Physical Stress Reaction

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In earlier times and particularly in indigenous Chinese medicine ginseng root was employed as a remedy for premature weakness or exhaustion induced by physical or mental stress. In our own time improved physical and mental activity has frequently been reported and confirmed as the most important effect of ginseng (Sonnenborn, 1987). The period of active work is extended and the onset of fatigue correspondingly delayed. Fatigue and weariness occurs after prolonged activity, manifesting itself as irritability, failing concentration, reduced ability to rationalise and consequently inefficient working. Certainly repeated laboratory experiments had confirmed improved running ability, increased climbing performance and prolonged swimming endurance of test animals (Hou, 1978; Fulder, 1993).

Other types of physical stress such as immobilisation and positive radial acceleration stresses can similarly be effectively countered. Under such conditions ginsenosides restrict any major changes in the weights of the adrenals, thymus, spleen and thyroid as compared with control animals and modify blood sugar and liver glycogen changes.

Positive gravity effects induced by radial acceleration generate considerable stress reaction. Kim and Koh (1964a), using 840 mice, found that a 2 mg/kg body weight/day injection of an ethanol extract of ginseng root increased tolerance to such stress. Mice that had been acclimatised to radial stress had decreased levels of total serum protein and ginseng increased the levels and prevented decrease in the albumin/globulin ratio at 3G and 5G forces.

From the time of the earliest swimming tests undertaken with mice by Brekhman and his Russian colleagues in 1957 there has been positive evidence of improved performance after oral administration or injection of ginseng extracts. Significantly the antifatigue action was more pronounced after a course of ginseng injections for a longer period. Ten years later trials were conducted during a period of 60 days with test swims every 5 days and the results were again positive. For the first 10 days on which the mice swam no ginseng was given but from the 11th to 40th days on alternate days half the mice received 0.1 ml per 20 g body weight per mouse of a 10 per cent aqueous liquid extract of ginseng root. The control group of mice received a corresponding injection of a 2 per cent solution of ethanol in water. Swimming commenced 20 minutes after an injection. At the end of the trial it was reported that the average swimming time of the control group was 47-61 minutes but for the test group it was 96117 minutes, an increase of almost 100 per cent. In addition 80 per cent of the control mice died as a result of complete physical exhaustion but only 40 per cent of the ginseng-treated animals succumbed (Brehkman, 1967).

Further work by the Brekhman group proved that extracts from wild and cultivated ginseng roots caused virtually the same responses in the swimming and rope-climbing trials. Testing individual Panax saponins, it was concluded that the potencies varied in the range from 100 to 1000 times greater than for crude root extract. The panaxosides A (=ginsenoside Rg1) and C (=ginsenoside Rd), both protopanaxatriol derivatives, were more potent than the panaxosides D (=ginsenoside Rc), E (=ginsenoside Rb1, 2) and F (=ginsenoside Ra) which are all protopanaxadiol derivatives. The panaxosides (=ginsenosides) were more potent than the aglycones panaxatriol and panaxadiol and potency was apparently related to the sugar content of the molecule. Thus panaxoside C (=ginsenoside Rd) with four sugar substituents is roughly twice as potent as panaxoside A (=ginsenoside Rg1) which possesses only three sugar units (Brekhman and Dardymov, 1969b).

In the early 1960's Kitagawa and Iwaki confirmed and expanded the swimming studies by using four different ginseng extracts viz. ether extract, alcohol extract, aqueous extract without prior extraction with an organic solvent and aqueous extract after extraction with ether, at dose levels of 200 mg/kg body weight (ether extract) or 100 mg/kg (other extracts). The mice were organised in groups of five and swam to exhaustion in water at 32° C. The recorded swimming times for control group mice varied in the range 34-194 seconds; mice treated with ginseng extract three days before swimming yielded times of 55-123 seconds (ether extract), 52-164 seconds (alcohol extract) and 80-198 seconds (total aqueous extract) and mice treated with ginseng extract one hour before swimming registered times of 74-280 seconds (ether extract), 131-577 (alcohol extract) and 104-242 seconds (total aqueous extract). Treated animals therefore shewed an improved performance in the range 60-200 per cent better than the control mice and the most effective treatment was one hour before exercise (Hou, 1978).

