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。     

Premenstrual mood changes in affective disorders.

Mood changes during the premenstrual phase have been the focus of considerable research in recent years. Although there has been significant progress in the diagnosis and etiology of major affective disorders, the relation between these disorders and menstrual changes remains controversial. There have been contradictory reports and speculations on women''s susceptibility to psychiatric disorders during the premenstrual phase. We describe three patients with a history of mood swings associated with menstruation in whom major affective disorders developed, necessitating intensive psychiatric treatment or admission to hospital. Among women who manifest menstrual mood changes, manic-depressive illness may develop only in a subgroup with genetic predisposition. In such cases the possibility of postpartum mania or depression should be kept in mind in follow-up.     

The use of lithium carbonate in the treatment of mood disorders

The use of lithium ions in the treatment of manic states is discussed. Lithium is possibly the only specific drug treatment presently available for the major psychoses and has met with enthusiasm in England, Scandinavia, Australia and, more recently, in Canada and the United States.A number of the published papers on the subject are not sufficiently comprehensive to provide guidance for even its empiric use; some lack the necessary controls and design to permit comparisons with other studies.Some clinicians with wide experience of lithium therapy do not maintain laboratory control of patients by ordering serum lithium determinations but rely entirely on clinical judgement in establishing drug schedules. This is not advised if one has little experience with lithium therapy because of the possible side effects and toxicity.     

Diffuse alveolar damage syndrome associated with amiodarone therapy.

Amiodarone is an effective antiarrhythmic that has been used in Europe for over a decade and has been available for investigational use in North America for a shorter time. It has several well recognized side effects. Recent reports have related pulmonary disorders to the use of this drug; fibrosing alveolitis has been found by lung biopsy. Amiodarone''s toxicity to the lung does not appear to be dose-related. Besides cessation of amiodarone administration, management of this complication includes steroid therapy. A case is described of nonspecific diffuse alveolar damage syndrome in a patient who had received amiodarone.     

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.     

Effect of Lithium on Rearing Activity in Rats

EVEN though the use of lithium salts is well established in the clinical treatment of manic states¹ and to a lesser extent in the prophylactic treatment of recurrent depression², there have been few reports of their effects on animal behaviour in laboratory conditions. One reason may lie in Schou's doubts³ as to whether lithium salts have any effects on behaviour outside the clinical context. This view was based on unpublished findings of I. M. Nielson, A. Amdisen, D. R. Maxwell and Schou himself and on the hypothesis that lithium serves to correct a specific biochemical or physiological imbalance characteristic of recurrent affective disorders⁴.     

纳米紫杉类药物在乳腺癌治疗中的研究现状

紫杉醇虽被证明在多种肿瘤治疗中均具有良好的效果,但其有一个严重的缺陷:水溶性低。临床使用中需使用聚氧乙烯蓖麻油(CremphorEL)或无水乙醇作为溶剂,但其在体内降解时能释放组胺,导致严重的过敏反应以及肾毒性和神经毒性等不良反应,此外还存在患者耐受性差、血药浓度低、靶向性差等不足。在乳腺癌的诊断和治疗中,纳米技术改变了紫杉醇制剂的特征参数而使药物表现出缓释、控释性及靶向性等优势,解决了传统紫杉醇制剂水溶性差的缺点,提高了药物的生物利用度,并明显降低了紫杉醇的毒性和副作用,给紫杉醇药物在体内运输提供了新途径。     

Estimating treatment coverage for people with substance use disorders: an analysis of data from the World Mental Health Surveys

Substance use is a major cause of disability globally. This has been recognized in the recent United Nations Sustainable Development Goals (SDGs), in which treatment coverage for substance use disorders is identified as one of the indicators. There have been no estimates of this treatment coverage cross‐nationally, making it difficult to know what is the baseline for that SDG target. Here we report data from the World Health Organization (WHO)'s World Mental Health Surveys (WMHS), based on representative community household surveys in 26 countries. We assessed the 12‐month prevalence of substance use disorders (alcohol or drug abuse/dependence); the proportion of people with these disorders who were aware that they needed treatment and who wished to receive care; the proportion of those seeking care who received it; and the proportion of such treatment that met minimal standards for treatment quality (“minimally adequate treatment”). Among the 70,880 participants, 2.6% met 12‐month criteria for substance use disorders; the prevalence was higher in upper‐middle income (3.3%) than in high‐income (2.6%) and low/lower‐middle income (2.0%) countries. Overall, 39.1% of those with 12‐month substance use disorders recognized a treatment need; this recognition was more common in high‐income (43.1%) than in upper‐middle (35.6%) and low/lower‐middle income (31.5%) countries. Among those who recognized treatment need, 61.3% made at least one visit to a service provider, and 29.5% of the latter received minimally adequate treatment exposure (35.3% in high, 20.3% in upper‐middle, and 8.6% in low/lower‐middle income countries). Overall, only 7.1% of those with past‐year substance use disorders received minimally adequate treatment: 10.3% in high income, 4.3% in upper‐middle income and 1.0% in low/lower‐middle income countries. These data suggest that only a small minority of people with substance use disorders receive even minimally adequate treatment. At least three barriers are involved: awareness/perceived treatment need, accessing treatment once a need is recognized, and compliance (on the part of both provider and client) to obtain adequate treatment. Various factors are likely to be involved in each of these three barriers, all of which need to be addressed to improve treatment coverage of substance use disorders. These data provide a baseline for the global monitoring of progress of treatment coverage for these disorders as an indicator within the SDGs.     

Lithium and Pregnancy—III,Lithium Ingestion by Children Breast-Fed by Women on Lithium Treatment

Children breast-fed by women on lithium treatment ingested lithium with the milk. Their serum lithium concentration was one-third to one-half the concentration in the nursing women''s serum. Bottle-feeding should be considered for children of women on lithium treatment.     

