What is xanthine

Xanthine is a purine base found in most human body tissues and fluids, certain plants, and some kidney stones. Xanthine is formed following enzymatic degradation of adenine and guanine. The term “xanthines” denotes a wide class of compounds whose central core (3,7-dihydro-purine-2,6-dione) is closely related to the DNA bases guanine and adenine (see Figures 1 and 2) ¹. Like nucleobases, xanthines are capable of forming hydrogen bonds, allowing their insertion in duplexes ² and guanine quadruplexes (G-quadruplexes) ³. Moreover, it has been shown that their self-association can give rise to four-stranded structures ⁴, which have attracted attention for applications in the field of molecular electronics ⁵. Moreover, methylxanthines are used as therapeutic agents acting, among others, as stimulants of the nervous system ⁶. The well-known caffeine, present in coffee and tea and various soft beverages, is none other than 1,3,7-trimethylxanthine (Figure 2). It is also worth noticing that 2′-deoxyxanthosine (dX) has been used in the extension of the genetic alphabet by purine pairing with a 2,4-diaminopyrimidine nucleoside, which has a hydrogen bonding pattern complementary to 2′-deoxyxanthosine (dX) ⁷.

Xanthine is an intermediate in the degradation of adenosine monophosphate to uric acid, being formed by oxidation of hypoxanthine. The methylated xanthine compounds caffeine, theobromine, and theophylline and their derivatives are used in medicine for their bronchodilator effects. Xanthine is found to be associated with Lesch-Nyhan syndrome and xanthinuria type 1, which are inborn errors of metabolism.

Purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Two of the bases in nucleic acids, adenine and guanine, are purines. Purines from food (or from tissue turnover) are metabolized by several enzymes, including xanthine oxidase, into uric acid. High levels of uric acid can predispose to gout when the acid crystalizes in joints; this phenomenon only happens in humans and some animal species (e. g. dogs) that lack an intrinsic uricase enzyme that can further degrade uric acid.

Figure 1. Xanthine

Figure 2. Xanthine derivatives

Xanthine oxidase deficiency

Hereditary xanthinuria is a condition that most often affects the kidneys. It is characterized by high levels of a compound called xanthine and very low levels of another compound called uric acid in the blood and urine. The excess xanthine can accumulate in the kidneys and other tissues. In the kidneys, xanthine forms tiny crystals that occasionally build up to create kidney stones. These stones can impair kidney function and ultimately cause kidney failure. Related signs and symptoms can include abdominal pain, recurrent urinary tract infections, and blood in the urine (hematuria). Less commonly, xanthine crystals build up in the muscles, causing pain and cramping. In some people with hereditary xanthinuria, the condition does not cause any health problems.

Researchers have described two major forms of hereditary xanthinuria, types 1 and 2. The types are distinguished by the enzymes involved; they have the same signs and symptoms.

Classically, Type 1 xanthinuria is caused by a mutation in xanthine dehydrogenase/oxidase (XDH/OX) gene mapped to chromosome 2p23.1, whereas Type 2 xanthinuria is caused by deficits of xanthine dehydrogenase/oxidase (XDH/OX) and aldehyde oxidase (AOX) caused by mutations in molybdenum cofactor sulfurase gene (MOCOS) localized on chromosome 18q12.2 ⁸. These different mutations lead to clinically undistinguishable types.

A third clinically distinct entity, molybdenum cofactor deficiency type A, is characterized by triple deficiency of xanthine dehydrogenase, aldehyde oxidase and sulfite oxidase. This rare lethal autosomal recessive disorder caused by mutations in MOCS1 gene (6p21.1) is characterized by early onset in infancy ⁹.

The combined incidence of hereditary xanthinuria types 1 and 2 is estimated to be about 1 in 69,000 people worldwide. However, researchers suspect that the true incidence may be higher because some affected individuals have no symptoms and are never diagnosed with the condition. Hereditary xanthinuria appears to be more common in people of Mediterranean or Middle Eastern ancestry. About 150 cases of this condition have been reported in the medical literature.

