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PubMed1999

[Therapeutic strategies in refractory bipolar disorder].

Lithium is still regarded as the first choice substance in the prophylactic treatment of bipolar disorder. However, approximately one third of patients with a "classic" course of bipolar affective disorder do not adequately respond to lithium prophylaxis. The introduction of carbamazepine and valproic acid allowed a more differential syndrome- and course-orientated approach to the prophylactic treatment of bipolar disorder for the first time. However, about 10 to 20 percent of patients still remain refractory to standard regimes. Therefore, criteria for resistance to prophylactic treatment have to be further established. It has been suggested that at least two adequate trials of more than 12 months duration with sufficient drug blood levels have to be performed before refractoriness should be assumed. A severe subtype of affective disorder with poor response to lithium and other treatment approaches is a rapid cycling course which is characterised by at least four affective episodes per year. Here we present an overview of the currently available alternatives for prophylactic treatment, i.e. anticonvulsants, combination treatment, adjunctive thyroxine, calcium channel blockers, and more experimental approaches for treating refractory bipolar disorder patients. Suggestions for optimizing the prophylactic treatment of bipolar disorder are summarized in an algorithm.

Algorithms↗
PubMed2006

Systematic review of pharmacotherapy of disruptive behavior disorders in children and adolescents.

RATIONALE: Pharmacotherapy is frequently considered in the treatment of disruptive behavior disorders (DBDs) in children and adolescents. There are, however, no systematic reviews of this literature. OBJECTIVES: The aim of this work is to determine whether medication is effective in treating pediatric disruptive behavior disorders and related problems of impulse control, as well as to examine differences in the treatment response and tolerability of different medication classes and agents. MATERIALS AND METHODS: Randomized controlled trials of the pharmacotherapy of DBDs in children and adolescents were reviewed, and a meta-analysis of 14 trials (823 participants) was conducted. RESULTS: There is some evidence of the effectiveness of medication in treating DBDs, with positive outcomes for lithium and risperidone in particular. Pharmacotherapy also demonstrated some efficacy in reducing symptoms of aggression. Medication was relatively well-tolerated, as indicated by equivalent dropout rates in medication and comparison groups. CONCLUSIONS: There are relatively few controlled trials of the pharmacotherapy of disruptive behavior disorders or other impulse control disorders, despite the importance of research in this area. Given the potential adverse effects of agents such as lithium and risperidone, a careful risk-benefit analysis is needed for each patient.

Adolescent↗
PubMed2006

Psychopharmacology of pediatric bipolar disorder: a review.

RATIONALE: Pediatric bipolar disorder (PBD) is a chronic and debilitating psychiatric illness. It is associated with many short-term and long-term complications including poor academic and social performance, legal problems and increased risk of suicide. Moreover, it is often complicated by other serious psychiatric disorders including attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder and substance use disorders. For these reasons, there is a need for effective treatment for PBD. OBJECTIVES: To review available data from published reports of the treatment of PBD, highlighting those treatment practices for which there is scientific evidence. To suggest directions for future research. MATERIALS AND METHODS: A comprehensive Medline search was performed to identify published reports from 1995 to 2006. Reports with the greatest methodological stringency received greater focus. RESULTS: There is limited evidence from double-blind, placebo-controlled trials regarding the treatment of PBD. Available data suggests that lithium, some anticonvulsants and second-generation antipsychotics may be equally beneficial in the acute monotherapy for youth with mixed or manic states. However, because of limited response to acute monotherapy, there is increased justification for combination therapy. There is very limited data on the treatment of the depressed phase of bipolar illness in the youth. Also, very few studies have addressed the treatment of comorbidities and maintenance/relapse prevention in PBD. CONCLUSION: Although significant progress was made in the treatment of youth with bipolar disorder, there is a need for more methodologically stringent research to more precisely define evidence-based treatment strategies for PBD.

Adolescent↗
PubMed2003

The epidemiology of cardiovascular defects, part 2: a study based on data from three large registries of congenital malformations.

