PK/PD modeling of a clazosentan thorough QT study with hysteresis in concentration-QT and RR-QT.

Clazosentan's potential QT liability was investigated in a thorough QT study in which clazosentan was administered intravenously as a continuous infusion of 20 mg/h immediately followed by 60 mg/h. Clazosentan prolonged the placebo-corrected change-from-baseline QT interval corrected for RR with Fridericia's formula (ΔΔQTcF) with the maximum QT effect occurring 4 h after the maximum drug concentration, apparently associated with vomiting. The delayed effect precluded the standard linear modeling approach. This analysis aimed at characterizing the concentration-QT relationship in consideration of RR-QT hysteresis, concentration-ΔΔQTcF hysteresis, and the influence of vomiting. Nonlinear mixed-effects modeling was applied to characterize pharmacokinetics and pharmacodynamics, i.e., ΔΔQTcF. Simulations were used to predict ΔΔQTcF for expected therapeutic dose used in Phase 3 clinical development. Correction for RR-QT hysteresis did not influence ΔΔQTcF to a relevant extent. Pharmacokinetics of clazosentan were best described by a linear two-compartment model. The delayed QT prolongation was characterized by an indirect-response model with loglinear drug effect. Vomiting had no statistically significant influence on QT prolongation despite apparent differences between subjects vomiting and not vomiting, probably since vomiting occurred mostly after the main QT prolongation. Following a simulated 3-h infusion of 15 mg/h of clazosentan, the upper bound of the predicted 90% CI for mean ΔΔQTcF was expected to exceed the 10-ms regulatory threshold of concern with maximum effect 3.5 h after end of infusion. TRN: NCT03657446, 05 Sep 2018.

Preventive Effect of Clazosentan against Cerebral Vasospasm after Clipping Surgery for Aneurysmal Subarachnoid Hemorrhage in Japanese and Korean Patients.

BACKGROUND: Clazosentan has been explored worldwide for the prophylaxis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). In a dose-finding trial (CONSCIOUS-1) conducted in Israel, Europe, and North America, clazosentan (1, 5, and 15 mg/h) significantly reduced the incidence of cerebral vasospasm, but its efficacy in Japanese and Korean patients was unknown. We conducted a double-blind comparative study to evaluate the occurrence of cerebral vasospasm in Japanese and Korean patients with aSAH. METHODS: The aim of this multicenter, double-blind, randomized, placebo-controlled, dose-finding phase 2 clinical trial, was to evaluate the efficacy, pharmacokinetics, and safety of clazosentan (5 and 10 mg/h) against cerebral vasospasm after clipping surgery in Japanese and Korean patients with aSAH. Patients aged between 20 and 75 years were administered the study drug within 56 h after the aneurysm rupture and up to day 14 post-aSAH. The incidence of vasospasm, defined as an inner artery diameter reduction of major intracranial arteries ≥34% based on catheter angiography, was compared between each treatment group. Cerebral infarction due to vasospasm at 6 weeks and patients' outcome at 3 months was also compared. RESULTS: Among 181 enrolled patients, 158 completed the study and were analyzed. The incidence of vasospasm up to day 14 after aSAH onset was 80.0% in the placebo group (95% CI 67.0-89.6), 38.5% in the 5 mg/h clazosentan group (95% CI 25.3-53.0), and 35.3% in the 10 mg/h clazosentan group (95% CI 22.4-49.9), indicating that the incidence of vasospasm was significantly reduced by clazosentan treatment (placebo vs. 5 mg/h clazosentan, p < 0.0001; placebo vs. 10 mg/h clazosentan, p < 0.0001). The occurrence of cerebral infarction due to vasospasm was 20.8% in the placebo group (95% CI 10.8-34.1), 3.8% in the 5 mg/h clazosentan group (95% CI 0.5-13.2), and 4.2% in the 10 mg/h clazosentan group (95% CI 0.5-14.3), indicating that clazosentan significantly reduced the occurrence of cerebral infarctions caused by vasospasm (placebo vs. 5 mg/h clazosentan, p = 0.0151; placebo vs. 10 mg/h clazosentan, p = 0.0165). The overall incidence of all-cause death and/or vasospasm-related morbidity/mortality was significantly reduced in the 10 mg/h clazosentan group compared with the placebo group (p = 0.0003). CONCLUSION: These results suggest that clazosentan prevents cerebral vasospasm and subsequent cerebral infarction, and could thereby improve outcomes after performing a clipping surgery for aSAH in Japanese and Korean patients.

