The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis an...

http://www.afboard.com/library/creatinemetabolism.pdf

Creatine and Creatinine Metabolism

Of 153 patients presenting with acute transient amnesia, 114 fulfilled the proposed strict diagnostic criteria for transient global amnesia (TGA). The prognosis of this group was excellent with the exception of a small subgroup (7%), largely identifiable because of atypically brief or recurrent attacks, who developed epilepsy of temporal lobe type on follow up. Computerised tomography (CT) scans performed on 95 patients were normal, evidence for covert alcoholism was lacking and there was a familial incidence of approximately 2%. By contrast, the group of 39 patients who did not meet the criteria for TGA had a significantly worse prognosis with a high incidence of major vascular events. The groups could not be distinguished on the basis of behavioural characteristics during the attack. The following classification was proposed: 1) pure TGA--attacks fulfilling the strict criteria, and of more than one hour in duration which do not require detailed investigation, 2) probable epileptic amnesia--attacks of less than an hour or rapidly recurrent, 3) probable transient ischaemic amnesia, a minority of cases with additional focal neurological deficits during the attack.

https://jnnp.bmj.com/content/jnnp/53/10/834.full.pdf

Syndromes of transient amnesia: towards a classification. A study of 153 cases.

γ-Aminobutyric acid (GABA), one of the main inhibitory neurotransmitters in the brain, interacts with three types of receptors for GABA - GABAA, GABAB and GABAC. GABAA receptors, associated with binding sites for benzodiazepines and barbiturates in the form of a receptor complex, control opening of the chloride channel. When GABA binds to the receptor complex, the channel is opened and chloride anions enter the neuron, which is finally hyperpolarized. GABAB receptors are metabotropic, linked to a cascade of second messengers whilst the physiological meaning of ionotropic GABAC receptors, mainly located in the retina, is generally unknown. Novel antiepileptic drugs acting selectively through the GABA-ergic system are tiagabine and vigabatrin. The former inhibits neuronal and glial uptake of GABA whilst the latter increases the synaptic concentration of GABA by inhibition of GABA-aminotransferase. Gabapentin, designed as a precursor of GABA easily entering the brain, was shown to increase brain synaptic GABA. This antiepileptic drug also decreases influx of calcium ions into neurons via a specific subunit of voltage-dependent calcium channels. Conventional antiepileptics generally inhibit sodium currents (carbamazepine, phenobarbital, phenytoin, valproate) or enhance GABA-ergic inhibition (benzodiazepines, phenobarbital, valproate). Ethosuximide, mainly controlling absences, reduces calcium currents via T-type calcium channels. Novel antiepileptic drugs, mainly associated with an inhibition of voltage-dependent sodium channels are lamotrigine and oxcarbazepine. Since glutamate-mediated excitation is involved in the generation of seizure activity, some antiepileptics are targeting glutamatergic receptors - for instance, felbamate, phenobarbital, and topiramate. Besides, they also inhibit sodium currents. Zonisamide, apparently sharing this common mechanism, also reduces the concentration of free radicals. Novel antiepileptic drugs are better tolerated by epileptic patients and practically are devoid of important pharmacokinetic drug interactions.

Mechanisms of Action of Antiepileptic Drugs

The blood-brain barrier (BBB) forms an interface between the circulating blood and the brain and possesses various carrier-mediated transport systems for small molecules to support and protect CNS function. For example, the blood-to-brain influx transport systems supply nutrients, such as glucose and amino acids. Consequently, xenobiotic drugs recognized by influx transporters are expected to have high permeability across the BBB. On the other hand, efflux transporters, including ATP-binding cassette transporters such as P-glycoprotein located at the luminal membrane of endothelial cells, function as clearance systems for metabolites and neurotoxic compounds produced in the brain. Drugs recognized by these transporters are expected to show low BBB permeability and low distribution to the brain. Despite recent progress, the transport mechanisms at the BBB have not been fully clarified yet, especially in humans. However, an understanding of the human BBB transport system is critical, because species differences mean that it can be difficult to extrapolate data obtained in experimental animals during drug development to humans. Recent progress in methodologies is allowing us to address this issue. Positron emission tomography can be used to evaluate the activity of human BBB transport systems in vivo. Proteomic studies may also provide important insights into human BBB function. Construction of a human BBB transporter atlas would be a most important advance from the viewpoint of CNS drug discovery and drug delivery to the brain.

Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development.

Creatine is a dietary supplement purported to improve exercise performance and increase fat-free mass. Recent research on creatine has demonstrated positive therapeutic results in various clinical applications. The purpose of this review is to focus on the clinical pharmacology and therapeutic application of creatine supplementation. Creatine is a naturally occurring compound obtained in humans from endogenous production and consumption through the diet. When supplemented with exogenous creatine, intramuscular and cerebral stores of creatine and its phosphorylated form, phosphocreatine, become elevated. The increase of these stores can offer therapeutic benefits by preventing ATP depletion, stimulating protein synthesis or reducing protein degradation, and stabilizing biological membranes. Evidence from the exercise literature has shown athletes benefit from supplementation by increasing muscular force and power, reducing fatigue in repeated bout activities, and increasing muscle mass. These benefits have been applied to disease models of Huntington's, Parkinson's, Duchenne muscular dystrophy, and applied clinically in patients with gyrate atrophy, various neuromuscular disorders, McArdle's disease, and congestive heart failure. This review covers the basics of creatine synthesis and transport, proposed mechanisms of action, pharmacokinetics of exogenous creatine administration, creatine use in disease models, side effects associated with use, and issues on product quality.

Clinical Pharmacology of the Dietary Supplement Creatine Monohydrate

Guanidino compound levels were quantitatively determined in serum, urine, liver, kidney, and brain of man and of some ureotelic animals. The guanidino compounds were separated over a cation exchange resin, using sodium citrate buffers, and detected with the fluorescence ninhydrin method. Species-specific differences in the levels of some guanidino compounds in the studied ureotelic animals are shown. α-Keto-δ-guanidinovaleric acid is a naturally occurring guanidino compound in ureotelic animals, and is not restricted to the pathobiochemistry to hyperargininemic patients. The fasting serum levels observed in beagles are the same as those found in hyperargininemic patients. In serum, liver, and kidney, the homoarginine, β-guanidinopropionic acid, and γ-guanidinobutyric acid levels are the highest in rats. The last two compounds have the highest levels of the studied guanidino compounds, with the exception of creatine, in kidney. Specific high levels of γ-guanidinobutyric acid and argininic acid are found in brain of rabbits.

Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals.

The levels of 12 guanidino compounds were determined in the serum and brain of mouse, rat, rabbit, and man using cation-exchange column chromatography with the fluorescence ninhydrin detection method. A comparative study of these compounds was made in the four groups studied, for serum and brain. In rabbit and man the different guanidino compounds were also determined in various brain regions. This study provides basic analytical data that could facilitate the interpretation of further biochemical and neurochemical studies dealing with guanidino compounds that are identified as being toxins in hyperargininemia and uremia.

Comparative study of guanidino compounds in serum and brain of mouse rat rabbit and man

The present study evaluates dose-dependent behavioral effects of acutely or subacutely administered single doses of vigabatrin (gamma-vinyl gamma-aminobutyric acid, gamma-vinyl GABA, CAS 60643-86-9) in audiogenic sensitive rats, in correlation with whole brain GABA metabolism. There was a discrepancy in timing between behaviorally observed maximal antiepileptic protection (4 h after i.p. administration of gamma-vinyl GABA) and on the other hand maximal inhibition of GABA-transaminase activity and maximal increase of whole brain GABA content (24 h after i.p. administration of gamma-vinyl GABA). This suggests that the antiepileptic properties of gamma-vinyl GABA not only depend on GABA-ergic neurotransmission. A possible explanation is a gamma-vinyl GABA-induced decrease of excitatory amino acids or increased glycine concentrations in the brain.

Behavioral effects of vigabatrin correlated with whole brain gamma-aminobutyric acid metabolism in audiogenic sensitive rats.