Hereditary xanthinuria diagnosis is based on estimation of uric acid in blood and urine ¹⁰. If hypouricemia is confirmed, detailed purine metabolic investigation follows, and includes measurement of xanthine and hypoxanthine in urine and plasma. High urinary levels of xanthine are then typical for classical hereditary xanthinuria. In about half of patients, ultrasonography reveals the presence of xanthine urolithiasis. Additional methods for diagnostic confirmation and/or identification of the type of xanthinuria include allopurinol loading test, xanthine oxidase assay and molecular analysis.

There is no curative treatment for hereditary xanthinuria. The only recommended treatment for patients with xanthinuria is a low purine diet and high intake of fluids ⁹. Because the solubility of xanthine is relatively independent of urinary pH, urine alkalinization has no effect (in contrast to patients with uric acid lithiasis) ¹¹. When kidney stones are present, a pyelolithotomy might be necessary.

The overall prognosis for hereditary xanthinuria is favorable, even though, in some cases, the disease progresses to end-stage renal failure ¹⁰.

Hereditary xanthinuria type 1

Hereditary xanthinuria type 1 is caused by mutations in the XDH gene that is inherited in autosomal recessive manner. An autosomal recessive pattern means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. The XDH gene provides instructions for making an enzyme called xanthine dehydrogenase. The xanthine dehydrogenase enzyme is involved in the normal breakdown of purines, which are building blocks of DNA and its chemical cousin, RNA. Specifically, xanthine dehydrogenase carries out the final two steps in the process, including the conversion of xanthine to uric acid (which is excreted in urine and feces). Mutations in the XDH gene reduce or eliminate the activity of xanthine dehydrogenase. As a result, the xanthine dehydrogenase enzyme is not available to help carry out the last two steps of purine breakdown. Because xanthine is not converted to uric acid, affected individuals have high levels of xanthine in their blood (hyperxanthinemia) and urine (xanthinuria) and very low levels of uric acid in their blood and urine. The excess xanthine can cause damage to the kidneys and other tissues. Xanthinuria leads to urolithiasis (kidney stones formation), hematuria (blood in urine), renal colic and urinary tract infections (UTIs), while some patients are asymptomatic and others suffer from kidney failure. Approximately 50% of patients with hereditary xanthinuria type 1 present with urinary tract infections, hematuria, renal colic, acute renal failure, and urolithiasis. A small number of patients also develop renal failure, arthropathy, myopathy, or duodenal ulcer ¹².

Hereditary xanthinuria type 2

Hereditary xanthinuria type 2 results from mutations in the MOCOS gene that is inherited in autosomal recessive manner. An autosomal recessive pattern means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. The MOCOS gene provides instructions for making an enzyme called molybdenum cofactor sulfurase. The molybdenum cofactor sulfurase enzyme is necessary for the normal function of xanthine dehydrogenase, described above, and another enzyme called aldehyde oxidase. Mutations in the MOCOS gene prevent xanthine dehydrogenase and aldehyde oxidase from being turned on (activated). The loss of xanthine dehydrogenase activity prevents the conversion of xanthine to uric acid, leading to an accumulation of xanthine in the kidneys and other tissues. The loss of aldehyde oxidase activity does not appear to cause any health problems.

Xanthine medications

The xanthines, caffeine and theobromine are the pharmacologically active components of a range of drinks such as coffee, tea, cocoa and soft drinks.

Xanthines also include medicines such as theophylline, used in the treatment of asthma.

Caffeine

Caffeine is a naturally occurring substance which stimulates the central nervous system and can temporarily relieve tiredness and increase alertness ¹³. While humans have no nutritional requirement for caffeine (caffeine is not an essential part of the human diet), most adults can safely consume moderate amounts of caffeine. Pregnant women can also safely consume caffeine, however they should consume less caffeine than non-pregnant women, to protect the health of their developing fetus.

