Oral Tolerability Research Articles

Randomized Controlled Clinical Study to Determine the Oral and Dermal Tolerability of an Experimental Denture Wipe.

PurposeTo evaluate oral and dermal tolerance following use and user acceptability of an experimental denture‐cleansing wipe. An exploratory objective was to develop a method to assess denture wipe effectiveness in removing debris from denture surfaces.Materials and MethodsThis was a single‐center, randomized, controlled, parallel‐group, examiner‐blind study in participants with ≥1 full/partial denture. Participants were randomized to clean their dentures with the denture wipe (n = 76) or water (n = 76) up to 4 times per day for 14 days. Tolerability was assessed by treatment‐emergent adverse events (TEAEs), oral soft tissue examination, and lead hand dermatological assessment. Acceptability was assessed by questionnaire. The feasibility of a methodology to assess the efficacy of the wipe at removing food particles was also evaluated through determination of the mass of chewed peanut particles that the wipe removed after a single use (n = 31).ResultsThe proportion of participants experiencing oral TEAEs by day 14 was 0.039% with the denture wipe (lip injury [n = 1], mouth injury [n = 2]) and 0.013% with the water rinse (coated tongue [n = 1]). There were no dermal TEAEs and no TEAE‐related study withdrawals. Skin irritation scores with the denture wipe remained unchanged from baseline. Comparing before vs. after cleaning with the denture wipe, a higher proportion of participants rated their dentures as feeling extremely/very fresh (28.9% pre‐/85.5% post‐cleaning), feeling extremely/very clean (34.2%/86.8%) and looking extremely/very clean (43.5%/85.5%). More denture‐wipe group participants than water‐rinse group participants were extremely/very satisfied with the amount of debris removed from their dentures (88.1% vs 72.4%). The methodology used to assess the weight of peanut particles captured from the wipes/dentures appeared to be a feasible investigation technique.ConclusionsThe denture wipe was generally well‐tolerated and had good user acceptability. The methodology for assessing the mass of peanut particles removed by denture wipes was successful.

Fetus delivery time in extraperitoneal versus transperitoneal cesarean section: a randomized trial

Objective: We compared the extraperitoneal cesarean section to transperitoneal cesarean on fetal delivery time.Material and methods: This randomized study included 210 pregnant women undergoing cesarean section for elective reasons, repeat cesarean (< four), or dystocia. Patients who required an urgent cesarean section, who were at high risk for obstetric or maternal bleeding, who had a uterine or adnexal mass, or who requested tubal ligation were excluded from the study. The primary outcome of the study was the skin incision-to-delivery time. The sample size was set to detect of 1-minute difference in fetal delivery time between groups (two-tailed hypothesis, α = 0.05, β = 0.10). Secondary outcome measures were total operation time, intraoperative nausea, gag reflex, vomiting, pain and anxiety for those receiving regional anesthesia, postoperative pain, change in hemoglobin, postoperative analgesic requirements, nausea, vomiting and shoulder pain, urogenital distress, time until gas passage, and neonatal outcome.Results: No significant difference occurred between the two groups for skin incision-to- delivery time (extraperitoneal cesarean 3.9 minutes [2.1–7.3] versus transperitoneal cesarean 4.2 minutes [1.9–8.2], p = .065). Significant differences regarding intraoperative pain, total operation time, postoperative pain at the surgical site and shoulder pain, analgesic requirements, time until gas passage, and oral tolerability favored the extraperitoneal group. No significant differences between groups occurred regarding other seconder outcome parameters.Conclusions: There is no clinically significant difference between extraperitoneal cesarean section and transperitoneal cesarean on fetal delivery time. Extraperitoneal cesarean reduces postoperative pain, analgesic requirements, and improves oral tolerability.

Initiating/maintaining long-acting injectable antipsychotics in schizophrenia/schizoaffective or bipolar disorder - expert consensus survey part 2.

