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ABSTRACT
Introduction: Methylxanthines can be found in any household worldwide. Although the utilization of its biological effect is still not well understood. In a world driven by big corporations, mass production of food items containing high levels of methylxanthines, growing demand and popularity arise, leading to the discussion if these substances can have detrimental effects on human health. The aim presented in this thesis is to review how these substances can be utilized in different types of therapies and to review the pharmacological potential of these substances. Furthermore, what are the advantages and disadvantages this type of therapy provides.
Methods: The theoretical part is concerned with structural and functional aspects of the following methylxanthines: Caffeine, Theophylline and Theobromine. Reviewing the mechanism by which they exert their function as well as the pharmacokinetic and pharmacodynamic properties. The practical part is concerned with specific diseased states where methylxanthines provide potential therapeutic effects. The method of obtaining information used in this part of the thesis is collected from scientific databases such as PubMed and Scopus.
Conclusions: In any event, based on what has been discovered so far, it is plausible to believe that the potential benefits of methylxanthines in human physiology outweigh any potential detrimental effects. Methylxanthine has a diverse set of molecular targets, making it an intriguing research topic. Methylxanthines are anticipated to be valuable pharmacological medicines in the future, either alone or in conjunction with other treatments.
Key-words: methylxanthines, caffeine, theophylline, theobromine
CONTENTS
LIST OF FIGURES
LIST OF ABBREVIATIONS
INTRODUCTION 13
THEORETICAL PART 15
METHYLXANTHINES 15
History of Methylxanthines 15
Types of methylxanthines 15
Chemical Structure of Methylxanthines 16
Function Of Methylxanthines 17
MECHANISM BY WHICH METHYLXANTHINES EXERT THEIR FUNCTION 18
Phosphodiesterase inhibition 18
Adenosine receptor antagonism 18
Histone deacetylase activator 19
Regulation of intracellular calcium through ryanodine receptor channel 20
PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF METHYLXANTHINES 23
Caffeine absorption, distribution, excretion and metabolism 23
Theophylline absorption, distribution, excretion and metabolism 25
Theobromine absorption, distribution, excretion and metabolism 27
Paraxanthine absorption, distribution, excretion and metabolism 28
Diseases and cases that can be treated by the use of methylxanthines. 30
PRACTICAL PART 32
Aims 32
Methods 32
RESPIRATORY DISEASE THERAPY 33
CARDIOVASCULAR DISEASE THERAPY 35
CANCER THERAPY 35
OBESITY AND DIABETES 38
NEUROLOGICAL AND NEURODEGENERATIVE DISEASE THERAPY 39
HUMAN FERTILITY 42
METHYLXANTHINES ROLE IN KIDNEY HEALTH 44
Diuresis 44
Natriuresis 45
Hemodynamics 46
Renin Secretion 46
METHYLXANTHINE DRUGS 47
Uniphyl 47
Elixophyllin (Theo-24) 47
Thesodate 47
Paracetduo 48
ADVERSE EFFECTS OF METHYLXANTHINES 49
13.3 Pregnancy 49
ADVANTAGES OF METHYLXANTHINES 50
Advantages in respiratory conditions 50
Attention and alertness 50
Increasing physical performance 50
Advantages in cardiac disease treatment and management 50
Circulation 51
Blood pressure 51
Advantages in weight loss 51
Cognition and brain health 51
DETRIMENTAL EFFECTS OF METHYLXANTHINES 53
CONCLUSION 57
LIST OF REFERENCES 58
LIST OF FIGURES
Figure 1. Chemical structure of methylxanthines
Figure 2. Influence of methylxanthines on human health
LIST OF TABLES
Table 1. Relative pharmacological potency of the methylxanthines Table 2. The caffeine content of some well-known energy drinks
LIST OF ABBREVIATIONS
AD – Alzheimer’s disease ANF – Atrial natriuretic factor ATP – Adenosine triphosphate AUC – Area under the curve
BBB – Blood Blood-brain barrier cADP – Cyclic adenosine diphosphate
cAMP – Cyclic adenosine monophosphate cGMP – Cyclic guanosine monophosphate CNS – Central nervous system
COPD – Chronic obstructive pulmonary disease CSF – Cerebrospinal fluid
CYP – Cytochrome P450
GFR – Glomerular filtration rate GIT – Gastrointestinal
HDL – High High-density lipoproteins MAO – Monoamine oxidase
NF-kB – Nuclear factor kappa light chain enhancer of activated B cells NHE3 – Sodium hydrogen antiporter 3
NT – Neurotransmitters O2 – Oxygen
PDE – Phosphodiesterase PK – Pharmacokinetic RBF – Renal blood flow RyR – Ryanodine receptor SCI – Spinal cord injury
SR – Sarcoplasmic reticulum
TGF – Transforming growth factor
Introduction Definition.
Methylxanthines are a special type of medicine made from the purine base xanthine. Both animals and plants make xanthine naturally. (Fredholm, 2010)
Methylxanthines are a big part of today‟s fast-paced world and can be found more or less in any household worldwide. The most common sources of methylxanthines can be found in regular household items like coffee, tea and chocolate. It has surely left its mark in history and continues to be a big part of modern society. Scientists worldwide have studied the various effects of methylxanthines. However, there are still many unanswered questions regarding the utilization of its biological effects, which are not well understood. (Gottwalt, 2020).
In a world driven by big corporations, mass production of food items, a new burden has been raised. Can the increased consumption of methylxanthines have negative effects on the human body? What are the health benefits and adverse effects of methylxanthines? And what pharmacological properties are there to be investigated for the purpose of medical treatment?
According to Fredholm (2010), methylxanthines have been present in human diets for a long period of time, according to historical and anthropological research. The intake of methylxanthines-containing goods is now unquestionably present and highly prevalent in human populations worldwide. Apart from the most typical methylxanthines‟ dietary sources, such as chocolate, tea or coffee, there are a growing number of items containing methylxanthine, which are gaining popularity, and also generating some concerns.
Energy drinks and dietary supplements are examples of this, which frequently hold much higher levels of methylxanthines than traditional sources. Caffeine has been the most thoroughly investigated methylxanthine, owing to its enormous prevalence in today’s diet. Therapeutic effects of methylxanthine have been documented in a variety of pathologic situations.
For decades, they have been utilized in medicine to treat various ailments, including respiratory disease, cardiovascular disease, and cancer. However, the processes underlying methylxanthines’ positive effects in such situations are not always clear.
The early signs of the use of methylxanthine in medicine is discussed, as well as the rising situations which have shown promise and have been suggested as prospective agents in therapy. Later sections will go through the current therapeutic uses in medicine. The chemical processes underlying methylxanthines’ positive benefits in various contexts will also be explained.
THEORETICAL PART
METHYLXANTHINES
History of Methylxanthines
The therapeutic effects of methylxanthine were important in its early history. Tea, for example, has long been utilized for medicinal purposes in India. There were overstated claims about the wholesome effects of coffee, tea, and cocoa drinks, just as there were pretentious statements about the harmful health repercussions of these beverages (Zubairy, & Patil, 2012).
Samuel Hahnemann (1755-1843) embraced a later perspective by finding the effects of coffee to be highly advantageous but expressing reservations about its usage because it disrupted a natural equilibrium. It was discovered early on that coffee’s effects were attributable to an active principle (Bizzo & Scancetti, 2015).
Hermann Emil Fischer (1852-1919) explained in a series of studies the chemistry of caffeine and its derivatives that were expressly acknowledged in his nomination of the Nobel Prize and presentation in 1902. His first significant project was caffeine research, which he completed when he was 29 years old. He discovered that caffeine has a heterocyclic skeleton similar to uric acid after oxidation with wet chlorine. He then found that it was a trimethylxanthine, although he battled to understand the structure of xanthine for quite some time (Szymański, 2017).
According to Sugimoto & Yachie (2014), theobromine was discovered among the dimethylxanthines in 1841. The name comes from the cocoa plant’s name and refers to Corte’s nickname for it, “the food of Gods” (Theobroma). In 1888, theophylline was discovered as a minor constituent in tea, and Fischer proposed a synthetic process and established the structure (Lelo & Miners, 1986). Theophylline was initially used in the clinic at the turn of the twentieth century as a diuretic, then in asthma treatment.
TYPES OF METHYLXANTHINES
Methylxanthines are naturally occurring alkaloid compounds that can be found in numerous plants. Methylxanthines can be found in 13 different orders in the plant
Kingdom, which in total means over 100 various species (Fredholm et al. 2001). The most prevalent types are caffeine, theophylline and theobromine. Their derivative plants are Coffea sp. for coffee, Camellia sinensis L. for tea and Theobroma cacao L. for cacao (Gramza-Michalowska et al.2021 ).
Caffeine, theophylline, and pentoxifylline are examples of pharmaceutically active methylxanthines. Theobromine, a fourth methylxanthine found in cocoa products but not employed as a medicine, has toxicological significance in nonhuman animal species (Potier & Cambar, 1997). There is also a methylxanthine which is not a plant derivative called paraxanthine. This compound is generated when caffeine is metabolized in the human body (Monteiro & Silva, 2019).
