Use of Physiologically Based Pharmacokinetic Modeling for Predicting Drug-Food Interactions: Recommendations for Improving Predictive Performance of Low Confidence Food Effect Models.

Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. This manuscript is part of a broader publication from the IQ Consortium's food effect physiologically based pharmacokinetic model (PBPK) modeling working group and complements previous publications by focusing on cases where the food effect was predicted with low confidence. Pazopanib-HCl, trospium-Cl, and ziprasidone-HCl served as model compounds to provide insights into why several food effect predictions failed in the first instance. Furthermore, the manuscript depicts approaches whereby PBPK-based food effect predictions may be improved. These improvements should focus on the PBPK model functionality, especially better reflecting fasted- and fed-state gastric solubility, gastric re-acidification, and complex mechanisms related to gastric emptying of drugs. For improvement of in vitro methodologies, the focus should be on the development of more predictive solubility, supersaturation, and precipitation assays. With regards to the general PBPK modeling methodology, modelers should account for the full solubility profile when modeling ionizable compounds, including common ion effects, and apply a straightforward strategy to account for drug precipitation.

Pharmacokinetic Drug-Drug Interactions Between Trospium Chloride and Ranitidine Substrates of Organic Cation Transporters in Healthy Human Subjects.

Trospium chloride, a muscarinic receptor blocker, is poorly absorbed with different rates from areas in the jejunum and the cecum/ascending colon. To evaluate whether organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion (MATE) 1 and MATE2-K are involved in pharmacokinetics, competitions with ranitidine, a probe inhibitor of the cation transporters, were evaluated in transfected HEK293 cells. Furthermore, a drug interaction study with trospium chloride after intravenous (2 mg) and oral dosing (30 mg) plus ranitidine (300 mg) was performed in 12 healthy subjects and evaluated by noncompartmental analysis and population pharmacokinetic modeling. Ranitidine inhibited OCT1, OCT2, MATE1, and MATE2-K with half maximal inhibitory concentration values of 186 ± 25 µM, 482 ± 105 µM, 134 ± 37 µM, and 35 ± 11 µM, respectively. In contrast to our hypothesis, coadministration of ranitidine did not significantly decrease oral absorption of trospium. Instead, renal clearance was lowered by ∼15% (530 ± 99 vs 460 ± 120 mL/min; P < .05). It is possible that ranitidine was not available in competitive concentrations at the major colonic absorption site, as the inhibitor is absorbed in the small intestine and undergoes degradation by microbiota. The renal effects apparently result from inhibition of MATE1 and/or MATE2-K by ranitidine as predicted by in vitro to in vivo extrapolation. However, all pharmacokinetic changes were not of clinical relevance for the drug with highly variable pharmacokinetics. Intravenous trospium significantly lowered mean absorption time and relative bioavailability of ranitidine, which was most likely caused by muscarinic receptor blocking effects on intestinal motility and water turnover.

Overactive bladder - pharmacological treatment.

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

Overactive bladder - pharmacological treatment

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

Designing robust immediate release tablet formulations avoiding food effects for BCS class 3 drugs.

Food induced viscosity in the gastrointestinal tract is reported to reduce the bioavailability of tablets containing BCS class 3 drugs, mainly by retarding their disintegration and dissolution of the active pharmaceutical ingredient. The role of formulation factors in minimizing this negative food effect is largely unknown. Combinations of disintegrants were studied together with soluble and insoluble fillers and trospium chloride as model drug substance. Different batches of tablets were compressed at 10 kN and 30 kN, by incorporating different combinations of croscarmellose sodium (CSS), cross-linked (CPD) and sodium starch glycolate (SSG) at low level i.e, 2% + 2% and high level i.e, 4% + 4% of compressional weight, while taking lactose as a soluble filler and dibasic calcium phosphate (DCP) and microcrystalline cellulose (MCC) as insoluble fillers. Under low viscous conditions, disintegration of DCP based tablets was faster compared to lactose based tablets, but under high viscous conditions, simulating the effect of an ingested FDA meal, the disintegration behavior was reverted. Increased compressional force prolonged the disintegration of lactose and DCP based formulations under fasted conditions. However, when evaluated under food viscosity conditions, DCP based tablets compressed at higher force showed rapid disintegration while no effect of increased compressional force in lactose based tablets was observed. MCC based tablets in particular showed largely prolonged disintegration times in viscous media irrespective of the disintegrant type and levels investigated. Disintegrant combinations possessing wicking ability with minimum or no gelling were found to reduce disintegration times. The disintegrant combination of CPD + CCS was effective in reducing disintegration and enhancing dissolution besides not being affected by changes in compressional force and their total proportion in the tablet. In conclusion, it is recommended to evaluate formulations under increased viscosity conditions during the development phase of tablets with an objective to minimize the negative effect of food viscosity on disintegration and dissolution.