ObjectiveThe aim of this study was to provide recommendations on initiating and maintaining long-acting injectable antipsychotics (LAIs) in individuals with schizophrenia/schizoaffective or bipolar disorder.MethodsA 50-question survey comprising 916 response options was completed by 34 expert researchers and high prescribers with extensive LAI experience, rating relative appropriateness/importance on a 9-point scale. Consensus was determined using chi-square test of score distributions. Results of 21 questions comprising 339 response options regarding LAI initiation, maintenance treatment, adequate trial definition, identifying treatment nonresponse, and switching are reported.ResultsExperts agreed that the most important LAI selection factor was patient response/tolerability to previous antipsychotics. An adequate therapeutic LAI trial was defined as the time to steady state ± 1–2 injection cycles. Experts suggested that oral efficacy and tolerability should be established before switching to an LAI, without consensus on the required time, and that the time for oral supplementation and next injection interval should be determined by the time to attainment of therapeutic LAI levels. Most experts agreed that ≥1 adequate LAI trial is needed to identify the lack of efficacy. There was little agreement about strategies for switching between LAIs.ConclusionExpert guidance may aid clinicians in their decisions regarding initiating/maintaining LAIs in individuals with schizophrenia/schizoaffective or bipolar disorder.

Palatability and oral cavity tolerability of THC:CBD oromucosal spray and possible improvement measures in multiple sclerosis patients with resistant spasticity: a pilot study.

Complaints about Δ9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex®; GW Pharma Ltd, Salisbury, UK) in the management of multiple sclerosis spasticity include unpleasant taste and oral mucosal anomalies. This pilot study assessed the use of sugar-free chewing gum and/or a refrigerated bottle of THC:CBD oromucosal spray to mitigate these effects. Patients with multiple sclerosis spasticity (n=52) at six sites in Italy who were receiving THC:CBD oromucosal spray and had associated oral mucosal effects were randomized into Group A (chewing gum; n=15); Group B (cold bottle; n=20); and Group C (cold bottle+chewing gum; n=17). Taste perception in patients receiving chewing gum±cold bottle intervention (Groups A and C combined) was significantly (p=0.0001) improved from baseline to week 4 while maintaining spasticity control. Patient comfort, satisfaction and treatment adherence may benefit from these interventions.

Safety and efficacy of abiraterone acetate (AA) in patients aged 75 or more with metastatic castration-resistant prostate cancer (mCRPC) in both pre-chemotherapy or post-chemotherapy settings: Real-life experience from thirteen Italian centers.

209 Background: Prostate cancer affects mainly elderly patients (pts) that have different comorbidities. AA is a selective androgen synthesis inhibitor that showed the efficacy in either chemotherapy (CT) naive pts or those pretreated with docetaxel. Its oral administration and good tolerability make it a manegeable treatment for elderly mCRPC pts. Methods: We collected retrospectively data regarding mCRPC pts aged ≥75 years treated with AA in 13 Italian Centers since April 2013. The median age was 79 years (r. 75-90) with 48% of pts being octagerians. Post CT pts had more extensive disease, higher baseline PSA and ECOG PS. Nearly all the pts had comorbidities, the most frequent being hypertension present in 146 pts (58%), 43 pts (17%) had diabetes type II. We evaluated duration of the AA treatment, overall response rate (ORR), 50% PSA decline, time to progression (TTP) and overall survival (OS). We reported all toxicities observed. Results: A total of 252 pts ,147 pre treated with docetaxel and 105 chemo naive, were included. Median duration of treatment with AA was 8,6 months in post CT and 11,5 in CT naive pts. ORR was 35,3% in pre docetaxel and 27,4% in post docetaxel group. 64 pts (65%) and 51 pts (46%) obtained 50% PSA reduction in pre and post docetaxel group, respectively. Median TTP was 8,6 in post docetaxel and 11,9 in CT naive pts. We observed a median OS of 13,8 months in post CT group while for CT naive pts data were not yet mature. AA was well tolerated with only 8 pts (3,2%) who discontinued treatment due to toxicity, while in 4 pts (1,6%) temporary dose reductions were performed. The most frequent G3 toxicities were hypertension and liver toxicity with 4 pts (1,6%) and 5 pts (2%), respectively. After progressing on AA, 85 pts (34%) received at least one subsequent treatment. 40 pts (15,9%) are still on treatment with AA. Conclusions: Even if almost all the pts reported comorbidities at AA start and 72 pts (28,6%) had PS ECOG 2, only a small proportion of them discontinued the treatment due to toxicity confirming that AA is well tolerated and efficient treatment also for elderly patients.