The caffeine content of a cup of coffee is generally estimated to be approximately 100 mg, and a cup of tea approximately 50 mg but may be greater depending on how the drink is prepared. For instance, an espresso is likely to have a higher caffeine concentration than a cup of instant coffee. Cola drinks contain up to 25 mg of caffeine per 100 mL. Energy drinks are likely to have an even higher caffeine content, and often contain other stimulants. Caffeine is also a component of certain medications, such as analgesic preparations and over the counter cold and flu preparations.

The approximate amounts of caffeine found in food and drinks are:

• one cup of instant coffee: 60 – 80 mg
• one cup (5 oz. cup) of filter coffee: 40 – 180 mg
• one cup (5 oz. cup) of tea: 20 – 90 mg
• one 375g can of cola: 48.75 mg
• one 250ml can of energy drink: 80mg
• Red Bull® energy drink 67 mg
• one 100g bar of milk chocolate: around 20 mg
• 2 tablets of Excedrin® 130 mg
• 1 cup of coffee ice cream 58 mg
• 12 oz. Coke® 46 mg
• Hershey® chocolate bar 10 mg
• 8 oz. hot chocolate 5 mg

Caffeine, as a lipophilic substance, is well absorbed from the gastrointestinal tract, crosses the placenta and can exert its stimulant effects on the fetus resulting in increased fetal activity and heart rate, and in some cases fetal arrhythmia.

Regular use of large amounts of caffeine have been associated with reduced fertility in both women and men ¹⁴. A meta-analysis of studies involving approximately 50,000 pregnant women in total suggested a slightly elevated rate of spontaneous abortion amongst women who drank more than 150 mg of caffeine per day during pregnancy ¹⁵. Stefanidou ¹⁶ reported a dose-response relationship between caffeine ingestion and recurrent miscarriage. After controlling for confounders, the odds ratio for recurrent miscarriage increased with increased daily caffeine intake in the periconceptional period and in early gestation. A prospective Danish study found a slight elevated rate of stillbirth amongst pregnant women who had consumed more than eight cups of coffee a day ¹⁷. A follow-up study by the same authors demonstrated that women who drank more than eight cups of coffee per day were at increased risk of a fetal death ¹⁸.

A number of studies have demonstrated an increased rate of cryptorchidism, anal atresia and cleft lip/palate amongst infants whose mothers consumed caffeine during pregnancy; however, these studies were limited by retrospective exposure assessment, small sample size and failure to adjust for other potential confounders including maternal smoking and alcohol consumption ¹⁹. A study by Schmidt ²⁰ identified an association between infant neural tube defect (NTD) risk and polymorphisms in a fetal and maternal gene involved in caffeine metabolism. The authors suggested that risk of neural tube defects may be increased in genetically susceptible individuals with caffeine consumption.

The data relating to the effects of caffeine on fetal growth in utero are mixed. Numerous studies ²¹, ²², ²³ have suggested a link between intrauterine growth restriction (IUGR) or low infant birth weight and caffeine consumption in pregnancy. A meta-analysis from 1998, which included approximately 50,000 pregnant women, suggested a slightly increased risk of having a baby with IUGR, if the mother had consumed more than 150 mg of caffeine per day ²⁴. More recent studies have also found a positive correlation between caffeine intake and low birth weight ²⁵ found reduced infant birth weight with maternal daily caffeine intake of more than 540 mg, whilst Sengpiel ²⁵ reported that maternal caffeine intake of more than 200 mg to 300 mg/day increased the odds for having a small for gestational age infant. Other studies have suggested that effects of maternal caffeine consumption on birth weight are restricted to male offspring only ²⁶, or to infants of women who are rapid caffeine metabolizers ²⁷. However, a review of the literature in 2000 demonstrated no evidence of an effect of even moderate to high caffeine consumption on in utero growth ²⁸ and another concluded that low infant birth weight cannot be clearly attributed to caffeine and cannot be separated from effects of other exposures such as maternal smoking and alcohol consumption ¹⁹.