Anticholinergic burden and comorbidities in patients attending treatment with trospium chloride for overactive bladder in a real-life setting: results of a prospective non-interventional study.

BACKGROUND: Elderly people are representative for the patients most likely to be treated with anticholinergics for overactive bladder (OAB). They often receive further drugs with anticholinergic properties for concomitant conditions. This increases the risk for side effects, including central nervous system disorders. Data on comorbidities and baseline anticholinergic burden of OAB patients seen in urological practice is scarce. Therefore, we included an epidemiological survey on these issues in our study which assessed the effectiveness and tolerability of trospium chloride (TC) in established dosages under routine conditions. METHODS: Outpatients (≥ 65 years of age), for whom treatment with TC was indicated, were eligible to participate in this non-interventional, prospective study performed in 162 urological practices in Germany. Epidemiological questions were evaluated by the Anticholinergic Burden (ACB) scale and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) at baseline. Efficacy was assessed by changes in symptom-related variables of OAB after treatment. Dosage regimen, duration of treatment, adverse events, withdrawals, and ease of subdivision of the prescribed SNAP-TAB tablet were documented. Patients and physicians rated efficacy and tolerability of treatment. Statistics were descriptive. RESULTS: Four hundred fourty-five out of 986 (47.54%) patients in the epidemiological population had a baseline ACB scale score > 0, 100 (24.72%) of whom a score ≥ 3. The median CIRS-G comorbidity index score for all patients was 5. 78.55% (608/774) of patients in the efficacy population received a daily dose of 45 mg TC. 60.03% (365/608) of them took this dose by dividing the SNAP-TAB tablet in three equal parts. Before-after-comparisons of the core symptoms of OAB showed clear improvements. An influence of the dosage scheme (1 × 45 mg TC/d vs 3 × 15 mg TC/d) on clinical outcome could not be observed. Most urologists and patients rated TC treatment as effective and well tolerated. 44 (4.37%) out of 1007 patients in the safety collective ended their treatment prematurely, while 75 patients (7.45%) experienced adverse events. CONCLUSIONS: Anticholinergic burden and comorbidities in elderly OAB patients are frequent. The acceptance of the SNAP-TAB tablet, which facilitates flexible dosing with TC, was high, which is supportive in ensuring adherence in therapy. TRIAL REGISTRATION: This non-interventional study was registered on October 29, 2014 with the number DRKS00007109 at the German Register of Clinical Studies (DRKS).

Transcutaneous posterior tibial nerve electrostimulation with low dose trospium chloride: Could it be used as a second line treatment of overactive bladder in females.