Chemical Structure of Methylxanthines
The purine base xanthine can be found in nearly all human fluids and tissues as well as in other species. Methylxanthines are methylated xanthine derivatives. Caffeine (1,3,7- trimethylxanthine), theophylline (1,3-dimethylxanthine), and theobromine (3,7- dimethylxanthine) are the most common methylxanthines found in nature. Plants do not create paraxanthine (1,7-dimethylxanthine), which is a dimethylated byproduct of caffeine and is an isomer of theobromine and theophylline. More complexly substituted methylxanthines include aminophylline (1,3-dimethyl-7H-purine-2,6-dione), pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxanthine), and IBMX (3-isobutyl-1-methylxanthine) (Monteiro & Silva, 2019).
Caffeine, unlike the others, is thought to have greater lipophilic properties, implying that it can smoothly disperse across cell membranes and penetrate the blood-brain barrier. The fact that methylxanthines are weak Bronsted bases should explain the imino nitrogen at position 9. The methyl group at position 1 distinguishes theobromine from caffeine. The methyl group provides caffeine with a variety of physicochemical features, some of which have been linked to significant increases in physiological effects. Several pharmacologically relevant synthetic modifications of naturally occurring methylxanthines have been developed (Monteiro & Silva, 2019).
An overview of the chemical structures of the various methylxanthines can be viewed in the following figure:
Figure 1. Chemical structure of methylxanthines (Iriti et al. 2010)
FUNCTIONS OF METHYLXANTHINES
Methylxanthines are a special type of medicine made from the purine base xanthine. Plants and mammals both make xanthine naturally. Dyphylline, theophylline and methylxanthines are used to treat airway obstruction caused by diseases such as chronic bronchitis, emphysema and asthma. Methylxanthines include theobromine (found in chocolate) and caffeine (found in coffee) (Barr & Camargo, 2003).
The most well-known and widely utilized methylxanthine is theophylline. It has an immunomodulatory, anti-inflammatory, and bronchoprotective impact at low doses. For its bronchodilator activity, greater doses are required; nevertheless, higher doses are frequently accompanied by toxicity (Fredholm et al. 2001).
Experts aren’t clear with methylxanthine operations. However, studies have shown that they inhibit phosphodiesterase, antagonize adenosine receptors, and their effects on histone deacetylase activity at low dosages may contribute to their immunomodulatory effects. Theophylline and dyphylline’s principal function is to aid in the maintenance of excellent airway control in chronic, persistent airway illnesses (Furukawa, & Bierman, 1983).
MECHANISM BY WHICH METHYLXANTHINES EXERT THEIR EFFECTS
Phosphodiesterase inhibition
Caffeine, theophylline and theobromine all exhibit the same properties when it comes to phosphodiesterase inhibition (Bradley 1989). There are numerous families and isoforms of PDE enzymes that all exert different properties. When we speak of phosphodiesterases mentioned here, we refer to the cyclic nucleotide PDE enzymes. The main function of PDEs is to cleave the phosphodiester bond in cAMP and cGMP, ending the intracellular signal pathway. By this action, PDEs regulate various important functions in the second messenger system (Corse 2012).
Methylxanthines increase intracellular levels of cAMP and cGMP by inhibiting the PDEs in a non-competitive manner. Relaxation of bronchial smooth muscle, pulmonary vascular vasodilation, diuresis, stimulation of the CNS, and stimulation of the heart are all caused by this signal (Bradley 1989).
Theophylline is an example of a nonspecific PDE inhibitor. It inhibits PDE 3, 4 and 5. Theophylline is used in the therapy of severe COPD and asthma. Its mechanism of action is to inhibit PDE and increase intracellular cAMP. Theophylline exerts many important effects on the lungs. For example, it leads to the relaxation of bronchial smooth muscle and bronchodilation. It also slows down fibrotic changes in the lungs, as well as playing a role in the inhibition of proinflammatory mediators (Brown 2007).
Adenosine receptor antagonism
Besides being inhibitors of phosphodiesterases, one of the main functions of methylxanthines is their involvement in adenosine receptor antagonism. Adenosine being the endogenous ligand. Adenosine receptors can be divided into four different groups in humans: A1, A2A, A2B and A3 receptors. They belong to the group of G-protein coupled receptors (Fredholm et al. 1997). Methylxanthines like caffeine and theophylline are able to influence A1 and A2A receptors situated in the brain and heart. They work in a non- selective manner leading to a stimulatory effect when these receptors are being
antagonized. This will lead to a stimulant effect in the brain as well as increasing the heart rate (Fredholm et al. 2001).
Adenosine receptors A1 and A2A are involved with the cardiovascular system. They regulate the heart, as well as myocardial O2 consumption. They are also involved in regulating the blood flow in coronary circulation (Gao et al. 2007). A2A receptors have shown to have a stronger anti-inflammatory effect compared to the latter (Hasko et al. 2008). Besides this, these two receptors also exert important functions in the brain. They are involved in releasing NT like dopamine and glutamate (Schiffmann et al. 2007).
Adenosine receptors A2B and A3 are situated at the periphery. These receptors are involved in the inflammatory processes and the response of the immune system.
Research shows how exogenous adenosine triggers bronchoconstriction in patients suffering from asthma. This led researchers to believe that the bronchodilatory effect caused by theophylline be because of adenosine receptor antagonism. The pathway for this action is not yet fully understood. Research has shown that bronchoconstriction produced by adenosine takes place in an indirect manner by the activation of the adenosine receptors A1 (neurons) and A3 receptors (mast cells). This leads the bronchial smooth muscles to contract due to an abrupt increase in intracellular calcium concentration. Methylxanthines are able to antagonize this effect directly. But they are also able to affect this indirectly by regulating the amounts of paracrine mediators which are released by mast cells (Fredholm et al. 2011).
When it comes to the effect in the brain, adenosine accumulates and binds receptors more tightly the longer one stays awake. Adenosine receptors in the basal forebrain are critical in transmitting mental weariness to the brain. Methylxanthines bind to these receptors with roughly equal affinity to adenosine, and it is through this antagonistic interaction that the medication stimulates the CNS. Methylxanthines also stimulate calcium uptake in diaphragmatic muscles through adenosine-mediated calcium channels, resulting in increased contraction force (Mattikow 1981).
Histone deacetylase activator
Inflammation is also regulated by the equilibrium between histone acetylation and histone deacetylation. The manifestation of inflammatory gene expression is determined by this
equilibrium. Inflammation triggers the activation of transcription factors like NF-kB. This will, in turn, activate histone acetylation and increase the expression of inflammatory genes. This action is ceased by histone deacetylases (Fredholm et al., 2011).
Histone deacetylase does become a critical regulator of inflammatory mediators during inflammation. Phosphoinositide-3-kinase-delta prevents histone deacetylase from being recruited to inflammatory sites, and methylxanthines have recently been demonstrated to block phosphoinositide-3-kinase-delta. Increased histone deacetylase recruitment to sites of inflammation limits the transcription of genes encoding inflammatory mediators, resulting in anti-inflammatory effects (Ito et al. 2010).
Research indicates that theophylline has the ability to increase the activity of histone deacetylases. This again is why therapeutic doses of theophylline exert anti-inflammatory properties, especially in combined therapy with, for example, glucocorticoids in the therapy of COPD or asthma (Cosio et al. 2004).
Regulation of intracellular calcium through ryanodine receptor channels
Methylxanthines have a wide range of pharmacological properties. Besides PDE inhibition, adenosine receptor antagonism, histone deacetylase activation, they also have the ability to act on ryanodine receptor channels.
Ryanodine receptor channels are intracellular calcium channels and explicitly bind ryanodine, a plant alkaloid (Fill and Copello 2002). These channels are localized in the sarcoplasmic reticulum and endoplasmic reticulum. Intracellular calcium is essential for the regulation of smooth muscle in the airways. The mechanism behind this is through the phosphorylation of myosin light chain kinase, which leads to contraction and dephosphorylation of myosin light chain kinase, which elicits relaxation (Fredholm et al. 2001).
There are three different types of ryanodine receptor channels: RyR1, RyR2 and RyR3. Type one is localized in skeletal muscle cells. While type two is localized in cardiac muscle cells, and type three can be found in neuronal cells. They all respond to cytosolic calcium levels; however, they are also influenced by other substances like ATP, magnesium, cADP, ribose and adenosine (Sitsapesan et al. 1995; Zalk et al. 1997). The
plant alkaloid ryanodine will, at low concentrations, stimulate these channels. In contrast, increased concentrations can lead to a paradoxical reaction that can close the RyR channels completely. Methylxanthines were not only found to stimulate RyR channels in muscle cells. They have also been found to influence RyR channels in pancreatic beta cells as well as in T lymphocytes, though the function here is not clear (Bruton et al. 2003; Ritter et al. 2001).
Caffeine and its correlation with RyR channels have been studied since the start of the 1900s. A great significant finding from these studies was that the effect posed by caffeine was dose-dependent and that there was a certain threshold value to be obtained. This threshold value was based on the effective concentration of caffeine that was required for its activation. This value was documented as 1-2 mM, reaching its peak value at 5-10 mM (Endo 1977; Fabiato 1983; Kirino 1982). Further down the line, studies were able to prove that caffeine was able to free calcium from endoplasmic reticulum reserves. By influencing RyR1 (skeletal muscle) and RyR2 (cardiac muscle) channels. Which proved the influence of caffeine by increasing the mean channel open time. (Rousseau et al. 1988). Caffeine is now a well researched RyR agonist (Fredholm et al. 2001).