The hypothesis that the methylxanthine, theobromine, which is found particularly in cocoa, could reduce the rate of preeclampsia, has not been confirmed ²⁹. A meta-analysis of 22 studies found no clear connection between coffee consumption during pregnancy and preterm delivery ³⁰. In a study by Barr ³¹ no effect on physical development parameters and IQ up to the age of 7.5 years in the children of 500 pregnant women who had consumed more than 150 mg of caffeine daily was found. One prospective study reported a weak association between the occurrence of hyperactivity at 18 months in children whose mothers had consumed caffeine-containing drinks during the pregnancy ³². Another study found no connection between caffeine use during pregnancy and attention deficit disorders ³³.

Regular coffee consumption during pregnancy has recently been associated with childhood acute leukemia in the offspring in a single study, with the risk increasing linearly with daily intake ³⁴.

A New Zealand study ³⁵ reported that the babies of women who consumed greater than 400 mg of caffeine per day during pregnancy were 1.65 times more likely to die of sudden infant death syndrome than the babies of women who consumed less caffeine. The New Zealand study ³⁵ also found that infants born to women who consumed high quantities of caffeine whilst pregnant were more likely to experience sleep apnea (difficulty breathing during sleep).

Summary

There is insufficient robust scientific evidence on which to provide a specific recommendation regarding the amount of caffeine that can be consumed during pregnancy without causing harm to the fetus. The data regarding caffeine consumption during pregnancy are contradictory. An association between caffeine intake and increased miscarriage risk, and possibly fetal demise has been reported but remains unproven. Similarly, various structural anomalies have been reported following caffeine exposure in utero but a causal association or consistent embryopathy has not been demonstrated.

Maternal caffeine consumption of less than 150 mg caffeine a day in pregnancy does not appear to affect fetal growth, and although an adverse effect on birth weight has been reported at higher doses by some, these data are inconsistent with respect to identifying a threshold dose for this effect. Single studies have suggested a possible association with childhood acute leukemia and hyperactivity, but these findings remain to be confirmed.

Pregnant women who consume more than 200 mg of caffeine daily (about two cups of brewed coffee) should reduce their caffeine consumption whilst pregnant. Health professionals advise individuals to reduce their caffeine consumption gradually, for example by replacing one caffeinated drink with a non-caffeinated alternative each day, in order to avoid withdrawal symptoms. Decaffeinated varieties are an option which contains little or no caffeine.

Energy drinks are not recommended during pregnancy as they may contain high levels of caffeine, and other ingredients not recommended for pregnant women.

Theobromine

Theobromine is the principal alkaloid (1.5–3%) of the cacao bean (Theobroma cacao); it is usually extracted from the husks of cacao beans, which contain 0.7–1.2% theobromine ³⁶. Theobromine is used principally to make caffeine ³⁷. Formerly, theobromine and its derivatives were used in diuretics, myocardial stimulants, vasodilators and smooth muscle relaxants ³⁸. Theobromine salts (calcium salicylate, sodium salicylate and sodium acetate) were used previously to dilate coronary arteries ³⁹ at doses of 300 to 600 mg per day ⁴⁰. There is no current therapeutic use of theobromine ⁴¹.

Theobromine in foods

Theobromine is found in chocolate, tea and cocoa products ⁴². Cacao is the major natural source of theobromine; the concentration in whole cacao beans and nibs (cotyledon) increases during the first day of fermentation and that in the shells increases subsequently ⁴³.

Theobromine has been reported in cacao husks and beans at 0.7–1.2% and 1.5–3% (15–30 g/kg) ³⁸. Levels have been reported to be 20 mg/kg in green coffee beans ⁴⁴, 0.15–0.20% in manufactured tea ⁴⁵ and 0.3% in dried mate ⁴⁶.