AIM: To evaluate the effect of adding low dose trospium chloride with transcutaneous posterior tibial nerve stimulation (TPTNS) in the treatment of overactive bladder (OAB) in females after failure of behavioral therapy. METHODS: We randomized 30 women with OAB, in two groups: G I received 30 min TPTNS, three times a week; GII received TPTNS plus 20 mg trospium chloride daily. OAB Symptom Score questionnaire (OABSS), Incontinence Impact Questionnaire-short form 7 (IIQ-7), 3 day voiding diary and urodynamics at weeks 0 and 8 were evaluated. RESULTS: The groups were similar before treatment. Eight weeks after treatment, the mean OABSS decreased significantly to 8.53 ± 1.30 for group II vs 10.0 ± 2.0 for GI (P < 0.024). The mean IIQ-7 score decreased significantly to 51.86 ± 17.26 in group I vs 31.99 ± 9.26 in group II (P < 0.001). Before treatment, 11 (73.3%) and 4 (26.7%) patients in each group had moderate and poor quality of life (QoL), respectively. After treatment, 6 (40%) and 14 (93.3%) had good QoL, 7 (46.7%) and 1 (6.7%) had moderate QoL in GI and GII, respectively. Two (13.3%) patients in GI had poor QoL. The mean frequency was reduced to 8.60 ± 0.83 vs 10.60 ± 2.32 for GII and GI respectively (P = 0.006). The cystometric capacity increased from 263.40 ± 50.45 to 377.80 ± 112.92 mL (P = 0.001) for GII vs 250.13 ± 56.24 to 296.40 ± 99.0 mL (P = 0.026) for GI. CONCLUSION: TPTNS combined with low dose trospium chloride proved to be more effective than TPTNS alone in the treatment of OAB in females.

Evaluation of Early-phase Biodistribution in 123I-ioflupane SPECT.

It is reported that pharmacokinetics after intravenous injection of 123I-ioflupane may reflect cerebral blood flow. In this study, the early-phase pharmacokinetics of 123I-ioflupane in 10 healthy volunteers was analyzed over time using dynamic single-photon emission computed tomography (SPECT) immediately after intravenous injection. We also examined the correlation between the 123I-IMP imaging and the 123I-ioflupane early-phase image for 14 cases in which both dopamine transporter (DaT) imaging by 123I-ioflupane and cerebral blood flow imaging by 123I-IMP were performed on the same camera. The time-activity curve between cerebellum (CBL) area and each area of anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA) showed distribution characteristics similar to 123I-IMP from immediately after intravenous injection until 20 minutes after administration, and there was no conspicuous washout. The regression line and the correlation coefficient of the Z-score of three-dimensional stereotactic surface projections (3DSSP) (decrease) of the early-phase imaging of 123I-ioflupane and the 123I-IMP imaging are y=0.7546x+0.3562, r=0.8169 (P<0.01) at 0-10 minutes of 123I-ioflupane, and y=0.7412x+0.3027, r=0.8280 (P<0.01) at 0-15 minutes of 123I-ioflupane, and y=0.7400x+0.2456, r=0.8449 (P<0.01) at 0-20 minutes of 123I-ioflupane, showing a strong correlation at all timings. Therefore, 123I-ioflupane early-phase pharmacokinetics after intravenous showed distribution characteristics similar to 123I-IMP, indicating the possibility that early images may be useful in a clinical practice.

Effect of Trospium Chloride on Cognitive Function in Women Aged 50 and Older: A Randomized Trial.

OBJECTIVES: This study aimed to investigate the effect of trospium chloride on cognitive function in postmenopausal women treated for overactive bladder (OAB). METHODS: Randomized double-blind placebo-controlled trial conducted from April 2013 to April 2015. Women aged 50 years or older seeking treatment for OAB were randomized to either trospium chloride XR 60 mg daily or placebo. Baseline cognitive function was assessed via Hopkins Verbal Learning Test-Revised (HVLT-R), Mini Mental Status Exam, Mini Mental Status X, Digit Span, Trails A, Trails B, and Epworth Sleepiness Scale. Cognitive function was reassessed at week 1 and week 4. A priori power analysis determined that 21 subjects were needed per group. RESULTS: Although 59 women were enrolled and randomized (28 trospium and 31 placebo), 45 completed assessment (21 trospium and 24 placebo). Mean age was 68 years, 78% were white, and 44% had previously taken OAB medication. For the primary outcome, there was no difference in HVLT-R total score between trospium and placebo groups at week 4 (P = 0.29). There were also no differences based on the other cognitive tests. There was a correlation between age and the following week-4 tests: HVLT-R total score (r = -0.3, P = 0.02), HVLT-R total recall subscale (r = -0.4, P = 0.007), Trails A (r = 0.4, P = 0.002), and Trails B (r = 0.4, P = 0.004). A linear regression model found that HVLT-R total score decreased by 0.372 points for each increased year of age. CONCLUSIONS: In women aged 50 years and older, there were no changes in cognitive function between those taking trospium and placebo. Cognitive function was correlated with age.