Delayed Wound Dehiscence of Anterior Knee Incisions in Patients Aged 20 Years and Younger: A Comparison of Subcutaneous Skin Closure.

BACKGROUND: Delayed wound dehiscence (DWD) typically occurs 2 to 7 weeks postoperatively and is characterized by wound gapping and drainage at a surgical site which has initial normal wound healing. This wound problem clinically mimics deep surgical site infection and, after eventual skin healing, leaves a cosmetically unattractive widened, atrophic surgical scar. METHODS: A single-center, retrospective analysis was completed of 252 knees, over a 13-year period, in 194 patients (average age, 14.9 y) undergoing patellar realignment surgery. All knees in this study were treated through an anterior midline knee incision from mid-patella to the tibial tubercle. At wound closure either a 2-0 polyglactin 910 (Vicryl) group (V) or polydioxane (PDS) group (P) suture was used for subcutaneous reapproximation and then the skin was closed with a 4-0 subcuticular Poliglecaprone 25 and IRGACARE (Monocryl) suture. Wound complications were recorded and analyzed by subcutaneous suture type, severity, size of involvement, duration, and treatment type. RESULTS: Of the 252 knees, there were 132 knees in the V group and 120 in the P group. A total of 195 surgeries were primary surgeries and 57 knees were through previous surgical scars. Eleven patients had surgeries in which 1 knee was in each study group. Overall there were 6.1% (8/132) of the V group and 1.7% (2/120) of the P group with DWD (P=0.11); hence there was a trend toward more DWD with Vicryl than PDS, but this did not meet statistical significance. Mean time to resolution of wound dehiscence was 26 days for V group and 46 days for the P group. The length of incision was demonstrated to be a statistically significant independent risk factor for the development of DWD, irrespective of suture type. CONCLUSIONS: The frequency of DWD in anterior knee incisions in our study population was 6.1% in the polyglactin 910 (Vicryl) group and 1.7% in the polydioxane (PDS) group. Although this analysis did not achieve statistical significance, a 3.5 times decrease in DWD when PDS was used is considered by the authors to be clinically significant. The authors have definitively switched from Vicryl to PDS for the subcutaneous skin closure at the knee in patients aged 20 years and younger in the push to make wound complications a nonevent. LEVEL OF EVIDENCE: Level IV.

Comparison of suture materials for subcuticular skin closure at cesarean delivery.

BACKGROUND: Subcuticular skin closure with suture after cesarean has been shown to result in lower rates of wound complications than with staple closure. However, the optimal choice of suture material for subcuticular skin closure is unclear. Vicryl (a braided multifilament synthetic suture; Ethicon, Somerville, NJ) and Monocryl (a monofilament synthetic suture; Ethicon) are the commonly used suture materials for subcuticular closure of transverse skin incisions after cesarean in the United States. Whereas in vitro and animal studies suggest multifilament suture materials may be associated with a higher risk of wound infection than monofilament sutures, clinical data on their relative effectiveness are limited. OBJECTIVE: We sought to test the hypothesis that Vicryl is associated with a higher rate of wound complications than Monocryl. STUDY DESIGN: This is a secondary analysis of data from a randomized trial in which pregnant women undergoing scheduled or unscheduled cesareans were randomly assigned to preoperative skin preparation with either chlorhexidine-alcohol or iodine-alcohol. Women with low transverse skin incisions who were closed with either 4-0 Monocryl or 4-0 Vicryl were included in this analysis. Choice of suture material was at the discretion of the operating physician. The primary outcome was superficial or deep surgical site infection within 30 days after cesarean. Secondary outcomes were other wound complications. Outcomes were compared between the 2 groups using univariable and multivariable statistics. RESULTS: Of 1082 patients who had follow-up after discharge in the primary trial, 871 had subcuticular suture: 180 with 4-0 Vicryl and 691 with 4-0 Monocryl. Skin closure with Vicryl or Monocryl did not significantly differ between women allocated to chlorhexidine-alcohol or iodine-alcohol (51.1% vs 49.4%, P = .67). There was no significant difference in the risk of surgical site infection in women closed with Vicryl compared with Monocryl (11 [6.1%] vs 35 [5.1%]; P = .58; adjusted odds ratio, 1.23; 95% confidence interval, 0.60-2.49). Rates of other wound complications were also not significantly different. Risks of surgical site infection were similar with Vicryl and Monocryl closure in all subgroups assessed. The relative risks were not materially affected by whether diabetes or obesity was present, cesarean was scheduled or unscheduled, primary or repeat cesarean, or the subcutaneous layer was closed. Post hoc power analysis indicated that we had 80% power to detect >2-fold difference in surgical site infections. CONCLUSION: Subcuticular skin closure with 4-0 Vicryl is associated with comparable rates of surgical site infection and other wound complications as 4-0 Monocryl. While this is an observational study with the potential for selection bias and residual confounding, our results suggest physician preference is acceptable for choice of subcuticular suture material at cesarean.