There were three objectives of this study: to investigate possible specificity in the association between specific cardiac defects and chromosomal anomalies; to evaluate ways of categorizing cardiac defects into larger groups with epidemiological similarities that could indicate similarities in etiology or pathogenesis; and to analyze the relationship between specific cardiac defects and diabetes. We pooled data on infants (aged 1 year or younger) with congenital cardiovascular defects from three large birth defect registries in California, Sweden, and France. The registries in Sweden and France obtained data through reporting from various sources; in California, medical records were reviewed. For severe congenital heart defects, the percentage of infants with identified chromosomal anomalies varied between 0.9% for d-TGV to 68.4% for ECD. In general, specific cardiac conditions have different risk factors. For example, conotruncal defects have been traditionally grouped, but the data presented in this paper indicates more differences for risk factors for the components of conotruncal defects: tetralogy of Fallot, d-TGV, common truncus, and DORV. In general, we suggest the strategy of "splitting" rather than "lumping" when searching for specific genetic factors and/or teratogens. Adequate analysis thus requires large registries or collaboration among registries. The findings did not support constellations between mothers' diabetes and specific defects.

Abnormalities, Drug-Induced↗
PubMed2001

A transformation system for the biocontrol yeast, Candida oleophila, based on hygromycin B resistance.

Lithium acetate transformation and electroporation were applied to the biocontrol yeast, Candida oleophila. The hygromycin B resistance gene, flanked by the phosphoglycerate kinase promoter and terminator of Candida tropicalis, served as the genetic selection marker. The transformation efficiency of electroporation was almost 400 times more efficient than that of the lithium acetate method. While incorporation of DNA, flanked by a sequence endogenous to C. oleophila, transpired apparently by homologous recombination, the integration of DNA (that did not contain C. oleophila DNA) occurred at random. Whereas transformants were observed with a linear segment of the plasmid, none were detected with the undigested plasmid. This system provides both a tool for the molecular analysis of the biocontrol mechanism of C. oleophila and a means of tagging C. oleophila for field studies.

Anti-Bacterial Agents↗
PubMed2006

Elevated urinary ADAM12 protein levels in lithium-treated bipolar patients.

ADAM (A Disintegrin And Metalloprotease)12 is a member of a family of integral membrane and secreted glycoproteins. ADAM12 has recently been detected in urine. In the present study we measured ADAM12 protein levels in urine from bipolar patients vs. healthy controls. Nineteen bipolar patients and 22 matched-control subjects were studied. Urine samples were concentrated and Western-blot analysis used to determine ADAM12 protein levels. The 92 kDa form of urine ADAM12 protein levels were highly elevated in Li-treated bipolar patients compared with normal controls. The 68 kDa form of urine ADAM12 protein levels did not differ. Future experiments are needed to explore a potential link between ADAM12 protein level elevation and lithium response.

ADAM Proteins↗
PubMed2006

Adjunctive olanzapine treatment in bipolar adolescents responding insufficiently to mood stabilizers. Four case reports.

This report was aimed to evaluate the efficacy of olanzapine treatment as an adjunct therapy to mood stabilizers in the treatment of four adolescents responding insufficiently to mood stabilizers. All patients were diagnosed with bipolar I disorder according to DSM IV criteria. YMRS (Young mania rating scale) and CGI (Clinical global impression, improvement and therapeutic effectiveness scales) were used to evaluate overall response of the episode to the drugs. All patients with no adequate response to mood stabilizers did respond to adjunctive olanzapine treatment (10-30 mg/per day). It has been suggested that antipsychotics may be useful as an adjunct to mood stabilisers in bipolar disorder. However, further research is warranted regarding the use of atypical antipsychotics in children and adolescents.

Adolescent↗
PubMed2005

Ion pair aggregates and reactions; experiment and theory.

Two methods have been developed for determining the aggregation equilibrium constants of lithium enolates based on the change in UV-vis spectrum with concentration and the effect of aggregation on proton-transfer equilibria. Dimers and tetramers are common. Substitution alpha to the carbonyl group generally reduces aggregation. Kinetic studies show that S(N)2 alkylations generally occur with the monomers, even in the presence of large amounts of aggregate. The qualitative chemistry is well modeled by ab initio computations at the HF level with modest basis sets; in these studies solvation is modeled by a combination of coordination of lithium cation with an ether oxygen and the electrostatic interaction of the resulting dipoles and quadrupoles with the solvent dielectric continuum.

Computer Simulation↗
PubMed2004

Influence of thermocycling on the optical properties of laboratory resin composites and an all-ceramic material.