Imaging analysis of Parkinson's disease patients using SPECT and tractography.

Parkinson's disease (PD) is a degenerative disorder that affects the central nervous system. PD-related alterations in structural and functional neuroimaging have not been fully explored. This study explored multi-modal PD neuroimaging and its application for predicting clinical scores on the Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Multi-modal imaging that combined 123I-Ioflupane single-photon emission computed tomography (SPECT) and diffusion tensor imaging (DTI) were adopted to incorporate complementary brain imaging information. SPECT and DTI images of normal controls (NC; n = 45) and PD patients (n = 45) were obtained from a database. The specific binding ratio (SBR) was calculated from SPECT. Tractography was performed using DTI. Group-wise differences between NC and PD patients were quantified using SBR of SPECT and structural connectivity of DTI for regions of interest (ROIs) related to PD. MDS-UPDRS scores were predicted using multi-modal imaging features in a partial least-squares regression framework. Three regions and four connections within the cortico-basal ganglia thalamocortical circuit were identified using SBR and DTI, respectively. Predicted MDS-UPDRS scores using identified regions and connections and actual MDS-UPDRS scores showed a meaningful correlation (r = 0.6854, p < 0.001). Our study provided insight on regions and connections that are instrumental in PD.

Combined low-dose antimuscarinics for refractory detrusor overactivity in children.

INTRODUCTION AND AIMS: Behavioral therapy and bowel management are the initial and mainstay treatments for overactive bladder (OAB). Antimuscarinic agents are initiated if these measures fail or symptoms are severe. This study reported the results of treatment with a high dosage of a single drug in children with refractory detrusor overactivity (DO). After the children maintained their previous antimuscarinic medication, a second antimuscarinic drug (trospium chloride) was added as a combination therapy. MATERIALS AND METHOD: Seventy-two children with DO were enrolled in this prospective study (Figure). They had persistent urgency and urgency urinary incontinence (UUI), even with behavioral bowel therapy, and used an optimized dosage of oxybutynine. All patients demonstrated DO at urodynamic study and started on oxybutynin and trospium chloride at the lowest weight-adjusted dose (10-20 mg/day for trospium chloride). A bladder diary was recorded for 3 days, and urodynamic studies were repeated at 3 and 6 months. RESULTS: Sixteen children (22.2%) became dry. Thirty-three children (45.8%) attained a significant decrease in incontinence from an average of 5 to 1.3 episodes per day. A statistically significant increase of mean cystometeric bladder capacity (P = 0.006) was also observed at the 6-month follow-up. The overall success rate was 68%, since 23 children (32%) discontinued combined treatment due to persistent symptoms and/or intolerable side effects. A total of 41 children (57%) reported no side effects, 25 (34.7%) reported mild side effects, six (8.3%) reported moderate side effects, and two withdrew from the study due to their side effects. CONCLUSIONS: The addition of low-dose trospium chloride to oxybutynine seemed to be an effective and safe treatment approach for children with DO who were refractory to high-dosage monotherapy. Different combinations with different antimuscarinics drugs could be evaluated in the future.

[High doses of trospium chloride in patients with idiopathic overactive bladder. Data of large-scale, multicenter observational program Resource].

PURPOSE: Evaluation of the efficacy and safety of different doses of trospium chloride in patients with idiopathic overactive bladder. MATERIALS AND METHODS: Large-scale observational program "Resource" included 669 patients with idiopathic OAB - 359 women and 310 men. At the first visit, all patients were assigned to use of trospium chloride at a standard dose of 45 mg per day. The results of treatment were evaluated during follow-up visits at 3, 6, 9 and 12 weeks. Depending on the results of examination, the dose was reduced in the presence of adverse events and increased in case of insufficient treatment effects. RESULTS: After 12 weeks, 102 patients have been receiving the drug at a dose of 30 mg/day, 241 - at a dose of 45 mg/day, 257 - at a dose of 60 mg/day, and 22 - at a dose of 75 mg/day. CONCLUSIONS: Individual approach to the selection of doses of trospium chloride in patients with idiopathic OAB can be quite effective and safe measure to achieve optimal clinical outcome with a good safety profile.

