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Aurintricarboxylic acid (ATA) inhibits protein synthesis directed by polyuridylic acid. All steps tested are inhibited by ATA. We conclude that inhibition of polyphenylalanine formation is an additive effect of inhibition of various steps in the protein synthetic machinery.
Fibrinolytic activity in biopsied colonic mucosa was examined in patients with ulcerative colitis, and most cases were found to have increased tissue fibrinolysis -- due mainly to tissue plasminogen activator -- in the affected mucosa. Five cases, 4 with elevated tissue fibrinolysis and 1 normal, were treated with an antifibrinolytic agent, tranexamic acid (trans-AMCHA) administered as an enema, to inhibit fibrinolysis of the affected mucosa directly. In patients with elevated mucosal fibrinolysis, 2 showed complete remission after tranexamic acid enema alone, and there was one remission in response to combination treatment with oral prednisolone. One case with slightly elevated mucosal fibrinolysis showed clinical improvement, although the radiological findings were unchanged. No response was observed in one case with normal tissue fibrinolysis. It is concluded that tranexamic acid may show a therapeutic effect in ulcerative colitis with elevated mucosal fibrinolysis when administered via an enema, which allows direct contact of the drug with the affected mucosa.
The crystal structures of four dipeptides that contain the stereochemically constrained gamma-amino acid residue gabapentin (1-(aminomethyl)cyclohexaneacetic acid Gpn) are described. The molecular conformation of Piv-Pro-Gpn-OH (1), reveals a beta-turn mimetic conformation, stabilized by a ten atom C[bond]H...O hydrogen bond between the Piv CO group and the pro S hydrogen of the Gpn CH(2)[bond]CO group. The peptides Boc-Gly-Gpn-OH (2), Boc-Aib-Gpn-OH (3), and Boc-Aib-Gpn-OMe (4) form compact, folded structures, in which a distinct reversal of polypeptide chain direction is observed. In all cases, the Gpn residue adopts a gauche,gauche (g,g) conformation about the C(gamma)[bond]C(beta) (theta(1)) and C(beta)[bond]C(alpha) (theta(2)) bonds. Two distinct Gpn conformational families are observed. In peptides 1 and 3, the average backbone torsion angle values for the Gpn residue are phi=98 degrees, theta(1)=-62 degrees, theta(2)=-73 degrees, and psi=79 degrees, while in peptide 2 and 4 the average values are phi=-103 degrees, theta(1)=-46 degrees, theta(2)=-49 degrees, and psi=-92 degrees. In the case of 1 and 3, an intramolecular nine-membered O[bond]H...O hydrogen bond is formed between the C[double bond]O of the preceding residue and the terminal carboxylic acid OH group. All four alpha-gamma dipeptide sequences yield compact folded backbone conformations; this suggests that the Gpn residue may be employed successfully in the design of novel folded structures.
The fibrinolytic inhibitor tranexamic acid affects certain experimental tumours; it prolongs survival (Lewis lung adenocarcinoma), decreases tumour weight (C3H breast carcinoma), and inhibits ascitic production (AH 130 rat hepatoma). However, it does not significantly influence DNA-synthesis in cell suspensions prepared from the same tumours.
Huntington's disease (HD) is an autosomal dominant, inherited and fatal neurodegenerative disorder for which there is, at present, no effective treatment or cure. Striatal medium spiny neurons (MSN) are the most sensitive in HD. Dysregulation of glutamate/calcium signaling pathway emerges as a possible cause of striatal MSN neurodegeneration in HD. Here we evaluated five clinically relevant glutamate pathway inhibitors using previously developed in vitro HD model. We found that folic acid, gabapentin and lamotrigine did not protect HD neurons from glutamate-induced cell death, but memantine and riluzole were protective. Our results provide further support to potential use of memantine and riluzole for treatment of HD.