Using 450 mice, the Swiss laboratories of Pharmaton Ltd. undertook large scale testing of their carefully prepared and standardised Ginseng Extract G115 (standardised mixture of the ginsenosides Rb1, Rb2, Rb3, Rc, Rd, Re, Rf, 20-gluco-Rf, Rg1, Rg2 and Rh1 in a constant ratio marketed by Pharmaton S.A., Lugano, Switzerland). Two dose levels of Ginseng Extract G115 were employed, 3 mg/kg mouse body weight/day (=0.06 mg/20 g) and 30 mg/kg mouse body weight/day (=0.6 mg/20 g), the former approximating to the clinical dose and the latter to ten times the clinical dose. Swimming performances in a water bath at 18° C were assessed after G115 administration for periods of 14, 21 or 28 days. During the test each mouse swam to exhaustion before being allowed to dry out in a warm air stream; after one hour of rest the swim was repeated and the recorded times for the two swims were averaged. The results revealed that mice treated with 0.06 mg/20 g/day for 14 days slightly improved their performance, but those receiving 0.6 mg/20 g/day improved their performances some 12-20 per cent when compared with control mice. For the 21 days test, those receiving 0.06 mg/ 20 g/day improved some 19-22 per cent as compared with the control group and those given 0.6 mg/20 g/day improved 20-27 per cent. The final group after 28 days yielded even better results, the 0.06 mg/20 g/day group improving by about 52 per cent as compared with control mice at the first test and, less well, by 38 per cent at the second test; with the higher dose (0.6 mg/20g/day) the first test improvement was about 48 per cent and the second test yielded about 38 per cent improvement (Ruckert, 1974). These results were convincing yet the Pharmaton group continued their work with 1000 mice and produced confirmatory evidence which also proved that better swimming performances were obtained if the ginseng extract was ingested over a longer period of time. Extending this work to human subjects and using Geriatric Pharmaton G115 (a standardised combination of ginseng G115, dimethylaminoethanol bitartrate, vitamins, mineral salts, trace elements and lipotropic substances produced by Pharmaton S.A., Lugano, Switzerland), enhanced performances were reported for athletes, middle-aged men and the elderly (Ruckert, 1975).

In Japan further proof was obtained using six techniques viz. exploratory movement, hole cross, rotating rod, sliding angle, spring balance and rectal temperature tests. Mice were exhausted by four hours of oscillation movements. Aqueous extracts of ginseng or its saponins were injected peritoneally on cessation of the exercise. The aqueous extract of ginseng root significantly accelerated the recovery of exploratory movement and raised the rectal temperature, and ginsenoside Rg1 and the lipophilic fraction of ginseng extract produced the most marked antifatigue effect in every test applied (Saito et al., 1974).

This anti-stress action in swimming and forced exercise endurance tests has been repeatedly confirmed in more recent publications (Banerjee and Iquierdo, 1982; Saito and Bao, 1984a; Luo et al., 1993; Grandhi et al., 1994). Nevertheless Han et al. (1985) had carefully considered Brekhman's swimming test experiments and came to the conclusion that pure ginsenosides did not yield the same results as impure ginseng preparations combining ginsenosides and antioxidants such as phenolic acids and maltol.

Using mice running to exhaustion in a treadmill, Filaretov et al. (1988) reported an increased working capacity of 132 per cent after a single dose of ginseng and 179 per cent after 7-day treatment. They concluded that there were two stages of adaptation controlled by the pituitary-adrenocortical system, a normal level and a higher state of excitation as the work load increased. Another explanation presented for this obvious delay in the onset of fatigue and weariness, and tested in rats and in human clinical studies, is the more economical release of body energy due to the more efficient use of glycogen and high energy phosphate during physical activity. Thus there is a decrease in muscle adenosine triphosphate (ATP), in glycogen, a large glucose polymer, and in creatine phosphate and a smaller accumulation of the muscle lactic and pyruvic acids than is normally encountered during the hard exercise that causes fatigue. The glycogen reserve was gradually used up probably at the expense of a higher lipid and fatty acid oxidation with reduced lactate and pyruvate levels in blood and a resultant raising of the aerobic/ anaerobic threshold to a higher production level (Sonnenborn, 1987).

