Tunichlorin: a nickel chlorin isolated from the Caribbean tunicate Trididemnum solidum.

Tunichlorin, a blue-green pigment isolated from the Caribbean tunicate Trididemnum solidum, has been identified as nickel(II) 2-devinyl-2-hydroxymethylpyropheophorbide a by chemical and spectroscopic methods, with confirmation by partial synthesis of dimethyl tunichlorin from chlorophyll a. Nickel chlorins have been reported from geological sources but not from living organisms. Its occurrence in a living system suggests a metabolic role for tunichlorin and may clarify the selective accumulation of nickel by marine tunicates. Because Trididemnum tunicates are associated with algal symbionts, tunichlorin may arise directly from the tunicate, from symbiotic algae, or from tunicate modification of an algal chlorin.     

Pharmacokinetics and metabolism of a COX-2 inhibitor, valdecoxib, in mice.

The pharmacokinetics and metabolism of valdecoxib, a potent cyclooxygenase-2 selective inhibitor, were investigated in mice. Valdecoxib was extensively metabolized after a single 5 mg/kg oral administration of [(14)C]valdecoxib and elimination of unchanged drug was minor (less than 1%) in male and female mice. The total mean percentage of administered radioactive dose recovered was 99.8% in the male mice and 94.7% in the female mice. Sixteen metabolites were identified in mouse plasma, red blood cells, urine, and feces. The main phase I metabolic pathway of valdecoxib in mice involved the oxidation of the 5-methyl group to form the active hydroxymethyl metabolite M1. M1 was further oxidized to the carboxylic acid metabolite M4, which underwent opening of the isoxazole ring to form M6 and M13. Phase II metabolism included glucuronide, glucoside, and methyl sulfone conjugations. M1 was also conjugated with glucuronic acid and glucose to yield M-G and M1-glucose, respectively. Three novel methylsulfone conjugates M20, M21, and M21-G were detected in blood or urine. Valdecoxib and M1 were the major radioactive components in plasma and red blood cells. The plasma area under the curve from zero to infinity (AUC(0-infinity)) values for valdecoxib and M1 were 3.58 and 0.850 microg. h/ml in males and 2.08 and 1.63 microg. h/ml in females, respectively. The RBC AUC(0-infinity) values for valdecoxib and M1 were 12.1 and 22.6 microg. h/g in males and 6.42 and 35.2 microg. h/g in females, respectively.     

Host protection against deliberate bacterial contamination of an extracellular matrix bioscaffold versus Dacron mesh in a dog model of orthopedic soft tissue repair

The resistance of two biomaterials, one synthetic and one biologic in origin, to deliberate bacterial infection was compared in a dog model of orthopedic soft tissue reconstruction. Twenty-four adult female dogs were randomly divided into two equal groups and a 2.0-cm-round full-thickness defect was created on the lateral surface of the stifle joint, leaving only the synovium and skin intact. The defect was surgically repaired with either Dacron trade mark mesh or a porcine derived extracellular matrix (ECM) scaffold material. The repair site was inoculated with 1 x 10(8) Staphylococcus aureus at the time of surgery and the dogs were survived for 28 days. Results showed a chronic pyogranulomatous inflammatory response at the Dacron trade mark implant sites versus a constructive tissue-remodeling response without residual inflammation at the ECM implant site. Three dogs in the group receiving the Dacron trade mark mesh were treated with Keflex trade mark (500 mg bid x 7 days) for signs of septicemia. A quantitative bacterial count of the implant sites at the time of sacrifice showed 6.52 x 10(5) +/- 1.2 x 10(6) and 6.5 x 10(2) +/- 1.8 x 10(3) bacteria per gram of tissue for the Dacron trade mark and ECM scaffold sites, respectively (P <.03). The ECM implant material was more resistant than the synthetic implant material to persistent infection following deliberate bacterial contamination and the ECM scaffold supported constructive tissue remodeling.     

A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors

Summary Purpose: SNS-032, (formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. The primary objective of the study was to establish the maximum tolerated dose (MTD), the maximum administered dose (MAD), dose limiting toxicity (DLT), and the recommended phase 2 dose for SNS-032 when administered as a weekly 1-h infusion. The secondary objective was to assess the safety and tolerability of SNS-032 and to evaluate its bioavailability as an oral solution. Methods: Patients with metastatic solid tumors or refractory lymphoma were treated with a starting dose of 4 mg/m² intravenously administered over 1-h with a cycle defined as 3 weekly doses of SNS-032 every 21 days. Three patient cohorts were utilized in the dose-escalation schema. Pharmacokinetic studies were performed. For the 13 and 16 mg/m² dose cohorts, the first dose of cycle 2 was given as an oral solution to estimate the oral bioavailability of the drug in humans. Results: A total of 21 patients were enrolled. Twenty treated patients received a total of 39 cycles of treatment. The most common treatment-related adverse events occurring with greater than 20% incidence were fatigue (25%) and nausea (20%). Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean C _max and AUC_0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 μg/ml and 0.103 to 0.553 μg h/ml, respectively. The CL and V _ss remained unchanged with increasing dose levels, averaging 38 l/h/m² and 212 l/m², respectively. Average oral bioavailability was 19% (range: 4–33%). Three (15%) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug. Conclusions: SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032 administered intravenously on days 1, 8, and 15 of each treatment cycle was not reached. Tumor progression or stable disease was determined to be the best response in all evaluable patients. At the dose levels tested, the oral bioavailability of SNS-032 ranged from 4–33%. The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed.     