Effectiveness of Solifenacin and Trospium for Managing of Severe Symptoms of Overactive Bladder in Patients With Benign Prostatic Hyperplasia.

This research is aimed to study the possibility of management of severe symptoms of overactive bladder (OAB) with solifenacin and trospium in patients who receive treatment with tamsulosin due to benign prostatic hyperplasia (BPH). The 338 men more than 50 years old (average age 58.4 years) diagnosed with BPH and severe symptoms of OAB were enrolled in the study. Over three episodes of urinary incontinence per day (registration according to bladder diaries), INTERNATIONAL PROSTATE SYMPTOM SCORE: over 19, OAB-V8 questionnaire score over 32, and urodynamic disorders diagnosed using cystometry and uroflowmetry were taken as a criterion of severe symptoms of OAB. Patients of the main group during 2 months received treatment with daily combination of solifenacin 5 mg and trospium 5 mg simultaneously with tamsulosin 0.4 mg. Patients of the control group were treated only with tamsulosin. First endpoint is a quantitative assessment of patients with BPH having severe symptoms of OAB. Second endpoint is a state of the patients' lower urinary tract after the treatment. In the main group, most of urodynamic indices normalized significantly. Number of episodes of incontinence reduced from middle level 3.4 (0.8) per day to 0.9 (0.7) per day. In the control group changes of urodynamic indices were not significant. Quantity of side effects did not exceed the level which is common for antimuscarinic monotherapy. Therefore, percentage of patients with severe symptoms of OAB is not less than 44% of all cases of prostatic hyperplasia accompanied by OAB symptoms. Combination of trospium and solifenacin in standard doses is an efficient and safe method of management of severe symptoms of OAB in the course of the treatment of with tamsulosin in patients more than 50 years of age.

Adherence to Oral Therapy for Urgency Urinary Incontinence: Results from the Anticholinergic Versus Botox Comparison (ABC) Trial.

OBJECTIVES: Medication adherence with urgency urinary incontinence (UUI) treatment is challenging and the best assessment methodology is uncertain. We sought to describe adherence with anticholinergic (AC) versus placebo (P) by comparing pill counts and MEMSCAP event data and to identify factors associated with adherence. METHODS: The randomized controlled AC versus Botox Comparison trial of women with moderate to severe idiopathic UUI included 126 participants initiating AC plus P bladder injection and 121 receiving P pills plus Botox injection. Adherence data on 243 participants (124 AC and 119 P) were calculated by pill count and MEMSCAP data for each 2-month interval during the 6-month study that allowed for dose escalation/drug change. Overall composite adherence estimates were calculated using the average of both methods and weighted by the duration of each 2-month interval. RESULTS: Treatment groups had no significant differences in dosing duration (P = 0.76) or mean adherence (AC, 83.3% [16.8] vs. P, 84.8% [13.8]). Only 53% of women met the dichotomous outcome of more than 80% adherence during all intervals. Correlation between adherence by pill counts versus MEMSCAP decreased over time with pill counts demonstrating higher adherence than MEMSCAP (r = 0.53, 0.50, and 0.36 for each 2-month interval). Lower adherence was associated with higher baseline incontinence severity and better UUI quality of life for the AC group and with current smoking status in both groups. CONCLUSIONS: Adherence using pill counts and MEMSCAP was reasonably correlated and similar in both the AC and P groups. In the AC group, higher baseline incontinence severity and better UUI Quality of Life were associated with decreased adherence. Smokers were less adherent.

Comparative effectiveness of combined low- and standard-dose trospium and solifenacin for moderate overactive bladder symptoms in elderly men and women.

