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PHARMACEUTICAL SCIENCEResearch Article

Anshul Shakya1, Shyam Sunder Chatterjee2 and Vikas Kumar 1* 1Department of Pharmaceutics, Indian Institute of Technology, Banaras Hindu University, India2Stettiner Straße 1, Karlsruhe, Germany

Received: December 10, 2014; Published: March 27, 2015

*Corresponding Author: Vikas Kumar, Neuropharmacology Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology, Banaras Hindu University, Varanasi-221005, India.

Efficacies of Fumaric Acid and its Mono and Di-Methyl Esters in Rodent Models for Analgesics and Anti-Inflammatory Agents

Introduction

Abstract

Introduction: Dimethyl fumarate (DMF) is medicinally used for treatments of psoriasis and multiple sclerosis, and monomethyl fumarate (MMF) is often considered to be its primary active metabolite. Fumaric acid (FA) and its hydrolysable conjugates have also been identified as anti-inflammatory and analgesic constituents of several herbal extracts often used for prevention and cure of in-flammatory disorders. Aim of the present study was to compare anti-inflammatory and analgesic efficacies of FA with those of MMF and DMF in rodent models.

Materials and Methods: Dose dependant efficacies of a single, 5 and 10 daily oral doses (2, 6, 18, and 54 mg/kg) of FA, MMF and DMF were compared in mice hot plate and acetic acid induced writhing tests for analgesics, and in carrageenan induced pedal oedema test in rats for anti-inflammatory drugs.

Results: Both MMF and DMF were as effective as FA in all three tests, and their efficacies always increased after their repeated daily doses. After 10 daily oral doses their increased efficacies in the hot plate test were more pronounced than those observed in the other two tests.

Conclusions: Esters of Fumaric acid are pro-drugs of the parent acid. Their efficacies as anti-inflammatory and analgesic agents increase with increasing number of treatment days. After prolonged treatments they more efficiently suppress central sensitivity to pain than peripheral sensitivity to inflammation.

Abbreviations: FA: Fumaric Acid; MMF: Monomethyl Fumarate; DMF: Dimethyl Fumarate; SEM: Standard Error of Mean

Keywords: Fumaric acid; Monomethyl fumarate; Dimethyl fumarate; Pain; Inflammation; Central pain sensitivity

Citation: Vikas Kumar., et al. “Efficacies of Fumaric Acid and its Mono and Di-Methyl Esters in Rodent Models for Analgesics and Anti-Inflammatory Agents”. EC Pharmaceutical Science 1.2 (2015): 73-85.

Increased sensitivity of the central nervous system to painful stimuli is a cardinal symptom of numerous chronic inflammatory dis-eases [1-3]. Exaggerated pain sensation and diverse mental health problems are the hallmark symptoms of all such diseases, and appro-priate combinations of psychoactive drugs with other therapeutic measures are currently the best effective ones for their prevention and cure [4-5]. Multiple sclerosis and psoriasis are some such inflammatory diseases with alter sensitivity to pain and other environmental stimuli [6-7]. Clinical efficacies of dimethyl fumarate and combinations of fumaric esters and their salts against both these inflammatory conditions have been well documented during more recent decades [8]. Despite extensive efforts though, the questions concerning their sites and modes of actions and the role of fumaric acid (i.e. hydrolytic products of methyl fumarates and other structurally diverse

CroniconO P E N A C C E S S

Efficacies of Fumaric Acid and its Mono and Di-Methyl Esters in Rodent Models for Analgesics and Anti-Inflamma-tory Agents

