 78 ± 12 g/d (P = 0.64) for CONTROL, LOW DDGS, and HIGH DDGS, respectively. Estimates of duodenal YCP flow were 0.15, 1.94, and 4.80 ± 0.66 g/d (P < 0.01) for CONTROL, LOW DDGS, and HIGH DDGS, respectively. Duodenal BCP flow tended to decrease with DDGS inclusion, but estimates were not affected by marker type. In addition, DDGS did not affect duodenal PCP supply and provided small amounts of duodenal YCP. Overall, the value of DDGS RUP determined in this study will contribute to a better understanding of the effect of this coproduct in ruminant nutrition.

Olive Leaf Extract as a New Topical Management for Oral Mucositis Following Chemotherapy: A Microbiological Examination, Experimental Animal Study and Clinical Trial

Oral mucositis is a common complication of intensive cancer chemotherapy and radiotherapy. Olive leaf extract was investigated through microbiological, experimental animal studies and clinical trial. The results were compared with the action of benzydamine HCl as positive control and normal saline as negative control. Thirty patients under intensive chemotherapeutic treatment were included in the microbiological part of the study for assessment of the oral flora changes, and the antimicrobial activity of olive leaf and benzydamine HCl against preisolated microoganisms were studied. Oral mucositis was induced through a combination of systemic administration of 5-fluorouracil as chemotherapeutic agent and mild abrasion of the left buccal mucosa of Forty-five male albino rats. An evaluation of the healed buccal mucosa was performed histologically under light microscope at days 7, 9 and 14 of the experiments. In the clinical part of the study, 62 cancer patients receiving intensive chemotherapy were randomized to receive olive leaf extract, benzydamine HCl or placebo local treatment for two weeks in a three period crossover design. WHO toxicity grading and OMAS mucositis score were applied at days 1, 8 and 15 of each cycle. In Conclusion; olive leaf extract was effective in reducing the incidence and decreasing the severity of oral mucositis when compared to benzydamine HCl and placebo groups. Accordingly we suggest using this medication for oral mucositis as a safe (herbal) and effective treatment modality

Comparation of Bioavailability: Two Dexlansoprazole Formulations in Beagle Dogs after a Single Dose Administration

The study was performed to determine oral bioequivalence of generic dexlansoprazole and reference formulation (Dexilant) in healthy dogs. A 2 period crossover balanced design was used with a 7 days washout period between the doses. Dexlansoprazole was analyzed by LC-MS/MS in the presence of omeprazole as internal standard. The mean ratio of parameters Cmax and AUC0-t and 90% confidence intervals of correspondents were calculated to determine the bioequivalence. The means AUC0-t for test and reference formulation were 4094.5 ug/L*h and 3684.9 ug/L*h, for AUC0-∞ were 4137.5 ug/L*h and 3709.6 ug/L*h and, for Cmax 1643.0 ug/L and 1498.2 ug/L, respectively. Geometric mean of the test /reference Pharmaceuticals 30 mg formulation individual percent ratio was 99.3% for AUC0-t, 100.6% for AUC0-∞ and 110.0% for Cmax. The 90% confidence intervals were 84.0% ~ 117.5%, 85.3% ~ 118.7%, 85.0% ~ 142.3%, respectively. It was concluded that pharmacokinetic data for test formulation were similar enough to original innovator, both formulations had the delayed releasing and double peak characteristics in dogs according to the rate and extent of absorption.

A randomized, double‐blind, crossover, placebo‐controlled comparative clinical trial of arginine aspartate plus adenosine monophosphate for the intermittent treatment of male erectile dysfunction

Efficacy and safety of l-arginine aspartate 8 g combined with 200 mg of adenosine monophosphate (AA) with placebo (PL) alone for intermittent treatment of mild-to-moderate erectile dysfunction (ED) were compared. The study design was a double-blind, PL-controlled, two-way crossover randomized clinical trial with 26 patients. Efficacy was assessed by International Index of Erectile Function (IIEF) and two additional validated questionnaires [the Erection Hardness Score (EHS) and the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS). During each crossover period, separated by a 2-week wash-out period, drugs were administered orally, 1-2 h before sexual intercourse. Primary endpoint was a change in the IIEF. Secondary endpoints were patient and investigator assessments of treatment success. Investigators' and patients' assessment of efficacy was significantly improved by the combination vs. PL (p = 0.01 and p = 0.04 respectively]. EHS and EDITS questionnaires were both improved by the combination (p = 0.015 and p = 0.017 respectively). There was no significant difference in terms of tolerance between AA and PL or severe adverse events. ED patients demonstrated significant improvements in all IIEF domains with the exception of the Sexual Desire and Orgasmic Domains when treated with AA compared with PL. This pilot phase II study showed that the on-demand oral administration at a high dosage of l-arginine aspartate-adenosine monophosphate combination may be effective in patients with mild-to-moderate ED, is very well tolerated and could be tested as a safe first-line therapy in a larger size phase III study.