Experiments were designed to address whether the pentacyclic triterpene tormentic acid isolated from the stem bark of the plant Vochysia divergens exerts oral anti-allodynic properties in two models of chronic pain in mice: neuropathic pain caused by partial ligation of the sciatic nerve and inflammatory pain produced by intraplantar injection of Complete Freund's Adjuvant. Oral administration of tormentic acid (30 mg/kg) twice a day for several consecutive days produced time-dependent and pronounced anti-allodynia effect in both ispsilateral and contralateral paws after plantar injection of Complete Freund's Adjuvant. The inhibition observed was 82+/-9% and 100+/-11%, respectively. Interestingly, tormentic acid did not inhibit paw oedema formation following Complete Freund's Adjuvant plantar injection. Tormentic acid (30 mg/kg, p.o.) and gabapentin (70 mg/kg, p.o.), given twice a day, inhibited markedly the neuropathic allodynia induced by partial ligation of the sciatic nerve, with inhibition of 91+/-19% and 71+/-16%, respectively. The anti-allodynic action of tormentic acid was not associated with impairment of the motor activity of the animals. Together, the present results indicate that tormentic acid or its derivatives might be of potential interest in the development of new clinically relevant drugs for the management of persistent neuropathic and inflammatory allodynia.
Some anticonvulsants show neuroprotective effects, and may be of use in reducing neuronal death resulting from stroke or traumatic brain injury. Here I report that a broad range of anticonvulsants protect cells in hippocampal slice cultures from death induced by oxygen/glucose deprivation (OGD). Hippocampal slice cultures were submitted to 1 h OGD and the resulting cell death was quantified 24 h later using a novel automated fluorescent scanning method. The classical anticonvulsants phenobarbital, phenytoin, ethosuximide, chlordiazepoxide and midazolam all significantly and dose-dependently reduced cell death induced by OGD. The newer anticonvulsants carbamazepine, felbamate, lamotrigine, tiagabine, and oxcarbazepine also had significant neuroprotective effects, but gabapentin, valproic acid (10 mM), levetiracetam and retigabine were not neuroprotective at a concentration up to 300 microM. In conclusion, several classical and newer anticonvulsants have neuroprotective properties in an in vitro model that simulates cerebral ischemia.
A stability-indicating, sensitive, simple and selective spectrofluorimetric method was developed for the determination of vigabatrin (VG) and gabapentin (GB). The method is based on the reaction between the two drugs and fluorescamine in borate buffer of pH 8.2 to give highly fluorescent derivatives that are measured at 472 nm using an excitation wavelength of 390 nm for both drugs. The optimum conditions were ascertained and the method was applied for the determination of VG and GB over the concentration range of 0.20-4.00 and 0.1-1.0 microg/ml, respectively with detection limits of 0.05 microg/ml (2.9 x 10(-7) M) and 0.06 microg/ml (2.3 x 10(-7) M) for VG and GB, respectively. The suggested method was applied, without any interference from the excipients, to the determination of the two drugs in their pharmaceutical formulations. Furthermore, the method was extended to the in-vitro determination of both drugs in spiked human urine. Interference from endogenous amino acids could be eliminated through selective complexation with copper acetate, the % recovery (n=4) is 98.0 +/- 7.05. Co-administered drugs such as lamotrigine, phenobarbitone, valproic acid, clopazam, carbamazepine, clonazepam and cimitidine did not interfere with the assay. The method is also stability-indicating; as the degradation product of vigabatrin: 5-vinylpyrrolidin-2-one, produced no interference with its analysis.
Crystallographic studies of myoglobin have shown that the haem pocket is lined with nonpolar amino-acid residues. In order to estimate the true polarity of the interior of proteins, certain studies have used bound fluorophores, the spectroscopic properties of which reflect the polarity of their environment. These studies have most often used 1-amino-8-naphthalene sulphonate (ANS) as a probe, but a more suitable probe, in principle, is 6-propionyl 2-(N,N-dimethyl)aminonaphthalene (PRODAN). We have synthesized a molecule with the advantageous spectroscopic properties of PRODAN but with a higher affinity for apomyogloblin: 2'-(N,N-dimethyl)amino-6-naphthopyl-4-trans-cyclohexanoic acid (DANCA), and report here its use to determine the polarity of the myoglobin haem pocket. Our results show that the pocket is actually a polar environment, and the polarity can be accounted for by peptide amide dipoles.