Fumaric acid is an intermediate of mitochondrial citric acid cycle involved in ATP synthesis, and has many other physiological func-tions in plants and all other cellular organisms [9]. Although fumaric acid has often be reported to be a bioactive constituents of diverse traditionally known medicinal plants [10-15], by far a vast majority of preclinical and clinical reports on fumarates deal mainly with its mono- and dimethyl-esters only [16-24]. Observations made during the course of our psychopharmacological and other studies with hydro alcoholic extracts of Fumaria indica strongly suggested that fumaric acid could be a major bioactive secondary metabolites of the plant involved in their efficacies observed in conventionally known rodent models of inflammation, pain, and other pathologies com-monly associated with central sensitivity syndromes [25-30]. However, such extracts are also enriched in other hydrolysable fumaric acid conjugates, and monomethyl fumarate has also been reported to be hepatoprotective constituent of the plant [31]. Available infor-mation on bioavailability of dimethyl fumarate (as judged by its blood levels observed after oral intake) and other observations made in cellular and other in vitro models suggests that it is readily hydrolyzed inside the gastrointestinal tract and that mono-methyl fumarate could be the orally bioactive metabolite of the di-ester [32-34]. Therefore it was interest to compare the efficacies of fumaric acid and its mono- and di-methyl esters in rodent models of inflammation and pain. The results of experiments suggesting that both the esters are pro-drugs of fumaric acid will be described and discussed in this communication. Possible implications of these findings for more rational understanding of the health benefits of fumaric acid and its conjugates commonly consumed with everyday meals, or with tra-ditionally known herbal remedies, will be pointed out also.

Adult male and female Charles Foster albino rats (150 ± 10g) and Wistar mice (20 ± 5g) acquired from the Central Animal House of the Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. They were housed in groups of six in polypropylene cages at an ambient temperature of 25oC ± 1oC and 45-55% relative humidity, with a 12:12h light/dark cycle. Unless stated otherwise, the animals were always provided with commercial food pellets (Amrut Laboratory Animal Feed; Pranav Agro Industries Ltd., Sangali, India) and water ad libitum. All experiments were conducted between 09.00 and 14.00h, and all animals were always acclimatized to laboratory conditions for at least one week before using them for the experiments. All experimental groups consisted of 6 animals each (3 males and 3 females in each group) and principles of laboratory animal care (NIH publication 85–23, revised in 1985) guidelines were always strictly followed. Prior approval (Dean/11-12/CAEC/324 dated 30.11.2011) from the Central Animal Ethical Committee of the Univer-sity was obtained.

Analytically pure fumaric acid (FA), mono-methyl fumarate (MMF) and di-methyl fumarate (DMF) were procured from Sigma-Al-drich, USA. Aspirin (Alkem Laboratories Ltd., India) and pentazocine (Ranbaxy, India) were used as reference drugs. Other chemicals and reagents used were of purest grade available from local suppliers.

All test substances were suspended in 0.3% w/v carboxymethyl cellulose (CMC; Central Drug House, Delhi, India) for oral adminis-trations. Their daily doses were always administered one hour before the start of other experimental procedures. Application volumes in all cases were 10 ml/kg, and the control animals were always treated accordingly with 10 ml/kg of the vehicle used (i.e. 0.3% w/v CMC). Pentazocine (10 mg/kg, i.p.), and aspirin (25 mg/kg, i.p.) were used as centrally and peripherally acting reference analgesic drugs respectively, whereas aspirin (100 mg/kg, p.o.) was used as a reference anti-inflammatory one. In all experiments, these reference drugs were always administered only one hour before the tests on the test days, whereas fumaric acid and its esters were administered once

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Animal

Drugs and chemicals

Drug treatment

Materials and Methods

fumarates encountered in plants and other cellular organisms) in fumarate therapies of inflammatory disorders still remain unanswered, or at the best can be answered speculatively only.


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daily for 10 consecutive days. Effect of a single, 5 and 10 daily oral doses of 2, 6, 18, and 54 mg/kg/day FA, MMF, or DMF were compared in hot plate and acetic acid induced writhing tests in mice and carrageenan induced pedal oedema tests using rats as experimental ani-mals.

Mice were pre-screened by placing them on a hot plate maintained at 55 ± 1°C and recording the reaction time in seconds for fore-paw licking or jumping [35]. Only those mice reacting within 15 sec (cut off time of the test) and did not show large variation when tested on four separate occasions (each 15 min apart) were used for the experiment. The time for forepaw licking or jumping on the heated plate of the analgesiometer was taken as an index of analgesic state of the animals recorded one hour after treatments on the 1st, 5th and 10th day of the experiment. Differences between the reaction time of a given animal on an observational day and on the last pre-selection sessions were calculated and used for comparing analgesic efficacies of test agents. The percentage (%) increase in response time by test drugs on day 1, 5 and 10 were calculated with respect to response of the tested dose (10 mg/kg; i.p) of the reference drug pentazocine on that day (considered as 100% possible response on the test day). These values were used for calculations of ED50 (i.e. the daily dose of the test agent with 50% efficacy of pentazocine observed on a test day) of test agents on a given observational day.

