Psychiatry-epitomes of progress: stimulants and hyperkinesis

Although used around the world since 1949, lithium has come into extensive use in psychiatry in the United States only within the past decade. Before initiating treatment with this drug, physicians must be familiar with the diagnostic scheme of the major affective disorders, the indications and contraindications to lithium''s use, and its principles of treatment, including evaluation before lithium therapy, criteria for monitoring blood levels and signs of impending toxicity.Despite earlier reports about the toxicity of lithium when it was promoted as a salt substitute, lithium is a safe drug. Its use not only has revolutionized the treatment of the major affective disorders, but has opened up new and broad avenues of research into the regulation of man''s emotions.     

锂盐的作用机制及临床应用研究进展

锂是人体内的一种微量元素且以化合物的形式广泛存在于自然界。作为一种古老的治疗精神疾病方面的药物,锂盐被用来治疗双相情感障碍已超过60年,而现在锂盐在临床上表现出来的新应用已经越来越引起医学界的广泛重视。现代研究表明,锂盐是一种强大的糖原合成酶激酶-3(GSK-3β)抑制剂,锂盐除对脑细胞过度活动起抑制作用外,还具有营养神经和保护神经、抗炎、抗氧化、抗癌、免疫调节以及对甲状腺功能亢进的治疗作用。锂盐化学结构相对简单,而且目前人们对锂盐的使用经验及对锂离子的血药浓度监测手段已日趋成熟,所以锂盐具有相当好的临床应用前景,未来更进一步加大对锂盐的临床应用及作用机制的研究力度。现就锂盐新发现的作用机制及临床应用作一综述。     

Lithium induces clearance of protease resistant prion protein in prion-infected cells by induction of autophagy

Lithium is used for several decades to treat manic-depressive illness (bipolar affective disorder). Recently, it was found that lithium induces autophagy, thereby promoting the clearance of mutant huntingtin and α-synucleins in experimental systems. We show here for the first time that lithium significantly reduces the amount of pathological prion protein (PrP^Sc) in prion-infected neuronal and non-neuronal cultured cells by inducing autophagy. Treatment of prion-infected cells with 3-methyladenine, a potent inhibitor of autophagy, counteracted the anti-prion effect of lithium, demonstrating that induction of autophagy mediates degradation of PrP^Sc. Co-treatment with lithium and rapamycin, a drug widely used to induce autophagy, had an additive effect on PrP^Sc clearance compared to treatment with either drug alone. In addition, we provide evidence that the ability to reduce PrP^Sc and to induce autophagy is common for diverse lithium compounds, not only for the drug lithium chloride, usually administered in clinical therapy. Furthermore, we show here that besides reduction of PrP^Sc-aggregates, lithium-induced autophagy also slightly reduces the levels of cellular prion protein. Limiting the substrate available for conversion of cellular prion protein into PrP^Sc may provide an additional mechanism for reduction of PrP^Sc by lithium-induced autophagy.     

Promise and Deceit: Pharmakos,Drug Replacement Therapy,and the Perils of Experience

The problem of lying as a feature of medication compliance has been well documented in anthropological and clinical literatures. Yet the role of the lie—its destabilizing effects on the continuity of drug treatment and therapy, as a technology of drug misuse, or as a way to understand the neuro-chemical processes of treatment (pharmacotherapy “tricking” or lying to the brain)—has been less considered, particularly in the context of opioid replacement therapy. The following paper is set against the backdrop of a three-year study of adolescents receiving a relatively new drug (buprenorphine) for the treatment of opiate dependency inside and outside of highly monitored treatment environments in the United States. Lies give order not only to the experience of addiction but also to the experience of therapy as well. In order to better understand this ordering of experience, the paper puts the widely discussed conceptual duality of the pharmakon (healing and poison) in conversation with a perilously overlooked subject in the critical study of pharmacotherapy, namely the pharmakos or the personification of sacrifice. The paper demonstrates how the patient-subject comes to represent therapeutic promise by allowing for the possibility of (and often performing) deceit.     