The study of the guanidino compounds in our laboratory started a few years after the description1 of the first patients with hyperargininemia2. These patients are characterized by neurological symptomatology with epilepsy and by an accumulation of guanidino compounds in the biological fluids. Most of the fguanidino compounds such as taurocyamine3, guanidino- acetic acid (GAA), Yrguanidinobutyric acid5, N -α-acetylargin.ine6, α-guan- idinoglutaric acid7, methylguanidine8 and a-keto-6-guanidinovaleric acid9, have been shown to be experimentally epileptogenic- Given these facts and with the possibility of a sensitive fluorescence detection method, we investigated the guanidino compounds in serum and cerebrospinal fluid (CSF) of patients with some neurological disorders including epilepsy.

Guanidino Compounds In Serum And Cerebrospinal Fluid Of Epileptic And Some Other Neurological Patients

Sir: The pathophysiology of transient global amnesia is unclear: often an ischaemic aetiology has been suggested, but epileptic and migrainous mechanisms have also been invoked. A familial incidence in this syndrome has rarely been reported.12 We describe a family with an unusual incidence of transient amnesic attacks and migraine. ER, a 72-year-old woman with 10 years of schooling, was admitted to hospital in March 1985, after a temporary attack of altered behaviour dominated by disturbance of memory. Two hours before she had been at home, conversing with her daughter-inlaw, when suddenly she became strange, astonished and did not recognise some household objects as familiar; she asked her daughter-in-law about her presence in the house. She was not able to remember having had a walk in the morning and having prepared a trip to Milan for the next day in order to attend an opera at La Scala Theatre (she had been very excited about this on the previous day). On admission she was still confused, disoriented in time but not in space. General examination, ECG and neurological examination were normal. She asked the same questions over and over again, showing great difficulties in grasping simple information. Other high cerebral functions, clinically evaluated, were preserved. Retrograde amnesia was present, covering a period of several weeks. During the examination she began to recover and after 1 h she was apparently normal. Blood parameters, EEG, CT brain scan and cerebro-vascular Doppler sonography, subsequently performed, were normal. Neuropsychological tests for memory (verbal and spatial span, Rey 15 Words, Rey Complex Figure), administered a month later, gave normal findings; at this time, only amnesia for the period of the attack still remained. The patient's history revealed that she had suffered from common migraine until the menopause, and her mother and two siblings had suffered from vascular headaches (common and classic migraine). Furthermore, a brother of hers, MR, a 76-year-old healthy man, with 7 years of schooling, had suffered from an acute, transient attack of amnesia at the age of 52: after a windy day spent hunting with some friends, he had a 6-8 hour long episode of amnesia, without loss of consciousness, during which he was able to speak, walk and drive. We examined this man, who had no physical abnormalities. Neuropsychological tests for memory proved normal. He was still able to describe the amnesic episode in sufficient detail, even though it happened more than 20 years before. His medical history was uneventful except for that episode and for migraine which in adolescence had been so marked that he had to interrupt high school. A sister had also had an episode of memory disturbances when she was young, but she had died many years before and we had no details about her. We think that, while ER suffered from a classical transient global amnesia attack, MR had probably had transient global amnesia with partial recollection of the episode, analogous to other rare observations.3 4 Previous reports about familial transient global amnesia'2 suggest that familial incidence may be explained by a high frequence of risk-factors for cerebro-vascular disease in the same family. Alternatively, it is possible that episodes of transient global amnesia in members of a same family are a coincidence, because of the frequent occurrence of this condition, which is certainly more frequent in medical practice than has been described. However, we would argue that the migraneous hypothesis of transient global amnesia is also compatible with a familial incidence of this syndrome and the presence of transient global amnesia and migraine in the same family supports this explanation. Even though the high frequency of both conditions can also be invoked to explain their association, this argument is not very convincing. We think that the hypothesis of a single mechanism underlying both transient global amnesia and migraine (the transient global amnesia-migraine connection5), as suggested by their presence in the same family, is an interesting one and should be the subject of further investigations.

https://jnnp.bmj.com/content/jnnp/49/6/716.2.full.pdf

P. Wiechert

Papers

Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals.

Comparative study of guanidino compounds in serum and brain of mouse rat rabbit and man

Behavioral effects of vigabatrin correlated with whole brain gamma-aminobutyric acid metabolism in audiogenic sensitive rats.

Guanidino Compounds In Serum And Cerebrospinal Fluid Of Epileptic And Some Other Neurological Patients

Taurocyamine in cerebrospinal fluid of neurological and psychiatric patients.