Acetic acid solution (15mg/ml) at the dose of 300mg/kg body weight was injected intraperitoneally and the numbers of writhings in the following 30 min period were counted [35]. A significant reduction in number of writhes in the drug treated groups in comparison to the vehicle treated one was considered as a positive analgesic response. The % inhibition of writhing responses by test drugs on day 1, 5 and 10 were calculate with respect to the response of the tested dose of aspirin (considered as its 100% possible response on the test day) in the test on that day. These values were used to estimate ED50 (i.e. the daily dose with 50% efficacy of aspirin in the test on the test day) of the test agents on a given observational day.

The test procedure described by Winter et al. [36] was used. In short, 0.1ml of a 1% carrageenan suspension in saline was injected in the sub-plantar region of the left hind paw. The paw was marked with ink at the level of its lateral malleolus for plethysmographic paw volume measurements. Paw volumes were measured before and 3h after the injection of carrageenan by mercury displacement method, and oedema volumes were calculated and expressed as change in paw volume, compared with the initial hind paw volume of each rat [37]. The % decrease in oedema volume by test drugs on day 1, 5 and 10 were calculated, and for estimating ED50 values of test agents the observed effects of aspirin (100 mg/kg, p.o.) on a test day was considered as 100% possible effect on that day.

Mean ± standard error of mean (SEM) were calculated for the observed values in each experimental group. Statistical analysis was performed by one way analysis of variance (ANOVA) followed by Dunnett: compare all vs. Control test. A P < 0.05 was considered statis-tically significant. All ED50 values, i.e. the estimated dose of a test agent (in mg/kg/day) which possesses 50% of the effect observed for the respective standard or reference drug used in a given test and on a given test day, were calculated by nonlinear regression using log dose vs. normalized response-variable slop by GraphPad Prism 5.

Even the highest tested daily oral doses of FA, MMF and DMF (54mg/kg/day for 10 days) were well tolerated by the animals. Mean body weights of all test groups increased linearly and significantly during the 10 experimental days (Ca. 0.8 gm for mice, and Ca. 8.5 gm for rats). Mean responses of the vehicle treated control groups, or of the reference drugs treated ones, in all tests remained almost con-stant on the first, 5th and 10th observational days.

Hot plate test in mice

Acetic acid writhing test in mice

Carrageenan induced pedal oedema test in rats

Statistical analysis

Results


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The mean reaction times on the hot plate for different test groups before start of the treatments varied between 8.87 ± 0.08 and 9.14 ± 0.11 seconds, and there were no statistically significant differences between these mean values of the groups used for the experiment. Mean reaction time of the vehicle treated control group on the 1st, 5th, and 10th day remained almost constant (9.01 ± 0.09, 8.83 ± 0.11 and 8.86 ± 0.10 seconds), whereas those of pentazocine (10 mg/kg; i.p.) treated one on day 1, 5 and 10 were 16.68 ± 0.13, 16.83 ± 0.10 and 17.30 ± 0.18 seconds, respectively. Except for their highest tested doses (54 mg/kg), no statistically significant effects of FA, MMF, or DMF treatments were observed one hour after their single oral doses (see Figure 1). However, one hour after their 5 or 10 daily oral doses statistically significant and dose dependant analgesic effects of FA, MMF and DMF were observed (see Figures 2 and 3). As judged by their calculated ED50 values on days 5 and 10 of the experiment (see Table 1), the efficacies of all three test agents increased consider-ably with the increasing numbers of treatment days; and there were no statistically significant differences between the calculated ED50 values of FA and its two esters tested on all observational days. However, even after their 10 daily highest doses tested (54mg/kg/day), their observed efficacies were lower than that of the tested dose of the reference drug pentazocine.

Hot plate test in mice

Figure 1: Effects of single oral dose of fumaric acid (FA), mono-methyl fumarate (MMF), di-methyl fumarate (DMF) and that of pentazocine (10 mg/kg, i.p.) on hot plate test in mice. Values are mean ± SEM of increase in reaction time (sec.), n = 6 animals in each group. *p < 0.05 compared to vehicle treated control.