Using adaptive model predictive control to customize maintenance therapy chemotherapeutic dosing for childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a common childhood cancer in which nearly one-quarter of patients experience a disease relapse. However, it has been shown that individualizing therapy for childhood ALL patients by adjusting doses based on the blood concentration of active drug metabolite could significantly improve treatment outcome. An adaptive model predictive control (MPC) strategy is presented in which maintenance therapy for childhood ALL is personalized using routine patient measurements of red blood cell mean corpuscular volume as a surrogate for the active drug metabolite concentration. A clinically relevant mathematical model is developed and used to describe the patient response to the chemotherapeutic drug 6-mercaptopurine, with some model parameters being patient-specific. During the course of treatment, the patient-specific parameters are adaptively identified using recurrent complete blood count measurements, which sufficiently constrain the patient parameter uncertainty to support customized adjustments of the drug dose. While this work represents only a first step toward a quantitative tool for clinical use, the simulated treatment results indicate that the proposed mathematical model and adaptive MPC approach could serve as valuable resources to the oncologist toward creating a personalized treatment strategy that is both safe and effective.     

Mood stabilizing drug lithium increases expression of endoplasmic reticulum stress proteins in primary cultured rat cerebral cortical cells

The mood stabilizing drug lithium is a highly effective treatment for bipolar disorder. Previous studies in our laboratory found that chronic treatment with the mood stabilizing drug valproate in rat brain increased the expression of endoplasmic reticulum (ER) stress proteins GRP78, GRP94 and calreticulin. We report here that in primary cultured rat cerebral cortical cells, expression of GRP78, GRP94 and calreticulin are increased not only by valproate, but also by lithium after chronic treatment for 1 week at therapeutically relevant concentrations. However, two other mood stabilizing drugs carbamazepine and lamotrigine had no effect on expression of GRP78, GRP94 or calreticulin. Chronic treatment with lithium for 1 week increased both mRNA and protein levels of ER stress proteins. In contrast to a classic GRP78 inducer thapsigargin, an inhibitor of the ER Ca2+ -ATPase, chronic treatment with lithium or valproate for 1 week modestly increased GRP78 expression in neuronal cells, had no effect on basal intracellular free Ca2+ concentration and does not induce cell death. These results indicate that lithium and valproate may increase expression of GRP78, GRP94 and calreticulin in primary cultured rat cerebral cortical cells without causing cell damage. These results also suggest that the mechanism of GRP78 increase induced by lithium and valproate may be different from that of thapsigargin.     

Recent advances in drug therapy for epilepsy.

Recent advances in drug therapy for epilepsy have contributed to the reduction in the proportion of persons whose epilepsy is uncontrolled. New knowledge of the pharmacokinetics of phenytoin has led to a better understanding of the drug''s bioavailability and uses. Carbamazepine has recently been introduced for the treatment of generalized tonic-clonic and partial seizures. Clonazepam has been found of particular benefit in the treatment of absence and myoclonic seizures. Valproic acid is a promising antiepileptic drug with broad-spectrum activity, and is particularly useful in the treatment of absence and myoclonic seizures, although further clinical experience is required before it can supplant ethosuximide as the preferred drug for the treatment of absence seizures. Monitoring of the plasma concentration of antiepileptic drugs has added greatly to the achievement of optimal drug therapy and the prevention of toxic effects.     

The future of bladder control-intravesical drug delivery, a pinch of pepper, and gene therapy

The incidence of urinary incontinence and overactive bladder problems will continue to grow as the population ages. Future treatments are likely to include an implantable drug delivery system, gene therapy, and the intravesical use of the vallinoids capsaicin and resiniferatoxin (RTX). An understanding of the urothelium is essential for effective design of these therapies. Intravesical anticholinergic drug treatment is currently not widely used, but intravesical pumps are under development to provide less cumbersome treatment methods and will provide nonsurgical options for patients who cannot tolerate oral anticholinergic agents. Research on the use of capsaicin as an intravesicular drug has had limited success, but trials have confirmed the efficacy of intravesical capsaicin for detrusor hyperreflexia. RTX is as effective as capsaicin but without side effects, such as pain and inflammatory neuropeptide release. RTX treatment may eliminate the need for surgical and other drug treatments of lower urinary tract dysfunction in patients with spinal cord injuries. Gene therapy will change the practice of urology by addressing the deficiencies that cause symptoms rather than attacking the symptoms themselves.     

Importance of Ribosomal Frameshifting for Human Immunodeficiency Virus Type 1 Particle Assembly and Replication

The recent development and use of protease inhibitors have demonstrated the essential role that combination therapy will play in the treatment of individuals infected with the human immunodeficiency virus type 1 (HIV-1). Past clinical experience suggests that due to the appearance of resistant HIV-1 variants, additional therapeutics will be required in the future. To identify new options for combination therapy, it is of paramount importance to pursue novel targets for drug development. Ribosomal frameshifting is one potential target that has not been fully explored. Data presented here demonstrate that small molecules can stimulate frameshifting, leading to an imbalance in the ratio of Gag to Gag-Pol and inhibiting HIV-1 replication at what appears to be the point of viral particle assembly. Thus, we propose that frameshifting represents a new target for the identification of novel anti-HIV-1 therapeutics.     