Caffeine‟s effect on RyR channels was compared with the effect of other methylxanthines. Theophylline, theobromine and paraxanthine, which are all naturally occurring methylxanthines, show multiple similarities to caffeine. They all are able to trigger Ca2+ release from SR vesicles. And they increase the binding of ryanodine to skeletal muscle. A study performed by Rousseau (1988) reported that the naturally occurring methylxanthines were able to trigger a larger amount of Ca2+ compared to caffeine.
When it comes to the RyR channels, numerous studies found verification that pore structures that are present inside RyR channels are identified to be the activation site for caffeine. More specifically, the C-terminal of these proteins. Meaning any defects or mutations found in these structures in RyR1 channels would lead to an altered response to caffeine. An example of this is central core myopathy which has multiple mutations in these areas (Du et al. 2004). Another substance that could alter caffeine‟s response is magnesium. Mg2+ is able to suppress caffeine, as well as some histological dyes.
This raises the question if methylxanthines could have an influence on different disorders where calcium release and signalling plays a significant role. We know that intracellular
Ca2+ release and signalling are important for a normal functioning brain and muscle response. Could methylxanthines play a role in how RyR channels work in neurodegenerative disorders? This issue will be discussed in a later part.
Besides affecting RyR channels in muscle cells, research shows the stimulation of calcium release in neuronal cells by causing increased levels of cytoplasmic Ca2+. Methylxanthines like caffeine, theophylline and 3-isobutyl-1methylxanthine lead to the activation of RyR channels in ganglionic neuronal cells. If we look at RyR channel activation in the brain, methylxanthines can influence brain neurons in the areas of the hippocampus, midbrain and Purkinje cells (Kano et al. 1995; Garaschuk et al. 1997; Sharma. 2003; Patel et al. 2009). Research shows that there could be a correlation between the consumption of methylxanthines and a decreased risk of developing Parkinson’s disease. Comparing caffeine and paraxanthine, caffeine provided a more negligible protective effect to dopaminergic neurons (Xu et al. 2010).
PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF METHYLXANTHINES
To understand how methylxanthines exert their function in the human body, we have to contemplate various parameters. After the ingestion of methylxanthines by animals or humans, these substances will dispense in all biofluids rather quickly. It will also penetrate all organic membranes. Like other chemical substances, methylxanthines do not lead to accumulation in tissue structures. They are immediately broken down by the liver and excreted (Fredholm et al., 2011).
To understand the different properties of each specific type of methylxanthine, we have to review them one by one starting with caffeine.
Caffeine absorption
In studies accomplished by (Walton et al. 2001) we can see that there is no significant difference between species when it comes to the absorption and bioavailability of caffeine. The test subjects used in this study were humans, dogs, rabbits and mice. After the administration of caffeine, there was an absolute absorption within the GIT. In human test subjects, this happened after 45 minutes of the administration, meaning 99% of the caffeine was absorbed. The majority of the caffeine was absorbed in the small intestine, but around 20% was found absorbed in the stomach (Chvasta and Cooke, 1971).
The plasma peak concentration after oral ingestion of 5 mg/kg of caffeine in a grown man shows the bioavailability of caffeine to be (Tmax) of 29.8 +- 8.1min. Reaching its peak concentration at 10.0 +- 1.0 Microgram/mL (Blanchard and Sawers 1983a).
Zandvliet et al. (2005) later performed a study where 80 mg of caffeine was administered, resulting in a plasma peak concentration of 1335 ng/mL. This amount can be found in a regular-sized cup of coffee (Monteiro & Silva, 2019).
In a study performed by (Statland et al. 1980), it was found that the average half-life of caffeine in serum was 5.7 hours. Smoking is said to decrease the half-life of caffeine.
When it comes to the concentration of caffeine administered, there was a study from (Kaplan et al., 1997) proposing a difference between the pharmacokinetic properties with high and low concentrations of caffeine.
Caffeine concentration of around 70 to 100 mg suggests linear pharmacokinetics, and this amount can be found in a regular cup of coffee. While increasing the dose to approximately 250 – 500 mg, the pharmacokinetics properties changed to non-linear. The half-life of caffeine increased as well, which can suggest an increase in the systemic and pharmacological effects.
While comparing different studies on caffeine absorption, we can determine if the route of administration will play a significant role in its bioavailability and how this can affect its efficacy.
Comparing the results of oral administration and intravenous administration, the numbers didn‟t change extensively. But if the caffeine was administered in the form of an enema, the absorption was lowered by approximately 3.5 times compared to oral ingestion. If caffeine was administered as inhalation, the bioavailability was reduced to 60% (Monteiro & Silva, 2019).
There are many factors that could affect the absorption of caffeine, but it appears that caffeine absorption from different types of food and drinks are not affected by age, gender, genetics, diseased state, abusers of drugs, alcohol or nicotine (Mumford et al. 1996).
Factors like consumption rate, temperature and different types of caffeine beverages have shown little influence on the PK properties of caffeine (Monteiro & Silva, 2019).
Caffeine distribution
To observe how caffeine distributes in tissues and organ systems, a study performed by Arnaud (1976) used radiolabeled caffeine. The results from this study show that caffeine does not accumulate in tissues as well as different organ systems for a long period of time. It is quickly absorbed and passes all biological membranes. Caffeine can therefore be found in all tissue fluids like, for example, blood plasma, CSF, saliva, bile, semen, breast milk and in the umbilical cord. Caffeine is also able to cross the blood-brain barrier (Arnaud 1976).
In a study performed by (McCall et al. 1982), radiolabeled caffeine -14C was used to trace caffeine movement through the blood-brain barrier. This was achieved by injecting rats
with intracarotid injections. The transport mechanism of caffeine crossing the BBB was found to be by simple diffusion, as well as by carrier mediated transport mechanisms. Raising the question if there are macromolecules that have complementary features to caffeine that is involved with the transportation of caffeine across the border.
Caffeine excretion
The main method of elimination of caffeine is renal excretion. Caffeine is extensively absorbed in the renal tubules, meaning approximately 98% will be absorbed this way. There was found a correlation between the clearance of caffeine and the output of urine. This means that clearance was dependent on the flow of urine. 7.5 mg/kg of caffeine was administered per os, and 70% was retrieved in the urine (Tang Liu et al. 1983). While under 2 % of the caffeine was found unaltered (Birkett and Miners 1991). If the dose was increased to around 1 gram which equals around 10 cups of coffee, the unaltered caffeine in the urine was decreased to only around 0.74 – 0.91% (Arnaud 1976).
Caffeine metabolism
Metabolism of caffeine is through first-order elimination. Multiple isoforms of CYP enzymes are responsible for the metabolism of caffeine. CYP1A2, which can be found in the human liver, makes up roughly 15% of the total amounts of CYPs. These enzymes are responsible for over 90% of the elimination of caffeine. It was found that there were vast individual differences in the activity of CYP1A2. These differences might be due to elements such as gender, genetic variation and others (Shimada et al. 1994; Gu et al. 1992).
Theophylline absorption
Like caffeine, theophylline is also immediately and fully absorbed in the GIT. The main difference is that theophylline rapidly absorbs before reaching the jejunal part of the intestines. Theophylline concentration in the jejunum was measured to be less than 10% compared to the duodenal concentration (Brouwers et al. 2005). The bioavailability of
absorbed dose was 0.99 +- 0.02, meaning 100% was absorbed (Hendeles et al. 1977). Food interaction decreased the rate of absorption by decreasing parameters like Tmax and cmax. But it didn’t affect the bioavailability (Jonkman et al. 1985).
Theophylline distribution
Theophylline levels in plasma possess nonlinear kinetics of elimination. Due to the narrow therapeutic index of theophylline, obtaining the proper concentration can be challenging. This is difficult due to the difference in metabolism in the test subjects. The therapeutic index is set to be from 10-20 mg/mL. Where concentration above this value is said to be toxic (Fleetham et al. 1981; Trnavska 1990). Theophylline ability to bind to the protein albumin in serum was measured to be 48.8 +- 6.2%. This was the case for healthy test subjects, a significant difference was noticed when comparing the values to non-healthy test subjects (Invast Larsson et al. 1992). When comparing theophylline to other methylxanthines like, for example, caffeine, it was found that theophylline possesses lower lipid solubility. Meaning less theophylline will penetrate organs like the liver, adipose tissue, muscle and brain. Whilst comparing theophylline concentration able to cross the BBB, this value was lower than in other tissue structures (Ståhle 1991). However, a study was conducted using pregnant rats to view the ability of theophylline to cross the placental barrier. It was found that theophylline was able to cross and disperse in the organ system of the fetus. But the amount of theophylline found in the rat fetuses brain was double the amount of the concentration in an adult brain. (Arnaud et al. 1982a).
