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In a double-blind controlled clinical trial on 51 patients with subarachnoid hemorrhage, tranexamic acid, 4 gm per day for ten consecutive days, did not favorably affect the outcome. Neither mortality nor rebleeding rates were improved after a follow-up of three months.
The anticonvulsant gabapentin is transported across biological membranes via the L-amino acid transport system (System-L). Absorption of gabapentin is saturable, and in-vitro data have previously demonstrated that both L-leucine and L-phenylalanine may compete with the intestinal transport of gabapentin. The purpose of this study therefore was to determine whether a high-protein meal would interfere with gabapentin absorption. Ten healthy volunteers received in a randomized, cross-over design, a single 600-mg dose of gabapentin in the fasting state and after a high-protein meal consisting of 80 gm total protein (4.1 g phenylalanine, 8.2 g leucine and 4.2 g isoleucine), 52 g carbohydrate, and 9 g fat. Plasma gabapentin concentrations were measured by HPLC at baseline, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 30 h. Calculated pharmacokinetic parameters included Cmax' Tmax' AUC and T1/2. In addition, a pharmacodynamic assessment (using visual analog scales) of gabapentin-related adverse effects was performed at 2 h post drug ingestion and was compared between study phases. Statistical analysis included Student's t-test for paired data, with significance assigned at P < 0.05. Cmax was significantly increased by 36% (3.87 +/- 1.15 vs 5.28 +/- .97 micrograms/ml, P = 0.002), and Tmax tended to be shorter (3.9 +/- 1.8 vs 2.8 +/- .35 h, P = 0.10), after the high-protein meal. Although AUC was increased by 11%, this did not achieve statistical significance. Despite significantly higher plasma concentrations at 2 h, subjects reported significantly fewer adverse effects after the high-protein meal. Potential mechanisms to explain these unexpected findings may be that the large amino acid load delivered with the high-protein meal enhanced gabapentin absorption via trans-stimulation, the process by which acutely increased intestinal luminal amino acid concentrations result in an acute up regulation in System-L activity. Conversely, the decrease in perceived adverse CNS effects of gabapentin following the high-protein meal may reflect CNS competition for System-L transport.
Both in vivo and in vitro experiments on wild-type Escherichia coli K-12 and mutant strains possessing only single 3-deoxy-d-arabino-heptulosonic 7-phosphate acid (DAHP) synthetase isoenzymes indicated that, under conditions when all three isoenzymes are fully repressed, sufficient chorismate is still formed for the synthesis of aromatic vitamins. Under repressed conditions both DAHP synthetase (phe) and (trp), but not DAHP synthetase (tyr), were shown to contribute to vitamin production.
The effectiveness of tranexamic acid treatment for sudden deafness was studied in detail. The results of treatment with tranexamic acid administration in 19 cases (25 ears) of sudden deafness and two historical control groups using various treatments were compared by the chi square contingency test. The data suggested that tranexamic acid treatment may be superior to traditional treatments especially if treatment is begun early. Among ears treated with tranexamic acid, 11 ears (44%) were healed or recovered remarkably, 8 ears (32%) recovered slightly and 6 ears (24%) were unchanged or worsened. Fibrinolysis in the inner ear may be the pathophysiology of sudden deafness. Treatment with tranexamic acid starting within 4 days after onset of symptoms was most effective in patients whose initial audiogram was flat or concave, initial average hearing loss at 5 frequencies (250 Hz, 500 Hz, 1000 Hz, 2000 Hz and 4000 Hz) was between 23 dB and 76 dB (mean; 45.1 dB) and was not accompanied by dizziness.
Seventy patients with subarachnoid haemorrhage due to ruptured intracranial aneurysms were managed by delayed intervention (third week) along with the prescription of antifibrinolytic drugs (tranexamic acid 6 g/daily). During the pre-operative period, 41 patients stayed in the same clinical status as on admission or improved, whereas 29 deteriorated due to rebleeding (4 cases), vasospasm (18 cases), large hematoma (4 cases), hydrocephalus (2 cases) and postarteriographic accident (1 case). Clipping the aneurysm was finally achieved in 42 patients only; with 3 deaths, 3 severe sequellae, 8 light handicaps, and 28 patients considered as cured with returning to previous occupations. As far as the whole series is concerned, these results yield a 38.5% rate of mortality, 20% morbidity, and 41.5% recovery. It is concluded that 1) Tranexamic acid was effective in reducing the risk or rebleeding, 2) Third week delayed intervention associated with this drug significantly reduced the operative mortality, but probably favoured vasospasm, and finally had no beneficial effect on the overall results concerning the entire series of patients.
Thirty one diabetic patients were prospectively randomized for treatment with or without tranexamic acid during vitrectomy for proliferative diabetic retinopathy. No significant difference in the occurrence of postoperative haemorrhage in the treated and untreated group was observed (37%/28% during the 1st postoperative week, and 25%/40% during the 2nd-4th postoperative weeks, respectively). The final visual result was similar in both groups.