Such observations suggest that ginseng extracts contain active principles that are capable of influencing pathways of substrate metabolism during sustained physical work. Possible explanations include the effect of the activation of the lactate-dehydrogenase enzyme in the liver, and muscle oxidation of fatty acids rather than glucose. The latter is possible as stress releases adrenocorticotrophin (ACTH) and thence hydrocortisone (cortisol) which stimulates the concentration of free fatty acids in the plasma thus permitting their utilisation as a source of energy. Hydrocortisone also moderately promotes oxidation of fatty acids in the cells, possibly as a consequence of reduced availability of glycolytic products after sustained work. The significantly raised oxygen capacity of the heart with an accompanying positive effect on the coronary reserve indicates the definite contribution of ginseng administration. Alternatively, it is possible that the antioxidant effects of phenolic substances such as salicylic and vanillic acids and so far unisolated phenolic compounds occurring in impure ginseng extracts are significant. Such compounds may remove substances from the unwanted sludges produced by abnormal oxidation at cell level.

Dose levels were considered in a study by Forgo and Kirchdorfer (1982) involving 30 established male athletes. Measuring parameters including maximum oxygen absorption, heart rate during physical effort and blood lactate levels they concluded that there was no significant difference between a commercial G115 ginseng extract containing a standardised 4 per cent of ginsenosides and a specially prepared standardised extract containing 7 per cent ginsenosides. Therefore large doses were not justified and most workers have used 2x100 mg capsules of ginseng extract per day for human subjects, the most satisfactory results being obtained with the standardised product.

Nevertheless Murano and Lo Russo (1984) in a 60-day clinical trial employed 40/80 mg ginseng extract G115 taken orally daily and 65 athletes (professional and amateur of both sexes and aged 18-70 years). The professional sportspeople shewed significantly improved mental parameters as compared to baseline but little change for physical parameters. The amateur athletes, presumably less fit, revealed both physical and mental improvements.

In Italy Pieralisi et al. (1991) also studied the effects of a standardised ginseng extract formulation on physical performances during exercise. A double-blind, randomized, crossover study involved 50 healthy, male, sports teachers aged 2147 years. Daily for 6 weeks the participants ingested either two placebo capsules or two capsules containing ginseng extract, dimethylaminoethanol bitartrate, vitamins, minerals and trace elements. After six weeks the treatments were reversed for a further six weeks, and finally a single-blind placebo washout period of one week was undertaken. Employing an exercise test regime with increasing work loads on a treadmill, it was found that the total work load and maximal oxygen consumption during exercise were significantly greater after taking ginseng capsules (p<0.0001) than after placebo ingestion. It was also noted that at the same work load, oxygen consumption, plasma lactate levels, ventilation, carbon dioxide production, and heart rate were significantly lower after ginseng administration than after placebo treatment. Pieralisi and his colleagues stated that the standardised ginseng preparation increased work capacity by improving muscular oxygen utilization and that the effects were more pronounced in the 23 participants with a maximal oxygen consumption below 60 ml/kg/min before the treatment than in sportsmen with levels of 60 ml/kg/min or higher. The authors stressed that the ginseng preparation employed was a combination of Ginseng Extract G115 with dimethylaminoethanol bitartrate, vitamins, minerals and trace elements and therefore the important constituents of ginseng probably played the vital role. As the effects on the choline-acetylcholine complex of dimethyl-aminoethanol bitartrate administration are somewhat ambiguous at the dose-level employed, further work using ginseng extract alone is desirable. The results obtained confirmed the earlier work of Forgo and Kirchdorfer (1981).

This apparent improvement of physical performance by increasing body resistance to stress and fatigue was also tested in normal healthy human subjects by Engels et al. (1996) using a randomised, double-blind, placebo-controlled programme. The test group of normal, healthy females was given 200 mg per person per day of a concentrated extract of P. pseudoginseng in addition to their normal supplement-free diet. Before and after the 8-week trial all participants performed a graded maximal cycle ergometry test to exhaustion and answered a standard habitual physical activity questionnaire. It was concluded that in normal healthy persons ginseng supplementation had no effect on maximal work output, resting, exercise and recovery oxygen uptake, ventilation, heart rate and blood lactic acid. Also, as habitual physical activity scores of all the participants, irrespective of whether they were ginseng or placebo takers, were almost identical before and after the 8-week trial period (p>0.05), it was suggested that chronic dietary supplementation with ginseng did not produce in normal healthy persons an enhancement of work performance or change in energy metabolism or improvement of recovery response from maximal physical output.

