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PubMed1999

Selective lithiation of 2-methyloxazoles. Applications to pivotal bond constructions in the phorboxazole nucleus.

[formula: see text] The lithiation of 2-methyloxazoles with alkyllithium and hindered lithium amide bases generally results in the competitive formation of a mixture of 5-lithio- and 2-(lithiomethyl)oxazole isomers. Herein a synthetically useful lithiation method which allows for the selective formation of 2-(lithiomethyl)oxazole is described. Diethylamine has been found to be a kinetically competent proton source that will mediate the equilibration of the kinetically formed 5-lithiooxazole to its more stable 2-(lithiomethyl)oxazole counterpart. Application of this metalation strategy with lithium diethylamide to two important bond constructions relevant to a projected phorboxazole synthesis is presented.

Alkylation↗
PubMed1999

Role of aggregates in Claisen acylation reactions of imidazole, pyrazole, and thioesters with lithium enolates in THF.

[formula: see text] Although phenyl esters react with both monomers and dimers or tetramers of two lithium enolates in THF, the reactions of phenyl thiobenzoates are relatively much faster with the monomers. Similarly, imidazole esters react primarily with the monomers but pyrazole esters react with monomers and aggregates. The results are rationalized by a mechanism in which coordination with two lithium cations within an enolate aggregate is required for the reaction of aggregates to compete with monomers.

Esters↗
PubMed1999

Aggregation and C-N rotation of the lithium salt of N,N-dimethyldiphenylacetamide.

[formula: see text] Two methyl 1H NMR signals for the Li salt of N,N-dimethyldiphenylacetamide are observed at low temperature and assigned to the monomer and dimer. From line shape analysis, the dimerization constant (K1,2) is 40 +/- 10 M-1 at 200 K (delta G degree = 1.5 kcal mol-1, delta H degree = 0.8 kcal mol-1, delta S degree = 12 eu) and the activation parameters are delta H++ = 5.5 kcal mol-1 and delta S++ = -18 eu. The C-N bond rotation is too fast to observe on the NMR time scale, indicating a rotation barrier of less than 10 kcal mol-1.

Acetamides↗
PubMed1994

A bayesian approach to Arrhenius prediction of shelf-life.

The use of a bayesian method for estimating the shelf-life of pharmaceutical formulations is evaluated and compared with classical linear regression. Using three real data sets, the greater flexibility provided by the bayesian approach is demonstrated. In particular, the bayesian approach enabled the consideration of cases when the error distribution is non-normal. However much more computation is required with the bayesian method.

Bayes Theorem↗
PubMed2002

Combining lithium and anticonvulsants in bipolar disorder: a review.

While the benefits of lithium in bipolar disorder are evident, its limitations as monotherapy are well recognized, particularly in bipolar depression. This has propelled trials of combined lithium-anticonvulsant therapy in many bipolar patients. The present review of the English-language literature examines both controlled and open studies of such combination therapy, including the risk of drug-drug interactions. Trials of lithium plus either carbamazepine or divalproex have generally produced favorable results, although increased rates of adverse effects may reduce treatment adherence. More recent reports suggest that lithium may be safely and effectively combined with lamotrigine, and perhaps with topiramate, although controlled studies are required. The combined use of lithium with newer, putative mood stabilizers, such as zonisamide or levetiracetam, cannot yet be recommended, but is an important area for future research. Provisional recommendations for combined treatment are provided.

Anticonvulsants↗
PubMed2002

Central pontine myelinolysis manifested by temporary blindness: a possible complication of lithium toxicity.

Central pontine myelinolysis (CPM) is removal of myelin material from neural elements in a way that is not clearly known as yet. In this case of CPM, blindness was encountered and was thought to be "hysterical." The blindness went away after four months. After reviewing the literature we suggest the CPM was a complication of lithium toxicity which affected the lateral geniculate nucleus which produced blindness.

Adult↗
PubMed2004

Reverse iontophoresis as a noninvasive tool for lithium monitoring and pharmacokinetic profiling.

