Impact of Irradiation on the Pharmacokinetics and Biotransformation of Tamoxifen.

BACKGROUND: The optimal procedure for combining radiotherapy (RT) with tamoxifen treatment is controversial as RT may alter the pharmacokinetics and biotransformation of tamoxifen. The present study investigated this potential interaction by assessing the pharmacokinetics of tamoxifen during concurrent and sequential RT. METHOD: Plasma tamoxifen concentration was measured in rats with or without RT 2.0 Gy (RT2.0Gy) or 0.5 Gy (RT0.5Gy) with ultra-high-performance liquid chromatography-tandem mass spectrometry after tamoxifen administration (10 mg/kg, p.o., n = 6). Tamoxifen was either administered 1 h after RT (concurrent condition) or 24 h after RT (sequential condition). RESULTS: Pharmacokinetic data analysis demonstrated that the area under the curve (AUC) and half-life of tamoxifen were 2,004 ± 241 h ng/ml and 6.23 ± 1.21 h, respectively, after tamoxifen administration (10 mg/kg, p.o.). The respective conversion rate of 4-hydroxytamoxifen, N-desmethytamoxifen, and endoxifen for tamoxifen metabolism was 20%, 16%, and 5%. The AUC value of tamoxifen in the RT0.5Gy group was 1.5- to 1.7-fold higher than in the sham and RT2.0Gy groups. The relative bioavailability of tamoxifen at concurrent RT0.5Gy and RT2.0Gy groups ranged from 127% to 202% and from 71% to 152%, respectively. The magnitude of endoxifen, which converted from 4-hydroxytamoxifen and N-desmethyltamoxifen, increased 3- to 5-fold in the concurrent RT groups. By contrast, the AUC of tamoxifen decreased by roughly 24% in the sequential RT2.0Gy group. The conversion ratio of endoxifen was four times higher than that in the sequential RT2.0Gy group compared with rats not exposed to RT. CONCLUSION: The current study provides advanced pharmacokinetic data to confirm the interaction between RT and hormone therapy. Our findings indicate that RT facilitates the metabolism of tamoxifen to active metabolites and thus imply that combination RT-tamoxifen has potential benefits for the treatment of hormone-dependent breast cancer.

Computational design and discovery of "minimally structured" hERG blockers.

Molecular knowledge of hERG blocking liability can offer the possibility of optimizing lead compounds in a way that eliminates potentially lethal side effects. In this study, we computationally designed, synthesized, and tested a small series of "minimally structured" molecules. Some of these compounds were remarkably potent against hERG (6, IC(50) = 2.4 nM), allowing us to identify the minimal structural requirements for hERG blocking liability.

Carpal tunnel syndrome in manual wheelchair users with spinal cord injury: a cross-sectional multicenter study.

OBJECTIVE: To investigate relationships between carpal tunnel syndrome, functional status, subject demographics, physical examination findings, and median nerve conduction study findings in manual wheelchair users with paraplegia. DESIGN: Multicenter cross-sectional study. One hundred twenty-six manual wheelchair-using individuals with chronic paraplegia answered self-administered questionnaires on demographics, symptoms, and functional status. They underwent physical examination specific for carpal tunnel syndrome and upper-limb nerve conduction studies. RESULTS: Fifty-seven percent of subjects had symptoms (72.2% bilateral); hand numbness was most common. Sixty percent of subjects had carpal tunnel syndrome physical examination findings (59.2% bilateral). Those with physical examination findings were more likely to have longer duration of injury (P = 0.003). Seventy-eight percent of subjects had electrophysiologic evidence of median mononeuropathy. Symptomatic subjects had significantly greater median-ulnar motor latency difference in the dominant hand (P = 0.02) and smaller compound muscle action potential amplitudes bilaterally (dominant hand, P = 0.01; nondominant hand, P = 0.04). Persons with carpal tunnel syndrome symptoms and physical examination findings had significantly worse functional status (symptoms, P < 0.001; physical examination, P = 0.02) and symptom severity scores (symptoms, P < 0.001; physical examination, P = 0.01), but a similar difference between subjects with and without median mononeuropathy was not seen. Logistic regression analysis revealed that the presence of symptoms was predicted by median-ulnar motor latency difference in the dominant hand (odds ratio, 4.38; 95% confidence interval 1.72-11.14) and sensory nerve action potential amplitude in the nondominant hand (odds ratio, 0.97; 95% confidence interval, 0.94-0.99). CONCLUSIONS: The interaction among symptoms, physical examination, and nerve conduction study findings is complex. Carpal tunnel syndrome and median mononeuropathy are highly prevalent and functionally significant. This study highlights the need for primary prevention and patient education for preserving upper-limb function.

Upper-limb joint power and its distribution in spinal cord injured wheelchair users: steady-state self-selected speed versus maximal acceleration trials.

OBJECTIVE: To compare upper-limb joint power magnitude and distribution between the shoulder, elbow, and wrist during maximal acceleration (MAC) versus steady-state, self-selected speed (SSS) manual wheelchair propulsion. DESIGN: Cross-sectional biomechanic study. SETTING: Research university and teaching hospital. PARTICIPANTS: Volunteer sample of 13 manual wheelchair users with spinal cord injury below T1. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Propulsive joint power magnitude and fractional distribution among upper-limb joints. RESULTS: Wilcoxon signed-rank testing revealed shoulder power was larger for MAC versus SSS (median peak, 101.5W; interquartile range [IQR], 74.6; median peak, 37.7W; IQR, 22.9; respectively) (P<.01). Elbow and wrist power were unchanged. Peak shoulder power fraction was larger for MAC versus SSS (median peak, 1.055; IQR, .110 vs peak, .870; IQR, .252) (P<.01). Peak elbow power fraction was smaller for MAC versus SSS (median peak, -.012; IQR, .144 vs peak, .146; IQR, .206) (P<.05). Peak wrist power fraction was smaller for MAC versus SSS (median peak, -.058; IQR, .057 vs peak, -.010; IQR, .150) (P<.05). CONCLUSIONS: Power at the shoulder was larger than at other joints. Peak shoulder joint power and power fraction was larger during MAC versus SSS propulsion. Elbow and wrist power fractions were smaller for MAC versus SSS propulsion. Higher joint power, present under MAC, may predispose manual wheelchair users to injury, particularly at the shoulder.