A Canadian group (Morris et al., 1996) also employing a cycle ergometer concluded that there was no ergogenic effect upon their 8 subjects (aged 27.2± 4.8 years) after ginseng ingestion (8 or 16 mg/kg body weight daily for 1 week). Although the rate of perceived exhaustion was significantly greater and the time to exhaustion was significantly shorter during the control ride than for the placebo and ginseng trial rides they concluded a negative result and unfortunately did not continue their trial over a longer period of time. Such results are not surprising in view of the findings of Forgo and Schimert (1985); using a 60-day treatment comprising ginseng extract G115, vitamins, minerals and trace elements they noted that professional sportsmen who would be at peak fitness shewed improved memory and attention reaction only whereas the less fit amateur players shewed both physical and mental improvement. In a subsequent paper Tesch et al. (1987), who studied a group of healthy, middle-aged men for two months in a placebo controlled trial, recorded the cardiocirculatory, metabolic and haematological characteristics during submaximal effort. They concluded that treatment with standardised ginseng G115 with added vitamins, minerals and trace elements (Gericomplex, Pharmaton S.A.) over a period yielded significantly lower heart rates and blood lactate levels at the same work load than in corresponding placebo trials although there was only a non-significant increase in the duration of exertion.

A slightly different approach was used by the Israeli team of Gross et al. (1995) who, in a 12-week report of an on-going study, investigated the effects of standardised ginseng extract G115 on pulmonary functions, oxygenation and general functions including walking capacity. The trial was limited to 15 severely ill patients (11 male, 4 female) with a mean age of 67±12 years. All the patients had severe chronic respiratory diseases and most were oxygen dependent at times. Initial medical histories, blood pressure and heart rate were recorded; then pulmonary functions, respiratory muscle strength and endurance were measured before the administration of 100 mg capsules of ginseng G115 twice a day for 12 weeks. Patients were reassessed every 6 weeks; spirometric data, strength and endurance of the respiratory system measured with a maximum pressure measuring device and 6 min walking distances were recorded and oxygen and carbon dioxide levels were obtained by arterial blood gas analysis. Collated results reveal that the daily ginseng G115 treatment improved pulmonary functions and oxygen capacity in patients with severe chronic pulmonary diseases. After 6 weeks treatment there was significant improvement of pulmonary function and a concomitant improvement in 6 min walking distance and this was maintained and slightly improved for the further 6 weeks, mean values being 600±93 m at the outset, increasing to 854±101 m after 6 weeks and to 1123±119 m after 12 weeks. Forced vital capacity, which normally decreases with age, was much increased from 32.1 per cent to 67.3 per cent (p<0.05) after 6 weeks and 72.8 per cent (p<0.01) after 12 weeks. The maximum ventilation volume, an index of ventilatory endurance, increased by 11 per cent (p<0.01) after 6 weeks and by an additional 7.3 per cent (p<0.01) after 12 weeks treatment. These increases indicated a significant improvement in respiratory muscle strength. The forced expiratory flow rates FEF50 and FEF75 which were initially very poor at 15.9 and 23.3 per cent respectively, increased to 22.6 per cent (p<0.05) and 28.7 per cent (p<0.02) respectively after 6 weeks and then to 27.7 per cent (p<0.01) and 30.1 per cent (p<0.05) respectively after 12 weeks, indicating improved effort independent airflow in the small airways. In addition there was a significant increase in oxygenation, PaO2 changing from 47.0±4 torr to 65.3±3 torr (p<0.05) after 6 weeks and 69.3±4 torr (p<0.01) after 12 weeks. As in the earlier work of Forgo's team, improvements in oxygen absorption and therefore aerobic metabolism are related to significantly reduced lactate levels and thus improved physical performance.

The results of recent work in Canada (Wang and Lee, 1998) using root saponins from P. quinquefolium in 4 day treatment of untrained rats at a dose level of 10-20 mg/kg daily indicated that prolonged aerobic endurance resulted at about 70 per cent VO2 max. Ginseng saponins increased the plasma free fatty acid level when compared against saline controls as well as maintaining the plasma glucose level during exercise. Glycogen levels in liver and skeletal muscles of exhaustively exercised animals were slightly higher in treated animals. Wang and Lee also concluded that ginseng functioned by altering the fuel homeostasis during prolonged exercise probably by raising free fatty acid utilisation in preference over glucose for cellular energy demands thus enhancing exercise endurance. They also emphasised that the ginsenosides Rb1 and Rg1 were necessary for enhanced aerobic exercise performance.

As the Chinese and Vietnamese soldiers used ginseng in wars of the 20th century and Russian astronauts and athletes also improved their performance with ginseng or eleutherococcus, it is obviously desirable that further and more prolonged careful work is undertaken with precisely standardised ginseng preparations including isolated ginsenosides and other ginseng phytopharmaceuticals and with healthy and less healthy human volunteers exhibiting a wider age range.

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