A review of selected chemical additives in cosmetic products.

The addition of chemical additives to consumer cosmetic products is a common practice to increase cosmetic effectiveness, maintain cosmetic efficacy, and produce a longer-lasting, more viable product. Recently, manufacturers have come under attack for the addition of chemicals including dioxane, formaldehyde, lead/lead acetate, parabens, and phthalate, as these additives may prove harmful to consumer health. Although reports show that these products may indeed adversely affect human health, these studies are conducted using levels of the aforementioned chemicals at much higher levels of exposure than those found in cosmetic products. When cosmeceuticals are used as per manufacturer's instructions, it is estimated that the levels of harmful additives found in these products are considerably lower than reported toxic concentrations.

Adverse events associated with biodegradable lactide-containing suture anchors.

PURPOSE: To evaluate the occurrence of adverse events and inflammatory reactions related to the use of biodegradable anchors. METHODS: A retrospective review of a consecutive series of arthroscopic shoulder procedures using biodegradable suture anchors performed by a single surgeon was undertaken. The database was purged of patient identifiers. The blinded data were analyzed for procedure type, anchor type and composition, associated procedures, and general demographic data. Anchor composition and number were recorded. A shoulder procedure after the index operation was considered an adverse event. The nature of these procedures was evaluated using medical records, operative images, and video, looking specifically for inflammatory reactions. Any anchor-related issues were documented. RESULTS: Three hundred sixty cases met the inclusion criteria. The procedure was a tendon repair (rotator cuff or biceps) in 265 cases and a labral repair (instability or SLAP) in 97, 2 of which were combined instability and tendon repairs. Nine different biodegradable anchors were identified, possessing 4 different polymer combinations. Adverse events (reoperations) were identified in 18 of 360 patients (5%): 13 tendon repairs and 5 labral/instability repairs. Only 2 were anchor related. In 1 tendon repair case, the anchor broke and an anchor fragment required removal. In 1 labral repair case, the anchor eyelet (a suture) loosened from the anchor body and eroded the humeral head. No cases of inflammatory synovitis were observed. No statistical difference in adverse event rates existed between tendon and labral repairs (P > .05). CONCLUSIONS: Anchor-specific adverse events occurred in 2 of 360 procedures (0.5%). One was anchor design related (the prominent head containing the suture eyelet broke off) in a poly-L-lactic acid (PLLA) anchor. One was anchor material related and occurred when the poly-levo (70%)/dextro (30%)-lactide anchor body reabsorbed, loosening the encased eyelet suture and allowing this suture to migrate into the joint. No inflammatory reactions were documented in the slowly degrading pure PLLA or more rapidly degrading biocomposite PLLA/ß-tricalcium phosphate-based anchors. LEVEL OF EVIDENCE: Level IV, retrospective review, therapeutic study.

Comparison of poliglecaprone-25 and polyglactin-910 in cutaneous surgery.