Orexin receptor antagonism for treatment of insomnia

To assess the utility of orexin receptor antagonism as a novel approach to treating insomnia. We evaluated suvorexant, an orexin receptor antagonist, for treating patients with primary insomnia in a randomized, double-blind, placebo-controlled, 2-period (4 weeks per period) crossover polysomnography study. Patients received suvorexant (10 mg [n = 62], 20 mg [n = 61], 40 mg [n = 59], or 80 mg [n = 61]) in one period and placebo (n = 249) in the other. Polysomnography was performed on night 1 and at the end of week 4 of each period. The coprimary efficacy end points were sleep efficiency on night 1 and end of week 4. Secondary end points were wake after sleep onset and latency to persistent sleep. Suvorexant showed significant (p values <0.01) dose-related improvements vs placebo on the coprimary end points of sleep efficiency at night 1 and end of week 4. Dose-related effects were also observed for sleep induction (latency to persistent sleep) and maintenance (wake after sleep onset). Suvorexant was generally well tolerated. The data suggest that orexin receptor antagonism offers a novel approach to treating insomnia. This study provides Class I evidence that suvorexant improves sleep efficiency over 4 weeks in nonelderly adult patients with primary insomnia.

Heated and Humidified High-Flow Oxygen Therapy Reduces Discomfort During Hypoxemic Respiratory Failure

Non-intubated critically ill patients are often treated by high-flow oxygen for acute respiratory failure. There is no current recommendation for humidification of oxygen devices. We conducted a prospective randomized trial with a final crossover period to compare nasal airway caliber and respiratory comfort in patients with acute hypoxemic respiratory failure receiving either standard oxygen therapy with no humidification or heated and humidified high-flow oxygen therapy (HHFO₂) in a medical ICU. Nasal airway caliber was measured using acoustic rhinometry at baseline, after 4 and 24 hours (H4 and H24), and 4 hours after crossover (H28). Dryness of the nose, mouth, and throat was auto-evaluated and assessed blindly by an otorhinolaryngologist. After the crossover, the subjects were asked which system they preferred. Thirty subjects completed the protocol and were analyzed. Baseline median oxygen flow was 9 and 12 L/min in the standard and HHFO₂ groups, respectively (P = .21). Acoustic rhinometry measurements showed no difference between the 2 systems. The dryness score was significantly lower in the HHFO₂ group at H4 (2 vs 6, P = .007) and H24 (0 vs 8, P = .004). During the crossover period, dryness increased promptly after switching to standard oxygen and decreased after switching to HHFO₂ (P = .008). Sixteen subjects (53%) preferred HHFO₂ (P = .01), especially those who required the highest flow of oxygen at admission (P = .05). Upper airway caliber was not significantly modified by HHFO₂, compared to standard oxygen therapy, but HHFO₂ significantly reduced discomfort in critically ill patients with respiratory failure. The system is usually preferred over standard oxygen therapy.

CALGB 170601: A phase III double blind trial of duloxetine to treat painful chemotherapy-induced peripheral neuropathy (CIPN).

CRA9013 Background: CALGB 170601 was a randomized, placebo-controlled phase III trial to determine whether duloxetine reduces painful chemotherapy-induced peripheral neuropathy (CIPN). The secondary study endpoint was treatment-related adverse events. Methods: The study used a double-blinded placebo-controlled crossover design with equally weighted randomization to one of two arms. Arm A participants received duloxetine followed by placebo. Arm B participants received placebo followed by duloxetine. The initial and crossover periods each consisted of six weeks of drug/placebo followed by one week of washout. Randomization was stratified by neurotoxic agent and high risk for developing painful CIPN. Eligible patients were 18 years or older with an average CIPN pain score &gt; 4/10 attributed to prior single agent taxane or platinum treatment. Participants took one capsule daily (30mg) for one week, and then two capsules (60mg) daily for four additional weeks. Participants completed the Brief Pain Inventory-Short Form (BPI-SF) at baseline and then weekly. The primary study endpoint was the change in BPI-SF scores within the initial treatment period. Analysis of covariance with an intent-to-treat approach was used to test the effect of treatment on change in pain score. Results: The target accrual goal (N = 231) was met, of which 185 (80%) completed the initial treatment period. Oxaliplatin was the most commonly received neurotoxic agent (59%). Individuals receiving duloxetine over the initial treatment period had a larger average decrease in pain score (mean change score = -1.09; S.E. = 0.19) than those receiving placebo (mean change score = -0.33; S.E. = 0.18) (p = 0.004). There was no difference in duloxetine efficacy based on the specific neurotoxic agent received. Severe (Grade 3) non-hematologic toxicity was reported by 11%, and 41% reported moderate (Grade 2) toxicities. The incidence of Grade 2+ fatigue, the most commonly reported side effect, was significantly higher in the duloxetine arm as compared to placebo (11% vs. 3%, p = 0.029). Conclusions: Duloxetine 60mg daily is an efficacious and well-tolerated intervention for the treatment of taxane or platinum-related painful CIPN.