OBJECTIVE: To increase the safety and effectiveness of treatments for overactive bladder (OAB) with moderate symptoms in elderly patients. PATIENTS AND METHODS: Patients were examined at the Urodynamic Department of the Regional Diagnostic Center (Vladivostok, Russian Federation) from September 1, 2012 to December 31, 2012. The assignment of patients [n = 177, average age 69. 4 years, 98 women (55.4%) and 79 men (44.6%)] was random and blind in this placebo-controlled study. Patients were distributed into subgroups according to the method of treatment as follows: group А1: n = 57, trospium 30 mg/day + solifenacin 10 mg/day; group А2: n = 61, trospium 15 mg/day + solifenacin 5 mg/day; group А3: n = 59, placebo. All patients underwent a urodynamic examination in accordance with international standards before and 2 months after treatment. ICIQ-SF questionnaires recommended by the International Continence Society (ICS) and bladder diaries were used to evaluate the clinical results. The clinical severity of the OAB symptoms and the effectiveness of the treatment were evaluated based on the frequency of episodes of incontinence (EI) per day. Three or fewer EI per day were considered moderate dysfunction of the lower urinary tract. RESULTS: Groups of elderly patients with moderate symptoms of OAB who were treated with standard- and low-dose trospium and solifenacin demonstrated a significant increase in the median values of reflex volume, bladder capacity, and detrusor compliance and a decrease in the frequency of urination and urinary urgencies. The frequency of EI in both of the main groups decreased by almost 2-fold in comparison to the initial data and reached the following values: group А1: 1.27 (-1.08), p ≤ 0.05; group A2: 1.49 (-1.18), p ≤ 0.05. The correlation with the decrease in the frequency of EI in these groups was r = 0.85 (p ≤ 0.01). The percentage of patients with a significant decrease (EI ≥1.0) among those treated with standard- and low-dose trospium and solifenacin increased synchronously, prompting us to suppose the absence of a direct correlation between medicine dose and therapeutic effect for moderate OAB symptoms. CONCLUSION: The combination of low-dose trospium and solifenacin provides good clinical and urodynamic effects in elderly patients with moderate symptoms of OAB. Combination of these drugs in standard doses for such patients is excessive.

Is ioflupane I123 injection diagnostically effective in patients with movement disorders and dementia? Pooled analysis of four clinical trials.

OBJECTIVES: To pool clinical trials of similar design to assess overall sensitivity and specificity of ioflupane I123 injection (DaTSCAN or ioflupane ((123)I)) to detect or exclude a striatal dopaminergic deficit disorder (SDDD), such as parkinsonian syndrome and dementia with Lewy bodies. DESIGN: Pooled analysis of three phase 3 and one phase 4 clinical trials. These four trials were selected because they were the four studies used for the US new drug application to the Food and Drug Administration (FDA). SETTING: Multicentre, open-label, non-randomised. PARTICIPANTS: Patients with either a movement disorder or dementia, and healthy volunteers. INTERVENTIONS: Ioflupane ((123)I) was administered. OUTCOME MEASURES: Images were assessed by panels of 3-5 blinded experts and/or on-site nuclear medicine physicians, classified as normal or abnormal and compared with clinical diagnosis (reference standard) to determine sensitivity and specificity. RESULTS: Pooling the four studies, 928 participants were enrolled, 849 were dosed and 764 completed their study. Across all studies, when images were assessed by on-site readers, ioflupane ((123)I) diagnostic effectiveness had an overall (95% CI) sensitivity of 91.9% (88.7% to 94.5%) and specificity of 83.6% (78.7% to 87.9%). When reads were conducted blindly by a panel of independent experts, the overall sensitivity was 88.7% (86.8% to 90.4%) and specificity was 91.2% (89.0% to 93.0%). CONCLUSIONS: In this pooled analysis, the visual assessment of ioflupane ((123)I) images provided high levels of sensitivity and specificity in detecting the presence/absence of an SDDD. Ioflupane ((123)I) imaging has the potential to improve diagnostic accuracy in patients with signs and symptoms of a movement disorder and/or dementia. TRIAL REGISTRATION NUMBER: NCT00209456.

[Treatment of overactive bladder in older women increased doses of antimuscarinic drugs safe and effective alternative to existing methods].