Principles of complex mechanisms of action of anticonvulsants including latest reports concerning new antiepileptic drugs (AED) are considered. Different aspects of new anticonvulsant drugs (2nd generation) from preclinical and clinical testing, pharmacokinetics, and mono or combination therapy in children and adults are summarized. In the following condensed synopsis pharmacological and clinical characteristics of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB) and tiagabine (TGB) as well as topiramate (TPM) and zonisamide (ZNS) are discussed. In addition to the mechanisms of action, pharmacokinetics, interactions, indications and dosages as well as side effects are considered. Important data concerning the effect and tolerability of anticonvulsant drugs can be obtained from controlled studies. In comparison to drugs of the first generation (phenobarbital [PB], primidon [PRD], phenytoin [PHT], carbamazepine [CBZ] and valproic acid [VPA]) the potential for interactions and side effects due to enzyme induction or inhibition is reduced by most of the anticonvulsant drugs of the second generation. New anticonvulsant drugs increase the spectrum of treatment and represent further steps with regard to the optimization of an individual therapy of the epilepsies.
Modification of the chemical and structural properties of zeolites has led to the preparation of an optimized zeolitic dispenser for insect attractants such as n-decanol and trimedlure. The impact of zeolite variables such as the framework Si/Al ratio, nature of compensating cation, nature and strength of acid groups, and pore dimensions on the kinetics of emission has been studied, and the results are as follows. Zeolite pore dimensions and the presence or absence of acid sites have the greatest effect on the rate of release, decreasing with decreasing pore diameter and increasing acidity. Further tuning of the release characteristics is achieved by controlling the polarity and the polarizability of the framework by increasing the Si/Al ratio and nature of the compensating cations, i.e., the higher the polarizability and the lower the polarity, the slower the release of attractants.
In 172 patients the thickness of the corneal graft was followed with frequent measurements during the first 14 days after operation. Three different graft thickness time courses were observed. Patients with keratitis, stromal dystrophy and corrosion or mechanical lesion showed a secondary rise in graft thickness on the 6th postoperative day, while patients with keratoconus and those treated with tranexamic acid showed no rise on the 6th day. Patients with Fuchs' dystrophy differed from the other groups in not reaching the maximal thickness until the 3rd postoperative day. The possible correlation of these three time courses with changes in the fibrinolytic system is discussed.
A series of conformationally restricted Gabapentin analogues has been synthesised. The pyrrolidine analogue (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride (3a) had an IC50 of 120 nM, similar to that of Gabapentin (IC50 = 140 nM), at the Gabapentin binding site on the alpha2delta subunit of a calcium channel. Compound (3a) also reversed carrageenan induced hyperalgesia in rats.
In a double-blind trial tranexamic acid (Cyclokapron) 1 g. four times a day for the first four days of menstruation, significantly decreased menstrual blood loss in women with menorrhagia for which no organic cause had been found. No difference in side-effects was noted between the active and placebo treatment.
21 patients (aged 28-81 years) with recent subarachnoid hemorrhage (10 saccular aneurysms, 3 arteriovenous angiomas, 8 normal angiograms) were continuously infused with tranexamic acid at a dosage of 5 g daily for up to 14 days. Therapy was surveyed by daily measurement of the available plasminogen activity (aPl) with the chromogenic substrate S-2251 and by a modified bioassay, whereby the concentration of tranexamic acid was determined thrombelastographically and expressed as antifibrinolytic equivalent. In addition, a battery of blood coagulation tests was performed daily. 5 patients died, 1 after postoperative stroke, 3 as a result of general complications during intensive care treatment, but only 1 due to rebleeding. 4 patients were successfully operated during the first week, 1 patient after 2 weeks. aPl fell from 99.2% (SEM 3.0%, n = 21) before treatment to 72.9% (SEM 3.5%, n = 21) after 24 h and to the therapeutic level between 50 and 60% from day 2 on. The mean steady state of the antifibrinolytic equivalent corresponded to about 150 micrograms/ml of tranexamic acid during infusion. Intra- and interindividual changes were relatively small for aPl, when compared with the antifibrinolytic equivalent measured by the bioassay. In 2 elderly patients tranexamic acid infusion had to be terminated because of clinical and laboratory signs of disseminated intravascular coagulation, whereby aPl fell below the therapeutic range, elucidating that this method is a sensitive indicator for a hypercoagulable state and useful for the surveillance of therapy with antifibrinoltic agents.
Since January 1st 1975, 310 patients with traumatic hyphaema have been treated with the antifibrinolytic drug tranexamic acid. One secondary haemorrhage has occurred, corresponding to a frequency of secondary haemorrhage of 0.32%. Eighty-five of these patients were treated as out-patients. In four patients with traumatic hyphaema, who were not treated with tranexamic acid, the serum content of activator inhibitor was determined daily. An increase was seen during the first five days after the trauma, followed by a marked fall on the 6th day. In the same four patients, the central corneal thickness was followed by daily measurements and compared to the variation in activator inhibitor.
