1.
Phase II trial of sorafenib in conjunction with chemotherapy and as maintenance therapy in extensive-stage small cell lung cancer.
Sharma, N, Pennell, N, Nickolich, M, Halmos, B, Ma, P, Mekhail, T, Fu, P, Dowlati, A
Investigational new drugs. 2014;(2):362-8
Abstract
OBJECTIVES Sorafenib is a multi-tyrosine kinase inhibitor of Raf kinase, VEGFR, and PDGFR. Angiogenesis is important for growth and progression of SCLC. This trial was conducted to evaluate whether the combination of cisplatin and etoposide plus concurrent and sequential sorafenib could prolong survival in patients with previously untreated SCLC. METHODS Previously untreated patients with extensive stage SCLC were treated with cisplatin and etoposide days 1, 2, 3 for four cycles, concurrent with sorafenib 200 mg orally bid starting day 1 cycle 1. Patients with no disease progression after four cycles continued sorafenib 400 mg orally bid as maintenance for maximum of 12 months. The primary endpoint was 1 year survival with response rate and safety as secondary endpoints. RESULTS A total of 18 patients were enrolled with 17 evaluable patients. One patient had a complete response, seven patients had a partial response (overall response rate of 47 %) and one patient had stable disease. Overall median survival was 7.4 months and 1 year survival was 25 %. The most common treatment-related adverse events included fatigue, anorexia, rash, diarrhea, neutropenia and weight loss. Grade 5 GI bleeding, pulmonary hemorrhage and neutropenia occurred in one pt (6 %) each. Accrual was halted on the basis of safety profile as well as preliminary efficacy data. CONCLUSIONS The combination of platinum based chemotherapy and sorafenib has significant toxicity at current dose levels and is associated with disappointing efficacy data.
2.
99mTc-MIBI myocardial perfusion imaging in myocarditis.
Sun, Y, Ma, P, Bax, JJ, Blom, N, Yu, Y, Wang, Y, Han, X, Wang, Y, Van Der Wall, EE
Nuclear medicine communications. 2003;(7):779-83
Abstract
Myocardial perfusion imaging with technetium-99m-labelled methoxyisobutyl isonitrile single photon emission computed tomography (99mTc-MIBI SPECT) has proven to be an important clinical procedure in assessing the severity of myocardial ischaemia. The uptake and clearance of 99mTc-MIBI by the myocardium is affected by cell viability and membrane integrity. Consequently, infectious diseases, such as myocarditis, may also affect myocardial perfusion by inducing local inflammation and necrosis. We compared 99mTc-MIBI myocardial perfusion imaging with other heart monitoring methods in order to assess its value in the diagnosis of children with Coxsackie viral myocarditis. We examined 46 patients (age, 3-12 years) with Coxsackie viral myocarditis using 99mTc-MIBI myocardial perfusion imaging and compared the perfusion data with myocardial enzymes, electrocardiographic findings and echocardiography. Regions of hypoperfusion were found in all 46 patients. Seventeen patients (37%) showed two or more areas of diminished perfusion. Myocardial hypoperfusion was mild-to-moderate (<30%) in 33 (72%) patients and severe (>30%) in 13 (28%) patients. Characteristic creatine-kinase isoenzyme (CK-MB) increases, ST-T segment changes and diminished heart function were significantly correlated with reduced myocardial perfusion (all comparisons P<0.05). The results of this study suggest that the presence of myocardial uptake of 99mTc-MIBI may be a marker of myocardial inflammation and necrosis. All 46 patients with Coxsackie viral myocarditis showed a certain degree of reduced perfusion. When the perfusion findings were compared with other parameters, it was shown that myocardial enzyme levels, ST-T segment changes and left ventricular function correlated well with the 99mTc-MIBI-established perfusion defect severity. 99mTc-MIBI SPECT imaging is therefore helpful in providing additional diagnostic information in patients with Coxsackie viral myocarditis.
3.
Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases.