PURPOSE: Transdermal iontophoresis was investigated as a noninvasive tool for drug monitoring and pharmacokinetic profiling. Lithium, a frequently monitored drug, was used as a model. The objectives were a) to demonstrate the linear dependence of the iontophoretic extraction flux of lithium on the subdermal concentration of the drug, b) to evaluate the capacity of iontophoresis to monitor sudden changes in the subdermal level, c) to investigate the utility of reverse iontophoresis as a tool in pharmacokinetic studies, and d) to examine the validity of an internal standard calibration procedure to render the method completely noninvasive. METHODS: Transdermal, iontophoretic extraction was performed in vitro using dermatomed pig-ear skin. The subdermal solution consisted of a physiological buffer containing lithium chloride at concentrations in the therapeutic range and two putative internal standards, sodium and potassium, at fixed physiological levels. The subdermal concentration of lithium was changed either in a stepwise fashion or by simulating one of two pharmacokinetic profiles. RESULTS: Lithium was extracted via electromigration to the cathode. A excellent correlation between subdermal lithium concentration and iontophoretic extraction flux was observed. Iontophoresis tracked sudden concentration changes and followed kinetic profiles. In addition, the effective elimination rate constant could be directly, and noninvasively, estimated from the extraction flux data. CONCLUSIONS: Reverse iontophoresis is a potentially useful and noninvasive tool for lithium monitoring.

Administration, Cutaneous↗
PubMed2006

[Therapy with lithium salts in child and adolescent psychiatry--clinical efficacy and practical recommendations].

Lithium salts are pharmacologically classified as mood stabilizers and are medications of first choice for the treatment of manic episodes and the prevention of relapse in bipolar disorders in children and adolescents. Moreover, these drugs can be used to treat episodic impulsive aggressiveness. With regard to their use in the treatment of children and adolescents, however, there are limitations to several preparations on the market in Germany. The evidence level for the treatment of acute mania in adolescents is II, while it is only III-IV for treatment of the same disorder in children. There is only anecdotal evidence of relapse prevention in bipolar disorder in childhood (level of evidence: V), whereas the level of evidence for adolescence is higher (IV). With respect to episodic impulsive aggressiveness, there is a good evidence base (II) for treatment of the disorder in both children and adolescents. An evidence level of II indicates that at least one well designed, randomized, controlled study has been carried out; an evidence level of III is based upon non-randomized studies, an evidence level of IV upon non-experimental studies, and an evidence level of V indicates that evidence is limited to reports or opinions stated by expert circles and consensus conferences, and to clinical experience. Due to the narrow therapeutic window, the dosage should be based on serum concentrations of lithium between 0.6 and 1.2 mmol/l and should be adapted according to the clinical picture. Usually, lithium preparations are administered twice a day: in the morning and in the evening. Side effects have to be monitored very carefully. Serum concentrations higher than 1.5 mmol/l are dangerous. All potential side effects, with the exception of very infrequently occurring renal damage, are reversible by means of dose reduction or, if necessary, by discontinuation of medication with lithium.

Adolescent↗
PubMed1999

Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder.

Protein kinase C (PKC) is a group of calcium and phospholipid-dependent enzymes, which plays a pivotal role in cell signaling systems. Recently accumulated evidence indicates that alterations in PKC activity play a significant role in the pathophysiology of bipolar disorder. A number of laboratories investigated the effect of mood stabilizers on the regulation of PKC activity in bipolar patients, in animals, and in cultured cells. Following chronic lithium treatment, PKC activation was significantly reduced in rat brains, as measured by the translocation of cytoplasmic PKC to the membrane compartment, or by quantitative binding of the PKC ligand, PDBu. The effect of the therapeutic concentration of lithium in attenuating PKC-dependent intracellular parameters was also demonstrated in cultured cells. More importantly, alterations in platelet PKC was shown in bipolar patients during the manic state of the illness. In comparison to patients with major depressive disorder, schizophrenia, or healthy controls, PKC activity was significantly increased in manic patients, suggesting that changes in PKC may be an illness-specific marker. Interestingly, enhanced PKC activity during mania was suppressed following mood-stabilizer treatment as manic symptoms improved. In parallel to the findings in platelets, postmortem studies demonstrate that membrane-associated PKC and stimulation-induced translocation of cytosolic enzyme to the membrane were also increased in frontal cortex of bipolar patients. Other studies suggest alterations in other signal transduction mechanisms in bipolar disorder. These include alterations in G protein activation, phosphatidylinositol (PI) signaling, cyclic AMP formation, and intracellular calcium homeostasis. The alterations of PKC activity in bipolar disorder may be related to changes in these other intracellular signaling mechanisms. Alternatively, the changes of PKC activity may be the core pathology of the illness. More studies are required to further characterize the association of PKC changes with bipolar disorder, using a proper neuronal model.

