Mevalonic acid

148.158

148.16

DTXSID5040546

Oily liquid

77.76000

-1

1.263g/cm3

151-152 °C @ Solvent: Benzene

364.128°C at 760 mmHg

188.204°C

In water, 6.0X10+4 mg/L at 25 deg C (est)

2-8°C

1.7X10-3 mm Hg at 25 deg C (est)

Henry's Law constant = 2.27X10-12 atm-cu m/mol at 25 °C (est)

pKa = 4.24 (est)

Hygroscopic crystals, mp 28 °C /delta-Lactone/|Hydroxyl radical reaction rate constant = 1.24X10-11 cu cm/molec-sec at 25 °C (est)

3

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

... The effect of topical mevalonic acid on the murine epidermal permeability barrier function /was investigated/, comparing it with that of cholesterol. Topical treatment with acetone caused linear increases in transepidermal water loss, in proportion to the number of treatments more rapidly in aged mice than in young mice. Administration of mevalonic acid on aged murine epidermis enhanced its resistance against damage and the recovery rate of barrier function from acute barrier disruption. In contrast, although cholesterol also had the same effect, it required a much higher amount than mevalonic acid. In young mice, neither mevalonic acid nor cholesterol had any effect on resistance against acetone damage nor the recovery rate from acetone damage. In the skin of mice topically administered with mevalonic acid, stimulation of cholesterol synthesis and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity were both observed, whereas none was seen with stimulation by equimolar cholesterol. These data indicate that a topical application of mevalonic acid enhances barrier recovery in aged mice, which is accompanied by not only acceleration of cholesterol synthesis from mevalonic acid but also stimulation of the whole cholesterol biosynthesis.|The influence of 2 different alcoholic beverages containing an equal amount of alcohol (48 g), 1 with mevalonic acid (beer) and 1 without (vodka), on the urinary excretion and serum concentration of mevalonic acid was investigated in 7 healthy subjects. Drinking 1 L of beer at night containing 608 ug/L mevalonic acid more than doubled the urinary excretion of mevalonic acid the following 12 hours, on average from 103 +/- 15 microg/12 h to 211 +/- 17 ug/12 hr (P < .001; 18% of the administered dose). Drinking the same amount of alcohol as vodka had no effect, but urinary mevalonic acid output increased slightly the following day (7 AM to 7 PM) after ingestion of both alcoholic beverages. Serum concentrations of mevalonic acid were significantly increased the following morning after ingestion of beer (from 3.22 +/- 0.20 ng/mL to 6.79 +/- 0.58 ng/mL) or vodka (from 3.23 +/- 0.37 ng/mL to 5.36 +/- 0.55 ng/mL, P < .002 for both). An increase in the ratio of lathosterol to cholesterol in serum, another indicator of 3beta-hydroxy-3beta-methylglutaryl coenzyme A reductase activity in the liver, was also observed (+18% and +25%, respectively). ... Studies using mevalonic acid as a marker of cholesterol synthesis must be carefully monitored regarding dietary mevalonic acid intake and alcohol consumption.|Mevalonic acid is a product of the enzyme HMG-CoA reductase which is essential for cholesterol biosynthesis. Fluvastatin (Sandoz compound XU 62-320) is a potent inhibitor of this enzyme and, hence, mevalonic acid production. In three separate studies, oral administration of fluvastatin at 12 and 24 mg/kg/day to mated rats from day 15 of gestation through weaning resulted in unanticipated maternal mortality at the time of parturition and during lactation. Microscopic evaluations performed in two studies revealed significant cardiac myopathy in the dying animals. Drug-related clinical signs, significant maternal body weight loss, and an increase in stillborn pups and neonatal mortality were also noted at one or both dose levels. Supplementation of fluvastatin administration with 500 mg/kg b.i.d. of mevalonic acid completely blocked and/or ameliorated the mortality, cardiac myopathy, and other adverse effects. These studies indicate that the adverse maternal effects observed with fluvastatin before or following parturition resulted from exaggerated pharmacologic activity at the dose levels administered, i.e., inhibition of the enzyme HMG-CoA reductase, its immediate product mevalonic acid, and cholesterol biosynthesis.|... Mevalonic acid prevented the inhibitory effect of atorvastatin on cytokine-stimulated vascular cell adhesion molecule-1 expression and subsequent adhesion of THP-1 monocytes to the cultured endothelial cells.

/EXPL/ Twenty eight patients with heterozygous familial hypercholesterolemia were treated with mevalonic acid (an inhibitor of cholesterol synthesis) for 45 days. Patients received a daily dose of 750 to 1500 mg mevalonic acid depending on plasma cholesterol levels. Results showed a significant reduction in cholesterol values whereas no significant difference was observed in HDL cholesterol and triglyceride levels.