BACKGROUND: Few clinical studies have compared deep absorbable sutures. Poliglecaprone-25 and polyglactin-910 are two of the most commonly used absorbable sutures in cutaneous surgery. OBJECTIVES: To compare the rate of suture extrusion, degree of lumpiness, and appearance of scars from wounds closed with poliglecaprone-25 and polyglactin-910. METHODS: Poliglecaprone-25 or polyglactin-910 was used for closure of the deep part of Mohs defects. The number of extruded sutures and the number of lumps were recorded at each follow-up visit. Photographs of 1-week and 3-month postoperative scars were rated on a visual analogue scale. RESULTS: One hundred forty patients completed the study. There was a statistically significant difference in the percentage of extruded sutures between poliglecaprone-25 (3.1%) and polyglactin-910 (11.4%) (p < .01). There was not a statistically significant difference in the percentage of lumps (both 22%) or overall appearance of scars at 1 week or 3 months. CONCLUSION: Poliglecaprone-25 resulted in significantly less extruded sutures than did polyglactin-910, although both resulted in the same degree of lumpiness and similar-appearing scars at 1 week and 3 months.

Proposed mechanism of cerebral vasospasm: our hypothesis and current topics.

Increased vascular contractility plays an important role in the development of cerebral vasospasm following subarachnoid hemorrhage (SAH). Increased vascular contractility can be attributed to either endothelial dysfunction or increased contractility of vascular smooth muscle. Endothelial damage and dysfunction cause impairment of endothelium-dependent vasodilation of the cerebral artery after SAH. In addition to endothelial damage and dysfunction, receptor upregulation in vascular smooth muscle contributes to the induction and enhancement of contractile responses to agonists. Our recent data revealed that feedback regulation of the activity of the G protein-coupled receptor and myofilament Ca(2+) sensitivity is impaired after SAH. This impaired feedback regulation is suggested to cause a sustained contractile response to various agonists, thereby contributing to increased vascular contractility. In addition, three current topics are reviewed: endothelin type A receptor antagonists, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for treatment, and cortical spreading depolarization for the mechanism of cerebral vasospasm.

Allergic contact dermatitis associated with Biosyn suture in a patient with gastroesophageal junction cancer.

A PUBMED literature review revealed no reports of allergic contact dermatitis to Biosyn(™) suture material. We present the first case of such an allergic reaction. The case emphasizes the need to remember that suture material can occasionally elicit an allergic dermatitis which may increase the complications and morbidity associated with any surgical procedure.

Efficacy and Safety of Clazosentan After Aneurysmal Subarachnoid Hemorrhage: An Updated Meta-Analysis.

BACKGROUND AND OBJECTIVES: Clazosentan has been studied to treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH).This meta-analysis of randomized controlled trials updates the current knowledge regarding the efficacy and safety of clazosentan compared with placebo after aSAH. METHODS: Databases were systematically searched for randomized controlled trials directly comparing the use of clazosentan and placebo for the treatment of cerebral vasospasm after aSAH. Additional eligibility criteria were the report of any of the outcomes of interest (vasospasm, morbidity, functional outcome, or mortality). The primary outcome was vasospasm-related delayed cerebral ischemia (DCI). The analyses were stratified by clazosentan dosage (low or high dose) and aneurysm treatment modality (clipping or coiling). The Cochrane RoB-2 tool was used for studies quality assessment. RESULTS: Six studies comprising 7 clinical trials were included, involving 2778 patients. Clazosentan decreased the risk of vasospasm-related DCI (risk ratio [RR] 0.56, 95% CI 0.38-0.81) and delayed ischemic neurological deficit (RR 0.63, 95% 0.50-0.80). Angiographic vasospasm (RR 0.54, 95% CI 0.47-0.61) was also decreased. Functional outcomes (favorable Glasgow Outcome Scale, RR 0.99, 95% CI 0.79-1.24) and death (RR 1.03, 95% CI 0.71-1.49) did not change. Meanwhile, adverse events were increased by clazosentan (RR 1.54, 95% CI 1.35-1.76). CONCLUSION: Clazosentan decreased vasospasm-related DCI and angiographic vasospasm but did not improve functional outcomes or mortality. Adverse events were increased by clazosentan.

