Background： Mitochondrial dysfunction plays an important role in the pathogenesis of amyotrophic lateral sclerosis （ALS）. We aimed to demonstrate mitochondrial dysfunction in ALS using a lactate stress test and to ...Background： Mitochondrial dysfunction plays an important role in the pathogenesis of amyotrophic lateral sclerosis （ALS）. We aimed to demonstrate mitochondrial dysfunction in ALS using a lactate stress test and to examine the relationship between mitochondrial dysfunction with motor deterioration. Methods： We enrolled 116 patients and observed clinical variables, including the survival state. Results： Patients with a rapid slope of revised ALS functional rating scales （ALSFRS-r） （〉20 U/year） exhibited the slowest elimination rate （median -4.67 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation, 590.15%）, the shortest duration （0.63 ± 0.28 years） and the worst ALSFRS-r （32.59±4.93）. Patients with a moderate slope ofALSFRS-r （1~20 U/year） showed a moderate elimination rate （median -11.33 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation, 309.89%）, duration （1.16± 0.45 years）, and ALSFRS-r （34.83 ± 6.11）. The slower progressing （〈10 U/year group） patients exhibited a rapid elimination rate （median： - 12.00 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation： 143.08%）, longer duration （median： 3 years, coefficient of variation： 193.33%）, and adequate ALSFRS-r values （39.58 ± 9.44）. Advanced-phase ALS patients also showed slower elimination rate （ER, quartiles - 17.33, -5.67, 4.00） and worse ALSFRS-r （34.88 ± 9.27）, while early-phase patients showed a more rapid ER （quartiles -25.17, -11.33, -3.50） and better ALSFRS-r （39.28 ± 7.59）. These differences were statistically significant. Multiple linear regression analysis revealed strong direct associations among ER, ALSFRS-r slope （standard beta = 0.33, P = 0.007）, and forced vital capacity （predict %） （standard beta = -0.458, P = 0.006, adjusted for ALSFRS-r, course and onset region）. However, the data obtained from 3 years of follow-up showed no statistically significant difference in the survival rates between the most rapid and slowest ER groups. Conclusion： There is a potential linear relationship between ER and motor deterioration in ALS. Slower ER might be associated with faster disease progression.展开更多
Background Previous studies have suggested that nomogram can simplize complicated calculations of several varibles. A simple nomogram was constructed to estimate absorption rate coefficient (k a) by using the peak t...Background Previous studies have suggested that nomogram can simplize complicated calculations of several varibles. A simple nomogram was constructed to estimate absorption rate coefficient (k a) by using the peak time (t peak ) and the elimination rate coefficient (k e) of drugs administered orally Methods The nomogram was based on the plasma concentration-time (C-T) curve equation and the function relation between t peak , k a and k e A mathematical analysis was presented for the construction of single chart nomogram To check the degree of accuracy of the developed nomogram, we used it to analyze retrospective profiles of 46 drugs and compared the k a values obtained graphically and those calculated by numerically solving the descriptive equation In addition, we measured the carbocisteine concentration of 18 healthy volunteers by HPLC with fluorescence detection To analyze performance error, the measured carbocisteine concentrations were compared with predicted concentrations by the k a obtained from the nomograms along with the other pharmacokinetic parameters Results The estimated of k a values from nomograms were in very close proximity with the numerical values The performance error was as follows: median performance error (MDPE) and median absolute performance error (MDAPE) were 1 32% and 18 15%, respectively Conclusions The developed nomogram is accurate and reliable The size of performance error meets the demand of clinical pharmacokinetics Therefore, the nomograms can offer another convenient and easy method for rational individualized dosage regimens展开更多
文摘Background： Mitochondrial dysfunction plays an important role in the pathogenesis of amyotrophic lateral sclerosis （ALS）. We aimed to demonstrate mitochondrial dysfunction in ALS using a lactate stress test and to examine the relationship between mitochondrial dysfunction with motor deterioration. Methods： We enrolled 116 patients and observed clinical variables, including the survival state. Results： Patients with a rapid slope of revised ALS functional rating scales （ALSFRS-r） （〉20 U/year） exhibited the slowest elimination rate （median -4.67 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation, 590.15%）, the shortest duration （0.63 ± 0.28 years） and the worst ALSFRS-r （32.59±4.93）. Patients with a moderate slope ofALSFRS-r （1~20 U/year） showed a moderate elimination rate （median -11.33 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation, 309.89%）, duration （1.16± 0.45 years）, and ALSFRS-r （34.83 ± 6.11）. The slower progressing （〈10 U/year group） patients exhibited a rapid elimination rate （median： - 12.00 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation： 143.08%）, longer duration （median： 3 years, coefficient of variation： 193.33%）, and adequate ALSFRS-r values （39.58 ± 9.44）. Advanced-phase ALS patients also showed slower elimination rate （ER, quartiles - 17.33, -5.67, 4.00） and worse ALSFRS-r （34.88 ± 9.27）, while early-phase patients showed a more rapid ER （quartiles -25.17, -11.33, -3.50） and better ALSFRS-r （39.28 ± 7.59）. These differences were statistically significant. Multiple linear regression analysis revealed strong direct associations among ER, ALSFRS-r slope （standard beta = 0.33, P = 0.007）, and forced vital capacity （predict %） （standard beta = -0.458, P = 0.006, adjusted for ALSFRS-r, course and onset region）. However, the data obtained from 3 years of follow-up showed no statistically significant difference in the survival rates between the most rapid and slowest ER groups. Conclusion： There is a potential linear relationship between ER and motor deterioration in ALS. Slower ER might be associated with faster disease progression.
文摘Background Previous studies have suggested that nomogram can simplize complicated calculations of several varibles. A simple nomogram was constructed to estimate absorption rate coefficient (k a) by using the peak time (t peak ) and the elimination rate coefficient (k e) of drugs administered orally Methods The nomogram was based on the plasma concentration-time (C-T) curve equation and the function relation between t peak , k a and k e A mathematical analysis was presented for the construction of single chart nomogram To check the degree of accuracy of the developed nomogram, we used it to analyze retrospective profiles of 46 drugs and compared the k a values obtained graphically and those calculated by numerically solving the descriptive equation In addition, we measured the carbocisteine concentration of 18 healthy volunteers by HPLC with fluorescence detection To analyze performance error, the measured carbocisteine concentrations were compared with predicted concentrations by the k a obtained from the nomograms along with the other pharmacokinetic parameters Results The estimated of k a values from nomograms were in very close proximity with the numerical values The performance error was as follows: median performance error (MDPE) and median absolute performance error (MDAPE) were 1 32% and 18 15%, respectively Conclusions The developed nomogram is accurate and reliable The size of performance error meets the demand of clinical pharmacokinetics Therefore, the nomograms can offer another convenient and easy method for rational individualized dosage regimens
