Study On Enhancing Performance Capacity By Caffeine Sustained-Release Tablets After Sleep Deprivation

INTRODUCTIONThe world is undergoing profound changes amid profound changes unseen in a century.In the turbulent situation,all countries in the world are making preparations for the corresponding military struggle.Non-war military operations and missions such as military deterrence,international peacekeeping,ocean-going escort,counter-terrorism and stability maintenance,rescue and disaster relief,and support for national social and economic development are becoming more frequent.All-weather,cross-time zone,high-intensity continuous combat will have an ununderestimated impact on the sleep quality and physical and mental state of the combatants.Long-term sleep deprivation will lead to the decline of cognitive function,operational ability,physiological and psychological functions of the combatants.How to effectively combat sleep deprivation,maintain alert state and high stress ability has become the focus of modern military medical research.It has been shown that central nervous system stimulants are drugs that can effectively improve the functional activities of central nervous system,including stimulants for brain function restoration,stimulants for respiratory center of bulbosa,stimulants for cerebral cortex,etc.They can effectively improve the combat performance and physical functions of combatants.It can be used in the short term to combat the negative effects of sleep deprivation.Drugs for improving the equipment and use ability of foreign troops have a history of several decades,but our army lags far behind in the research and equipment of such drugs.Therefore,it is necessary to develop such drugs based on the actual situation of our army,and systematically evaluate the effects of such drugs on fighting sleep deprivation,battlefield fatigue,enhancing the operational ability of soldiers,and drug safety.It provides theoretical and practical basis for improving the combat effectiveness in wartime.As a central nervous stimulant commonly used clinically and readily available in food,caffeine promotes nervous system activation,enhances brain alertness and logic,maintains cognitive function,improves mood,improves work efficiency,and enhances skeletal muscle contraction,which helps the body react quickly.Common caffeine,however,has a shorter half-life,a faster peaking time,and less durable effects.It requires multiple doses to intervene or combat the adverse effects of long-term sleep deprivation,which is not conducive to battlefield use.Based on the above needs,we adopted gel skeleton technology to develop sustained release tablets of caffeine,which has been approved by the former General Logistics Department and Health Department for clinical study.With mature technology,stable quality,easy availability of raw materials,low cost,easy to carry and take,the gel skeleton tablet is especially suitable for the equipment and support of military special needs drugs.The main pharmacological effects of caffeine are as follows:(1)it has excitatory effects on the main parts of the central nervous system,firstly in the cerebral cortex.In low doses(50-200mg),arousal,mental activity,reduction of fatigue,drowsiness,and increased ability to perform sustained mental work were observed,but did not improve newly learned motor skills in delicate muscle coordination work or precise timing work.When the dose is increased(200-500mg)can produce tension,anxiety,irritability,insomnia,headache,tremor,anaesthesia and other central excitatory symptoms.Further doses may cause convulsions and vomiting.(2)Caffeine can stimulate the cerebrovascular motor center of the bulbar,so that blood pressure slightly rise.(3)Directly relax smooth muscle.(4)Diuretic effect.(5)Promote gastric secretion.(6)Can increase the ability of muscle activity.Caffeine acts as a central nervous system stimulant through four main mechanisms at the cellular level:(1)As an agonist for ryanodine receptor(Ry R),it can trigger the release of calcium pool sensitive to anodyne,thereby promoting the release of calcium ions in the sarcoplasmic reticulum,increasing the intracellular concentration of calcium ions,and enhancing the sensitivity of muscle fibers to calcium ions.(2)Inhibit phosphodiesterase and increase the concentration of cyclic adenosine phosphate(c AMP)in tissues and muscles;(3)It has antagonistic effect on γ-aminobutyric acid receptor;(4)Central adenosine receptor(A)antagonists.Studies have shown that sleep deprivation will have a negative impact on people’s attention,memory,reaction,calculation,cognitive function,working ability,physiological and psychological and emotional states,and long-term sleep deprivation will also cause a series of blood biochemical and nervous system changes.Operational ability refers to the physiological and psychological characteristics of an operator to complete a certain job,which comprehensively reflects the internal potential of an individual,including physical and mental work ability.The complex environment of the battlefield tests the comprehensive operational ability of the combatants,which requires a high degree of concentrated attention,keen reaction,good memory,accurate calculation and stable emotional and psychological ability to support,and lasting concentrated attention is the basis of various functions and operational ability to play.At present,there are many kinds of attention testing tools,and different attention testing tools have different characteristics.One or more testing tools can be selected according to the research purpose,observation index and research conditions.Based on previous literature search,practical use and evaluation feedback of various relevant test tools,as well as the needs of complex battlefield environment,we improved a traditional attention measurement tool called continuous performance test(CPT).And integrate other operational ability assessment tools into a common terminal for testing the operational ability level of the tested personnel.The focus of this study is the reliability and validity of the improved attention measurement tool,the effect of sleep deprivation on cognitive function and working ability of healthy people,and the actual efficacy of caffeine sustained-release tablets developed by us in enhancing the working ability after sleep deprivation.Part Ⅰ An improved continuous performance test and clinical evaluationObjective: To explore the reliability and validity of the improved attention measurement tool.Methods: Thirty healthy subjects completed three versions of CPT assessment in the same period of time.CPT1 was the traditional version of CPT;CPT2 added selective attention assessment on the basis of CPT1;and CPT3 changed the fixed time interval to random time interval on the basis of CPT2.The correct response time,correct number,wrong number and missing number of subjects were observed to