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Novel treatments for bipolar disorder.

Treatments other than lithium have recently emerged as equally important in the management of bipolar disorder. The spectrum of efficacy of newer treatments differs from lithium and among the novel drug treatments valproate, generally used as the better tolerated divalproex form, principally benefits manic symptomatology both acutely and in prophylaxis. Atypical antipsychotic drugs have demonstrated efficacy in reducing acute manic symptoms. No controlled evidence of efficacy in prophylaxis has been published. Lamotrigine has demonstrated efficacy in both acute bipolar depression and maintenance efficacy in rapid cycling bipolar patients, especially those patients with bipolar II disorder, which is principally manifested as depression. Randomised, double-blind, placebo- controlled studies provide good evidence that regimens of risperidone or olanzapine in combination with lithium or valproate provide greater improvement in acute mania than the mood stabilisers alone. Similarly, valproate combined with antipsychotics provided greater improvement in mania than antipsychotic medication alone and resulted in lower dosage of the antipsychotic medication. A positive but unclear placebo-controlled study of omega-3 fatty acids added to lithium in bipolar disorder needs confirmation in standard clinical trial paradigms. Several other drugs that were reported as beneficial in various facets of bipolar disorder in open trials have not differed from placebo when studied in randomised, placebo-controlled trials.

Acetates↗

Prophylactic tranexamic acid decreases bleeding after cardiac operations.

Thirty-eight patients undergoing a cardiac operation randomly received either tranexamic acid, a potent inhibitor of plasminogen, or placebo in an effort to determine whether prophylactic antifibrinolytic therapy reduces chest tube drainage. Twelve-hour blood loss was 750 +/- 314 (standard deviation) ml in the placebo group and 496 +/- 228 ml in the drug group (p = 0.0057). Fibrin split products were present more frequently in patients in the placebo group (17 of 20 compared with four of 18 in the drug group; p = 0.0002). Tranexamic acid markedly decreased plasminogen availability (112 +/- 104 units in the placebo group versus 36 +/- 18 units in the drug group, p = 0.0058). Plasma fibrinogen concentrations were similar in the placebo and drug groups. Patients in the placebo group received more fresh-frozen plasma and more mediastinal shed blood than those in the drug group. No coagulation-related complication occurred in the group receiving tranexamic acid. We conclude that prophylactic tranexamic acid can be administered safely to inhibit fibrinolysis during cardiac operations, decrease postoperative bleeding, and possibly decrease the frequency of blood product transfusion.

Adult↗

Antifibrinolytic therapy for prevention of hemorrhage during surgery of the thyroid gland.

The amount of fibrinolytic activity in the thyroid gland equals that of the prostate. In order to examine the effect of the antifibrinolytic drug tranexemic acid on perioperative bleeding saline or tranexemic acid were given randomized double blind to 76 consecutive patients who came for scheduled thyroid surgery. No significant differences were found in perioperative bleeding between patients in the treatment group (n = 39) and control group (n = 37).

Adenoma↗

Involvement of cyclic AMP in carotenogenesis and cell differentiation in Blakeslea trispora.

Cyclic adenosine 3',5'-monophosphate (cyclic AMP) was detected in single and mated cultures of Blakeslea trispora. Cyclic AMP levels increased on mating the plus and minus mycelia. Trisporic acid and beta-carotene levels were much higher in synthetic mucor medium supplemented with glycerol as compared to that with glucose. Cyclic AMP induced significant morphological changes in plus and minus strains were comparable to those induced by mating event.

Carotenoids↗

Hemostatic effect of tranexamic acid mouthwash in anticoagulant-treated patients undergoing oral surgery.

We carried out a placebo-controlled, double-blind, randomized study of the hemostatic effect of tranexamic acid mouthwash after oral surgery in 39 patients receiving anticoagulant agents because of the presence of cardiac valvular stenosis, a prosthetic cardiac valve, or a vascular prosthesis. Surgery was performed with no change in the level of anticoagulant therapy, and treatment with the anticoagulant agent was continued after surgery. Before it was sutured, the operative field was irrigated in 19 patients with 10 ml of a 4.8 percent aqueous solution of tranexamic acid (an inhibitor of fibrinolysis) and in 20 patients with a placebo solution. For seven days thereafter, patients were instructed to rinse their mouths with 10 ml of the assigned solution for two minutes four times a day. There were no significant differences between the two treatment groups in base-line variables, including the level of anticoagulation at the time of surgery. Eight patients in the placebo group had a total of 10 postoperative bleeding episodes, whereas only 1 patient in the tranexamic acid group had a bleeding episode (P = 0.01). There were no systemic side effects. We conclude that local antifibrinolytic therapy is effective in preventing bleeding after oral surgery in patients who are being treated with anticoagulants.

Adult↗

Determination of gabapentin in serum using solid-phase extraction and gas-liquid chromatography.

