Evaluating cardiac risk: exposure response analysis in early clinical drug development.

The assessment of a drug's cardiac liability has undergone considerable metamorphosis by regulators since International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use E14 guideline was introduced in 2005. Drug developers now have a choice in how proarrhythmia risk can be evaluated; the options include a dedicated thorough QT (TQT) study or exposure response (ER) modeling of intensive electrocardiogram (ECG) captured in early clinical development. The alternative approach of ER modeling was incorporated into a guidance document in 2015 as a primary analysis tool which could be utilized in early phase dose escalation studies as an option to perform a dedicated TQT trial. This review will describe the current state of ER modeling of intensive ECG data collected during early clinical drug development; the requirements with regard to the use of a positive control; and address the challenges and opportunities of this alternative approach to assessing QT liability.

Criteria to Screen for Traumatic Cervical Spine Instability: A Consensus of Chiropractic Radiologists.

OBJECTIVE: The purpose of this study was to establish consensus on a radiographic definition for cervical instability for routine use in chiropractic patients who sustain trauma to the cervical spine. METHOD: We conducted a modified Delphi study with a panel of chiropractic radiologists. Panelists were asked to rate potential screening criteria for traumatic cervical spine instability when assessing cervical spine radiographs. Items rated as important for inclusion by at least 60% of participants in round 1 were submitted for a second round of voting in round 2. Items rated for inclusion by at least 75% of the participants in round 2 were used to create the consensus-based list of screening criteria. Participants were asked to vote and reach agreement on the final screening criteria list in round 3. RESULTS: Twenty-nine chiropractic radiologists participated in round 1. After 3 rounds of survey, 85% of participants approved the final consensus-based list of criteria for traumatic cervical spine instability screening, including 6 clinical signs and symptoms and 5 radiographic criteria. Participants agreed that the presence of 1 or more of these clinical signs and symptoms and/or 1 or more of the 5 radiographic criteria on routine static radiographic studies suggests cervical instability. CONCLUSION: The consensus-based radiographic definition of traumatic cervical spine instability includes 6 clinical signs and symptoms and 5 radiographic criteria that doctors of chiropractic should apply to their patients who sustain trauma to the cervical spine.

Comparison of the Pharmacokinetics of Ketorolac Tromethamine After Continuous Subcutaneous Infusion and Repeat Intramuscular Bolus Injections in Healthy Adult Subjects.

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that exhibits analgesic activity with no sedative or anxiolytic properties. Twelve healthy male subjects were enrolled in a study to receive either of 2 treatments over 2 periods in an open-label, randomized, 2-way crossover design: (A) 120 mg of ketorolac tromethamine administered as a continuous subcutaneous infusion over a 24-hour period; or (B) an identical total daily dose administered as 4 intramuscular bolus injections of 30 mg each given every 6 hours (current labeled treatment regimen). The pharmacokinetic and safety profiles were evaluated for both treatments. Both modes of administration have similar values for area under the curve (AUC) and half-life (t1/2 ), suggesting that continuous subcutaneous infusion and repeated intramuscular bolus injections have similar bioavailability. The peak plasma concentration (Cmax ) was 40% lower when ketorolac was administered as a continuous subcutaneous infusion compared with repeat intramuscular bolus injections. The concentration at steady-state (Css ) for continuous subcutaneous infusion was between the Cmax and Ctrough values obtained following the 4 intramuscular injections. Both treatment arms were well tolerated.

Conservative treatment of a rock climber with a SLAP lesion: a case report.

This case report describes the clinical presentation and conservative treatment of a patient who suffered from a superior labrum anteroposterior (SLAP) tear of the shoulder after a rock climbing session. The 26 year old man had injured his right shoulder while trying to reach a distant socket with his shoulder 90° abducted and in extreme external rotation. After initial treatment failure in chiropractic, the patient sought an orthopaedist and physiotherapy care. A contrast magnetic resonance examination revealed a SLAP lesion. Awaiting orthopaedic consultation and in the absence of clinical improvement the patient sought care from a second chiropractor. Clinical examination revealed a mild winging of the right scapula and the presence of trigger points in the rotator cuff muscles, biceps, rhomboids and serratus anterior. The chiropractic treatment then included soft tissue mobilization and the prescription of strengthening exercises of the serratus anterior and rotator cuff muscles. After 4 sessions, the patient did not feel any pain and gradually resumed all his recreational activities. Clinicians should be aware that SLAP lesions are difficult to identify clinically and that manual therapy might be an important component of conservative treatment of SLAP lesions.