The study included 95 female patients of 65 to 74 years (average age 67,1 years), who previously (more than 6 months before this study) took a course of monotherapy with hydrochloride trospium in higher dosages with unstable or weak effect. In this study, all patients were divided into three groups and were treated with two antimuscarinic drugs. The majority of older women suffering from OAB and treatment-resistant taking one antimuscarinic drug in high doses showed a significant positive progress in a state by adding a second antimuscarinic agent. The received side effects do not exceed thereof in comparison with treatment with a single drug.

Safety analysis of 10 clinical trials and for 13 years after first approval of ioflupane 123I injection (DaTscan).

Ioflupane is an analog of cocaine that binds reversibly with high affinity to the dopamine transporter (DaT) protein, a marker for presynaptic terminals in dopaminergic nigrostriatal neurons. Ioflupane (123)I Injection is also known as DaTscan or DaTSCAN ((123)I-ioflupane is also called (123)I-2-ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)nortropane or (123)I-FP-CIT). The diagnostic efficacy of DaTscan has been described elsewhere. Here, we present a comprehensive analysis of the safety of DaTscan starting from initiation of clinical development through 13 y after the date of first market approval. Safety data in the sponsor's clinical development safety database from 10 completed DaTscan clinical trials were pooled, and postapproval experience was summarized from standardized aggregate safety reports submitted to regulatory agencies. A total of 1,180 clinical trial subjects (92% of 1,284 subjects planned to receive DaTscan in the clinical trials) received DaTscan. Percentages of subjects with adverse events by category were as follows: all (22%), considered at least possibly related to DaTscan by the investigator (4%), any severe (3%), headache (4%), nausea (2%), dizziness (2%), nasopharyngitis (1%), and injection site hematoma (1%). Four percent of subjects had at least 1 serious adverse event; 5 subjects (<1%) had serious adverse events that led to death. All serious adverse events, including those that led to death, were deemed by an expert clinician to be unrelated to DaTscan. An estimated half a million market doses of DaTscan (for single use) were administered from July 2000 through the July 2013 reporting period. In postapproval safety assessment, 1 death was reported 20 d after (and unrelated to) DaTscan administration. Two spontaneously reported serious adverse drug reactions (ADRs) and 32 spontaneously reported nonserious ADRs were submitted, approximately half of which are identified in labeling. Headache (in clinical trials) and injection site pain (postapproval) were the most commonly reported events or reactions. Although adverse events were reported for 1 in 5 clinical trial subjects, most were mild and considered unrelated to DaTscan administration. Severe events were uncommon, and no serious adverse event occurring in more than 1 subject was deemed related to DaTscan administration. In postapproval experience, the frequency of ADRs spontaneously reported was less than 1 per 10,000 doses administered. Comprehensive safety data show that DaTscan was well tolerated.

Individual-reader diagnostic performance and between-reader agreement in assessment of subjects with Parkinsonian syndrome or dementia using 123I-ioflupane injection (DaTscan) imaging.

UNLABELLED: Establishing an early, accurate diagnosis is fundamental for appropriate clinical management of patients with movement disorders or dementia. Ioflupane (123)I Injection (DaTscan, (123)I-ioflupane) is an important adjunct to support the clinical diagnosis. Understanding individual-reader diagnostic performance of (123)I-ioflupane in a variety of clinical scenarios is essential. METHODS: Sensitivity, specificity, interreader, and intrareader data from 5 multicenter clinical studies were reviewed. The different study designs offered an assortment of variables to assess the effects on the diagnostic performance of (123)I-ioflupane: on-site versus 3-5 blinded image readers, number of image evaluations, early/uncertain versus late/confirmed clinical diagnosis as reference standard, and subjects with movement disorders versus dementia. RESULTS: Eight hundred eighteen subjects had individual-reader efficacy data available for analysis. In general, sensitivity and specificity were high and comparable between on-site versus blinded independent readers. In subjects with dementia, when the clinical diagnosis was made at month 12 versus baseline, specificity improved from 77.4%-91.2% to 81.6%-95.0%. In subjects with movement disorders, this effect was observed to an even greater extent, when diagnostic performance using month-18 diagnosis as a reference standard (sensitivity, 67.0%-73.7%; specificity, 75.0%-83.3%) was compared versus month-36 diagnosis (77.5%-80.3% and 90.3%-96.8%, respectively). Diagnostic performance was similar in subjects with dementia (74.4%-89.9% and 77.4%-95.0%, respectively) and subjects with movement disorders (67.0%-97.9% and 71.4%-98.4%, respectively). In most of the comparisons, between-reader agreement was very good (almost perfect), with κ ranging from 0.81 to 1.00. Within-reader agreement, measured in 1 study, was 100% for 3 blinded readers. CONCLUSION: Individual-reader diagnostic performance, as assessed by measuring sensitivity and specificity of (123)I-ioflupane to detect the presence or absence of striatal dopaminergic deficit, using the clinical diagnosis as a reference standard, was high in subjects with either movement disorders or dementia and was similar in on-site readers versus blinded analyses. Between- and within-reader agreements were very good (almost perfect). Longer follow-up between imaging and clinical diagnosis improved the diagnostic accuracy, most likely due to improvement in the clinical diagnosis reference standard, rather than changes in reader accuracy.