Endothelin receptor antagonists for subarachnoid hemorrhage.

BACKGROUND: A subarachnoid hemorrhage (SAH) is a serious and potentially life-threatening condition where blood leaks out of blood vessels over the surface of the brain. Delayed ischemic neurological deficit (DIND) and the related feature of vasospasm, where patients experience a delayed deterioration, have long been recognized as the leading potentially treatable cause of death and disability in patients with SAH. Endothelin is a potent, long-lasting endogenous vasoconstrictor that has been implicated in the pathogenesis of DIND. Therefore, endothelin receptor antagonists (ETAs) have emerged as a promising therapeutic option for SAH-induced cerebral vasospasm. OBJECTIVES: To assess the efficacy and tolerability of ETAs for SAH. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 11), MEDLINE (1950 to December 2011), EMBASE (1946 to December 2011) and the Chinese Biomedical Database (1978 to December 2011). In an effort to identify further published, unpublished and ongoing trials we searched additional Chinese databases, ongoing trials registers, Google Scholar and Medical Matrix, handsearched journals, scanned reference lists, and contacted researchers and pharmaceutical companies. SELECTION CRITERIA: We only included randomized controlled trials (RCTs) that compared an ETA with placebo for SAH in adult (18 years of age or older) patients who met the diagnostic criteria for SAH based on clinical symptoms, with confirmation on computerized tomography scan results or angiography. Two review authors independently selected RCTs according to the inclusion criteria. We resolved disagreements by discussion with a third review author. DATA COLLECTION AND ANALYSIS: Two review authors independently selected relevant articles and assessed their eligibility according to the inclusion and exclusion criteria. We resolved disagreements by discussion with a third review author. We used the random-effects model and expressed the results as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included four RCTs with 2024 participants that compared ETAs with placebo for SAH. All RCTs were multicenter, double-blind studies with a low risk of bias. ETAs reduced the incidence of DIND (RR 0.80; 95% CI 0.67 to 0.95) and angiographic vasospasm (RR 0.62; 95% CI 0.52 to 0.72) but did not reduce the incidence of unfavorable outcomes (RR 0.87; 95% CI 0.74 to 1.02) or mortality (RR 1.05; 95% CI 0.77 to 1.45). ETAs increased the incidence of hypotension (RR 2.53; 95% CI 1.77 to 3.62) and pneumonia (RR 1.56; 95% CI 1.23 to 1.97). AUTHORS' CONCLUSIONS: ETAs appear to reduce DIND and angiographic vasospasm but there were adverse events and the impact on clinical outcome is unclear. Additional well-designed RCTs are needed.

Formaldehyde-releasers in cosmetics in the USA and in Europe.

BACKGROUND: Frequencies of sensitization to formaldehyde among US patients patch tested for suspected contact dermatitis are higher than in Europe. Cosmetics are an important source of contact with formaldehyde. OBJECTIVES: To acquire data on the frequency of use of formaldehyde-releasers in cosmetics sold in the USA and Europe and their use concentrations. To assess whether any observed differences may contribute to the discrepancies in sensitization rates. METHODS: Enquiries with Food and Drug Administration (FDA), the European Cosmetics Association, and the Dutch Cosmetics Association. Reading the labels of skin care cosmetics in a local drugstore. RESULTS: The FDA provided data on the presence of formaldehyde and releasers. Nearly one fifth of all cosmetics contain a releaser. In 25% of 496 examined skin care products, releasers were present. In comparable FDA data categories, the percentage was 24. No data were found on use concentrations of the releasers in cosmetics in either the USA or Europe. CONCLUSIONS: The percentages of stay-on skin care products containing a formaldehyde-releaser are virtually identical in the USA (FDA data) and our local drugstore sample. However, this does not necessarily imply that cosmetics play no part in the differences in formaldehyde sensitization rates.

Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 1. Characterization, frequency and relevance of sensitization, and frequency of use in cosmetics.