Seventy-four patients with recent subarachnoid haemorrhage were randomly allocated to placebo or tranexamic acid treatment. Fibrinolytic activity in the blood and cerebrospinal fluid was assessed before treatment, one week later and two weeks later. The natural history of fibrinolysis following subarachnoid haemorrhage was obtained from analysis of the placebo group. Following subarachnoid haemorrhage, fibrin degradation products and plasminogen activity in the cerebrospinal fluid were elevated. Subsequently, fibrin degradation products in the cerebrospinal fluid fell progressively over the following 2 weeks. Changes in cerebrospinal fluid plasminogen activity correlated with those of blood plasminogen activity. Complications such as rebleeding, hydrocephalus or cerebral thrombosis could not be predicted from analysis of fibrinolytic activity. Tranexamic acid treatment resulted in a reduction in cerebrospinal fluid and blood plasminogen activity. The relevance of fibrinolysis in cerebrospinal fluid and blood to the management of subarachnoid haemorrhage is discussed.
We identified by gas chromatography-mass spectrometry the unusual substance cis-4-hydroxycyclohexanecarboxylic acid (4-HCH) in the urine of a child. Urinary excretion of 4-HCH and intestinal bacteria were both suppressed by neomycin treatment. We propose that 4-HCH is a by-product of bacterial metabolism.
The most common post-operative complication of adenotonsillectomy is an excessive bleeding. This problem persists although the laboratory investigations may exclude hemocoagulative anomalies and the anamnesis is able to show the presence or not of genetic factors or constitutional disease. Even if the surgical operation is performed in a technical proper way, the risk of bleeding is still present. Therefore we have valued new prospects of application in pediatric O.R.L. of a peptide fraction from bovine factor VIII. This compound has proved to be able to reduce the bleeding time. We valued the action of this drug compared with that of tranexamic acid and in comparison with the results obtained before treatment. Furthermore, we have also investigated the possibility of influence of this drug on haemocoagulative parameters and we have concluded that the drug does not show any effect on them.
A rapid capillary electrophoresis method for the quantification of gabapentin, a new anticonvulsant drug, in serum was developed. The assay involves derivatization of gabapentin with fluorescamine to provide a chromophore for UV-fluorescence detection. The migration time is about 11 min. The assay was linear between 0 and 20 mg/l. No other therapeutic drugs or amino acids interfered with the gabapentin peak. The relative standard deviation is 2.4% at a mean of 11 mg/l (n = 17). The mean serum level for 52 patients on this drug was 5.2 mg/l with a range of 0-12 mg/l.