Centrifugation in sucrose density gradients of partially purified extracts from six species of fungi, i.e., Rhizopus stolonifer, Phycomyces nitens, Absidia glauca (Phycomycetes), Aspergillus nidulans (Ascomycetes), Coprinus lagopus, and Ustilago maydis (Basidiomycetes), indicate that the five enzymes catalyzing steps two to six in the prechorismic acid part of the polyaromatic synthetic pathway sediment together. The sedimentation coefficients for these enzymes are very similar in the six species and are comparable to those previously observed for the multienzyme complexes (arom aggregates) of Neurospora crassa and Saccharomyces cerevisiae. These results are interpreted as indicating the presence in each of these fungi of arom aggregates, presumably encoded by arom gene clusters similar to those in N. crassa and S. cerevisiae. Evidence has also been obtained for the presence in two species (A. nidulans and U. maydis) and the absence in the other four species of a second dehydroquinase isozyme which is distinguishable from the synthetic activity on the basis of both thermostability tests and S values. This second dehydroquinase, which is apparently involved in the catabolism of quinic acid via a pathway similar to that in N. crassa, is inducible in A. nidulans (as it is in N. crassa), but constitutive in U. maydis. These comparative findings are discussed in relation to the organization, evolution, and possible functional relationships of synthetic and catabolic aromatic pathways in fungi.
Effects of TKG01 on gastric ulcers and gastric secretion in rats were investigated in comparison with those of TA903, which is the equimolar clathrate compound of TKG01 anhydride with beta-cyclodextrin. The doses were adjusted on a molecular weight basis to include the same amount of TKG01 anhydride. Water-immersion stress ulcers were dose-dependently (100, 300 mg/kg) inhibited by TA903 given orally, but only significantly inhibited by TKG01 (300 mg/kg). TA903, given orally, even in low doses (30, 100 mg/kg) potently inhibited HCl-ethanol ulcers, whereas TKG01 did not inhibit these ulcers. Both TA903 and TKG01, given orally (100, 300 mg/kg), showed similar inhibition of indomethacin ulcers. TA903, given intraduodenally (100, 300 mg/kg), dose-dependently inhibited gastric secretion (volume, acid output and pepsin output) in pylorus-ligated rats, but TKG01 only inhibited pepsin output (100, 300 mg/kg). These results showed that TA903 had a broader spectrum of anti-ulcer effects than TKG01 and the mechanism of TA903 could involve both its cytoprotective activity and its anti-secretory effect.
Chorismate mutase from Streptomyces aureofaciens was purified 12-fold. This enzyme preparation did not show any activity when tested for anthranilate synthetase, prephenate dehydrogenase, or prephenate dehydratase. The catalytic activity of chorismate mutase has a broad optimum between pH 7 and 8. The initial velocity data followed regular Michaelis-Menten kinetics with a K(m) of 5.3 x 10(-4) M, and the molecular weight of the enzyme was determined by sucrose gradient centrifugation to be 50,000. Heat inactivation of chorismate mutase, which occurs above temperatures of 60 C, is reversible. The enzyme activity can be restored even when chorismate mutase is treated at the temperature of a boiling-water bath for 15 min. Heat-denatured and renatured enzymes showed the same Michaelis constant and the same molecular weight as the native enzyme. l-Phenylalanine, l-tyrosine, l-tryptophan, and metabolites of the aromatic amino acid pathway were tested as potential modifiers of chorismate mutase activity. The activity of the enzyme was inhibited by none of these substances. Chorismate mutase of S. aureofaciens was not repressed in cells grown in minimal medium supplemented with l-phenylalanine, l-tyrosine, or l-tryptophan.
Three familial generations (five members with hereditary angioneurotic edema) have been evaluated under clinical and immunological standpoints. A therapeutic trial with tranexamic acid was carried out. The five members with hereditary angioneurotic edema showed: decreased values of total hemolytic activity (CH50), deficit of C4 (between 8 and 23 percent of the normal value), and normal levels of C3 and C9. C3PA was normal in four members and decreased in one. Asymptomatic familial members had normal serum complement levels; only three cases showed diminished values of CH50, C4, C-1-INH and C3PA. Therapeutic trial with tranexamic acid demonstrated the usefulness of this agent in the treatment of angioneurotic edema; it showed slighter adverse reactions than those derived from other therapeutic modalities. Screening of asymptomatic familial members is pointed out in order to detect low plasma values of C1-IHN.
The effect of tranexamic acid on the growth of three human tumor cell lines (lung squamous cell carcinoma QG-56, lung adenocarcinoma PC-12 and ovarian carcinoma OC-1) was investigated in vitro and in vivo in nude mice. Tranexamic acid exhibited no direct cytotoxicity in vitro, but it inhibited the growth of all the three cell lines as tumors in nude mice. Prominent deposition of fibrin or fibrinogen around tumor cells at the advancing border were observed only in the tumors of treated animals.