In this part of a series of review articles on formaldehyde-releasers and their relationship to formaldehyde contact allergy, formaldehyde-releasers in cosmetics are discussed. In this first part of the article, key data are presented including frequency of sensitization and of their use in cosmetics. In Europe, low frequencies of sensitization have been observed to all releasers: 2-bromo-2-nitropropane-1,3-diol 0.4-1.2%, diazolidinyl urea 0.5-1.4%, imidazolidinyl urea 0.3-1.4%, quaternium-15 0.6-1.9% (for DMDM hydantoin no recent data are available). All releasers score (far) higher prevalences in the USA; the possible explanations for this are discussed. The relevance of positive patch test reactions has been insufficiently investigated. In the USA, approximately 20% of cosmetics and personal care products (stay-on products: 17%, rinse-off products 27%) contain a formaldehyde-releaser. The use of quaternium-15 is decreasing. For Europe, there are no comparable recent data available. In the second part of the article, the patch test relationship of the releasers in cosmetics to formaldehyde contact allergy will be reviewed and it will be assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals who have contact allergy to formaldehyde.

Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 2. Patch test relationship to formaldehyde contact allergy, experimental provocation tests, amount of formaldehyde released, and assessment of risk to consumers allergic to formaldehyde.

This is the second part of an article on formaldehyde-releasers in cosmetics. The patch test relationship between the releasers in cosmetics to formaldehyde contact allergy is reviewed and it is assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals with contact allergy to formaldehyde. There is a clear relationship between positive patch test reactions to formaldehyde-releasers and formaldehyde contact allergy: 15% of all reactions to 2-bromo-2-nitropropane-1,3-diol and 40-60% of the reactions to the other releasers are caused by a reaction to the formaldehyde in the test material. There is only fragmented data on the amount of free formaldehyde in cosmetics preserved with formaldehyde donors. However, all releasers (with the exception of 2-bromo-2-nitropropane-1,3-diol, for which adequate data are lacking) can, in the right circumstances of concentration and product composition, release >200 p.p.m. formaldehyde, which may result in allergic contact dermatitis. Whether this is actually the case in any particular product cannot be determined from the ingredient labelling. Therefore, we recommend advising patients allergic to formaldehyde to avoid leave-on cosmetics preserved with quaternium-15, diazolidinyl urea, DMDM hydantoin, or imidazolidinyl urea, acknowledging that many would tolerate some products.

Delayed foreign-body reaction to absorbable implants in metacarpal fracture treatment.

BACKGROUND: First-generation bioabsorbable implants have been associated with a high complication rate attributable to weak mechanical properties and rapid degradation. This has led to the development of stronger devices with improved durability. However, the modern implants have raised concerns about potential late-occurring adverse reactions. QUESTIONS/PURPOSES: This retrospective study addressed the following questions: Can absorbable implants consisting of trimethylene carbonate, L-lactide, and D,L-lactide provide adequate fixation for healing of a metacarpal fracture? Will these implants obviate a second removal operation? What complications can occur in the reaction to implant breakdown? PATIENTS AND METHODS: Twelve unstable, displaced, metacarpal fractures were studied in 10 consecutive patients (seven men, three women; mean age, 36.4 years; range, 18-75 years). The fractures were treated with absorbable plates and screws consisting of the aforementioned copolymers and designed to resorb in 2 to 4 years. Nine patients (10 fractures) were available for clinical and radiographic followups (mean, 45.7 months; range, 34-61 months). RESULTS: Fracture healing was uneventful in all cases. Four patients experienced a foreign-body reaction during the second postoperative year and required surgical débridement to remove implant remnants. Histologic examination confirmed the diagnosis of a foreign-body reaction. Two other patients reported a transient local swelling that subsided without treatment. CONCLUSIONS: Our results indicate these absorbable implants for metacarpal fractures achieved adequate bone healing but simply postponed the problem of foreign-body reactions. Patients treated with bioabsorbable implants should be advised of potential late complications and should be followed for at least 2 years, possibly longer.

Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan.