Theophylline excretion
By administering radiolabeled theophylline to rat test subjects, the rate of elimination could be determined. However, when administering radioactive theophylline p.o and i.v, there were no noteworthy differences in metabolism and elimination. After 24 hours, 70 +- 7% of the concentration was eliminated in urine. 6+- 1% was found in carbon dioxide. And amounts under 1% remained in the body (Arnaud and Welsch 1980b). The elimination of plasma concentration occurs by means of first-order elimination. The half-life of theophylline is found to be between 4-8 hours. While the AUC would disproportionately
rise with dose, suggesting probable capacity limited elimination (Teunissen et al. 1985). Renal clearance of theophylline is determined by urine flow, and excretion is dependent on urine output. Theophylline is fully reabsorbed in the renal tubules. (Tang Liu et al. 1983).
Theophylline metabolism
The metabolism of theophylline happens according to various isoforms of cytochrome P450. Mainly CYP1A2, CYP2E1 and CYP3A4. 90% of theophylline is eliminated in the liver of adults. At the same time, the remaining unchanged amounts are eliminated by the kidneys (Troger and Mayer 1995).
Theobromine absorption
Theobromine, like caffeine and theophylline, is also completely absorbed. About 1% can be found in faeces excreted in unchanged form (Arnaud and Welsch 1979a). As the previous methylxanthines mentioned, theobromine bioavailability is also 100%. Bioavailability was found to be 0.96+- 0.02 (Tarka et al. 1983). When it comes to research on theobromine in general, less research has been performed compared to caffeine and theophylline. It was found that the absorption rate would decrease if the dose of theobromine was increased, which means that the peak blood level would be delayed with an increased dose of theobromine. Some studies found evidence that the bioavailability of theobromine would decrease with the intake of food items containing chocolate. (Shiverly et al. 1985).
Theobromine distribution
The p.o administration of radiolabeled theobromine to rat test subjects was to investigate how these substances disperse in tissue structures. After 24 hours post-administration, the result from this study shows that theobromine and its metabolites did not accumulate in the organ systems. Values as low as 0.4% were found in the liver, and 2% was found in the large intestines (Arnaud and Welsch 1979a). Like the previous methylxanthines,
theobromine is also able to cross the placental barrier (Arnaud and Getaz 1983). Another study using rat test subjects determined that the mean value of a fraction of unbound theobromine was 0.88 (Bonati et al. 1984).
Theobromine excretion and metabolism
The main route of excretion of theobromine is through urine. The amount which had been eliminated after the administration of theobromine was valued at 84+- 8% (Arnaud and Welsch 1979a). Compared with theophylline, they both share the same renal clearance properties. Theobromine is also fully reabsorbed in renal tubules. And the clearance is dependent on the urine flow. And the excretion of urine is dependent on the urine output (Tang Liu et al. 1983). Administration of radiolabeled theobromine in rat test subjects showed faecal excretion of 11+- 1%. 10% was found to be in unchanged form (Arnaud and Welsch 1979a). Theobromines half-life was found to be around 6.1+- 0.7h (Drouillard et al. 1978). There were grave differences between species. Studies performed on rat test subjects where different doses of theobromine were administered showed linear pharmacokinetics. The administered doses differed from 1-100 mg/kg. The AUC values increased proportionally to the dose (Bonati et al. 1984). Theobromine is also metabolized by specific isoforms of CYP enzymes (Campbell et al. 1987a).
Paraxanthine absorption and distribution
Paraxanthine, like all previous methylxanthines mentioned in this section, is likely to be absorbed fully from the GIT after p.o administration (Lelo et al. 1989). The difference between paraxanthine research compared to the other methylxanthines is the fact that there are no foods containing paraxanthine. Therefore studying its metabolic properties is a bit more challenging than the latter. We know that paraxanthine is a metabolite of caffeine. And when caffeine has been consumed, around 80% is metabolised to paraxanthine. Meaning the serum level of paraxanthine is higher than the serum level of caffeine. This property is essential to investigate when it comes to the pharmacological properties of caffeine, to understand if it‟s the effect of caffeine or the effect of paraxanthine which is at work. (Benowitz et al. 1995).
Paraxanthine excretion and metabolism
The excretion of paraxanthine if consumed p.o was found to be 60% in humans. This amount was found unchanged in the urine. When caffeine was consumed in the same manner, the amount of paraxanthine found in the urine was six times that value (Arnaud and Welsch 1980a). Renal clearance of paraxanthine is dependent on urine flow, and excretion is dependent on urine output. The total renal clearance is 0.90 L/h/kg. As previously mentioned methylxanthines, paraxanthine is fully reabsorbed by renal tubules and is also eliminated by means of first-order elimination. The mean half-life was set to be around one h. Whilst the rate of elimination was approximately 0.70 L/h/kg. Other parameters like the volume of distribution was 1.50 L/kg. These values portray paraxanthine doses of around 10mg/kg. If this dosage was increased to around 15 or 30 mg/kg, a shift happens. And the linear kinetics change to non-linear kinetics and the AUC increases but now in a disproportionated manner to the dose. (Bortolotti et al. 1985; Arnaud and Enslen 1992). Paraxanthine is also metabolized by the manners of CYP enzymes (Campbell et al. 1987b).
DISEASES AND CASES THAT CAN BE TREATED BY THE USE OF METHYLXANTHINES
Specific pharmacological functions have been assigned to all-natural methylxanthines. Methylxanthines are particularly tempting and intriguing therapeutic options since they have such substantial biological effects while having a low toxicity. Caffeine stimulates the respiratory system and the central nervous system (CNS), as well as stimulating the heart, dilatation of the coronary arteries, and relaxation of smooth muscle. Theobromine’s most significant property is that it acts as a heart stimulant (Monteiro & Silva, 2019).
Table 1. Relative pharmacological potency of the methylxanthines (Gramza- Michalowska et al.2021).
The rewarding benefits of coffee and tea use, the two main methylxanthine sources with long-term beneficial effects, are well documented. Greater energetic arousal, higher hedonic tone, increased self-reported alertness, improved psychomotor performance, and improved focus have all been associated with coffee (caffeine) use. Tea has been highly suggested as an able agent for the treatment and prevention of various human illnesses, and some of the alleged impacts have been linked to the methylxanthines characteristics and total content, at least to some extent (Ogawa & Sano, 2001). Some of the positive effects related to methylxanthines could be attributed to their high antioxidant content. The pharmacological usage or potential of methylxanthine is discussed in the practical part of this thesis in the context of various health issues.
Figure 2. Influence of methylxanthines on human health (Gramza-Michalowska et al. 2021).
PRACTICAL PART
Aims
The aim of this thesis is to use recent scientific publications to review different types of methylxanthines and how they can be used in clinical practice. To discuss and review different types of therapies available today and to explore the pharmacological potential of these substances. Another aim is to discuss potential harm and side effects related to drug therapy as well as the consequences of the increased consumption on a daily basis. To view the advantages and disadvantages of these types of therapies.
Methods
The method of obtaining information used in this part of the thesis is collected from scientific databases such as PubMed, Scopus, Researchgate and Google Scholar. The scientific papers and research articles have been carefully selected according to the relevance of this thesis topic.
RESPIRATORY DISEASE THERAPY
Methylxanthines have been shown to be useful in the treatment of a wide range of ailments. Surprisingly, all three principal natural methylxanthines, theophylline, theobromine and caffeine, have been used to treat illnesses such as newborn apnea, asthma, and cough (Oñatibia-Astibia, & Franco, 2016).
Methylxanthines were initially recognized to have medicinal potential in the treatment of asthma. Phosphodiesterase inhibition, which relaxes human airway smooth muscle, is assumed to be the compound responsible for the bronchodilatory effects attributed to methylxanthines in this case. Adenosine receptor inhibition has also been postulated as a potential asthma therapy strategy. By inhibiting chitinase, methylxanthines may also help those with bronchial asthma (Tilley, 2011).
According to Weinberger & Hendeles (1996) theophylline is a strong bronchodilator that has been widely used in the treatment of asthma as it was first presented as a medical therapy for the disease in 1922. Theophylline should be utilized instead of the other methylxanthines since it diffuses better in bronchial tissue.
Another xanthine derivative that has been explored as a bronchodilator is doxofylline. Chronic obstructive pulmonary disease (COPD) is a common inflammatory lung illness that develops over time, and methylxanthine has been related to an anti-inflammatory effect in this condition (Shukla & Mishra, 2009).
Compounds from the xanthine family have long been used to treat apnea of prematurity as first-line, effective and safe ventilatory stimulants in addition to their therapeutic usage against asthma. Methylxanthines have been utilized as the primary medication for this illness in clinical practice since the 1970s. Apnea occurs when the respiratory drive is immature, resulting in decreased oxygen saturation in the blood, bradycardia and a halt of breathing. It may be severe enough to necessitate positive pressure ventilation. Methylxanthines have been shown to be helpful in lowering the number of apneic attacks and the need for short term mechanical ventilation (Schmidt & Tin 2006)
Supinski & Kelsen (1984) suggest that theophylline and caffeine have long been of the standard of excellence in treatments for preventing and alleviating respiratory illnesses. Caffeine reduces breathing hypoxia while improving minute ventilation, diaphragmatic
contraction, CO2 sensitivity, neural respiratory drive and respiratory muscle function. It has also been shown to boost significantly resting hypercapnic and hypoxic ventilatory responses in humans, which are predominantly mediated by peripheral chemoreceptors in the carotid bodies.