After oral administration of [13C2] mevalonic acid at night, 20% +/- 0.7% of the dose was excreted in urine the following 12 hours, and only trace amounts thereafter. No [13C2] mevalonic acid could be detected in serum the following morning. We conclude that the absorption of dietary mevalonic acid and alcohol-induced mevalonic acid synthesis affects the urinary excretion and serum concentration of this cholesterol precursor.|Urinary excretion of mevalonic acid was investigated as an indicator of cholesterol synthesis. In normolipemic volunteers, excretion of mevalonic acid averaged 3.51 +/- 0.59 (SD) ug/kg x day1; (n = 24) and was not different from patients with hypercholesterolemia (3.30 +/- 0.92 ug/kg x day1; n = 24). In patients with cerebrotendineous xanthomatosis, the excretion was significantly higher (8.55 +/- 1.92 ug/kg x day1; n = 6, P < 0.001) but comparable to volunteers treated with cholestyramine (6.69 +/- 2.6 ug/kg x day1; n = 5). A significant correlation was found between 24-hr excretion of mevalonic acid and cholesterol synthesis (r = 0.835; n = 35; P < 0.001). The coefficient of variation of excretion of mevalonic acid during 3 consecutive days was small (9.8%; n = 7). However, urinary output of mevalonic acid was significantly higher during the night (164 +/- 14 ug/12 hr) than during the day (129 +/- 9 ug/12 hr; n = 11; P < 0.05). In patients treated with simvastatin (40 mg/day) for 6 weeks, the ratio of mevalonic acid to creatinine in a morning urine sample decreased significantly compared to pretreatment values (110 +/- 25 ug/g vs. 66 +/- 25 ug/g; P < 0.001). Furthermore, the ratio of mevalonic acid to creatinine in a morning urine sample correlated with the ratio from the 24-hr collection period (r = 0.714; n = 34; P < 0.001). The results indicate that the analysis of urinary mevalonic acid, either in 24-hr collection or in a single morning sample, is an attractive method for evaluation of long and very short term changes of the rates of cholesterol synthesis.|... Plasma mevalonic acid (MVA) concentrations were correlated (i) with increased rates of whole-body cholesterol synthesis (measured by sterol-balance methods) in patients treated with cholestryamine resin (ii) with decreased rates of whole-body sterol synthesis (indicated by conversion of labeled acetate to sterol in freshly isolated mononuclear leukocytes) in out-patients after 4 weeks on a cholesterol-rich diet. In addition, a diurnal rhythm of plasma MVA concentrations was observed in patients whose activities were strictly controlled on a metabolic ward. At the peak of the rhythm (between midnight and 3 a.m.) MVA concentrations were 3-5 times greater than at the nadir (between 9 a.m. and noon). Furthermore, a relationship between the diurnal rhythm of plasma MVA and endogenous cholesterol synthesis is suggested by /the/ finding that the plasma MVA rhythm was suppressed by cholesterol feeding (1,200 mg/day) and abolished by a 12-day fast...

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Defects of cholesterol biosynthesis comprise a heterogeneous group of disorders... . Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) are due to allelic defects in mevalonate kinase, an enzyme located proximally in the pathway of cholesterol and nonsterol isoprene biosynthesis. Clinically, patients affected with these disorders present with recurrent febrile attacks. This is the only manifestation in most patients with HIDS, and, in the case of classical mevalonic aciduria, is part of a severe multisystemic disease, including malformations, severe failure to thrive and neurological abnormalities. ... The diagnosis of MVA and HIDS is based on determination of mevalonic acid in urine followed by determination of enzyme activity...|/SIGNS AND SYMPTOMS/ The febrile crises /in mevalonate kinase deficiency/ are similar to those observed in hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). Pathogenic mutations in the mevalonate kinase gene in both disorders have demonstrated a common genetic basis.|/CASE REPORTS/ Mevalonic aciduria is a rare disease that is a consequence of a deficiency of mevalonate kinase, an inborn error in the biosynthesis of cholesterol. Approximately 30 cases have been reported. ... Data on two siblings with mevalonic aciduria /are contributed/ to the recognition of this subject. Both were born after uneventful pregnancies. Their parents were healthy and not consanguineous. They had normal somatic and psychomotor development until they were around 2 years old. After the second year of life they developed mental retardation, ataxia and hypotonia. MRI showed cerebellar atrophy of both hemispheres and vermis. One sibling, from the age of 10 years onwards, suffered from complex partial seizures that were controlled with levetiracetam and lamotrigine. At 11 and 12 years of age, respectively, they were able to walk without help, but their gait was broad and ataxic. Their speech was dysarthric, fine motor skills were impaired as result of cerebellar ataxia, and they had moderate mental retardation. Diagnosis of mevalonic aciduria was made at this age through urinary organic acid analysis by gas chromatography-mass spectroscopy, which revealed high urinary excretion of mevalonic acid. They are currently 18 and 17 years old, respectively, show mental retardation and are able to walk but with difficulty. In our patients, ataxia due to cerebellar atrophy and mental retardation have been the predominant clinical manifestations. In mildly affected patients who survive infancy, these seem to be the predominant findings.|/CASE REPORTS/ The analysis of amniotic fluids of two pregnancies at risk for mevalonic aciduria showed a 3277-fold elevation as compared to controls in the first case, diagnostic of an affected fetus, and a normal value in the second one. Mevalonic acid concentration was much increased in tissues of the affected and aborted fetus. Concentrations ranged from 840 to 1120 mumol/kg in various tissues and were as high as 1810 umol/kg in brain. Concentrations in control fetal tissues were approximately 1 umol/kg.|For more Human Toxicity Excerpts (Complete) data for MEVALONIC ACID (7 total), please visit the HSDB record page.

Acid, Mevalonic

Precursor in the biosynthesis of cholesterol

A stable isotope dilution assay using D3-mevalonic acid was developed and applied to the study of mevalonic aciduria. The method also appears to be suitable for the evaluation of different therapeutic regimens in patients with hypercholesterolemia. Mevalonic acid was isolated by liquid partition chromatography and quantified as the underivatized lactone by means of ammonia chemical ionization selected ion monitoring capillary gas chromatography-mass spectrometry...