[Trospium chloride once daily for overactive bladder syndrome: results of a multicenter observational study]. / Trospiumchlorid als Einmalgabe bei überaktiver Blase: Ergebnisse einer multizentrischen Beobachtungsstudie.

BACKGROUND: An extended release form of trospium chloride (Urivesc 60 mg® slow release capsules) was recently approved for the treatment of overactive bladder syndrome (OAB). A multicentric, prospective observational study was conducted under routine private practice conditions to assess the safety and efficacy of this treatment in this indication, as well as the effect on quality of life parameters. PATIENTS AND METHODS: A total of 305 patients with OAB syndrome (mean age 60 years, 79% females) were evaluated in this prospective, non-interventional observation study. All patients received trospium chloride once daily (Urivesc® 60 mg extended release capsules) in accordance with the approved prescribing instructions. At the start of therapy and after a treatment period of 4 and 13 weeks (median) the patient urological endpoints and quality of life parameters were assessed. Safety and tolerability were evaluated from the documentation of all adverse events occurring during the entire observation period. RESULTS: Mean daily frequency of micturition decreased over the treatment period with once daily trospium chloride from 11.7 ± 4.3 to 7.7 ± 2.9 per 24 h (p<0.0001). In parallel the mean individual urine volume voided increased from 169.3 ± 79.8 ml to 238.4 ± 122.0 ml (p<0.0001). The proportion of patients with incontinence fell from 36.7% at the initiation of therapy to 20.3% at the end of therapy. Furthermore, the mean number of incontinence pads used declined from 3 per day to 1 per day. More than one third of initially incontinent patients (39.3%) needed no incontinence pads at the end of the treatment period. Quality of life parameters improved significantly in all five subsections recorded (i.e. daily life, family life, sleep quality, self esteem and ability to travel). The safety and tolerability of Urivesc 60 mg extended release was good, with a particularly low incidence of mouth dryness (1% of patients) reported. No central nervous system (CNS) associated adverse events and no serious adverse events occurred. CONCLUSION: As a once daily formulation prescribed under normal private practice conditions, the new trospium chloride extended-release formulation consistently demonstrated efficacy and tolerability for treatment of OBS. Treatment with once daily trospium chloride 60 mg extended release capsules significantly improved the frequency of micturition and nocturia, as well as incontinence episodes and use of absorptive pads in this patient population, accompanied by an improvement in quality of life. The reason for the good tolerability, in particular the relatively low incidence of mouth dryness, is probably due to the lower peak plasma concentration of trospium (cmax) enabled by the modified-release galenical form employed by the 60 mg extended release formulation. Once daily administration enabled enhanced compliance for the modified release formulation and associated improved tolerability. The limited access of trospium to the CNS afforded by the intact blood-brain barrier and absence of metabolic interaction potential via cytochrome P450 are established characteristics of trospium chloride. This infers a lower potential to impair cognitive function and a lower potential for metabolic interactions with concomitant medications. In the context of elderly patients and multimorbid and polypharmacy scenarios, the sum of these characteristics may afford distinct advantages in treating OAB patients.