Finally, methylxanthines, specifical theobromine, are expected to have antitussive properties. In conscious guinea pigs, the citric acid-induced cough was found to be efficiently suppressed by theobromine in vivo. In fact, the same study found that it had a positive effect on humans. Theobromine suppresses cough by suppressing afferent nerve activation, which is perceived to be induced by phosphodiesterase inhibition and inhibition of bronchoconstricting adenosine A1 receptors( Smit, 2011).
CARDIOVASCULAR DISEASE THERAPY
Pharmacologically, methylxanthines have been utilized to treat cardiovascular diseases. Anginal syndrome and congestive heart failure are two examples of disorders that can be treated by means of theobromine. Methylxanthines have also been used to treat bradyarrhythmias, particularly when there is a rise in the appearance of extracellular adenosine (Riksen & Rongen, 2011).
According to Chou & Benowitz (1994), methylxanthines such as theophylline, theobromine, and caffeine have been reported to have an active vasodilator impact on coronary arteries, with effects ranging from caffeine to theobromine. In humans, blood vessel microcirculation is improved by caffeine treatment.
Long-term moderate tea and coffee consumption was linked to a lower risk of coronary heart disease and stroke in healthy people. Another recently documented effect of methylxanthines on cardiovascular health is theobromine’s ability to raise high-density lipoprotein (HDL) cholesterol levels. Reduced HDL cholesterol levels in the blood are thought to be an independent and inverse risk factor for cardiovascular disease (Neufingerl & Trautwein, 2013).
CANCER THERAPY
Several examples of good effects of methylxanthine consumption/administration in cancer situations have been gathered. Several methylxanthine-containing items have been linked to positive results, such as cocoa extracts (used to treat human breast cancer) and coffee, which has been linked to a protective effect against colon cancer (Ohta, & Sitkovsky, 2011).
Tea extracts have antimetastatic and anticancer potential in the treatment of renal cell carcinoma and bladder cancer, while the distinction between chemopreventive and chemotherapeutic effects is still debated (Yang & Wang, 1993). Caffeine appears to be necessary for tea’s anti-carcinogenic qualities, as decaffeinated teas have very little (or none) cancer-fighting properties (Bode & Dong, 2007).
According to animal research, caffeine may even have a beneficial effect on a variety of cancers. Skin, lung, and mammary cancers are examples of this. Theobromine, like caffeine, has been linked to cancer-fighting properties. In fact, theobromine has been shown to slow tumor growth by inhibiting angiogenesis (Barcz & Skopinska-Rózewska, 1998).
Finally, theophylline has been shown to trigger cell death in human prostate, ovarian and lung cancer cell lines. Theophylline use in the treatment of chronic lymphocytic leukaemia has also been demonstrated to be beneficial in some studies with an impact, including the activation of apoptosis (Hirsh et al. 2004).
Apart from having a direct cancer-fighting impact, methylxanthines have also been demonstrated to improve the tumoricidal efficacy of common anticancer medications like mitomycin C, thiotepa, cisplatin, methotrexate, cyclophosphamide, doxorubicin, and vincristine. Caffeine-assisted chemotherapy has even been advocated as a treatment option for a number of cancer types (Hayashi et al. 2005). Theobromine and pentoxifylline, in addition to caffeine, were discovered to have positive synergistic effects with cancer chemotherapy drugs (Janitschke & Grimm, 2020).
It is assumed that the synergistic action of methylxanthines (particularly caffeine) with anticancer medications that cause damage to DNA and cancer management is due to a DNA repair inhibitor altering effect. This action would have an impact on post-replication repair of sublethally damaged DNA, leading to a rise in the number of lethal chromosomal abnormalities, boosting cytotoxicity and antitumor activity (Byfield et al. 1981; Fingert et al. 1986). Caffeine has been demonstrated to block DNA repair enzymes directly (Block et al. 2004).
In addition to chemotherapy, methylxanthines appear to have a radiation sensitizing effect, as shown in various cell lines. Cell cycle interference, most likely via G2/M checkpoint arrest, would also be involved in the sensitization mechanism, putting damaged-DNA repair in jeopardy (Jiang et al. 2000). Methylxanthines have also been suggested to be beneficial when used in conjunction with tumor therapies that are adversely affected by hypoxia, such as radiotherapy because they have been shown to improve tumor oxygenation and perfusion significantly (Bush et al. 1978).
Finally, other favourable effects triggered by coffee in cancer treatments may be achieved by reducing their hazardous detrimental effects. As a matter of fact, persistent caffeine pre- treatment has been proven to provide considerable radioprotection, and intratumoral or topical use has been shown to reduce harmful, detrimental effects in animal models while maintaining effectiveness (Shojaei-Zarghani, & Azami-Aghdash, 2020). These findings add to the growing body of data that methylxanthines have the significant pharmacological potential for application in cancer treatments, either directly or as co-adjuvants.
OBESITY AND DIABETES
In the context of obesity, dietary methylxanthines and products containing methylxanthines have been claimed to have advantageous effects. For example, several theories have been presented to support tea’s efficacy in preventing obesity by influencing metabolism through various processes, such as lipase inhibition, thermogenesis stimulation, appetite modulation, and caffeine synergism (Carrageta & Silva, 2018).
According to Lee & Ross (2005), caffeine disrupts glucose and fatty acid metabolism, which adds to the possibility of weight gain. Caffeine’s weight-loss effect may be due to a triggered decline in blood triglyceride levels, which may impede fatty acid delivery to adipose tissue and lead to fat loss. However, the modulation of lipolysis appears to be the technique that is more consistently implicated in caffeine-induced body fat loss. Caffeine, through increasing hormone-sensitive lipase activity, was considered to trigger a shift in substrate preference from glycogen to lipids and suppressing glycogen phosphorylase activity, resulting in a decreased dependence on glycogen (Okumura & Miyashita, 2012).
Natriuresis is also aided by methylxanthines. In fact, improved sodium excretion, magnesium, calcium phosphate, chloride and other urinary solutes may accompany methylxanthine-induced increases in urine flow.
Another area of methylxanthines study that has been revealed is its potential utility in the field of diabetes. One of the most serious health problems associated with today’s global eating choices and every day routines is diabetes mellitus. Because both caffeinated and decaffeinated coffee were connected to a lower risk of diabetes, caffeine may not be the only factor impacting the advantages of coffee. Caffeine was found in humans to reduce glucose absorption and improve insulin sensitivity. Coffee isn’t the only beverage with methylxanthine that has been associated with a lower incidence of type 2 diabetes. Tea drinking has also been linked to a decreased chance of contracting the disease. Tea was also found to lower glucose intolerance and raise insulin levels, making it a viable collaborative in the prevention or treatment of diabetes pathogenesis (Bojar & Fussenegger, 2018).
NEUROLOGICAL AND NEURODEGENERATIVE DISEASE THERAPY
In reality, the effects of methylxanthines on the neurological system have been well- documented. Analgesic medications affect the central and peripheral nervous systems in a variety of ways (Oñatibia‐Astibia & Martínez‐Pinilla, 2017).
When paired with other traditional analgesics, the use of methylxanthines, primarily caffeine, as an analgesic has been shown to maximize pain reduction. The anti- inflammatory properties of methylxanthine (caffeine, pentoxifylline, and theophylline) have been attributed to two primary mechanisms: non-selective adenosine receptor antagonism and non-selective phosphodiesterase inhibition (Lee et al. 2014; Janitschke & Grimm, 2021).
The reported improvement in locomotive function is another intriguing impact of methylxanthines. Recently, it was discovered that paraxanthine had a far larger effect on locomotor activation than coffee, theophylline, or theobromine (Okuro & Nishino, 2010). Other research backs up the benefits of coffee in enhancing motor performance in people with neurodegenerative disorders, citing mechanisms of neurorestoration and neuroprotection by trophic proteins.
Other benefits of caffeine in the neurological system have been established in the past, including post-lumbar puncture prophylaxis, reduced neuronal damage following an ischemic assault, and neuroprotective qualities against spinal cord injury (SCI) (Madeira, & Santiago, 2017). Theophylline, on the other hand, has been shown to reduce the occurrence of spike-wave discharges successfully (Ates et al. 2004).
Caffeine’s psychostimulatory effect is arguably the most well-known, and it’s why so many people drink coffee with it. Even when sleep deprivation is present, caffeine activates the CNS in a dose-dependent manner, resulting in sensations of greater alertness and the ability to sustain an intellectual endeavour, as well as decreased weariness and lethargy (Beaumont et al. 2005; Lozano et al. 2007). Caffeine has also been shown to help with attention and information processing. Caffeine has been recommended as a potential option for memory loss reduction (Cunha 2008), and numerous prospective studies have demonstrated that regular coffee or caffeine consumption protects against cognitive decline
(Terry & Phifer, 1986). Other recent prospective studies have linked high plasma caffeine levels to a lower risk of dementia, especially in people who already have mild cognitive impairment.