The purposes were to determine the difference of color and translucency of dental laboratory resin composites and an all-ceramic material, and to compare the changes in optical properties after thermocycling. Three shades for enamel appearance of two laboratory resin composites (ART; Artglass, TES; Tescera) and all-ceramic material (EMP; Empress 2) were chosen, and three disk specimens for each shade and thickness (0.8, 1.3 and 1.8 mm) were made. Color and spectral reflectance were measured before and after thermocycling over white and black backgrounds. Contrast ratio (CR) and translucency parameter (TP) were calculated. Before and after thermocycling, CR of 1.8 mm specimens did not differ between the materials. After thermocycling, CR and TP of TES were not changed significantly; however, ART and EMP showed increased CR and decreased TP in some shades (p = 0.05). Color change of three materials after thermocycling was not significant. CR increased in inverse proportion to TP (r = - 0.93, p < 0.01). In TES, change of translucency after thermocycling was lower than those of other materials regardless of the specimen thickness. TES seemed to yield more predictable curing performance.

Cementation↗
PubMed2006

Chronic lithium treatment has antioxidant properties but does not prevent oxidative damage induced by chronic variate stress.

This study evaluated the effects of chronic stress and lithium treatments on oxidative stress parameters in hippocampus, hypothalamus, and frontal cortex. Adult male Wistar rats were divided into two groups: control and submitted to chronic variate stress, and subdivided into treated or not with LiCl. After 40 days, rats were killed, and lipoperoxidation, production free radicals, total antioxidant reactivity (TAR) levels, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were evaluated. The results showed that stress increased lipoperoxidation and that lithium decreased free radicals production in hippocampus; both treatments increased TAR. In hypothalamus, lithium increased TAR and no effect was observed in the frontal cortex. Stress increased SOD activity in hippocampus; while lithium increased GPx in hippocampus and SOD in hypothalamus. We concluded that lithium presented antioxidant properties, but is not able to prevent oxidative damage induced by chronic variate stress.

Animals↗
PubMed2003

Long-term responsiveness to lithium as a pharmacogenetic outcome variable: treatment and etiologic implications.

The importance of genes in the etiology of bipolar disorder has been substantiated through family, twin, and adoption studies. Bipolar disorder is treated at the prophylactic and episodic levels; lithium is one of the most common forms of prophylactic treatment. Recently, pharmacogenetics has come to play an active role in the elucidation of genetic factors that may play a role in modulating lithium response. This strategy has provided hope for advancements in understanding the genetics of lithium-responsive bipolar disorder. This review encompasses studies that have used populations of lithium responders and non-responders to carry out family, linkage, or association studies, as well as some insight into possible mechanisms by which lithium produces its prophylactic effect. Although data examining the pharmacogenetics of bipolar disorder remain scarce, this is a promising avenue of investigation to help genetically define more homogeneous populations or to search for genetic predictors of drug response.

Antimanic Agents↗
PubMed2005

Treatment of mania in children and adolescents.

Bipolar disorder (BPD) is a severe and complex illness that seriously disrupts the lives of those afflicted. Increased rates of suicide attempts and completions, poorer academic performances, disturbed interpersonal relationships, increased rates of substance abuse, legal difficulties, and multiple hospitalizations all have been associated with BPD. At least 1% of children and adolescents have this disorder. This commentary is designed to review and summarize the recent literature on the treatment of manic and/or hypomanic phases of BPD in children and adolescents.

Adolescent↗
PubMed1985

Components of purified sarcolemma from porcine skeletal muscle.