Dark chocolate contains the largest amount of theobromine per serving of any type of eating chocolate; concentrations vary widely (0.36–0.63%) owing to the initial large difference in the theobromine content in chocolate liquors, but one 1-oz bar of dark chocolate contained 130 mg theobromine, and one 1-oz bar of milk chocolate contained 44 mg theobromine. The theobromine content of chocolate foods prepared from home recipes using standard chocolate sources (i.e., cocoa and baking chocolate) varies widely (24 mg per serving in chocolate brownies to 724 mg in chocolate frostings); chocolate frostings have relatively higher theobromine levels (0.055–0.213%) than chocolate cakes. The methylxanthine (theobromine and caffeine) content of manufactured chocolate foods and beverages varies according to food source and within different brands of the same item ⁴⁷.

Theobromine side effects

It has been stated that ‘in large doses’ theobromine may cause nausea and anorexia ⁴⁸ and that daily intake of 50–100 g cocoa (0.8–1.5 g theobromine) by humans has been associated with sweating, trembling and severe headache ⁴⁹. In a study of 13 volunteers who consumed 200 mg theobromine orally three times during a 24-h period, no clinical symptom or other pharmacological activity was observed ⁵⁰. Ingestion of theobromine in sweet chocolate at a dose of 6 mg/kg body weight per day had no effect on clinical parameters in 12 human subjects ⁵¹.

Theophylline

Theophylline is a bronchodilator. Theophylline is used to prevent and treat symptoms such as wheezing, shortness of breath, and chest tightness caused by asthma, chronic bronchitis, emphysema, and other lung diseases. It relaxes and opens air passages in the lungs, making it easier to breathe.

Theophylline controls symptoms of asthma and other lung diseases but does not cure them. Continue to take theophylline even if you feel well. Do not stop taking theophylline without talking to your doctor.

Theophylline works by relaxing muscles in the lungs and chest, making the lungs less sensitive to allergens and other causes of bronchospasm.

Theophylline comes as a tablet, capsule, solution, and syrup to take by mouth. It usually is taken every 6, 8, 12, or 24 hours. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take theophylline exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Take theophylline with a full glass of water on an empty stomach, at least 1 hour before or 2 hours after a meal. Do not chew or crush the extended-release (long-acting) theophylline tablets; swallow them whole. Extended-release capsules (e.g., Theo-Dur Sprinkles) may be swallowed whole or opened and the contents mixed with soft food and swallowed without chewing.

Theophylline side effects

Theophylline may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away.

• upset stomach
• stomach pain
• diarrhea
• headache
• restlessness
• insomnia
• irritability

If you experience any of the following symptoms, call your doctor immediately:

• vomiting
• increased or rapid heart rate
• irregular heartbeat
• seizures
• skin rash

Xanthine oxidase inhibitor

Allopurinol and Febuxostat are xanthine oxidase inhibitor drugs that is used to treat gout and high levels of uric acid in the blood (hyperuricemia) caused by certain cancer medications, and kidney stones. Xanthine oxidase inhibitor works by causing less uric acid to be produced by the body. High levels of uric acid may cause gout attacks or kidney stones. Allopurinol is used to prevent gout attacks, not to treat them once they occur.

These medicines are available only with your doctor’s prescription.

Allopurinol side effects

Allopurinol may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• upset stomach
• diarrhea
• drowsiness

Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them, call your doctor immediately:

• skin rash
• painful urination
• blood in the urine
• irritation of the eyes
• swelling of the lips or mouth
• fever, sore throat, chills, and other signs of infection
• loss of appetite
• unexpected weight loss
• itching

Allopurinol may cause other side effects. Call your doctor if you have any unusual problems while taking this allopurinol.

Febuxostat side effects

Febuxostat may cause side effects. Tell your doctor if either of these symptoms is severe or does not go away:

• nausea
• joint pain

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• rash; skin redness or pain; swelling or blistering of lips, eyes or mouth; skin peeling; or fever and other flu-like symptoms
• chest pain
• shortness of breath
• slow or difficult speech
• dizziness or faintness
• weakness or numbness of an arm or leg
• yellow eyes or skin; dark urine; or pain or discomfort in right upper stomach area

Febuxostat may cause other side effects. Call your doctor if you have any unusual problems while taking this febuxostat.

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