The claimed neuroprotective potential of methylxanthines is among the major sources of current interest in them. Within this scope, a substantial amount of scientific study has been undertaken, indicating potential neuroprotection pathways, while other epidemiological studies offer promise. In the context of neurodegenerative disease, these neuroprotective actions have been better revealed. The most common disorders that are contributing to the current worrying neurodegenerative epidemic are Parkinson’s and Alzheimer’s diseases, which have unclear etiologies and are presently being treated with insufficient resources used in therapy (Rivera-Oliver & Díaz-Ríos, 2014).
Caffeine consumption has been linked to a decrease in the occurrence of two of the most common neurodegenerative illnesses, with evidence of such favourable benefits coming from both animal and human research (Prediger, 2010). Adenosine receptor antagonism, specifically the A2A and A1 receptor subtypes, has been proposed as a therapeutic benefit and the principal target of caffeine’s neuroprotective effects in such complicated neurological disorders (Dore et al. 2011).
Protection against blood-brain barrier disruption is another prevalent mechanism for caffeine’s positive effects in Alzheimer’s and Parkinson’s diseases. This incidence has been connected to Alzheimer’s disease (Kalaria 1999) and, to a slightly lesser degree, Parkinson’s disease pathogenesis (Kortekaas et al. 2005). Additionally, selective adenosine A1 receptor antagonists have been suggested as prospective therapy targets in patients suffering from cognitive impairments due to diseases such as Alzheimer’s and Parkinson’s disease (Mioranzza et al. 2011).
The discussed findings are backed up by epidemiological findings. The discovery of a relationship between persistent caffeine or coffee usage in middle age as well as a dramatically reduced risk of neurological disease illnesses such as Alzheimer’s disease is, in reality, epidemiology’s most important finding (Eskelinen et al. 2009).
In both prospective and retrospective investigations, the role of long-term caffeine consumption on this pathology has been studied, with chronic caffeine use being linked to a decreased risk of illness occurrence as well as disease prevention. In this research,
lifetime consumption of coffee is taken into account, with regular coffee drinking defined as nearly every day. Several studies have found that drinking three coffee cups per day provides the most effective protection (Rivera et al. 2014b; Ren & Chen, 2020).
Caffeine has been associated with a decreased chance of developing Parkinson’s disease, progression, similar to Alzheimer’s disease, albeit the processes involved in the process are yet unknown. The molecular mechanisms through which adenosine receptor inhibition protects dopaminergic neurons from degeneration remain unknown (Ren & Chen, 2020).
Caffeine and selective adenosine A2A receptor antagonists appear to be a promising therapy for Parkinson’s disease-related dopaminergic neurodegeneration, according to epidemiologic and experimental findings. Caffeine has been found in rat models to prevent the loss of nigral dopaminergic neurons, suggesting that caffeine may play a role in neuronal degeneration (Chen et al. 2001).
Furthermore, persistent blockade of adenosine A2A receptors has been demonstrated to alleviate Parkinson’s disease-related motor deficits. Monoamine oxidase (MAO), particularly the MAO-B variant, is another well-known molecular target for Parkinson’s disease treatment (Petzer and Petzer 2015). Caffeine, as well as other caffeine-derived substances, was demonstrated to inhibit this enzyme, searching for effective dual-targeted drugs that act on both primary treatment targets for Parkinson’s disease particularly tempting. Another mechanism through which caffeine fights Parkinson’s disease is the blood-brain barrier stabilization (Petzer and Petzer 2015).
In Alzheimer’s disease cases, the exact mechanism of caffeine-induced protection is still unknown. Caffeine appears to have a positive impact on Machado-Joseph illness, in addition to the previously mentioned benefits in the circumstances of Alzheimer’s and Parkinson’s disease (Monteiro & Silva, 2019).
HUMAN FERTILITY
Several studies have looked into the effects of methylxanthines on human fertility. Surprisingly, the results range substantially between the sexes and are still a source of heated discussion. According to a study, excessive maternal caffeine consumption is linked to lower fertility in women who are attempting to conceive. In the case of the male reproductive system, however, modest caffeine consumption appears to be safe. Additionally, coffee appears to promote the nutritional assistance of spermatogenesis by Sertoli cells, which should improve male fertility overall (Jiang et al. 1984).
Male infertility is sadly rather frequent, accounting for almost half of the issues that couples with fertility issues face. Because sperm quality is an important sign of male reproductive health, most cases of male subfertility or infertility rather than a shortage of spermatozoa are caused by a loss of sperm function.
In contrast to the aforementioned epidemiologic suggestions about female fertility, methylxanthines have been researched in the context of the function of the sperms, and beneficial effects have been discovered. The positive benefits of methylxanthines were also linked to their activities as phosphodiesterase inhibitors, which regulated cAMP levels.
Indeed, higher cAMP levels are connected to increased motility, and evidence suggests that after spermatozoa have been released from storage in the male reproductive canal, cAMP- dependent phosphorylation is involved in spermatozoa motility activation. Increases in cAMP and intracellular calcium have been related to various stages of the fertilization process; thus both pathways could be important.
Tea was recently proposed as one of the frequent dietary components containing methylxanthines to trigger beneficial results in male fertility. The glycolytic profile of cultivated Sertoli cells was found to be altered by a tea extract (white tea), promoting lactate generation. Lactate has been found to work as an anti-apoptotic factor in growing germ cells in addition to its function as a metabolic substrate. As a result, white tea consumption has been linked to improved male reproductive health (Rahman & Wang, 2018).
White tea has also been recommended as a better media supplement for sperm storage, which would avoid the negative impacts of refrigeration. These studies give persuasive
evidence of white tea’s pharmacological potential when it comes to male reproductive health despite the fact that it is known to be high in methylxanthine. Although numerous tea components, such as catechins and L-theanine, have been linked to a variety of health benefits, at least some of the benefits linked to male fertility can be attributed to caffeine concentration. Caffeine has been demonstrated to affect Sertoli cell metabolism and enhance, on its own, lactate generation stimulation at doses that match moderate dietary intake (Dias & Oliveira, 2015). Caffeine has also been suggested as a useful adjuvant when it comes to in vitro fertilization after it was shown that it increased the likelihood of conception in gilts and sows utilizing boar sperm. However, further research is needed to properly comprehend methylxanthines’ when it comes to the conservation of sperms and male fertility in general.
METHYLXANTHINES ROLE IN KIDNEY HEALTH
Until the mid-nineteenth century, when more powerful diuretics became available, theophylline, for example, was commonly used to increase urine production. Because of the tubular fluid reabsorption blockage along the proximal renal tubule, both methylxanthines have a mild diuretic effect (Osswald & Schnermann, 2011). Methylxanthines are weak renal vasodilators that compete with adenosine to prevent preglomerular vasoconstriction. Caffeine and theophylline promote renin production by inhibiting adenosine receptors and removing endogenous adenosine’s general inhibitory brake effect. Despite the fact that theophylline’s medicinal use is primarily limited to the treatment of extrarenal illnesses like asthma, interest in methylxanthines’ renal effects has remained high.
Diuresis
Caffeine, among other methylxanthines, can cause people and experimental animals to have more urine flow. Caffeine doses of 300 mg or more have been known to cause substantial acute diuresis, roughly comparable to four to five cups of coffee. A positive fluid balance improves methylxanthines’ diuretic efficacy, but a negative fluid balance reduces the diuretic response (Marx & Jouret, 2016).
The diuretic effect of caffeine appears to be modified by habit and age, with caffeine’s diuretic effects being reduced even more as people get older and have had more caffeine exposure. Overall, caffeine’s poor potential to promote water excretion and produce a constant net loss of water with research that found caffeine had no effect on 24-hour urine volume and was not connected to negative fluid balance symptoms when given for
11 days. While caffeine enhanced urine flow at rest relative to caffeine-free fluid consumption, urine flow fell to the same degree during exercise, which was linked to similar increases in plasma catecholamine concentrations. In a smaller trial, a group of high-altitude mountaineers did not notice any variations in hydration status when tea was the primary fluid source compared to non-tea fluid intake. As a result, the standard rule against drinking caffeinated beverages for volume replacement may need to be changed in light of the fact that moderately caffeinated beverages do not appear to induce significant fluid loss (Scott & Brown, 2004).
In rat renal papillary collecting duct cells, caffeine at high concentrations in a calcium-free environment has been demonstrated to suppress the calcium rise caused by vasopressin, perhaps reducing the increase in cyclic AMP (cAMP) and vasopressin’s influence on water permeability. Caffeine appears to deplete endoplasmic calcium reserves, suggesting that it works through interacting with ryanodine-sensitive calcium-release channels. Methylxanthines seem to cause a solute diuresis that is primarily or entirely solute diuresis.
Natriuresis
Methylxanthines enhance urine flow, resulting in more urinary solutes such as salt, magnesium, chloride, phosphate and calcium, being excreted. Caffeine’s enhanced calcium excretion could have repercussions for calcium homeostasis. In individuals with rheumatic illnesses, pretreatment with indomethacin or meclofenamate reduced theophylline’s natriuretic effect, while theophylline induced a transitory reversal of indomethacin’s anti natriuresis and antidiuresis. (Rieg & Vallon, 2005). The discovery that long-term caffeine treatment increased plasma and kidney atrial natriuretic factor (ANF) activity supports the theory that methylxanthines have indirect effects on urine excretion.