L'objectif de ce rapport de cas est de décrire la présentation clinique et le processus thérapeutique d'un patient ayant subi une déchirure de la partie supéroantérieure du labrum (SLAP) de l'épaule droite suite à une séance d'escalade. L'homme de 26 ans s'est infligé cette blessure à l'épaule droite en tentant d'atteindre une prise éloignée en maintenant son épaule en position abduction à 90° avec rotation externe extrême. Après un premier échec thérapeutique en chiropratique, le patient a consulté un orthopédiste et un physiothérapeute. Un examen par résonance magnétique avec contraste a révélé une lésion de type SLAP du labrum. Dans l'attente d'une consultation orthopédique et en l'absence de progrès clinique le patient a de nouveau consulté en chiropratique. L'examen a révélé un léger décollement scapulaire droite et des points gâchettes dans les muscles de la coiffe des rotateurs ainsi que dans les muscles biceps, rhomboïdes et dentelé antérieur. Le patient a été traité au moyen de mobilisations des tissus mous et des exercices de renforcements du dentelé antérieur et de la coiffe des rotateurs ont été prescrit. Après 4 séances, le patient ne ressentait plus aucune douleur et effectuait un retour à ses activités récréatives. Les cliniciens doivent être conscients que les lésions de type SLAP sont difficiles à identifier cliniquement et que les thérapies manuelles semblent être un élément important du traitement conservateur des lésions de type SLAP.

Evaluation of the effect of food and gastric pH on the single-dose pharmacokinetics of cabozantinib in healthy adult subjects.

Cabozantinib is a small molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib exhibits a pH-dependent solubility profile in vitro. Two phase 1 clinical pharmacology studies were conducted in healthy subjects to evaluate whether factors that may affect cabozantinib solubility and gastric pH could alter cabozantinib bioavailability: a food effect study (study 1) and a drug-drug interaction (DDI) study with the proton pump inhibitor (PPI) esomeprazole (study 2). Following a high-fat meal (study 1), cabozantinib Cmax and AUC were increased (40.5% and 57%, respectively), and the median tmax was delayed by 2 hours. Cabozantinib should thus not be taken with food (patients should not eat for at least 2 hours before and at least 1 hour after administration). In the DDI study (study 2), the 90% confidence intervals (CIs) around the ratio of least-squares means of cabozantinib with esomeprazole versus cabozantinib alone for AUC0-inf were within the 80%-125% limits; the upper 90%CI for Cmax was 125.1%. Because of the low apparent risk of a DDI, concomitant use of PPIs or weaker gastric pH-altering agents with cabozantinib is not contraindicated.

Subtle radiographic presentation of a pleural effusion secondary to a cancer of unknown primary: a case study.

Carcinoma of unknown primary sites is a clinical syndrome that represents many types of cancer. The mortality rate associate to this type of cancer is elevated and a rapid medical referral is required for patients presenting this condition. Pleural effusion may be the only visible sign. We report a case of pleural effusion secondary to a cancer of unknown primary site in a 60-year-old man that sought chiropractic care for radiating low back pain. The radiographic studies revealed a pleural effusion as one of the only significant finding. This article will address the clinical presentation, radiographic studies and a discussion on the radiographic detection of pleural effusion.

Les cancers de sites primaires inconnus représentent un syndrome clinique englobant de nombreux types de néoplasie. Le taux de mortalité associé à ce type de cancer est élevé et une consultation médicale rapide est nécessaire chez les patients présentant cette affection. Un épanchement pleural peut être le seul signe radiographique visible. Nous rapportons un cas d'épanchement pleural secondaire à un cancer de sites primaires inconnus chez un homme de 60 ans qui consultait en chiropratique pour une lombalgie irradiante. Les études radiographiques ont révélé un épanchement pleural comme une trouvaille fortuite. Nous avons inclus la présentation clinique, les examens radiographiques et une discussion sur la détection d'un épanchement pleural.

Fracture of the lateral tubercle of the posterior talar process caused by a rock-climbing fall: a case report.

The purpose of this case report is to describe the clinical presentation of a patient who suffered from a fracture of the lateral tubercle of the posterior talar process caused by a fall while rock-climbing. The initial evaluation revealed diffuse ankle swelling, tenderness, and pain at the distal aspect of both malleoli. Plain film radiography revealed a fracture of the posterior process of the talus. Computed tomography (CT) outlined the extension of the fracture line in the postero-lateral aspect of the body of the talus with minimal displacement. The patient was treated conservatively with an Aircast© walking boot for 6 weeks (non-weight-bearing) followed by a 2-week period of partial weight bearing. At the 8 week follow-up, he reported minimal tenderness and normal ankle function. Clinicians should be aware that talar fracture identification on plain films is difficult and computed tomography or magnetic resonance imaging may be required.