A new promising candidate to overcome drug resistant herpes simplex virus infections

Infections with Herpes simplex viruses (HSV) belong to the most common human diseases worldwide, resulting in symptoms ranging from painful, but commonly self-limiting lesions of the orofacial or genital tract to severe infections of the eye or life-threatening generalized infections. Frequent HSV-reactivations at the eye may lead to the development of herpetic stromal keratitis, which is one of the major causes of infectious blindness in developed countries. The vast majority of life-threatening generalized infections occur in immunocompromised individuals, such as transplant recipients or patients suffering from advanced human immunodeficiency virus (HIV) infection with concurrent HSV-reactivation. Over the past decades, Acyclovir (ACV) became the golden standard for the treatment of HSV infections. However, long-term antiviral treatment, as it is required mainly in immunocompromised patients, led to the emergence of resistances towards ACV and other antivirals. Therefore, there is a clear need for the development of new potent antivirals which combine good oral bioavailability and tolerability with low side effects. In the current study we present SC93305 as a novel potent antiviral substance that proved to be highly effective not only against different HSV-1 and HSV-2 strains but also towards ACV- and multi-resistant HSV-1 and HSV-2 isolates. SC93305 shows comparable antiviral activity as reported for ACV and very importantly it does not interfere with the activation of specific immune cells. Here we report that SC93305 does not affect the biological function of dendritic cells (DC), the most potent antigen presenting cells of the immune system to induce antiviral immune responses, nor T cell stimulation or the release of inflammatory cytokines. Thus, SC93305 is a new and promising candidate for the treatment of HSV-1 and HSV-2 infections and in particular also for the inhibition of drug-resistant HSV-1/2 strains.

Novel pH responsive supramolecular hydrogels of chitosan hydrochloride and polyoxometalate: In-vitro, in-vivo and preliminary safety evaluation

In the current study, electrostatically-driven pH responsive, supramolecular hydrogels of the trilacunary Wells-Dawson-type 15-tungsto-2-phosphate polyanion (P2W15) and chitosan hydrochloride (ChCl) were prepared, using methacrylic acid as pH responsive agent using benzoyl peroxide (BPO) as initiator. The prepared hydrogels were characterized by FT-IR, SEM, XRD and thermal analyses (TGA-DSC). The swelling and pH based P2W15 release profile of the hydrogels showed maximum swellability and release at pH 7.4. Different mathematical models were applied, showing that P2W15 release followed supercase transport-II mechanism and zero-order kinetics. The cytotoxicity results showed that free and embedded P2W15 exhibited dose-dependent cytotoxicity against cancer cell lines (MCF-7; HeLa) with minimal effects on normal cells (Vero). The developed hydrogels were administered to the rabbits for determining the pharmacokinetic behavior of the polyanion. Moreover, the developed hydrogel system as well as polyanion concentration used were also checked for its oral tolerability and safety evaluation in rabbits. The histopathological studies, serum chemistry (except blood glucose level) and hematological investigations exhibited that administered hydrogel suspension at maximal tolerable dose (4000mg/kg body weight) and polyanion concentration used (20mg) were safe from in-vivo point of view. The developed hydrogels exhibited desirable qualities of a drug delivery system that can be used for the delivery of the embedded polyanion.

Kerion Type of Tinea Capitis Treated with Double Pulse Dose Terbinafine

Objective: Tinea capitis is a common dermatophyte infection affecting hair and skin which always requires systemic treatment to get a clinical and mycologic cure, preventing relapse, and infection spread. Griseofulvin has been the antifungal therapy of choice for tinea capitis, but it often requires higher doses and a longer duration than recommended. Thus, effective alternative antifungal with good oral tolerability and shorter course of treatment are therefore required. The objective of this report is to evaluate the effectiveness of double pulse dose terbinafine for tinea capitis alternative therapy.Method: A case of kerion type of tinea capitis in a two-year-old girl was reported. Diagnosis was established based on clinical manifestations of alopecia, presented as erythematous macule with pustules, hemorrhagic crusts, and scales on the scalp, accompanied with occipital lymphadenopathy. Fungal culture showed growth of Microsporum canis (M. canis) colonies. Patient was treated with doubled pulse dose terbinafine 125 mg/day and 2% ketoconazole shampoo for two months.Result: Clinical improvements were found on 35th day of follow up, while mycologic cure was achieved on 60th day of follow up. Tolerability was excellent and no side effects observed.Conclusion: Double pulse dose terbinafine is effective for kerion type of tinea capitis. Key words: double pulse dose, kerion, M. canis, terbinafine, tinea capitis