A gas-liquid chromatographic method for the determination of gabapentin (Neurontin) is described. The method involves extracting 0.5 mL of acidified sample by C18 solid-phase column, derivatization with MTBSTFA plus 1% tBDMCS, and analysis on an HP-1 column with a flame-ionization detector. Quantitation was performed with peak-height ratios of gabapentin to a gabapentin analogue [(1-aminomethyl-1-cycloheptyl) acetic acid] as the internal standard. The assay had a limit of detection of 0.2 mg/L and a linear range from 0.5 to 30.0 mg/L. Several compounds were analyzed for potential interference, and none interfered with the assay.

Acetamides↗

A GABA(B) mystery: the search for pharmacologically distinct GABA(B) receptors.

The classification of neurotransmitter receptors into distinct pharmacological subtypes is of major importance in drug discovery. This quest is particularly important for neurotransmitter systems that are widely distributed. Because gamma-aminobutyric acid (GABA) receptors, both GABA(A) and GABA(B), are found throughout the neuroaxis, they are likely involved in all central nervous system functions. Accordingly, the therapeutic promise of GABA(B) receptor manipulation depends upon the identification of subtypes than can be specifically targeted.

Acetates↗

[Evidence-based pharmacotherapy of neuropathic pain syndromes].

Neuropathic pain can severely reduce quality of life. Double blind, placebo controlled studies confirm the efficacy of the treatment of painful neuropathy, postherpetic neuralgia and trigeminal neuralgia with tricyclic antidepressants, ion channel blockers, opioids and lipoic acid. The numbers-needed-to-treat (NNT) with monotherapy to achieve pain reduction of at least 50% are in the range of 2 to 4. Recent studies indicate that patients can benefit from combinations of opioids and tricyclic antidepressants or opioids and gabapentin.

Amines↗

Inhibitory effect of prolonged oral administration of cetraxate hydrochloride on experimentally-induced intestinal metaplasia in Wistar rats.

The effect of cetraxate hydrochloride (Neuer) on the induction of intestinal metaplasia by intragastric instillation of 5% NaOH solution was investigated in Wistar rats. Oral administration of cetraxate, beginning 2 days after NaOH treatment, resulted in a significant increase in antral mucosal blood flow and a significant reduction in the incidence and amount of intestinal metaplasia in experimental week 25, but no significant changes in basal acid secretion or antral mucosal pH. On histological examination, goblet cell metaplasia were frequently seen. These results show that the increased gastric blood flow produced by cetraxate hydrochloride may be associated with the suppression of induction of intestinal metaplasias.

Administration, Oral↗

Occupational exposure to hexahydrophthalic anhydride: air analysis, percutaneous absorption, and biological monitoring.

Urinary hexahydrophthalic acid (HHP acid) levels were determined in 20 workers occupationally exposed to hexahydrophthalic anhydride (HHPA) air levels of 11-220 micrograms/m3. The levels of HHP acid in urine increased rapidly during exposure and the decreases were also rapid after the end of exposure. The elimination half-time of HHP acid was 5 h, which was significantly longer than in experimentally exposed volunteers, possibly indicating distribution to more than one compartment. There was a close correlation between time-weighted average levels of HHPA in air and creatinine-adjusted levels of HHP acid in urine collected during the last 4 h of exposure (r = 0.90), indicating that determination of urinary HHP acid levels is suitable as a method for biological monitoring of HHPA exposure. An air level of 100 micrograms/m3 corresponded to a postshift urinary HHP acid level of ca. 900 nmol/mmol creatinine in subjects performing light work for 8 h. Percutaneous absorption of HHPA was studied by application of HHPA in petrolatum to the back skin of three volunteers. The excreted amounts of HHP acid in urine, as a fraction of the totally applied amount of HHPA, were within intervals of 1.4%-4.5%, 0.2%-1.3%, and 0%-0.4% respectively, indicating that the contribution from percutaneous absorption is of minor importance in a method for biological monitoring.

Adult↗

No additive effect of tranexamic acid and naproxen on corneal deswelling. A study on oedema after uncomplicated intracapsular cataract extraction with anterior chamber lens implantation.

The influence of systemic antifibrinolytic and antiprostaglandin medication on post-operative central corneal thickness was studied. Thirty patients underwent uncomplicated intracapsular cataract extraction with implantation of anterior chamber lens. The patients received either tranexamic acid, naproxen or both. The post-operative oedema did not differ significantly between the three groups studied. Models for studying changes in central corneal thickness are discussed. A review of the influence of drugs on corneal thickness is presented.

Aged↗

Pharmacodynamic profile of a novel inhibitor of the hepatic glucose-6-phosphatase system.