Animals↗
PubMed1999

Lithium and synaptic plasticity.

Lithium, a small cation, has been used in the treatment of bipolar disorders since its introduction in the 1950s by John Cade. Extensive research on the mechanism of action of lithium has revealed several possible targets. For some time, the most widely accepted action of lithium was its inhibitory effect on the synthesis of inositol, resulting in depletion of inositol with profound effects on neuronal signal transduction pathways. However, several studies show that some effects of lithium are not mediated through inositol depletion. Recent findings demonstrate that lithium directly inhibits, in a non-competitive fashion, the activity of glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase highly expressed in the central nervous system. Interestingly, inhibition of GSK-3beta has been shown to regulate neuronal plasticity by inducing axonal remodelling and increasing the levels of synaptic proteins. These findings raise the possibility for developing new therapeutic approaches for the treatment of bipolar disorders.

Antimanic Agents↗
PubMed1999

Latency and episodes before treatment: response to lithium maintenance in bipolar I and II disorders.

OBJECTIVES: To test whether longer treatment-delays or more pretreatment illness episodes are followed by diminished response to lithium maintenance. METHODS: In 360 DSM-IV bipolar I (n = 220) or II (n = 140) patients, effects of latency from illness onset to starting lithium and number of pretreatment episodes were evaluated by survival analysis based on the number of months stable before a first recurrence on lithium. Factors associated with treatment latency were identified by regression modeling. Relationships of time, episode number, and morbidity before treatment to the overall proportion of time ill on lithium were also tested by nonparametric correlation. RESULTS: Latency to first lifetime lithium maintenance averaged 8.3 years, with 9.3 episodes/subject. Time stable before a first recurrence on lithium averaged 29.6 months and was unrelated to treatment latency (in terciles) or to a high (> or = ten), intermediate (four-nine), or low (< four) number of prior episodes. Overall morbidity during 4.6 years of lithium maintenance was also unrelated to these pretreatment factors. More episodes/year and percentage of time ill before treatment anticipated shorter treatment latency, with greater relative improvement, but were unrelated to morbidity during treatment. CONCLUSIONS: Treatment latency and prelithium episode number were unrelated to morbidity during treatment. Although multiple untreated episodes can lead to severe disability, lithium evidently can greatly limit morbidity, even after years of delay and multiple episodes of bipolar illness.

Adult↗
PubMed1999

Prophylactic efficacy of lithium administered every second day: a WHO multicentre study.

OBJECTIVES: To study the prophylactic efficacy of lithium administered every second day to patients with bipolar disorder or recurrent unipolar depressive disorder. METHODS: The study was carried out as a WHO multicentre study in five different psychiatric clinics: Russia (Moscow), Canada (Montreal), India (Lucknow), Germany (Munich) and South Korea (Pusan), with the lithium tablets being supplied from Denmark (Copenhagen). Participation in the study was conditional on the patient having been in prophylactic lithium treatment for the preceding 2-year period and having been free of depressive or manic phases during the preceding 6 months. After a 2-month baseline period during which lithium was administered every day, the treatment was changed to lithium intake every second day, this regimen in most cases being continued for 22 months. RESULTS: Forty-seven patients, 42 with a diagnosis of bipolar disorder and five with a diagnosis of recurrent unipolar depressive disorder, participated in the study. The number of patients from each centre ranged from six to 11. The mean lithium dose every second day was 36 mmol lithium, leading to a mean 12-h standard serum lithium concentration during the last month of treatment at 0.78+/-0.16 mmol/L. Lithium intake every second day was effective in 38 out of 47 patients. The remaining nine patients had recurrences, a number not differing from the 16 patients in the same group of 47 patients who, during the 2-year period preceding the study, had recurrences. The mean 12-h standard serum lithium concentration was lower in the patients who had recurrences than in those who stayed euthymic. The results suggest that to be effective when administered every second day, lithium must be given in a dose leading to a 12-h standard serum lithium concentration at 0.8 mmol/L or above. CONCLUSIONS: In the dose administered, lithium intake every second day was as effective as lithium intake every day. The amount and severity of lithium-related side effects were apparently not influenced by the change to lithium intake every second day.