PHASE 1 DEVELOPMENT OF ALZ-801, A NOVEL BETA AMYLOID ANTI-AGGREGATION PRODRUG OF TRAMIPROSATE WITH IMPROVED DRUG PROPERTIES, SUPPORTING BRIDGING TO THE PHASE 3 PROGRAM

ALZ-801 is a novel, orally bioavailable, small-molecule prodrug of tramiprosate with improved pharmacokinetics and oral tolerability. The initial tramiprosate Phase 3 program in mild-to-moderate Alzheimer’s disease (AD) included two studies with >2,000 patients but did not show significant separation on co-primary outcomes. In these studies, ∼60% of patients were carriers of the e4 allele of the apolipoprotein E gene (APOE4), and ∼14% were homozygous for APOE4. A subgroup intention-to-treat analysis of APOE4/4 patients showed that tramiprosate 150mg BID produced a significant and clinically meaningful improvement on cognition (ADAS-cog), and a positive trend on function (CDR-SB), at 65 and 78 weeks, on top of standard of care symptomatic therapy. Tramiprosate also showed a favorable safety profile: the most common AE was nausea. Safety data from Phase 3 tramiprosate studies support bridging to the ALZ-801 safety database, based on bioequivalence. To advance the clinical development of ALZ-801 into Phase 3, we have completed single dose and 14-day multiple ascending dose Phase 1 bridging studies in healthy elderly volunteers to evaluate safety, tolerability and pharmacokinetics. Compared with oral tramiprosate, oral ALZ-801 delivered an equivalent plasma exposure of tramiprosate with over 50% lower inter-subject variability. Oral ALZ-801 also prolonged plasma tramiprosate terminal half-life to ∼24 hours. Administration of ALZ-801 with food markedly reduced the incidence of GI symptoms as compared to the fasted state, while maintaining plasma tramiprosate exposure. An immediate release tablet formulation of ALZ-801 was developed, which displayed exposure and low variability similar to the loose filled capsule formulation. ALZ-801 also showed excellent dose proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on the single and multiple dose pharmacokinetics of ALZ-801, the steady-state plasma exposure of the active drug tramiprosate following oral BID dosing of ALZ-801 immediate release tablet has been determined. The data indicate that 265mg BID of ALZ-801 will achieve a steady-state tramiprosate exposure that is equivalent to 150mg BID of oral tramiprosate. These bridging data will support the Phase 3 development of ALZ-801, an optimized prodrug of tramiprosate with improved GI toleration and low inter-subject pharmacokinetic variability, in APOE4/4 homozygous AD subjects.

Gelucire and Gelucire-PEG400 formulations; tolerability in species used for non-clinical safety testing after oral (gavage) dosing.

The selection of a vehicle for oral formulations of compounds to be used in non-clinical safety studies is a challenge for poorly soluble compounds. Typically a compromise between solubility and tolerability has to be reached. Vehicle tolerability data are not readily available for a number of vehicles, and a series of oral tolerability studies were, therefore, conducted with Gelucire and Gelucire:PEG400 formulations in rats, dogs and minipigs in order to determine tolerable daily dose volumes in these species. Gelucire and Gelucire:PEG400 formulations were assessed in studies for up to 5 days in minipigs, 7 days in rats and up to 39 weeks in dogs. Gastrointestinal side effects in terms of soft and/or liquid faeces were noted in all species, but the sensitivity to these effects differed between species with the dog being the most sensitive. It was concluded that Gelucire:PEG400 (90:10) was tolerated in Beagle dogs when administered at 1 ml kg(-1) once daily for 39 weeks, and 100% Gelucire was tolerated in the rat and the minipig when administered once daily at 5 ml kg(-1) for 5 days. Copyright © 2016 John Wiley & Sons, Ltd.