Gabapentin is a novel anticonvulsant drug. The anticonvulsant mechanism of gabapentin is not known. Based on the amino acid structure of gabapentin we explored its possible effects on glutamate and gamma-aminobutyric acid (GABA) metabolism in brain as they may relate to its anticonvulsant mechanisms of action. Gabapentin was tested for its effects on seven enzymes in the metabolic pathways of these two neurotransmitters: alanine aminotransferase (AL-T), aspartate aminotransferase (AS-T), GABA aminotransferase (GABA-T), branched-chain amino acid aminotransferase (BCAA-T), glutamine synthetase (Gln-S), glutaminase (GLNase), and glutamate dehydrogenase (GDH). In the presence of 10 mM gabapentin, only GABA-T, BCAA-T, and GDH activities were affected by this drug. Inhibition of GABA-T by gabapentin was weak (33%). The Ki values for inhibition of cytosolic and mitochondrial forms of GABA-T (17-20 mM) were much higher than the Km values for GABA (1.5-1.9 mM). It is, therefore, unlikely that inhibition of GABA-T by gabapentin is clinically relevant. As with leucine, gabapentin stimulated GDH activity. The GDH activity in rat brain synaptosomes was activated 6-fold and 3.4-fold, respectively, at saturating concentrations (10 mM) of leucine and gabapentin. The half-maximal stimulation by gabapentin was observed at approximately 1.5 mM. Gabapentin is not a substrate of BCAA-T, but it exhibited a potent competitive inhibition of both cytosolic and mitochondrial forms of brain BCAA-T. Inhibition of BCAA-T by this drug was reversible. The Ki values (0.8-1.4 mM) for inhibition of transamination by gabapentin were close to the apparent Km values for the branched-chain amino acids (BCAA) L-leucine, L-isoleucine, and L-valine (0.6-1.2 mM), suggesting that gabapentin may significantly reduce synthesis of glutamate from BCAA in brain by acting on BCAA-T.
A 31-y-old epileptic man developed coma and shock after suicidally ingesting large amounts of valproic acid and gabapentin. His peak valproic acid, level was 1306.9 micrograms/mL (therapeutic range = 30-100 micrograms/mL). His peak gabapentin level was 60.0 micrograms/mL (therapeutic range = 2.0-8.0 micrograms/mL). His hypotension was refractory to crystalloid and pressor infusions, but resolved during concurrent hemoperfusion and hemodialysis to enhance elimination of valproic acid. Concurrent hemoperfusion and hemodialysis, in series, produced a maximum valproic acid plasma clearance of 55.4 mL/min versus a maximum reported intrinsic valproic acid plasma clearance of 10.6 mL/min. concurrent hemoperfusion and hemodialysis, in series, should be considered in hemodynamically unstable patients with valproic acid poisoning whose clinical condition is worsening in spite of aggressive supportive care.
The effects of locally deposited fibrin and of tranexamic acid-induced antifibrinolysis on forming granulation tissue were studied in the light of a recently developed method for treatment of postoperative fistulas by occlusion with a fibrin clot. Perforated teflon cylinders, either empty or fibrin-filled, were implanted subcutaneously in rats and extracted after 2 weeks. Fibrin deposition was found to stimulate granulation tissue ingrowth into the cylinders but it did not change the fibrinolytic activity in the granulation tissue. A significantly higher fibrinolytic activity was, however, found in the tissue fluid collected from the space between the granulation tissue and the implanted fibrin clot compared to tissue fluid from cylinders implanted empty. Tranexamic acid significantly reduced the fibrinolytic activity on the granulation tissue and delayed lysis of the implanted fibrin clot. It also reduced granulation tissue ingrowth but it did not abolish the positive effects of the clot on granulation tissue formation.
Self-injurious behavior is a common clinical problem in children with Lesch-Nyhan syndrome, an X-linked disorder of purine metabolism. This behavior is not observed in other conditions associated with increased serum concentrations of uric acid, hypoxanthine, and xanthine. Various neurotransmitters appear to play a pivotal role in self-injurious behavior. The authors present a patient with Lesch-Nyhan syndrome, whose self-injurious behavior was effectively treated with gabapentin, and discuss possible mechanisms of action.
After a single oral dose of 25 mg/kg tranexamic acid in 37 patients with cataract as the sole eye disease, the concentration of the drug was measured in both the serum and the aqueous at various intervals following intake. The serum concentration was highest after three h (average 15.44 mg/l), but a trace of tranexamic acid (0.7 mg/l) could still be found after 19 h. In the aqueous, the concentration was likewise highest after three h (average 1.62 mg/l), but, following this, the fall in tranexamic acid concentration was very gradual and after 19 h was found to be 1.3 mg/l. In two patients who had received 25 mg/kg three times daily for three days, an aqueous concentration of 2.3 mg/l was found eight h after the final intake.