Adult↗
PubMed2000

Serotonin in mania and in the mechanism of action of mood stabilizers: a review of clinical studies.

OBJECTIVES: Serotonin (5-hydroxytryptamine, 5-HT) was implicated in the pathophysiology of manic-depressive illness as early as 1958. Although extensive evidence has accumulated since then to support 5-HT's role in depression, relatively fewer studies examined its role in mania. The purpose of this paper was to review and summarize the current state of knowledge on the role of 5-HT in mania and its treatment. METHODS: We systemically reviewed clinical studies of 1) 5-HT function in mania and 2) 5-HT in the mechanism of action of mood stabilizers, including lithium and anticonvulsants. RESULTS: Review showed that cerebrospinal fluid, postmortem, platelet, neuroendocrine challenge, and tryptophan depletion studies provided some evidence to support the hypothesis that a 5-HT deficit is involved in mania and that enhancement of 5-HT neurotransmission exerts a mood-stabilizing effect. CONCLUSIONS: There is some evidence from clinical studies for the contribution of 5-HT in mania and in the mechanism of action of mood stabilizers. However, it is very likely that other neurotransmitters also play important roles. Future directions for research include 1) in vivo study of 5-HT receptor subtypes using positron emission tomography, 2) investigation of the interaction between 5-HT and other neurotransmitter systems, and 3) determination of the relationships between diagnostic subtypes of mania and 5-HT function and other neurotransmitter systems.

Anticonvulsants↗
PubMed2000

The impact of lithium prophylaxis on the course of bipolar disorder: a review of the research evidence.

A critical review is provided of the available research evidence concerning the efficacy and effectiveness of lithium prophylaxis in bipolar disorder. It is emphasized that, in spite of the limitations of available placebo-controlled trials and naturalistic studies, lithium is the only drug whose prophylactic activity in bipolar disorder is convincingly proved, and remains the first-choice medication in the long-term treatment of bipolar patients. The impact of lithium prophylaxis is likely to be less significant on atypical and comorbid cases of bipolar disorder than in typical manic depressive illness, but the superiority of other medications over lithium in the long-term treatment of those cases is at present not convincingly proved by research. Currently available research evidence does not seem to support the idea that lithium exerts its prophylactic effect on relapses but not on recurrences of bipolar disorder. Clinicians should be aware of the fact that the drop-out rate in bipolar patients receiving long-term lithium prophylaxis is high even if treatment surveillance is accurate, and that complete suppression of recurrences is a relatively rare outcome of prophylaxis.

Antimanic Agents↗
PubMed2000

The high affinity inositol transport system--implications for the pathophysiology and treatment of bipolar disorder.

The 'inositol-depletion hypothesis' postulates that the therapeutic effects of lithium are due to inhibition of inositol monophosphatase, which leads to depletion of brain cells of myo-inositol and consequently to dampening of phosphoinositide (PI) signaling. This article examines the potential relevance of an alternative mechanism for inositol depletion: inhibition of myo-inositol uptake that proceeds via the sodium/myo-inositol cotransport (SMIT). We discuss recent in vitro experiments that show a pronounced downregulation of SMIT after chronic treatment with lithium, carbamazepine, and valproate at therapeutically relevant concentrations. It is concluded that downregulation of SMIT could represent a common mechanism of action of mood stabilizers.

Antimanic Agents↗
PubMed2000

Calcium channel antagonists for the treatment of bipolar disorder.

Calcium channel antagonists (CCAs) have many clinical applications, including their possible use in the treatment of bipolar disorder. Two justifications for this last application are some overlap in physiological activities of CCAs with those of lithium, and a possible association between bipolar disorder and calcium dysregulation. While the data from earlier studies support the use of verapamil in treating bipolar mania. more recent better-controlled trials have not. This paper reviews the available body of data regarding CCAs in the treatment of bipolar disorder, concluding there is presently limited support for their efficacy.

Antimanic Agents↗