The Efficacy of AR101, a Peanut-Derived Pharmaceutical for Oral Immunotherapy (OIT), Is Maintained and Tolerability Is Increased with Low-Dose Maintenance Therapy

The Efficacy of AR101, a Peanut-Derived Pharmaceutical for Oral Immunotherapy (OIT), Is Maintained and Tolerability Is Increased with Low-Dose Maintenance Therapy

Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age

PurposeThe objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. MethodsThe first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. FindingsDelafloxacin Cmax and AUC0–∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0–∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0–∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in the creatinine clearance in the elderly men and women. Delafloxacin was well tolerated at the tested doses, with gastrointestinal adverse effects observed more commonly at doses ≥1200 mg. ImplicationsDelafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (≥1200 mg).

Abstract 4514: PQR309: A potent, brain-penetrant, dual pan-PI3K/mTOR inhibitor with excellent oral bioavailability and tolerability

Abstract The phosphatidylinositol 3-kinase (PI3K) signaling pathway is frequently activated in tumors and promotes oncogenic cell transformation, proliferation and tumor growth. PQR309, a novel dual inhibitor of PI3K and mTOR, is currently in Phase I clinical development in cancer patients. PQR309 binds potently and specifically to the ATP binding pocket of all PI3K class I isoforms and mTORC1/2, attenuates PI3K signaling and inhibits tumor cell growth. The preclinical pharmacological and toxicological characterization of PQR309 is presented here. Methods: PQR309 pharmacokinetics/-dynamics (PK/PD) were investigated in rats and mice. Tissue samples from plasma, brain and liver were analyzed by LC/MS detecting PQR309 distribution as well as blood insulin and glucose. Toxicological studies were performed in rats and dogs. Effects on neurological, hematopoietic, respiratory, lymphoid, reproductive and cardiovascular system as well as general health were monitored. The metabolic fate of PQR309 was analyzed in rat, dog and human hepatocytes. Results: PQR309 PK studies in rats, mice and dogs revealed dose-proportional PK, both PO and IV, with a half-life of 5-8 hours in plasma, brain and liver, allowing for once a day oral application. As on-target effect, increase of blood insulin and glucose could be observed within hours after oral dosage in rats, which makes both molecules suitable as PD markers. In in vivo PC-3 rat tumor xenograft models, PQR309 effectively inhibited PI3K signaling in tumors and reduced tumor growth at 10 mg/kg oral dosing. Preclinical toxicity testing showed no signs of cardiotoxicity (including lack of hERG binding), phototoxicity (3T3 NRU test) or mutagenicity (AMES test) for PQR309. No marked effect on CYP450 activity was observed making PQR309 a good combination partner in cancer therapy. As for other PI3K inhibitors, PQR309 leads at elevated doses to a fully reversible loss of body weight and appetite in rats and dogs. No further significant adverse events were observed when testing PQR309 for 28 days in these species. Conclusions: PQR309 potently inhibits class I PI3K isoforms and mTORC1/2 and shows anti-tumor effects in vitro and in vivo. The physico-chemical properties of PQR309 result in good oral bioavailability and equal distribution between plasma and brain. Pre-clinical data led to initiation of a Phase I clinical study of PQR309 in solid tumors. Citation Format: Vladimir Cmiljanovic, Robert A. Ettlin, Florent Beaufils, Walter Dieterle, Petra Hillmann, Juergen Mestan, Anna Melone, Thomas Bohnacker, Marc Lang, Natasa Cmiljanovic, Bernd Giese, Paul Hebeisen, Matthias P. Wymann, Doriano Fabbro. PQR309: A potent, brain-penetrant, dual pan-PI3K/mTOR inhibitor with excellent oral bioavailability and tolerability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4514. doi:10.1158/1538-7445.AM2015-4514

Single- and Multiple-dose Pharmacokinetics of Samidorphan, A Novel Opioid Antagonist, in Healthy Volunteers