On the first day of the experiment, statistically significant effects of FA and MMF treatments were observed after their highest tested doses (54 mg/kg) only, and those of DMF were observed after its two highest doses (18 and 54 mg/kg) tested (see Figure 4). However, clear dose dependant efficacies of all the three test agents were observed after their 5 and 10 daily oral doses (see Figures 5 and 6). Although aspirin like analgesic effects of all the three test agents increased with increasing number of treatment days, efficacies of their highest tested oral doses (54 mg/kg/day) on all observational days were always lower than that of tested intraperitoneally adminis-tered dose of the reference anti-inflammatory and analgesic drug. Although the calculated ED50 value (see Table 1) of MMF on day 5 of the experiment was numerically a bit higher than those of FA or DMF, there were no statistically significant differences in the calculated ED50 values of fumaric acid and its two esters tested on all test days.

Acetic acid writhing test in mice

Figure 2: Effects of 5 daily oral doses of fumaric acid (FA), mono-methyl fumarate (MMF), di-methyl fumarate (DMF) and that of pentazocine (10 mg/kg, i.p.) on hot plate test in mice. Values are mean ± SEM of increase in reaction time (sec.), n = 6 animals in each group. *p < 0.05 compared to vehicle treated control.

Figure 3: Effects of 10 daily oral doses of fumaric acid (FA), mono-methyl fumarate (MMF), di-methyl fumarate (DMF) and that of pentazocine (10 mg/kg, i.p.) on hot plate test in mice. Values are mean ± SEM of increase in reaction time (sec.), n = 6 animals in each group. *p < 0.05 compared to vehicle treated control.


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Figure 4: Effects of single oral dose of fumaric acid (FA), monomethyl fumarate (MMF), dimethyl fumarate (DMF) and that of aspi-rin (25 mg/kg, i.p.) in acetic acid induced writhing test. Values are mean ± SEM of number of writhing in each group, n = 6 animals in each group. *p < 0.05 compared to vehicle treated control group.

Figure 5: Effects of 5 daily oral doses of fumaric acid (FA), monomethyl fumarate (MMF), dimethyl fumarate (DMF) and that of aspirin (25 mg/kg, i.p.) in acetic acid induced writhing test. Values are mean ± SEM of number of writhing in each group, n = 6 animals in each group. *p < 0.05 compared to vehicle treated control group.

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Efficacies of Fumaric Acid and its Mono and Di-Methyl Esters in Rodent Models for Analgesics and Anti-Inflam-matory Agents

Figure 6: Effects of 10 daily oral doses of fumaric acid (FA), monomethyl fumarate (MMF), dimethyl fumarate (DMF) and that of aspirin (25 mg/kg, i.p.) in acetic acid induced writhing test. Values are mean ± SEM of number of writhing in each group, n = 6 animals in each group. *p < 0.05 compared to vehicle treated control group.

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Aspirin (100 mg/kg) significantly reduced the pedal oedema volume on all the three test days. Although numerically the efficacy of the anti-inflammatory drug observed in this experiment on days 5 and 7 were somewhat higher than those observed on days 5 and 7, there were no statistically significant differences between its efficacies observed on all the three test days (calculated results now shown). Statistically significant and dose dependant reductions in the paw volumes of the FA, MMF, and DMF treated groups were also observed on the all the three test days (see Figure 7, 8 and 9). The mean carrageenan induced oedema volumes of even the lowest tested oral dose (2 mg/kg/day) of FA-, or of MMF-, or of DMF- treated groups on all test days were statistically significantly lower than those of the corresponding vales of the vehicle treated control group. As judged by their estimated ED50 values in this test (see Table 1), fumaric acid seems to be as effective as its mono- or dimethyl esters on all the three test days. However, efficacy of the tested aspirin dose (100 mg/kg administered only once on each test day) on the three test days was always higher than those of the highest tested ones of fumaric acid and its esters (54 g/kg/day).

Carrageenan induced pedal oedema test in rats


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Figure 7: Effects of single oral dose of FA, MMF and DMF as well as aspirin (100 mg/kg). Values are mean ± SEM of oedema volume (ml) of rats (n = 6) on carrageenan induced pedal oedema test. *p < 0.05 compared to vehicle treated control rats.

Figure 8: Effects of 5 daily oral doses of FA, MMF and DMF as well as aspirin (100 mg/kg). Values are mean ± SEM of oedema vol-ume (ml) of rats (n = 6) on carrageenan induced pedal oedema test. *p < 0.05 compared to vehicle treated control rats.