L'objectif de ce rapport de cas est de décrire la présentation clinique d'un patient qui a subi une fracture du tubercule latéral du processus talaire postérieur suite à une chute d'escalade. L'évaluation initiale a révélé un œdème diffus de la cheville et de la douleur sur l'aspect distal des deux malléoles. Les radiographies ont révélé une fracture de l'apophyse postérieure du talus. La tomodensitométrie a démontré que la ligne de fracture atteignait l'aspect postéro- latérale du corps du talus avec déplacement minimal. Le patient a été traité avec une botte Aircast© pour 6 semaines (sans mise en charge) suivie d'une période de 2 semaines de mise en charge partielle. Après 8 semaines, il rapporte un inconfort minimal ainsi qu'une fonction normale de sa cheville. Les cliniciens doivent être conscient que ce type de fracture requiert une évaluation minutieuse des radiographies. La tomodensitométrie ou l'imagerie par résonance magnétique sont parfois nécessaires.

A delayed diagnosis of bilateral facet dislocation of the cervical spine: a case report.

OBJECTIVE: To review the case of a patient suffering from bilateral facet dislocation of the cervical spine. CLINICAL FEATURES: A 53-year-old male was involved in a car accident and was transported to the hospital. Cervical radiographs were taken at the emergency department and interpreted as normal. Four days later, he consulted a chiropractor where radiographs of the cervical spine were repeated. The examination revealed bilateral cervical facet joint dislocation at C5-C6 as well as a fracture involving the spinous process and laminae of C6. INTERVENTION AND OUTCOME: The patient was referred to the hospital and underwent surgery. CONCLUSION: Patients involved in motor vehicle accidents often consult chiropractors for neck pain treatment. A high index of suspicion due to significant history and physical examination findings should guide the clinician in determining the need for reviewing the initial radiographs (if taken and available) or request repeat studies, regardless of the initial imaging status.

OBJECTIF: Examiner le cas d'un patient souffrant d'une dislocation facettaire bilatérale de la colonne cervicale. CARACTÉRISTIQUES CLINIQUES: Un homme de 53 ans a été transporté à l'hôpital à la suite d'un accident de voiture. Les radiographies cervicales prises à l'urgence ont été jugés normales. Quatre jours plus tard, les radiographies de la colonne cervicale ont été répétées chez un chiropraticien. L'examen a révélé une dislocation facettaire bilatérale à C5­C6, ainsi qu'une fracture impliquant l'apophyse épineuse et les lames de C6. INTERVENTION ET RÉSULTAT: Le patient a été envoyé à l'hôpital où il a subi une intervention chirurgicale. CONCLUSION: Les patients impliqués dans des accidents de véhicules automobiles consultent souvent les chiropraticiens pour le traitement des douleurs cervicales. Un indice élevé de suspicion dû à l'histoire importante et aux résultats de l'examen physique doit pousser le clinicien à déterminer la nécessité de réviser les radiographies initiales (si disponibles) ou à demander la répétition des examens, peu importe l'interprétation initiale de l'imagerie.

Performance of different population pharmacokinetic algorithms.

BACKGROUND: There has been an increased focus on population pharmacokinetics (PK) to improve the drug development process since the "Critical Path paper" by the Food and Drug Administration. This increased interest has given rise to additional algorithms. OBJECTIVES: The purpose of this exercise was to compare the new algorithms iterative-2-stage (ITS) and maximum likelihood expectation maximization (MLEM) available in ADAPT 5 with other methods. METHODS: A total of 29 clinical trials with different study designs were simulated. Different algorithms were used to fit the simulated data, and the estimated parameters were compared with the true values. The algorithms ITS and MLEM were compared with the standard-2-stage, Iterative-2-Stage (IT2S) method in the IT2S package and the first-order conditional estimate (FOCE) method in NONMEM version VI. Imprecision and bias for the population PK parameters, variances, and individual PK parameters were used to compare the methods. RESULTS: Population PK parameters were well estimated and bias low for all nonlinear mixed effect modeling approaches. These approaches were superior to the standard-2-stage analyses. The algorithm MLEM was better than IT2S and ITS in predicting the PK and variability parameters. Residual variability was better estimated using MLEM and FOCE. A difference in the estimation of the variance exists between FOCE and the other methods. Variances estimated with FOCE often had shrinkage issues, whereas MLEM in ADAPT 5 had practically no shrinkage problems. Using MLEM, a reduction from 3000 to 1000 samples in the expectation maximization step had no impact on the results. CONCLUSIONS: The new algorithm MLEM in ADAPT 5 was consistently better than IT2S and ITS in its prediction of PK parameters, variances, and the residual variability. It was comparable with the FOCE method with significantly fewer shrinkage issues in the estimation of variance. The number of samples used in the expectation maximization step with MLEM did not influence the results.

Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures.

BACKGROUND: Long QT syndrome (LQTS) is characterized by corrected QT interval prolongation leading to torsades de pointes and sudden cardiac death. LQTS type 2 (LQTS2) is caused by mutations in the KCNH2 gene, leading to a reduction of the rapidly activating delayed rectifier K+ current and loss of human ether-à-go-go-related gene (hERG) channel function by different mechanisms. Triggers for life-threatening arrhythmias in LQTS2 are often auditory stimuli. OBJECTIVES: To screen KCNH2 for mutations in patients with LQTS2 on an electrocardiogram and auditory-induced syncope interpreted as seizures and sudden cardiac death, and to analyze their impact on the channel function in vitro. METHODS: The KCNH2 gene was screened for mutations in the index patients of three families. The novel mutations were reproduced in vitro using site-directed mutagenesis and characterized using the Xenopus oocyte expression system in voltage clamp mode. RESULTS: Novel KCNH2 mutations (Y493F, A429P and del234-241) were identified in the index patients with mostly typical LQTS2 features on their electrocardiograms. The biochemical data revealed a trafficking defect. The biophysical data revealed a loss of function when mutated hERG channels were coexpressed with the wild type. CONCLUSIONS: In all families, at least one patient carrying the mutation had a history of seizures after auditory stimuli, which is a major trigger for arrhythmic events in LQTS2. Seizures are likely due to cardiac syncope as a consequence of mutation-induced loss of function of the rapidly activating delayed rectifier K+ current.

Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans.

BACKGROUND: Cyclosporine (INN, ciclosporin) is a cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) substrate whose bioavailability increases when administered with grapefruit juice. It is unknown whether pomelo, a closely related citrus fruit, interacts with cyclosporine in humans. In addition, a case study reports that cranberry juice interacts with warfarin, a drug with a narrow therapeutic range. Cranberries have a high content of flavonoids, compounds with various metabolic effects, including interaction with P-gp in vitro. Although the effect of flavonoids is less evident in vivo, cranberry juice has become a very popular beverage, and it was deemed important to investigate whether it has an effect on the disposition of cyclosporine, another drug with a narrow therapeutic range. METHODS: In an open-label, randomized, 3-way crossover study with a 14-day washout period between each dose, 12 healthy male volunteers received single oral 200-mg doses of cyclosporine according to the following regimens: 200 mg cyclosporine administered with 240 mL of pomelo juice, cranberry juice, or water under fasting conditions. Multiple whole blood samples were collected up to 36 hours after each dose. Concentrations were determined via a liquid chromatography-tandem mass spectrometry method. RESULTS: Administration of pomelo juice with cyclosporine increased the area under the curve from time 0 to the last measurable concentration (AUCt), area under the curve from time 0 to infinity (AUCinf), and maximum blood concentration (Cmax) of cyclosporine with ratios of least squares means of 119.4% (95% confidence interval [CI], 113.4%-125.8%), 118.9% (95% CI, 113.8%-124.3%), and 112.1% (95% CI, 102.3%-122.8%), respectively. All 3 variables exhibited statistically significant increases (with Bonferroni adjustment), with P = .0001 for AUCt and AUCinf and P = .0167 for Cmax; however, only the increase in AUCt was judged to be clinically significant with a 95% CI outside the 80% to 125% boundaries. Cranberry juice had no clinically significant effect on the overall disposition of cyclosporine. After administration of cyclosporine with cranberry juice, the ratios of least squares means for AUCt, AUCinf, and Cmax for cyclosporine were 95.0% (95% CI, 90.3%-100.1%), 93.4% (95% CI, 89.2%-97.8%), and 95.2% (95% CI, 86.9%-104.2%), respectively. CONCLUSION: These results suggest that pomelo juice increases the bioavailability of cyclosporine, possibly by inhibiting CYP3A or P-gp activity (or both) in the gut wall. However, drinking a glass of cranberry juice does not appear to significantly influence the disposition of cyclosporine.