The primary mechanism of methylxanthine-induced natriuresis is considered salt transport obstruction through the proximal convoluted tubule. In humans, both theophylline and aminophylline, as measured by lithium clearance, reduced proximal solute reabsorption. Methylxanthines’ ability to inhibit proximal Sodium chloride reabsorption is related to their ability to act as adenosine receptor antagonists. When compared to aminophylline or theophylline, xanthine derivatives like doxofylline and enprofylline, which have a low affinity for adenosine receptors but a similar ability to inhibit PDE, have only marginal effects on natriuresis, implying that adenosine receptor inhibition is critical for the natriuretic action.
Natriuresis is caused by the suppression of the A1 adenosine receptor subtype, according to strong experimental evidence. The use of A1 adenosine receptor antagonists to block phosphate uptake was linked to a dose-dependent increase in cellular cAMP synthesis and protein kinase C activity. If an increase in arterial blood pressure is caused by coffee, it should be investigated whether blood pressure has a direct role in limiting tubular
reabsorption and affecting sodium hydrogen antiporter 3 (NHE3) distribution (Osswald & Schnermann, 2011).
Hemodynamics
Several investigations in sedated dogs concur that intrarenal infusions of methylxanthines have no substantial effect on renal blood flow (RBF); however, the renal vascular tone may be modestly reduced due to small blood pressure drops. Furthermore, neither theophylline nor caffeine modifies renal plasma flow in people to the amount that clearance methods can detect (Robertson & Oates, 1981).
Theophylline had no effect on norepinephrine release or RBF in isolated perfused rabbit kidneys under baseline circumstances, likely due to the lack of a basal sympathetic tone. Theophylline, on the other hand, marginally enhanced norepinephrine release in response to renal nerve stimulation, which was followed by a decrease in the vasoconstrictor response to nerve stimulation. Theophylline inhibited the vasoconstrictor response to exogenous norepinephrine in the same way (Moreau & Lebrec, 1992).
Finally, theophylline completely reversed the drop in glomerular filtration rate (GFR) caused by dipyridamole and indomethacin in rheumatic patients, demonstrating that some of indomethacin’s vascular effects are mediated by adenosine. Xanthines’ PDE- inhibitory actions may contribute to TGF inhibition by lowering interstitial adenosine levels.
Renin Secretion
Despite stimulating the highly antinatriuretic renin-angiotensin system, methylxanthines can cause natriuresis. Theophylline increased plasma renin activity in dogs without affecting plasma levels of norepinephrine and epinephrine or blood pressure, indicating that the increase was not mediated by the renal baroreceptor or adrenergic receptors.
Even when dogs were given propranolol, theophylline enhanced renin release. Similarly, oral caffeine given to rats for 10 days resulted in a significant increase in renin secretion. Even while it was previously considered that theophylline’s impact was mediated by PDE inhibition and the subsequent increase in cellular cAMP levels, it now appears that methylxanthines’ stimulation of renin is at least partly, if not entirely, a result of adenosine receptor inhibition. (Reid & Ganong, 1972).
METHYLXANTHINE DRUGS
Uniphyl
It belongs to the drug family “Methylxanthines” and has the generic name theophylline. Indications: Symptomatic treatment and disorders with reversible airflow obstruction, such as chronic asthma, bronchitis, emphysema. Theophylline can be used in combination with other medications. Bronchodilators are a class of drugs that include theophylline. Bronchodilators are drugs that relax the smooth muscles in the lungs’ bronchial tubes (air channels). By boosting the passage of air through the bronchial tubes, they reduce cough, wheezing, shortness of breath, and disturbed breathing (Fredholm, 1979). Common adverse effects include nausea, vomiting, headaches and insomnia. Severe adverse effects include persistent vomiting, cardiac arrhythmias and seizures. Overdose can be deadly (Rxlist 2021).
Elixophyllin (Theo-24)
It belongs to the drug family “Methylxanthines” and has the generic name theophylline. Indication: Is used for the symptomatic relief of symptoms. As well as disorders with reversible airflow obstruction, such as chronic asthma, other chronic lung diseases, emphysema and chronic bronchitis. Theo-24 is a bronchodilator. To avoid wheezing and shortness of breath, it must be taken on a regular basis. It works by relaxing the muscles surrounding the airways, allowing you to breathe more easily. It also reduces the lungs’ irritating reaction (Fredholm, 1979). Common adverse effects are nausea, vomiting, headache and insomnia. Severe adverse effects include persistent vomiting, cardiac arrhythmias, seizures, overdoses that can be deadly (Rxlist 2021).
Thesodate
It belongs to the family „‟Methylxanthines‟‟ and has the generic name theobromine. Theobromine is an adenosine receptor antagonist affecting A1 and A2 receptor types. Indications: Thesodate is used as a heart stimulant, diuretic and vasodilator. By the same mechanism as caffeine, it can possibly be used to treat fatigue and orthostatic hypotension as well. The common adverse effects are nausea, vomiting and loss of appetite. Other
effects like anxiety tremors, restlessness and insomnia might also occur (National Institute of Health 2021).
Paracetduo (Norwegian product)
It belongs to the family „‟Methylxanthines‟‟ and has the generic name caffeine. It‟s a combination product containing 500 mg paracetamol and 65 mg caffeine. Caffeine‟s effect in this combination is to increase the effect of paracetamol and decrease symptoms like fatigue which is common during a diseased state.
Indications: Short term treatment of fever, for example, due to the common cold or influenza virus. Mild to moderate pain like headaches, tooth ache, period cramps, muscle and joint pain. Common side effects which might arise are dizziness, anxiety. Rarer side effects are allergic reactions, pruritus, rashes, anaemia, liver function can be affected (Felleskatalogen 2021).
ADVERSE EFFECTS OF METHYLXANTHINES
Because of their narrow therapeutic range, methylxanthines have a high rate of side effects. Milder side effects such as vomiting, nausea, increased stomach acid secretion, palpitations, polyuria, tremors, sleeplessness and headaches are more common when drug concentrations in the blood are smaller than 20 mcg/ml. Many of these are similar to the side effects of too much coffee (Stavric, 1988)
When drug concentrations in the blood surpass 20 mcg/ml, severe consequences include arrhythmias, intractable vomiting, irregular heartbeat (slow or rapid), allergic skin reactions, seizures or cardiac arrest. Because of the risk of dose-related side effects, the dosage is started at the lowest level possible and gradually increased until a therapeutic benefit is achieved (Stavric, 1988).
Any patient who has had a hypersensitivity reaction to a xanthine-derivative-containing medicine should avoid methylxanthines. When any of the following criteria apply to the patient in issue, precautions must be taken: Consider cardiovascular disease, hepatic impairment, cystic fibrosis, hypo or hyperthyroidism, pregnancy, peptic ulcer disease or seizure disorder (Riksen & Rongen, 2011).
Pregnancy
Methylxanthines are a type of medicine classified as pregnancy category C. The medication passes into breast milk through the placenta. Only if the advantage of standing outweighs the danger of damaging the fetus can it be used during pregnancy. In these cases, careful dose adjustment and monitoring are essential (Soyka, 1979).
ADVANTAGES OF METHYLXANTHINES
Advantages in Respiratory Conditions.
Although it is yet to be confirmed whether dietary chocolate or methylxanthines are useful in preventing cough or lessening the severity of cough, the evidence seems promising. Several FDA-approved drugs for asthma and other respiratory diseases contain theophylline as an active component. Patients with asthma, coughing, and other respiratory tract problems may benefit from theobromine. Caffeine can help open the airways and reduce bronchitis symptoms like wheezing, coughing, and shortness of breath, according to an analysis of seven clinical research (Monteiro & Silva, 2019).
Attention and Alertness
Caffeine has been shown in multiple clinical studies at low-to-moderate doses to improve mental alertness. Non-regular users and those who were sleep-deprived had significantly more pronounced impacts. In a 36-person trial, caffeine demonstrated dose-dependent effects on alertness and attentiveness. When those who do not regularly use caffeinated items consumed large levels of caffeine, their brain performance improved significantly. Regular and tolerant users may still feel the same symptoms, though to a lesser extent (Ruiz-Oliveira & Luchiari, 2019).
Increasing physical performance
“Caffeine consumption improves exercise performance in a wide range of exercise tasks,” according to a significant body of data. Muscle endurance, strength, aerobic endurance, and anaerobic power were all improved. Caffeine is especially beneficial for anaerobic exercises such as sprinting or jumping. This effect could be attributed to its anti-fatigue properties as well as its ability to improve physical strength, power output and endurance (Wachamo, 2017).
Advantages in cardiac disease treatment and management
Moderate chocolate consumption lowered the risk of heart disease and stroke, according to a new meta-analysis of 14 trials. Cocoa and its main compound, theobromine, were found to have a protective role in metabolic and heart health in two separate studies (Higgins & Walters, 2011).