PurposeSamidorphan (3-carboxamido-4-hydroxy naltrexone) is a novel opioid receptor antagonist that is currently in clinical development. The oral dose pharmacokinetics, safety, and tolerability of samidorphan were evaluated in 2 double-blind, placebo-controlled, randomized studies in healthy adults. MethodsThe first study investigated single, ascending doses of 3.7 to 55.7 mg of samidorphan in 16 healthy adults; the second study evaluated multiple ascending doses of 10 or 20 mg of samidorphan administered for 7 days in 30 healthy adults. FindingsAcross the two studies, 39 of 46 subjects were male; 32 were white, 11 were black, and 3 were hispanic. Mean age was 34.9 years and mean weight was 84.2 kg. In both studies, samidorphan was rapidly absorbed, with a Tmax of 1 hour, and AUC increased with increasing dose. Samidorphan plasma levels declined in a monoexponential manner, with a half-life of ~7 to 9 hours. After multiple doses, steady state was approached by day 6 and achieved by day 7 after the 10-mg dose, but steady state was not reached for the 20-mg dose. Accumulation was low, with accumulation ratios <1.65. In both studies, samidorphan was generally well tolerated, with somnolence reported as the most common adverse event. ImplicationsIn these single- and multiple-dose studies in healthy volunteers, samidorphan exhibited a pharmacokinetic profile consistent with once-daily dosing.ClinicalTrials.gov identifier: NCT00800319.

Prophylaxis with levofloxacin: bacterial infections and antimicrobial resistance in hematological malignancies.

Studies evaluating bacterial prophylaxis of patients under high risk for the development of febrile neutropenia have been published since the 1980s.1-3 Initially, trimethoprim with sulfamethoxazole was used, but this is associated with an unacceptable risk of myelosuppression. Thus, fluoroquinolones became the treatment of choice worldwide, due to their good oral tolerability, broad antimicrobial spectrum, bactericidal activity, ability to preserve anaerobic gut microorganisms, and lack of myelotoxicity. Ciprofloxacin was initially used in this scenario, but the need to treat Streptococcus viridans led to a progressive trend to prescribing levofloxacin due to its better activity against this microorganism.4 Recent studies suggest that antibacterial prophylaxis with levofloxacin should be started when a neutropenia episode, secondary to chemotherapy, is expected. Decreasing rates of febrile neutropenic episodes and even all-cause mortality have been correlated with this approach.3,5,6 However, two aspects of this widely practiced procedure remain controversial and under discussion. First, it appears that the greatest benefit of antibiotic prophylaxis is restricted to patients who are expected to develop long and severe episodes of neutropenia (longer than seven days with neutrophils < 100 × 109 cells/L).7,8 Second, increasing rates of fluoroquinolone resistance in this group of patients have been described in the medical literature, including in hematological services where this routine was adopted. The widespread use of antimicrobials in incorrectly selected patient populations and the rise in bacterial resistance to these drugs exemplify a well-known phenomenon in the field of antimicrobial therapy. Indeed, the massive use of Scientific comment

Milk - An Effective Low-Attenuation Computed Tomography Oral Contrast Medium

Background: To evaluate gastrointestinal pathology in computed tomography (CT) scan, optimum distention, mural visualization and gastrointestinal tract discrimination are necessary. High attenuation oral contrast material in the form of iodine solution has drawbacks in mural visualization and tolerance. Milk can be used as a low attenuation CT oral contrast agent in gastrointestinal tract discrimination and mural visualization with better tolerance. Objective: The purpose of our study was to compare the effectiveness, cost, and tolerance of milk and iopamiro (iodinated positive contrast medium) in patients undergoing abdominal CT with oral and IV contrast media. Materials and Methods: Two hundred and twelve patients were purposively assigned to receive either whole milk (n = 110) or iopamiro (n = 100). Results were independently reviewed by radiologists. Degree of bowel distention, mural visualization and gastrointestinal tract discrimination were qualitatively scored on a 4- point scale. A questionnaire regarding oral contrast tolerability was provided to each patient. Cost comparison of the two agents was performed. Results: No statistically significant differences were seen between whole milk and iopamiro with respect to degree of bowel distention and gastrointestinal tract discrimination for all segments of bowel studied (p &gt; 0.05). Mural visualization is better with whole milk compared with iopamiro (p &lt; 0.05). Significantly more patients ranked milk as pleasant in taste compared with iopamiro (p &lt; 0.05). Milk was better tolerated than iopamiro, with fewer gastrointestinal side effects, including abdominal discomfort (p = 0.065), cramping (p = 0.309), nausea (p = 0.001), vomiting (p = 0.003) and diarrhea (p = 0.347). The cost per patient for iopamiro is 900 BDT compared with 60 BDT for milk. Conclusion: Whole milk is comparable to iopamiro with respect to bowel distention and gastrointestinal tract discrimination and better in bowel wall visualization and has better patient acceptance, and fewer adverse symptoms. Milk is a costeffective alternative to iopamiro as a low-attenuation CT oral contrast agent. Journal of Enam Medical College; Vol 3 No 2 July 2013; Page 71-76 DOI: http://dx.doi.org/10.3329/jemc.v3i2.16126