Survey of spine surgeons on attitudes regarding osteoporosis and osteomalacia screening and treatment for fractures,fusion surgery,and pseudoarthrosis

Background contextOsteoporosis and osteomalacia are significant risk factors for fracture and spine instrumentation failure. Low-energy fractures are becoming increasingly more common because of an increase in life expectancy and age of the population. Decreased bone density is an independent risk factor for instrumentation failure in spinal fusion operations.PurposeTo assess the awareness and practice patterns of spine surgeons regarding metabolic bone disorders and osteoporosis with emphasis on fracture care and arthrodesis.Study design/settingQuestionnaire study.Patient sampleSpine surgeons attending the “Disorders of the Spine” conference (January 2007, Whistler, British Columbia, Canada).Outcome measuresRespondent reported frequencies of diagnostics, screening, and treatment methods for patients with low-energy spine fractures, pseudoarthrosis, and those undergoing spinal arthrodesis.MethodsA ten-question survey was administered to orthopedic surgeons and neurosurgeons who treated spine fractures and degenerative spine conditions in their practice. The survey was given to those who were attending a continuing medical education spinal disorders conference. The survey asked about treatment patterns with respect to osteoporosis and osteomalacia workup and treatment for patients with low-energy spine fractures, pseudoarthrosis, and those undergoing spinal arthrodesis.ResultsOf the 133 surgeons to whom the questionnaire was distributed at this meeting, 114 questionnaires were returned that corresponds to a response rate of 86%. Twenty-one surveys were excluded because of incomplete biographical information, resulting in a total of 93 completed questionnaires that were available for analysis. When treating patients with low-energy spine fractures, 60% checked dual-energy X-ray absorptiometry (DEXA) and 39% checked metabolic laboratories (of those who did not order laboratories and DEXA about 63% refer for treatment). Before instrumented fusion, 44% of those queried checked DEXA and 12% checked metabolic laboratories (vitamin D, parathyroid hormone [PTH], and calcium [Ca]). Before noninstrumented fusion, 22% checked DEXA and 11% checked metabolic laboratories. Before addressing pseudoarthrosis, 19% checked DEXA and 20% checked metabolic laboratories.ConclusionsDespite of the large number of elderly patients undergoing spine care and the high incidence of osteoporosis and/or osteomalacia in this population, a large portion of the spine surgeons who responded to the survey reported that they do not perform routine osteoporosis/osteomalacia workups. Of those who do perform workups, some commented that it will change their surgical plan or preoperative treatment. It appears that there is a need for increased awareness among spine specialists regarding osteoporosis screening and treatment. Osteoporosis practice patterns may also be affected with newly evolving government quality reporting regulations.     

Use of end-systolic volume changes with exercise to detect left ventricular dysfunction in patients with coronary artery disease

To determine if end-systolic volume changes (ΔESV) in response to exercise were of value in detecting left ventricular dysfunction and compare it with other presently used criteria, 41 normal subjects and 122 patients with coronary artery disease (≥70 percent cross sectional luminal narrowing) were studied. All had upright maximal bicycle stress tests using equilibrium ra-dionuclide imaging in the left anterior oblique (LAO) projection. The sensitivity, specificity, and predictive value were determined for several criteria which included the following defined as normal responses: ΔEF≤5 absolute units, ΔEF>0, ΔESV<0, and a combination criterion of ΔEF>0 and ΔESV<0. The ΔESV criterion had a greater sensitivity than the ΔEF>0 criterion at 83% (101/122) and 66% (80/122) (p≤0.001), respectively, and was comparable to the EF≥5 criterion at 85% (104/122). The specificity of the ΔESV criterion was superior to the ΔEF≥5 criterion at 93% (38/41) and 80% (33/41) (p<0.01), respectively, and comparable to the ΔEF>0 criterion at 95% (39/41). This relationship was also apparent when those patients with infarctions were excluded. The end-systolic volume response to stress has a high sensitivity, specificity, and predictive value for detecting left ventricular dysfunction, perhaps due to the fact that it is a measure of left ventricular contractility. The end-systolic volume response to stress is superior in specificity to the ΔEF≥5 criterion and superior in sensitivity to the ΔEF>0 criterion. A combination of ΔEF>0 and AESV<0 appears to be a promising criterion for detecting left ventricular dysfunction.     

Metabolism and excretion of [(14)C]celecoxib in healthy male volunteers.

We determined the disposition of a single 300-mg dose of [(14)C]celecoxib in eight healthy male subjects. The [(14)C]celecoxib was administered as a fine suspension reconstituted in 80 ml of an apple juice/Tween 80/ethanol mixture. Blood and saliva samples were collected at selected time intervals after dosing. All urine and feces were collected on the 10 consecutive days after dose administration. Radioactivity in each sample was determined by liquid scintillation counting or complete oxidation and liquid scintillation counting. Metabolic profiles in plasma, urine, and feces were obtained by HPLC, and metabolites were identified by mass spectrometry and NMR. [(14)C]Celecoxib was well absorbed, reaching peak plasma concentrations within 2 h of dosing. [(14)C]Celecoxib was extensively metabolized, with only 2.56% of the radioactive dose excreted as celecoxib in either urine or feces. The total percentage of administered radioactive dose recovered was 84.8 +/- 4.9%, with 27.1 +/- 2.2% in the urine and 57.6 +/- 7.3% in the feces. The oxidative metabolism of celecoxib involved hydroxylation of celecoxib at the methyl moiety followed by further oxidation of the hydroxyl group to form a carboxylic acid metabolite. The carboxylic acid metabolite of celecoxib was conjugated with glucuronide to form the 1-O-glucuronide. The percentages of the dose excreted in the feces as celecoxib and the carboxylic acid metabolite were 2.56 +/- 1.09 and 54.4 +/- 6.8%, respectively. The majority of the dose excreted in the urine was the carboxylic acid metabolite (18.8 +/- 2.1%); only a small amount was excreted as the acyl glucuronide (1.48 +/- 0.15%).