Clinical experience of targeted therapy

Drug targeting (i.e. administration of a drug-carrier conjugate which delivers active drug selectively to a particular tissue) has recently evolved into a new subdiscipline of experimental pharmacy/pharmacology. However, clinical experience with targeted therapy is very limited to date. This review summarizes human studies of targeted therapy. Indications for which drug targeting has been attempted include neoplastic disorders, fungal infections, enzyme replacement, hematologic and immune disorders, and iron storage disease. To date, no single drug targeting system is recommendable for routine clinical use, but present results justify further clinical evaluation in a number of situations.     

Apoptosis and autophagy in hepatocarcinoma cells induced by different forms of lithium salts

Hepatocellular carcinoma (HCC) is an aggressive cancer that is resistant to drug therapy. It is believed that the development of HCC is correlated with misregulation of programmed cell death. Discovery of effective inducers of HCC cell death is very important for HCC therapy. The aim of this work was to identify structural changes leading to the death of HCC cells exposed to nanosized and original forms of lithium salts. Structural features of autophagy and apoptosis were revealed in HCC cells after their incubation with various forms of lithium salts by light, electron microscopy, and flow cytometry. It was shown that nanosized forms of lithium carbonate and lithium citrate had a pronounced effect on HCC-29 cells. Of these forms, the nanosized lithium citrate induced mainly apoptosis, while the nanosized form of lithium carbonate, along with apoptosis, induced autophagic death of HCC cells.     

Inhibition of heart formation by lithium is an indirect result of the disruption of tissue organization within the embryo

Lithium is a commonly used drug for the treatment of bipolar disorder. At high doses, lithium becomes teratogenic, which is a property that has allowed this agent to serve as a useful tool for dissecting molecular pathways that regulate embryogenesis. This study was designed to examine the impact of lithium on heart formation in the developing frog for insights into the molecular regulation of cardiac specification. Embryos were exposed to lithium at the beginning of gastrulation, which produced severe malformations of the anterior end of the embryo. Although previous reports characterized this deformity as a posteriorized phenotype, histological analysis revealed that the defects were more comprehensive, with disfigurement and disorganization of all interior tissues along the anterior-posterior axis. Emerging tissues were poorly segregated and cavity formation was decreased within the embryo. Lithium exposure also completely ablated formation of the heart and prevented myocardial cell differentiation. Despite the complete absence of cardiac tissue in lithium treated embryos, exposure to lithium did not prevent myocardial differentiation of precardiac dorsal marginal zone explants. Moreover, precardiac tissue freed from the embryo subsequent to lithium treatment at gastrulation gave rise to cardiac tissue, as demonstrated by upregulation of cardiac gene expression, display of sarcomeric proteins, and formation of a contractile phenotype. Together these data indicate that lithium's effect on the developing heart was not due to direct regulation of cardiac differentiation, but an indirect consequence of disrupted tissue organization within the embryo.     

Guidelines for treating epilepsy in the age of felbamate,vigabatrin, lamotrigine,and gabapentin.

For the first time in 15 years, new antiepileptic medications are available for the treatment of patients with seizure disorders. These drugs have demonstrated efficacy in animal models of epilepsy and in controlled clinical trials. Felbamate was licensed in 1993 for use as adjunctive therapy or monotherapy in adults with partial or tonic-clonic seizures and as adjunctive therapy for children with the Lennox-Gastaut syndrome. Gabapentin was approved January 1994 as adjunctive therapy in patients 12 years or older with partial seizures, with or without secondary generalization. Lamotrigine is expected to be approved this year for the treatment of partial and tonic-clonic seizures in adults. Last, a new drug application has been filed for vigabatrin this year, with possible licensing next year. These four anticonvulsants present new options in the treatment of patients with refractory epilepsy and are not merely congeners of previously available treatments. They have unique clinical spectrums and are reported to be safer and better tolerated than conventional therapy. Trials to compare their use with that of conventional therapy have not been done, and their use in the initial treatment of patients with epilepsy is not completely clear.     