Vismodegib for the treatment of basal cell skin cancer

The pharmacology, clinical efficacy, adverse effects, cost, and place in therapy of vismodegib are reviewed. Vismodegib, the first oral treatment for basal cell carcinoma (BCC), was recently approved for the treatment of patients with locally advanced or metastatic BCC whose cancer is refractory to standard treatments or who are not candidates for surgery or radiation. Vismodegib is a small molecule that potently inhibits signal transduction in the hedgehog signaling pathway, demonstrates nonlinear pharmacokinetics, and has a half-life of 13 days. Agents that increase gastrointestinal pH may reduce the solubility and bioavailability of vismodegib. It is effective in both locally advanced and metastatic BCCs, with response rates ranging from 30% to 60% in two clinical trials. Vismodegib is available as a 150-mg capsule, and the approved dosage is 150 mg orally once daily. The most common adverse effects of vismodegib include mild-to-moderate hair loss, muscle cramps, taste disturbance, and weight loss. The estimated cost of one month of treatment with vismodegib is $7500. Vismodegib was recently approved for the treatment of locally advanced or metastatic BCC that is refractory to standard treatments or if patients are not candidates for surgery or radiation. Vismodegib may have little effect on the treatment of BCC, given its high cost, the high cure rates achieved with standard therapies, and its unacceptable toxicity profile in patients with a non-life-threatening disease. However, vismodegib's novel mechanism of action, oral dosage form, preliminary efficacy, and tolerability compared with cytotoxic chemotherapy may make it an attractive candidate for the treatment of other cancers.

2283 – Safety and tolerability of aripiprazole once-monthly initiated in adults with schizophrenia stabilized on atypical oral antipsychotics other than aripiprazole

Objective Evaluate the safety and tolerability of aripiprazole once-monthly (ARI-OM) initiation in patients stabilized on oral antipsychotics other than aripiprazole. Previous pivotal Phase III trials have evaluated initiating ARI-OM in patients stabilized on oral aripiprazole 1 . Methods Eligible patients were treated with oral atypical antipsychotics other than aripiprazole with a history of oral aripiprazole tolerability. The study included a screening phase (30 days) and a treatment phase (28 days). Patients were stabilized per investigator's judgment for ≥14 days on risperidone, olanzapine, quetiapine, or ziprasidone, before administration of ARI-OM (400 mg). Current oral antipsychotic was co-administered with ARI-OM for 2 weeks to determine safety and tolerability of a single ARI-OM dose following treatment initiation. Safety assessments were adverse events (AEs); extrapyramidal symptoms (EPSs) using standard objective rating scales; Columbia-Suicide Severity Rating Scale; clinical laboratory measures; and weight changes. Results 60 patients initiated ARI-OM, while continuing treatment for ≤2 weeks with oral risperidone (n=24), quetiapine (n=28), ziprasidone (n=5) or olanzapine (n=3). Treatment-emergent (TE) AEs (≥5%) were fatigue, injection-site pain, and restlessness (risperidone); insomnia, dystonia, injection-site pain, and toothache (quetiapine); and muscle spasm, tooth abscess, and toothache (ziprasidone). Prior olanzapine did not cause any AEs. Incidence of TE-EPSs were similar in all groups ( Conclusions The AE profile of patients receiving ARI-OM concomitant with oral atypical antipsychotics other than aripiprazole was consistent with prior reports 1 .

Single dose pharmacokinetics and absolute bioavailability of mirabegron, a ?3-adrenoceptor agonist for treatment of overactive bladder

Mirabegron is a potent and selective β3-adrenoceptor agonist in development for treatment of overactive bladder. Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel-group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91). After oral dosing (25 - 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.

Analysis of pharmaceutical interventions carried out via electronic prescriptions†

BackgroundHospital pharmacists play an important role in pharmacotherapy. Pharmaceutical care contributes to securing efficacy and safety in the use of medicines. Validation of the prescriptions allows pharmacists to detect, prevent...