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Figure 9: Effects of 10 daily oral doses of FA, MMF and DMF as well as aspirin (100 mg/kg). Values are mean ± SEM of oedema volume (ml) of rats (n = 6) on carrageenan induced pedal oedema test. *p < 0.05 compared to vehicle treated control rats.

Test Agent ED50 (mg/kg/day) (Regression Coefficient)Day 1 Day 5 Day 10

Hot Plate Test in MiceFumaric acid > 54 37.69 (0.98) 5.17 (0.99)Mono-methyl fumarate > 54 30.26 (0.98) 5.06 (0.98)Di-methyl fumarate > 54 38.11 (0.99) 4.88 (0.99)Acetic Acid Induced Writhing Test in MiceFumaric acid > 54 35.21 (0.99) 19.85 (0.91)Mono-methyl fumarate > 54 40.50 (0.99) 15.00 (0.91)Di-methyl fumarate > 54 33.82 (0.97) 16.99 (0.91)Carrageenan-Induced Pedal Edema Test in RatsFumaric acid 8.64 (0.98) 5.56 (0.99) 3.60 (0.99)Mono-methyl fumarate 10.37 (0.99) 4.81 (0.98) 2.89 (0.99)Di-methyl fumarate 11.00 (0.99) 4.22 (0.98) 2.32 (0.95)

Table 1: Estimated ED50 values* (mg/kg/day) of pure fumaric acid (FA), monomethyl fumarate (MMF) and dimethyl fumarate (DMF) in different tests.*The estimated doses of the test agents which had 50% of the observed effects of the tested doses of the standard drugs used in a test, i.e., Pentazocine (10 mg/kg; i.p.) in the hot plate test, Aspirin (25 mg/kg; i.p.) in the acetic acid writhing test, and Aspirin (100 mg/kg; p.o) in carrageenan test. These values were calculated by nonlinear regression analysis using log dose vs. normalized response-variable slop by GraphPad Prism 5.


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Fumaric acid and its conjugates are bio-active constituents of many plants [9], and their therapeutic uses against diverse allergic and inflammatory conditions are well known since decades [18]. Observations reported in this communication reveal that fumaric acid is as active as its di- or mono-methyl esters in rat carrageenan edema test for aspirin like non-steroidal anti-inflammatory agents, and that their observed efficacies in both the tests for analgesics in mice used in this study were also identical. Their efficacies in all the three rodent models always increased progressively with increasing numbers of treatment days. These observations not only add further experimental evidences in favor of the conviction that esters and other hydrolysable conjugates of FA are pro-drugs of the acid, but also suggest that regular oral intake of fumarates can suppresses the sensitivity of peripheral inflammatory responses as well as those of the central nervous system to peripheral painful stimuli. Moreover, they indicate also that biological mechanisms and processes involved in their anti-inflammatory activities are not necessarily like those of aspirin, and that their sites of actions lie most probably within the gastrointestinal tract.

Although statistically significant and aspirin like anti-inflammatory effects of single doses of FA and its esters were observed even after their 2 mg/kg oral doses (Figure 7), such were not the cases for their analgesics like efficacy in the acetic acid writing test in mice for aspirin like anti-inflammatory and analgesic drugs. Moreover, unlike aspirin and most traditionally known non-steroidal anti-inflammatory drugs, FA and its esters were found to possess centrally acting analgesics like efficacies in the hot plate test, and their efficacies in this test were always much higher than those observed in the acetic acid writhing test for aspirin like drugs. These obser-vations reveal that FA and its esters are most probably more potent suppressors of central sensitivity to pain than those of peripheral inflammatory responses. After single oral doses, their statistically significant effects in both the tests for anti-nociceptive agents were observed only after their higher doses tested (18 or 54 mg/kg), whereas after their 10 daily oral doses significant antinociceptive ef-fects of FA and its esters in both the tests for analgesics were also observed after their lowest daily dose tested (2 mg/kg/day). These observations could indicate that either their bioaccessibility or their oral bioavailability increases with increasing number of treatment days. Available information on oral bioavailability of fumarates (as judged by observed blood levels of FA and its esters only) have re-vealed though that circulating blood levels of FA are not altered even after their fairly high oral doses [32-34]. In view of the fact that FA is rapidly metabolized inside the gastrointestinal tract (where rapid enzymatic hydrolysis of its esters are also known to occur), these observations strongly suggest that metabolic process involved in the utilization of this acid inside the gastrointestinal tract are also involved in the modes of actions of the acid.