Lithium increases expression of p21WAF/Cip1 and survivin in human glioblastoma cells

Lithium is the most widely prescribed mood stabilizer, but the precise molecular mechanisms underlying its therapeutic function are not yet fully elucidated. Recent preclinical and clinical evidence indicates its neuroprotective and neurotrophic effects. As a tight coupling of function and metabolism in the central nervous system between glial cells and neurons has recently been detected, lithium's effect on glial cells may participate also in the total beneficial effects of this drug. The aim of the present study was to analyze molecular mechanisms induced in human glioblastoma A1235 cells by the treatment with lithium, especially its influence on the expression of apoptosis-related genes. Lower levels of lithium (0.5 mmol/L and 2 mmol/L) did not cause any cytotoxicity or changes in the cell cycle phase distribution following 72 h incubation. However, a higher dose (20 mmol/L) was cytostatic for glioblastoma cells, and caused accumulation of cells in G₂/M phase of the cell cycle. The treatment with lithium did not alter the levels of Bcl-2 or procaspase-3 and did not cleave PARP, but increased the levels of p21^WAF/Cip1 and survivin. Thus, increased expression of p21^WAF/Cip1 (a protein with antiapoptotic function), and survivin (a protein that supports the growth of cells by suppression of apoptosis and promotion of cell proliferation) may be the early events in the long-term cell response to lithium that are involved in the beneficial effects of this drug.     

The interaction between dopamine D2-like and beta-adrenergic receptors in the prefrontal cortex is altered by mood-stabilizing agents

Several studies have suggested the involvement of biogenic monoaminergic neurotransmission in bipolar disorder and in the therapy for this disease. In this study, the effects of the mood-stabilizing drugs lithium, carbamazepine or valproate on the dopaminergic and adrenergic systems, particularly on D2-like and beta-adrenergic receptors, were studied both in cultured rat cortical neurones and in rat prefrontal cortex. In vitro and in vivo data showed that stimulation of beta-adrenergic receptors with isoproterenol increased cyclic adenosine monophosphate (cAMP) levels and this effect was significantly inhibited by lithium, carbamazepine or valproate. The activation of dopamine D2-like receptors with quinpirole decreased the isoproterenol-induced rise in cAMP in control conditions. This inhibition was observed in vivo after chronic treatment of the rats with carbamazepine or valproate, but not after treatment with lithium or in cultured rat cortical neurones after 48 h exposure to the three mood stabilizers. Dopamine D2 and beta1-adrenergic receptors were found to be co-localized in prefrontal cortical cells, as determined by immunohistochemistry, but western blot experiments revealed that receptor levels were differentially affected by treatment with the three mood stabilizers. These data show that mood stabilizers affect D2 receptor-mediated regulation of beta-adrenergic signalling and that each drug acts by a unique mechanism.     

How does the mood stabilizer lithium bind ATP,the energy currency of the cell: Insights from solid-state NMR

BackgroundLithium, in the form of a salt, is a mood stabilizer and a leading drug for the treatment of bipolar disorder. It has a very narrow therapeutic range and a variety of side effects. Lithium can replace magnesium and other cations in enzymes and small molecules, among them ATP, thereby affecting and inhibiting many biochemical pathways. The form of binding of lithium ions to ATP is not known.MethodsHere we extract the binding environment of lithium in solid ATP using a multi-nuclear multi-dimensional solid-state NMR approach.ResultsWe determine that the coordination sphere of lithium includes, at a distance of 3.0(±0.4) Å, three phosphates; the two phosphates closest to the ribose ring from one ATP molecule, and the middle phosphate from another ATP molecule. A water molecule most probably completes the fourth coordination. Despite the use of excess lithium in the preparations, sodium ions still remain bound to the sample, at distances of 4.3–5.5 Å from Li, and coordinate the first phosphate and two terminal phosphates.ConclusionsSolid-state NMR enables to unravel the exact coordination of lithium in ATP showing binding to three phosphates from two molecules, none of which are the terminal gamma phosphate.General significanceThe methods we use are applicable to study lithium bound to a variety of ATP-bound enzymes, or to other cellular targets of lithium, consequently suggesting a molecular basis for its mode of action.     