This study investigated the potential QT liability of the selective endothelin-1 A receptor antagonist clazosentan at a therapeutic (20 mg/h) and supratherapeutic (60 mg/h) intravenous (i.v.) dose. A randomized, placebo- and moxifloxacin-controlled, double-blind, 3-period, crossover study was conducted in 36 healthy subjects receiving clazosentan (20 mg/h followed by 60 mg/h i.v. for 3 h each), placebo (i.v. for 6 h), and moxifloxacin (single oral dose of 400 mg concomitantly with placebo i.v. for 6 h). At least three replicate ECGs were extracted from Holter recordings at predefined time points from 1 h pre-dose to 24 h after end of infusion. Pharmacokinetic blood sampling was performed for concentration/QT analysis (primary endpoint). For moxifloxacin, the lower bound of the 90% confidence interval (CI) of baseline- and placebo-corrected QTcF (ΔΔQTcF) was > 5 ms at its maximum plasma concentration together with a positive slope of the concentration/QT regression line demonstrating assay sensitivity. For clazosentan, time of peak exposure preceded maximum ΔΔQTcF by 4 h indicating delayed QT-prolonging effects leading to invalidity of the concentration/QT analysis. The secondary by-time-point analysis revealed QT liability of clazosentan (i.e., upper bound of 90% CI ∆∆QTcF > 10 ms). Delayed QT prolongation (i.e., hysteresis) was predominantly observed in subjects with nausea and vomiting, potentially caused by vagal reaction and/or decreases in potassium concentration. By contrast, there was no association with other adverse events, food intake, or concomitant medication. In conclusion, clazosentan at therapeutic and supratherapeutic doses has QT liability with hysteresis effects being associated with nausea and vomiting.

Risk of gastrojejunal anastomotic stricture with multifilament and monofilament sutures after hand-sewn laparoscopic gastric bypass: a prospective cohort study.

BACKGROUND: Gastrojejunal (GJ) stricture is one of the most common late complications after laparoscopic Roux-en-Y gastric bypass (LRYGBP) with a hand-sewn anastomosis. The object of this study was to assess the risk of stricture for two types of resorbable suture (multifilament and monofilament) in a series of LRYGBPs performed by the same surgeon. DESIGN: Prospective cohort study. The study population consisted of a series of consecutive morbidly obese patients who underwent primary hand-sewn LRYGBP between March 2004 and May 2008 at the University Hospital in Getafe, Madrid, Spain. The study comprised 242 LRYGBPs with a four-layer continuous hand-sewn anastomosis using absorbable 3/0 gauge suture. The suture material was Ethicon Vicryl multifilament in the first 105 cases and Ethicon Monocryl monofilament in the following 137 cases. All patients were followed up monthly for the first 6 months and then every 6 months after that. RESULTS: The mean BMI was 46 +/- 4 for the multifilament cohort and 48 +/- 6 for the monofilament cohort with no significant difference between the two (p = 0.567). There were no anastomotic leaks, and no cases of marginal ulcer, abscess, abdominal sepsis, deep vein thrombosis, or pulmonary embolism were recorded. No cases required conversion to open surgery, and perioperative mortality was zero. In all, 11 cases of stricture (4.4%) were recorded, 10 in the multifilament suture cohort (9.5%), and only one in the monofilament suture cohort (0.7%; p = 0.001). The odds ratio was 14.3 (95% CI = 1.8-113.4). The mean outpatient follow-up period was 30 months (range = 6-42). CONCLUSIONS: Anastomotic GJ stricture is a common and well-known complication of laparoscopic gastric bypass for morbid obesity. Hand sewing with monofilament suture significantly lowered the frequency of this complication, and hence, monofilament should be the suture material of choice for this suturing technique.

Safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of lecozotan in healthy young and elderly subjects.