It is well recognized that fumarate metabolism has numerous biological functions, including those regulating metabolic homeo-stasis and oxidative and other stress responses [9]. Earlier observations in our laboratories have revealed that Fumaria indica extracts enriched in FA and its conjugates are efficient stress response suppressing agents with adaptogenic like efficacies in animal models [28], and that FA could as well be their quantitatively major bioactive constituents [30]. Although we have not yet experimentally veri-fied the possibility that repeated daily oral doses of FA and its hydrolysable conjugates alters allostatic load in rodents, the observations reported in this communication strongly suggest that such could indeed be the case. Therefore, efforts to experimentally verify this possibility using a mouse bioassay specially designed and pharmacologically validated for such purposes were made in our laborato-ries [38].

In any case, it remains certain that FA is an orally active anti-inflammatory agent with modulating effects on central sensitivity to peripheral pain stimuli, and that rapid hydrolysis of its therapeutically used esters inside the gastrointestinal tract can also contribute to their therapeutically and experimentally observed bioactivity profiles. Since efficacy of fumarates in the carrageenan oedema test observed after their single oral doses were much higher than those observed in the hot plate and acetic acid induced writhing tests, it seems reasonable to assume that biological mechanisms and processes involved in peripheral inflammatory responses are their pri-mary pharmacological targets. Although aspirin like anti-inflammatory and analgesic efficacies of fumarates in carrageenan oedema

Discussion


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FA, like other structurally diverse phytochemicals commonly consumed with everyday meals and drinks, or with herbal remedies, alters the functions of adaptive cellular stress pathways, and stress response regulating efficacies of repeated daily oral doses of FA containing and other adaptogenic herbal extracts in rodent models have often been demonstrated [26,39-44]. Amongst numerous bioactive secondary plant metabolites with such efficacies and bactericidal activities, FA and its esters are structurally the simplest ones with well documented clinical efficacy, safety profiles, and broad spectrums of therapeutically interesting bioactivities. Due to its acidity and bactericidal activities, FA is also often used as a food preservative and as farm animal growth stimulator as well. Like for other organic acids used as food additives, the later mentioned uses of FA is mainly due to its interactions with cellular processes inside the gastrointestinal tract regulating gut microbial ecology and other digestive functions [45]. Since gut microbial ecology is also involved in metabolic control of the functions the central nervous systems [46-47], and stress responses and central sensitivity are also regulated by gut microbiota [48-49], it seems reasonable to assume that alterations in gut microbial ecology and other functions of the gastrointestinal tract are also involved in the observed effects of repeated daily oral doses of fumarates observed in this study. If such would also the case in human, it can be expected that regular intake naturally occurring fumarates could as well be a cheap and well tolerated therapeutic alternative for prevention and cure of diverse medical conditions commonly associated with gastric disorders and other inflammatory conditions leading to fibromyalgia and central sensitivity syndromes [50]. Although a recent clinical report have demonstrated beneficial effects of a Fumaria indica extract for treatment of colic pain in children [51] and medicinal uses of other FA accumulating plants for treatment of inflammatory gastric diseases and pain in traditionally known systems of been known since long, as yet little concentrated efforts have been made to clarify the sites and modes of actions of FA inside the gastrointestinal tract.

Conclusion

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and acetic acid writhing tests also increased with increasing number of treatment days, such increases in their efficacies were quan-titatively more pronounced for their pentazocine like centrally acting analgesic agents in hot plate test. These observations indicate that after their repeated daily doses fumarates are fairly potent suppressors of central sensitivity and that peripheral inflammation regulating processes are involved in their brain function modulating efficacies.

Observation reported in this communication, taken together with our current understanding on the role of microbiota-gut-brain axis in regulation of food intake and metabolic homeostasis, point out the necessity of repeated oral doses studies for more rationally defining the therapeutic potentials of FA and its hydrolysable conjugates. They also suggest that fumaric acid is a valuable tool for identifying novel pharmacological target and more effective drug leads urgently needed for prevention and cure of numerous chronic diseases caused mainly by malfunctioning of the digestive systems.

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