The effect of leucovorin on the therapeutic index of fluorouracil in cancer patients

Fluorouracil has been in clinical use as an anticancer drug for 30 years. Although this drug has a broad spectrum of anticancer activity, including significant activity against the common solid tumors of the gastrointestinal system, only a minority of patients treated with fluorouracil experience an objective response to therapy. Furthermore, in randomized clinical trials completed to date, it has not been possible to demonstrate that fluorouracil therapy significantly prolongs the life span of patients with advanced cancer. Recent laboratory studies have indicated that leucovorin can enhance the cytotoxicity of fluorouracil in vitro, evidently by enhancing inhibition of the key enzyme, thymidylate synthetase, by the fluorouracil metabolite, FdUMP (fluorodeoxyuridine monophosphate; a stable inactive FdUMP-reduced folate-thymidylate synthetase complex is formed). Pilot, uncontrolled studies of leucovorin-fluorouracil combinations have suggested that leucovorin may significantly increase both the clinical efficacy and the clinical toxicity of fluorouracil in cancer patients. These findings have led to the initiation of several randomized, controlled studies of leucovorin plus fluorouracil versus fluorouracil alone in the treatment of patients with advanced colorectal cancer. Three of these studies have recently completed patient accrual, and the preliminary results of each of the three studies indicate that leucovorin-fluorouracil combinations will have a better therapeutic index than fluorouracil used alone in this disease. Further follow-up of these studies will be needed to determine whether leucovorin-fluorouracil combination therapy will prolong the life span of patients with colorectal cancer.     

Effects of lithium carbonate on hematopoietic cells in patients with persistent neutropenia following chemotherapy or radiotherapy.

Neoplasm therapy is restricted by the haematological side effects of tumour-destructive therapy, requiring expensive supportive care to some extent to overcome and treat leucopenia and its consequences. An effective and very cost-effective alternative for treating neutropenia is to administer lithium carbonate. Lithium leads to a release of hematopoietic growth factors (CSF) and therefore to proliferation of neutrophil granulocytes. Normally, recombinant CSF is only administered when there are indications of severe neutropenia because of the high costs involved, all the more evident in the long-term treatment of persistent leucocytopenia. On the other hand, CSF and leucocytes play an essential role in tumour immunology and with regard to response rates to cytostatic drugs. Lithium salts have shown that they can increase the number of neutrophil granulocytes quite significantly and, to a lesser extent, the number of eosinophil granulocytes and lymphocytes as well. The average number of erythrocytes does not change significantly. Patient tolerability to lithium carbonate therapy is very good. It can be used to treat patients with chronic leucopenia following chemotherapy or radiotherapy extremely cost-effectively. Unfortunately this treatment has not won acceptance in clinical oncology in the face of highly cost-intensive treatment with recombinant CSF.     

The role of oral acyclovir in the management of genital herpes simplex.

Oral acyclovir is an antiviral nucleoside analogue that has recently been released in Canada for use in selected patients with genital infections by the herpes simplex virus. First episodes of genital herpes should be treated with oral acyclovir as soon as the diagnosis is considered. Most people with recurrent genital herpes do not require systemic drug therapy. Selected patients with severe or long-lasting recurrences, recurrences associated with long prodromal periods (greater than 12 to 24 hours) or systemic complications such as erythema multiforme and eczema herpeticum may receive measurable benefit from treatment at the onset of symptoms. In most patients frequently recurrent disease can be suppressed with long-term therapy. Since long-term safety beyond 1 year has not been established, suppressive therapy should be stopped at least once per year to reassess the recurrence pattern. Acyclovir has not been adequately tested for safety in pregnancy and should not be prescribed for pregnant women unless the potential benefits outweigh the risks. Careful attention to disease severity, accurate diagnosis and exclusion of other causes of genital lesions will ensure that the drug is used only when beneficial.     

Accelerated clinical discovery using self-reported patient data collected online and a patient-matching algorithm

Patients with serious diseases may experiment with drugs that have not received regulatory approval. Online patient communities structured around quantitative outcome data have the potential to provide an observational environment to monitor such drug usage and its consequences. Here we describe an analysis of data reported on the website PatientsLikeMe by patients with amyotrophic lateral sclerosis (ALS) who experimented with lithium carbonate treatment. To reduce potential bias owing to lack of randomization, we developed an algorithm to match 149 treated patients to multiple controls (447 total) based on the progression of their disease course. At 12 months after treatment, we found no effect of lithium on disease progression. Although observational studies using unblinded data are not a substitute for double-blind randomized control trials, this study reached the same conclusion as subsequent randomized trials, suggesting that data reported by patients over the internet may be useful for accelerating clinical discovery and evaluating the effectiveness of drugs already in use.