Circulation
In postmenopausal women with high cholesterol, consumption of flavanol-rich cocoa on a regular basis increased blood circulation. Methylxanthines have the ability to raise blood levels of a chemical molecule called (-)-epicatechin, which may help with the circulation of blood. By expanding blood vessels and promoting urine, theobromine, which is plentiful in cocoa, may help to reduce blood pressure (diuretic) (Doehner & Hambrecht, 2002).
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At doses ranging from 250 to 1,000 mg, theobromine significantly lowers blood pressure. Furthermore, a Cochrane review of 35 trials on cocoa consumption and heart health published in 2017 revealed that it lowers blood pressure. Caffeine, on the other hand, may harm heart health by raising blood pressure and boosting lipid profiles, whilst theobromine and chocolate may have the opposite impact (DiSario & Sanowski, 1991).
Advantages in weight loss
Ephedrine and caffeine in combination enhanced fat burning and weight reduction while also reducing blood lipids. Caffeine is still a popular element in fat burner supplements sold over the counter. It may help with weight loss by increasing energy consumption and metabolic rate. In addition, caffeine may help with weight loss management by breaking down stored fat (Greenway, 2001).
Cognition and brain health
According to preliminary data, methylxanthines and their dietary sources, such as tea, coffee, and cocoa, may help people with neurodegenerative disorders, including Parkinson’s and Alzheimer’s. People who drank caffeinated coffee had a lower risk of acquiring Parkinson’s disease than those who did not, according to one study. Even those who were genetically susceptible to the disease saw a reduction in their risk (Moreira & Barros, 2016).
Drinking 3 to 5 cups of coffee per day in midlife lowered the incidence of dementia or Alzheimer’s disease by roughly 65 percent in old age, according to a long-term study of 1,400 adults. Coffee was found to improve brain function in one study. Caffeinated coffee
drinking in moderation was linked to a lower risk of dementia and Alzheimer’s disease later in life (Eskelinen & Kivipelto, 2010).
In a large cohort study of 43,599 men and 164,825 women, caffeine coffee drinkers had a decreased suicide rate. It is possible that this is related to caffeine’s tendency to increase dopamine levels (Tuenter & Pieters, 2018).
DETRIMENTAL EFFECTS OF METHYLXANTHINES
Concerns about putative toxicity are valid, given that organic methylxanthines are biopesticidal in levels known to occur in plants and are thought to be biosynthesized by plants as a defensive mechanism against insect feeding.
The acute toxicity of methylxanthines in humans is extremely low. For example, the acute hazardous dose for caffeine is supposed to be around 10 g/day, which is equivalent to consuming instant coffee of up to 100 cups. It’s crucial to note that people’s susceptibility to methylxanthines varies, and some of those differences may be inherited (Boison, 2011). Consumption of caffeine-rich diet supplements, as well as caffeine mixed with illegal narcotics, can have negative consequences. As a result, the rapidly growing energy drink market should be monitored because these beverages contain amounts ranging from 50 mg to an alarming 500 mg per can or bottle; they should be avoided (Fredholm, 2010).
Table 2. The caffeine content of some well-known energy drinks (Joris et al. 2012)
Although severe damage from high caffeine consumption is rare, it can cause a variety of intoxication symptoms, including increased breathing, headache, seizures, gastrointestinal difficulties, arrhythmia, sleeplessness, agitation, tachycardia, nausea and in other cases death. Chronic effects of excessive caffeine use can manifest as gastrointestinal and renal system dysfunctions, as well as liver and muscle dysfunctions. Caffeine/coffee consumption has been linked to a number of other negative effects in occasional investigations. For example, epidemiologic studies have linked increased coffee consumption to an increased risk of ischemic stroke, refuting some of the positive vascular function effects (Martin & Bracken, 1987).
The question of whether or not caffeine should be categorized as a substance of abuse has been a source of debate for some time. Some argue that it does because it fosters dependency through tolerance promotion, positive reinforcement and the occurrence of withdrawal symptoms after cessation of use. Others argue that the danger of physical addiction to caffeine is limited and that discontinuation is painless and rapid. Furthermore, according to many studies, moderate coffee consumers do not acquire any physiologic dependence on caffeine (Fredholm, 2010).
Other mammals, including pets, are very poisonous to theobromine. The causes for this differential toxicity are unknown, but it should be noted that this is a classic example of a chemical whose mechanisms of action differ greatly between humans and other mammals. Because theobromine has a longer half-life than caffeine, its harmful effects in vulnerable species may be amplified, increasing systemic exposure. Clinical research, driven by the discovery of negative effects in some animals, have usually concluded that theobromine is safe for humans when used in moderation. Because of its low toxicity in humans, research on theobromine’s long-term effects is restricted. Nonetheless, one such study found that long-term ingestion of substantial amounts of cocoa products was associated with sweating, shaking, and severe headaches (Adamafio, 2013).
Although theophylline and caffeine have certain similarities as it pertains to toxicological and pharmacological qualities, the first has been hypothesized to have more harmful consequences. Caffeine was chosen over theophylline in the treatment of respiratory diseases because of this. Theophylline’s longer half-life, which is roughly twice that of caffeine, may explain its more pronounced hazardous effects. Theophylline’s unwanted effects are proportional to its plasma levels, and they usually appear when it exceeds 20
mg/L. Nausea (including vomiting), headache, gastroesophageal reflux and increased acid secretion are all popular detrimental effects of theophylline use. Theophylline can produce convulsions and heart arrhythmias at larger doses (Pal & Chattopadhyay, 2016).
Chronic toxicity can occur as a result of excessively high doses or specific conditions that impair its clearance, such as concurrent drug changes or illness states. Chronic theophylline toxicity should have comparable characteristics to acute toxicity. In patients who endured chronic overdosing, induced at lower serum concentrations than those who received a single acute overdose, the changes should include greater vulnerability to the medication, more frequent seizures, and significant arrhythmias. These findings prompted clinical recommendations that patients with chronic theophylline toxicity get extracorporeal drug removal assistance (hemoperfusion or hemodialysis) (Adamafio, 2013).
Furthermore, there is substantial proof that methylxanthines may have adverse effects on the male reproductive system, which should be considered against the good effects outlined in the previous section. Testicular atrophy and spermatogenesis have been linked to methylxanthines.
In a number of investigations, theobromine was repeatedly found to have negative effects on animal male reproductive systems. However, the methylxanthine concentrations that cause some of these effects are rather high, and obtaining them through human consumption would be challenging (Atik & Tolcos, 2017).
Despite the fact that methylxanthine is generally regarded as safe at quantities obtainable through routine ingestion, the most prevalent concern remains prenatal exposure. In humans, methylxanthines can penetrate the placental barrier, allowing fetus exposure, which can be dangerous because the growing fetus may lack fully formed detoxification enzymes.
Several investigations on methylxanthine prenatal exposure and its negative effects have been undertaken. In terms of reporting methylxanthine’s negative influence on pregnancy, epidemiological research is split. Caffeine use had no effect on the outcome of a pregnancy or the development of the kids in general, according to an early study (Franco, R., Oñatibia-Astibia & Martínez-Pinilla, 2013)
Animal research has revealed evidence of methylxanthine’s potentially harmful effects during pregnancy. Caffeine has been demonstrated to disrupt proper differentiation of the sex of the embryonic testes in rats at moderate concentrations. Another study found that theobromine had an effect on postnatal and prenatal offspring development. A theobromine-rich diet significantly decreased newborn relative limb size and inhibited embryo growth and proangiogenic tissue activity in mice in that study (Qian, & Zhang, 2020).
Skopinski and colleagues (Skopioski et al. 2011) conducted a thorough analysis of the current research on prenatal methylxanthine exposure in animals. They found that prenatal exposure can create changes in the developing organism that can last a lifetime. They do admit, however, that judgments based on the existing data may be premature and even contentious.
CONCLUSION
Methylxanthines have been found in the human diet for generations, and their pharmacological activity has been known for at least a century. Several chemical targets have been found since then, suggesting complicated cellular chemistry for methylxanthines. Such a diverse spectrum of molecular functions generated a flurry of scientific effort, with far-reaching implications for the biomedical study. It is reasonable to expect this trend to continue for some time, given the undeniable potential of these compounds in various therapeutic contexts and the fact that there is still much to think about and clarify.
In any event, based on what has been discovered so far, it is plausible to believe that the potential benefits of methylxanthines in human physiology outweigh any potential detrimental effects. Methylxanthine has a diverse set of molecular targets, making it an intriguing research topic. The ability to design/disclose multiple-target-directed compounds that act on various targets should also be appealing.
Methylxanthines are anticipated to be valuable pharmacological medicines in the future, either alone or in conjunction with other treatments. New uses may emerge as a result of the potential that methylxanthines have demonstrated in specific new sickness scenarios. Furthermore, as the concept of functional foods evolves, methylxanthines could be easily included in the development of meals with putative disease prevention properties. Epidemiologic research should be expanded since it will help to narrow the target populations for future preventive and treatment strategies.
More technological advancements, such as neuroimaging techniques, will provide tools for better understanding methylxanthine physiology, allowing this field of research to flourish. It is hoped that when more is learned about the molecular and physiologic functions of methylxanthines, they will be able to achieve the potential predicted by present understanding in some of the most severe diseases.
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