The glucose-6-phosphatase (G-6-Pase) system catalyzes the terminal enzymatic step of gluconeogenesis and glycogenolysis. Inhibition of the G-6-Pase system in the liver is expected to result in a reduction of hepatic glucose production irrespective of the relative contribution of gluconeogenesis or glycogenolysis to hepatic glucose output. In isolated perfused rat liver, S-3483, a derivative of chlorogenic acid, produced concentration-dependent inhibition of gluconeogenesis and glycogenolysis in a similar concentration range. In fed rats, glucagon-induced glycogenolysis resulted in hyperglycemia for nearly 2 h. Intravenous infusion of 50 mg . kg-1. h-1 S-3483 prevented the hyperglycemic peak and subsequently caused a further lowering of blood glucose. In 24-h starved rats, in which normoglycemia is maintained predominantly by gluconeogenesis, intravenous infusion of S-3483 resulted in a constant reduction of blood glucose levels. Intrahepatic concentrations of glucose-6-phosphate (G-6-P) and glycogen were significantly increased at the end of both in vivo studies. In contrast, lowering of blood glucose in starved rats by 3-mercaptopicolinic acid was accompanied by a reduction of G-6-P and glycogen. Our results demonstrate for the first time in vivo a pharmacologically induced suppression of hepatic G-6-P activity with subsequent changes in blood glucose levels.

Animals↗

Complications of antifibrinolysis therapy after prostatectomy.

As part of a trial to compare the effectiveness of various agents which have been claimed to reduce blood loss after prostatectomy, tranexamic acid (AMCA) was given pre-operatively and post-operatively to 6 patients having routine transurethral resections. Three of these developed indissoluble intravesical blood clots which persisted until they were evacuated surgically 5 to 17 days after cessation of AMCA therapy. AMCA cannot be recommended for routine use after prostatectomy.

Cyclohexanecarboxylic Acids↗

Novel anticonvulsants in the treatment of alcoholism.

There have been many recent developments in the pharmacological management of alcohol withdrawal and alcohol dependence. Although previous treatments had included benzodiazepines as their mainstay, the use of these agents in the alcoholic population is problematic. Benzodiazepines are themselves addictive and they may increase the risk of alcohol relapse. Non-benzodiazepine anticonvulsants such as carbamazepine, valproic acid, gabapentin, vigabatrin and topiramate have been shown to be excellent treatments of both alcohol withdrawal and the prevention of alcohol relapse. Although none of these agents have yet been approved by the FDA, there is growing evidence in the literature to support their use.

Alcohol Deterrents↗

Changes in mitochondrial proteins during neuroblastoma differentiation.

The evolution of three major mit-proteins was followed in neuroblastoma cells cultured in different conditions of differentiation. 1 methyl cyclohexane carboxylic acid (CCA) was found to stimulate the synthesis of the three mit-protein markers. This result, compared to the effects of oligomycin, an inhibitor of mitochondrial function, favours the hypothesis that CCA induces in vitro neurogenesis through a general metabolic alteration.

Animals↗

Effect of local antifibrinolytic treatment with tranexamic acid in hemophiliacs undergoing oral surgery.

The objectives of the present clinical investigation were to examine the effects in hemophiliacs of local antifibrinolytic treatment with tranexamic acid on the incidence of postoperative bleeding after oral surgery and on the amount of replacement therapy needed to control bleeding. The study compared three groups of patients. The patients in group A received high doses of factor concentrate and systemic antifibrinolytic treatment with tranexamic acid. In group B local antifibrinolytic treatment with tranexamic acid was added to the treatment received by group A. Group C received replacement therapy to raise factor levels to approximately 10% of the normal value perioperatively, combined with systemic and local antifibrinolytic treatment (mouth rinse) with tranexamic acid. The study demonstrated that local antifibrinolytic therapy with tranexamic acid as a supplement to the currently used systemic therapy significantly reduces the incidence of postoperative bleeding. The results of the study further suggest that replacement therapy can be reduced during oral surgery in the hemophilic patient provided that local and systemic inhibition of fibrinolysis is instituted.

Administration, Oral↗

The nitric oxide-cyclic GMP-protein kinase G-K+ channel pathway participates in the antiallodynic effect of spinal gabapentin.

The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG) pathway on gabapentin-induced spinal antiallodynic activity was assessed in spinal nerve injured rats. Intrathecal gabapentin, diazoxide or pinacidil reduced tactile allodynia in a dose-dependent manner. Pretreatment with NG-L-nitro-arginine methyl ester (L-NAME, non-specific inhibitor of NO synthase NOS), 7-nitroindazole (neuronal NO synthase inhibitor), 1H-[1,2,4] -oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor), but not NG-D-nitro-arginine methyl ester (D-NAME) or okadaic acid (protein phosphatase 1 and 2 inhibitor) prevented gabapentin-induced antiallodynia. Pinacidil activity was not blocked by L-NAME, D-NAME, 7-nitroindazole, ODQ, KT-5823 or okadaic acid. Moreover, KT-5823, glibenclamide (ATP-sensitive K+ channel blocker), apamin and charybdotoxin (small- and large-conductance Ca2+-activated K+ channel blockers, respectively), but not margatoxin (voltage-gated K+ channel blocker), L-NAME, 7-nitroindazole, ODQ or okadaic acid, reduced diazoxide-induced antiallodynia. Data suggest that gabapentin-induced spinal antiallodynia could be due to activation of the NO-cyclic GMP-PKG-K+ channel pathway.

Amines↗