Chen, T, Berenson, J, Vescio, R, Swift, R, Gilchick, A, Goodin, S, LoRusso, P, Ma, P, Ravera, C, Deckert, F, et al
Journal of clinical pharmacology. 2002;(11):1228-36
Abstract
The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa), a new-generation bisphosphonate, were evaluated in 36 patients with cancer and bone metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone turnover were determined in plasma and urine after three consecutive infusions (qx28 days) of 4 mg/5 min (n = 5),4 mg/l5 min (n = 7),8 mg/15 min (n = 12), or 16 mg/15 min (n = 12). Zoledronic plasma disposition was multiphasic, with half-lives of 0.2 and 1.4 hours representing an early, rapid decline of concentrations from the end-of-infusion C(max) to < 1% of C(max) at 24 hours postdose and half-lives of 39 and 4526 hours describing subsequent phases of very low concentrations between days 2 and 28 postdose. AUC0-24 h and C(max) were dose proportional and showed little accumulation (AUC0-24 h ratio between the third and first dose was 1.28). Prolonging the infusion from 5 to 15 minutes lowered C(max) by 34%, with no effect on AUC0-24 h. Urinary excretion of zoledronic acid was independent of infusion duration, dose, or number of doses, showing average Ae0-24 h of 38% +/- 13%, 41% +/- 14%, and 37% +/- 17%, respectively, after 4, 8, and 16 mg. Only trace amounts of drug were detectable in post 24-hour urines. Renal clearance (Ae0-24 h)/(AUC0-24 h) was on average 69 +/- 28,81 +/- 40, and 54 +/- 34 ml/min after 4,8, and 16 mg, respectively, and showed a moderate correlation (r = 0.5; p < 0.001) with creatinine clearance, which was 84 +/- 23, 82 +/- 25, and 80 +/- 40 ml/min for the dose groups at baseline. Adverse events and changes from baseline in vital signs and clinical laboratory variables showed no relationship in terms of type, frequency, or severity with zoledronic acid dose or pharmacokinetic parameters. Zoledronic acid produced significant declines from baseline in serum and/or creatinine-corrected urine C-telopeptide (by 74%), N-telopeptide (69%), pyridinium cross-links [19-33%), and calcium (62%), with an increasing trend (by 12%) in bone alkalinephosphatase. There was no relationship of the magnitude and duration of these changes with zoledronic acid dose, Ae0-24 h, AUC0-24 h or C(max). The antiresorptive effects were evident within 1 day postdose and were maintained over 28 days across all dose levels, supporting monthly dosing with 4 mg zoledronic acid.
4.
Randomized comparison of T-type versus L-type calcium-channel blockade on exercise duration in stable angina: results of the Posicor Reduction of Ischemia During Exercise (PRIDE) trial.
Lee, DS, Goodman, S, Dean, DM, Lenis, J, Ma, P, Gervais, PB, Langer, A, ,
American heart journal. 2002;(1):60-7
Abstract
BACKGROUND Mibefradil is a T-type calcium-channel antagonist and arterial vasodilator with negative chronotropic effects. It is not known if T-type calcium-channel blockade is superior to L-type calcium-channel blockade in patients with stable angina pectoris. METHODS A multicenter, randomized, double-blind trial was conducted in patients with documented coronary disease and stable angina to compare a 360 mg dose of diltiazem CD with 100 mg dose of mibefradil. The primary end point was change in time to symptom-limited exercise termination from baseline to 8 weeks. Secondary efficacy parameters included time to onset of persistent ST-segment depression, time to awareness of angina, and change in exercise duration from baseline to 2 and 4 weeks of treatment. RESULTS A total of 121 patients were randomized to mibefradil and 113 to diltiazem CD. At 8 weeks, the increase in exercise duration was 24.5 seconds greater in the mibefradil group (P =.017; 95% CI 4.4-44.7 seconds). At 8 weeks, time to development of > or =1 mm ST-segment depression was greater by 45.3 seconds (P =.0025; 95% CI 16.2-74.5) with mibefradil, but time to development of angina was not significantly different. CONCLUSION T-type calcium-channel antagonism with mibefradil improved treadmill exercise parameters compared with diltiazem in patients with chronic stable angina. Further investigation and development of antagonists of T-type calcium channels with fewer adverse drug interactions is warranted and may be promising in the management of ischemic heart disease.