AIMS: To determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral immediate release (IR) lecozotan in healthy young and elderly subjects. METHODS: Three randomized, double-blind, placebo-controlled, sequential, ascending dose Phase I studies of lecozotan were conducted. In a single-dose study, ascending doses of 2, 5 and 10 mg were administered to cohorts of eight young subjects. In the two ascending 14-day multiple-dose studies, 41 young subjects received 0.1, 0.25, 0.5, 1 and 5 mg q12h of lecozotan or placebo and 24 elderly received 0.5 mg and 5 mg q12h of lecozotan or placebo. Assessments included safety evaluations, a complete PK profile and PD. RESULTS: Lecozotan was safe and well tolerated at steady state up to 5 mg q12. The maximum tolerated dose after multiple doses was >10 mg (5 mg q12). In the single-dose study, the maximum tolerated dose was 10 mg. Dose-limiting mild-to-moderate adverse events included paraesthesia, dizziness and visual disturbances peaking at t(max) and disappearing concomitantly with plasma concentrations. No clinically relevant changes in vital signs, ECG intervals or routine laboratory tests occurred. Lecozotan did not significantly change cognitive function, EEG or hormone levels. PK was characterized by rapid absorption, dose proportionality, extensive distribution and rapid elimination. The mean CL/F was approximately 35% lower in the elderly. CONCLUSIONS: Lecozotan IR was safe and well tolerated after administration of multiple oral doses up to 5 mg q12h in young and elderly subjects. These results support the development of lecozotan in patients with Alzheimer's disease.

Effect of orally administered KF66490, a phosphodiesterase 4 inhibitor, on dermatitis in mouse models.

Due to the broad anti-inflammatory and immunomodulatory actions of phosphodiesterase (PDE) 4 inhibitors, it has been proposed that PDE4 inhibitors might be efficacious for skin disorders such as atopic dermatitis. KF66490 is a newly developed PDE4 inhibitor that inhibits PDE4B (IC(50)=220 nM) and the production of tumor necrosis factor (TNF)-alpha by mouse peritoneal exudated cells stimulated with lipopolysaccharide (IC(50)=855 nM). To evaluate efficacy of KF66490 in atopic dermatitis (AD) models, on skin inflammation induced by repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB) on ear in BALB/c mice and on spontaneously AD-like skin diseases in NC/Nga mice. BALB/c mice were sensitized with 0.3% w/v TNCB applied to the ear on day-7, followed by application three times a week from days 0 to 21. NC/Nga mice spontaneously developed dermatitis symptoms under conventional conditions. Test compounds were administered orally once daily during experiments. In the TNCB-induced dermatitis model, KF66490 significantly inhibited the increase in ear thickness and interleukin (IL)-4 and IL-1beta levels in the ear. Histopathological and immunohistochemical analysis revealed that KF66490 significantly inhibited the proliferation of fibroblasts and CD3-positive T cells infiltration into the ear. In addition, KF66490 significantly suppressed the development of dermatitis in NC/Nga mice on all observation days, except for 5 and 6 weeks after the first dose. Furthermore, KF66490 produced less potent emetic effects than the first generation PDE4 inhibitor, rolipram. The present results suggest that KF66490 has excellent potential as an oral medicine for the treatment of atopic dermatitis.

Increased incidence of pancreatic fistulas after the introduction of a bioabsorbable staple line reinforcement in distal pancreatic resections.

Pancreatic fistula is a major cause of morbidity after distal pancreatic resection. When resections are performed with linear stapling devices, the use of bioabsorbable staple line reinforcement has been suggested to decrease the rate of pancreatic fistula. Our objective was to investigate the incidence of pancreatic fistula when using the Gore Seamguard staple line reinforcement in stapled distal pancreatic resections. A retrospective review of 30 consecutive patients with stapled distal pancreatectomy was conducted. A broad definition of pancreatic fistula was used. Clinicopathologic factors and outcomes were compared between groups. Pancreatic fistula was diagnosed in 11 of 15 patients (73%) and three of 15 patients (20%) in the Seamguard and non-Seamguard groups, respectively (P = 0.002). Pancreatic parenchymal transection at the neck of the gland was associated with pancreatic fistula, whereas laparoscopic procedures, splenic preservation, or additional organ resection were not. On multivariate analysis, the association between Seamguard use and pancreatic fistula was significant (P = 0.005). In conclusion, after introduction of the Gore Seamguard bioabsorbable staple line reinforcement, we experienced a significant increase in the rate of pancreatic fistula. This experience raises concern about the efficacy of this device in limiting pancreatic fistula after stapled distal pancreatic resection.