investigate the modified CPT3 validity,and its reliability was tested by the broken half reliability and repeated reliability.Results: Among the three versions of CPT,the correct rate of CPT1 was the highest,the correct response time was the shortest,and the error rate and omission rate were the lowest,indicating that the difficulty of traditional CPT1 was low,and the performance differentiation of young healthy subjects was not high.Compared with CPT1,the correct rate of CPT2 and CPT3 decreased,the correct response time increased,and the error rate and omission rate increased to varying degrees(P<0.01);The correct rate of CPT3 was lower than that of CPT2,and the error rate,omission rate and correct response time were significantly higher than those of CPT2(P<0.01),the correct rate distribution of CPT1 and CPT2 was more than 95% with narrow distribution,and the correct rate distribution of CPT3 was wider than that of CPT1 and CPT2,which fully indicated that CPT3 was more difficult than CPT1 and CPT2 and had the highest performance differentiation among young healthy subjects.The broken half reliability of the three versions of CPT is greater than 0.8,the repeat reliability of CPT1 and CPT2 is less than 0.5,indicating insufficient stability,and the repeat reliability of CPT3 is0.964,greater than 0.8.Conclusion: The modified version of CPT3 is an effective attention test tool.It can distinguish special subjects(such as energetic,agile young healthy subjects such as soldiers,athletes,etc.)more,and can be used for the evaluation of the effect of continuous operation test and the detection and observation of drug improvement attention in special scenarios.Part two: The effects of sleep deprivation on cognitive function and performance capacity of healthy peopleObjective: To investigate the effects of sleep deprivation on cognitive function and working ability in healthy people.Methods: According to the preliminary results of the randomized,double-blind,placebo parallel controlled clinical trial on the Effects of caffeine sustained release tablets on sustained attention under sleep deprivation,a parallel controlled formal trial was conducted with continuous sleep deprivation for 36 hours and single administration of 300 mg caffeine sustained release tablets or placebo in SD18 h.PASS 15 software was used to estimate the sample size required for the formal test.According to the shedding rate of about 20%,the sample size of both the placebo group and the experimental group was 28,with a total of 56 cases.In this study,60 subjects were actually recruited,and 30 subjects were respectively in the placebo group and the experimental group.28 participants in the placebo group and 29 in the trial group who actually completed the entire course),After unblinding,the changes in the scores of CPT(continuous work test),STROOP(color word test)and continuous addition test,as well as the scores of POMS(emotional state)and SSS(Stanford Sleepiness Scale)before and after sleep deprivation in the placebo group were studied.All statistical tests were conducted by a two-sided test,and a P value less than or equal to 0.05 was considered statistically significant.Results: To exclude the influence of circadian rhythm on the results of the trial,differences in the accuracy and mean correct response time of the CPT,STROOP and continuous addition tests were statistically significant(SD5 vs.SD29)and(SD11 vs.SD35)in the placebo group compared with a time interval of 24 hours after the sleep deprivation trial began(P<0.05.weak(SD2),key index(CPT accuracy),and relevant auxiliary index were statistically significant in all subjects at 2 h after the start of the experiment(SD2),17 h after the start of the experiment(SD17,before administration),and in the placebo group(SD2 and restorative sleep wake)(P<0.05).Conclusion: Continuous sleep deprivation has significant effects on cognitive function and operational ability of healthy people,and the longer the sleep deprivation,the more significant the effects.After a long period of sleep deprivation and a short period of restorative rest,some of their ability to function was not fully recovered.Part Three: Study on enhancing performance capacity by caffeine sustained-release tablets after sleep deprivationObjective: To investigate the effects of caffeine sustained-release tablets on the improvement of work ability and drug safety after sleep deprivation.Methods: According to the preliminary results of the randomized,double-blind,placebo parallel controlled clinical trial on the Effects of caffeine sustained release tablets on sustained attention under sleep deprivation,a parallel controlled formal trial was conducted with continuous sleep deprivation for 36 hours and single administration of 300 mg caffeine sustained release tablets or placebo in SD18 h.PASS 15 software was used to estimate the sample size required for the formal test.According to the shedding rate of about 20%,the sample size of both the placebo group and the experimental group was 28,with a total of 56 cases.In this study,60 subjects were actually recruited,and 30 subjects were respectively in the placebo group and the experimental group.There were 28 subjects in the placebo group and 29 subjects in the experimental group who actually completed the whole experiment.The correct rate of SD23 h CPT was set as the main index(preliminary experimental conclusion).The accuracy and average correct reaction time of STROOP(color word test)and continuous addition test,the score of POMS(emotional state)and SSS(Stanford Sleepiness Scale),and the accuracy and average correct reaction time of CPT in other times except SD23 h were auxiliary test indexes.The test scores and safety of sleep deprivation at different time points were compared between the experimental group and the placebo group.All statistical tests were conducted using a two-sided test,and a P value less than or equal to 0.05 would be considered statistically significant.Results: The accuracy of SD23 h CPT in the placebo group and the experimental group was 77.95% ± 12.76% and 88.43% ± 7.02%,respectively,P=0.0003<0.05,the results were statistically different.At different time points of sleep deprivation,there were significant differences in several auxiliary indexes(P<0.05),there was no significant difference in the safety indexes(P>0.05).Conclusions: A parallel controlled trial of 300 mg single administration in SD18 h with continuous sleep deprivation for 36 hours can complete the efficacy and safety evaluation of the effects of caffeine sustained-release tablets on the ability to function after sleep deprivation.Studies have shown that compared with blank placebo,300 mg caffeine sustained-release tablets can significantly improve the rapid response ability,continuous work ability,calculation ability,subjective fatigue,emotional and emotional state of subjects after sleep deprivation,with good safety.