Sarcolemmal membranes were isolated from porcine skeletal muscle by modifications of a LiBr-extraction technique. Latency determinations of acetylcholinesterase, ouabain-sensitive p-nitrophenylphosphatase, [3H]ouabain binding, and (Na+ + K+)-ATPase activities indicated that 65-76% of the membranes were sealed inside-out vesicles. The preparations were enriched in cholesterol and phospholipid, and demonstrated adenylate cyclase activity and both cAMP and cGMP phosphodiesterase activities. An indication of the purity of this fraction was that the Ca2+-ATPase activity (0.13 mumol Pi mg-1 min-1 at 37 degrees C) was 3.8% of that of porcine skeletal muscle sarcoplasmic reticulum preparations. Pertussis toxin specifically catalyzed the ADP-ribosylation of a Mr 41,000 sarcolemmal protein, indicating the presence of the inhibitory guanine nucleotide regulatory protein of adenylate cyclase, Ni. An endogenous ADP-ribosyltransferase activity, with several membrane protein substrates, was also demonstrated. The addition of exogenous cAMP-dependent protein kinase or calmodulin promoted the phosphorylation of a number of sarcolemmal proteins. The calmodulin-dependent phosphorylation exhibited an approximate K 1/2 for Ca2+ of 0.5 microM, and an approximate K 1/2 for calmodulin of 0.1 microM. 125I-Calmodulin affinity labeling of the sarcolemma, using dithiobis(succinimidyl propionate), demonstrated the presence of Mr 160,000 and 280,000 calmodulin-binding components in these membranes. These results demonstrate that this porcine preparation will be valuable in the study of skeletal muscle sarcolemmal ion transport, protein and hormonal receptors, and protein kinase-catalyzed phosphorylation.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Chemical modification of rabbit skeletal muscle phosphorylase kinase with phenylglyoxal.

Nonactivated phosphorylase kinase from rabbit skeletal muscle is inactivated by treatment with phenylglyoxal. Under mild reaction conditions, a derivative that retains 10-15% of the pH 8.2 catalytic activity is obtained. The kinetics of inactivation profile, differential effects of modification on pH 6.8 and 8.2 catalytic activities, and the insensitiveness of the modified enzyme to activation by ADP reveal that the 10-15% of catalytic activity remaining is very likely due to intrinsic catalytic activity of the derivative rather than to the presence of unmodified enzyme molecules. The kinetic results also suggest that the inactivation is correlatable with the reaction of one molecule of the reagent with the enzyme without any prior binding of phenylglyoxal. The phenylglyoxal modification reduces the autophosphorylation rate of the kinase. Autophosphorylated phosphorylase kinase is inactivated by phenylglyoxal at a much slower rate than the inactivation of nonactivated kinase. Thus, phenylglyoxal modification influences the phosphorylation and vice versa. The modified enzyme can be reactivated by treatment with trypsin or by dissociation using chatropic salts. The activity of the phenylglyoxal-modified enzyme after trypsin digestion or dissociation with LiBr reaches the same level as that of the native enzyme digested with trypsin or treated with LiBr under identical conditions. The results suggest that the effect of modification is overcome by dissociation of the subunits of phosphorylase kinase and that the catalytic site is not modified under conditions when 85% of the pH 8.2 catalytic activity is lost. Among various nucleotides and metal ions tested, only ADP, with or without Mg2+, afforded effective protection against inactivation with phenylglyoxal. At pH 6.8, 1 mM ADP afforded complete protection against inactivation. Experiments with 14C-labeled phenylglyoxal revealed that ADP seemingly protects one residue from modification. This result is in agreement with the kinetic result that the inactivation seemingly is due to reaction of one molecule of the reagent with the enzyme. The results confirm the existence of a high-affinity ADP binding site on nonactivated phosphorylase kinase and suggest the involvement of a functional arginyl residue at or near the ADP binding site in the regulation of of pH 8.2 catalytic activity of the enzyme.

Adenosine Diphosphate↗
PubMed1989

Opioid receptors in rat cardiac sarcolemma: effect of phenylephrine and isoproterenol.

The present study demonstrates the presence of opioid receptors in the rat cardiac sarcolemma isolated by the hypotonic LiBr-shock procedure. Opioid binding was measured by using [3H]U69 593, [3H](2-D-penicillamine,5-D-penicillamine)enkephalin ([3H]DPDPE) or [3H][D-Ala2,MePhe4,Gly-(ol)5]enkephalin ([3H]DAGO) as selective radioligands for K, delta and mu opioid receptors, respectively. Both the K- and delta-selective ligands exhibited highly specific (75-86%) binding, saturable at a concentration of about 20 nM. No specific binding for the selective agonist DAGO was observed. A marked increase in both [3H]U69 593 and [3H]DPDPE binding was observed after incubation of the sarcolemma with the alpha-adrenoceptor agonist phenylephrine or with the beta-adrenoceptor agonist isoproterenol. These stimulatory effects were associated with an increase in the Bmax values, a decrease in the Kd values, and were completely antagonized by the respective antagonists phentolamine and propranolol.

Analgesics↗