Failure of acetylmethadol in treatment of narcotic addicts due to nonpharmacologic factors.

Acetylmethadol, a new narcotic substitute, has a longer duration of action than methadone. Seventeen subjects, former heroin users currently under methadone treatment, entered a study of the toxicity and efficacy of this drug. Only nine subjects completed the assessment phase of the study and began the acetylmethadol phase, and only one completed the 8-week study phase. Hence, no conclusions can be drawn about acetylmethadol''s efficacy. The high attrition rate was unrelated to pharmacologic factors; the subjects were concerned that if this drug was effective there would be no methadone to take home and hence no opportunity to trade, sell or "play with" (that is, combine with other drugs) the latter. This study emphasizes the difficulty in determining the efficacy of specific drug treatments for opiate-dependent patients.     

The Effects of Lithium on a Neuronal in Vitro Orcadian Pacemaker

Previous studies have suggested a causal connection between abnormalities of the circadian system and affective disorders. The effectiveness of lithium or rubidium as a treatment for affective disorders and the ability of lithium or rubidium to influence circadian pacemakers has stimulated research into the mechanism of lithium's action on circadian systems. In this study we used a neuronal in vitro circadian pacemaker preparation, the eye of the mollusc Bulla, to examine the cellular effects of lithium and rubidium. Continuous extracellular LiCl application lengthens the period of the circadian rhythm of the Bulla pacemaker in a concentration-dependent manner. Rubidium was found to be more effective than lithium in period lengthening. Stable phase delays were generated by 2-h pulses of 395 mM LiCl applied extracellularly from zeitgeber time (ZT) 5-7 (mid subjective day). Concomitant continuous application of 16 mM LiCl and light (a depolarizing agent) generated period lengthening substantially greater than the arithmetic sum of the modest period lengthening of each treatment alone. Furthermore, LiCl pulses, applied together with depolarizing extracellular KC1 concentrations, yielded an increasing magnitude of phase delays with increasing KC1 concentration. These data suggest that LiCl acts intracellularly on the circadian pacemaker cells by entering through a voltage-dependent channel, most likely a sodium channel.     

Epipodophyllotoxin VP 16213 in Treatment of Acute Leukaemia—Haematosarcoma and Solid Tumours

Epipodophyllotoxin VP 16213 (4-demethyl-epipodophyllotoxin-β-D-ethylidene glucoside), given to 250 patients with various types of malignant disease, induced apparently complete remissions in four out of eight cases of acute monocytoid and acute myelomonocytoid leukaemia but only one complete regression and six incomplete remissions in 21 cases of reticulosarcoma. Incomplete regressions occurred in patients with Hodgkin''s disease, lymphosarcoma, melanoma, and carcinoma of the breast, ovary, testis, bladder, kidney, and thyroid. Seemingly complete regressions of malignant pleural effusion occurred when the drug was given systemically. Toxic side effects interfered with treatment in 40 patients but stopped it in only nine. No signs of toxicity were seen in 114 patients and in 85 the side effects were negligible. VP 16213 represents an advance in the treatment of acute monocytoid leukaemia, which has been up till now insensitive to any drug.     

Lithium and hematopoiesis.

Some of lithium''s effects on blood cell formation suggest that the element may be of value in treating hematologic disorders. Lithium enhances granulopoiesis and thereby induces neutrophilia. Two possible mechanisms of action are suggested: a direct action on the pluripotent stem cells, or an inhibition of the suppressor cells (thymus-dependent lymphocytes) that limit hematopoiesis. Lithium also inhibits erythropoiesis. Although most studies use concentrations at or above pharmacologic levels there is evidence that lithium plays a role in normal cell metabolism.     

Substrate Competitive GSK-3 Inhibitors strategy and Implications

Glycogen synthase kinase-3 (GSK-3) is a highly conserved protein serine/threonine kinase ubiquitously distributed in eukaryotes as a constitutively active enzyme. Abnormally high GSK-3 activity has been implicated in several pathological disorders, including diabetes and neuron degenerative and affective disorders. This led to the hypothesis that inhibition of GSK-3 may have therapeutic benefit. Most GSK-3 inhibitors developed so far compete with ATP and often show limited specificity. Our goal is to develop inhibitors that compete with GSK-3 substrates, as this type of inhibitor is more specific and may be useful for clinical applications. We have employed computational, biochemical, and molecular analyses to gain in-depth understanding of GSK-3's substrate recognition. Here we argue that GSK-3 is a promising drug discovery target and describe the strategy and practice for developing specific substrate-competitive inhibitors of GSK-3.     

Lithium suppresses signaling and induces rapid sequestration of beta2-adrenergic receptors

Lithium is a monovalent cation used therapeutically to treat a range of affective disorders (1), although the cellular mechanisms of lithium regulation that might contribute to its therapeutic effects at the level of neurotransmitter receptors are not known. Herein we report the ability of lithium to stimulate the internalization of beta2-adrenergic receptors. Lithium treatment of A431 human epidermoid carcinoma cells resulted in a rapid, prominent desensitization and internalization of beta2-adrenergic receptors. The ability of these receptors to generate a cyclic AMP response was strongly inhibited by lithium, at concentrations therapeutic in humans. Receptors for the serotonin (5HT1c) and for opiates (mu-opioid), in sharp contrast, resisted the effects of lithium on internalization. These data provide the first receptor-based mechanism to be described for lithium that could explain, in part, the therapeutic effects of lithium on affective disorders.     

Antihypertensive Pharmacology

Although drug treatment of hypertension is associated with improved survival and decreased vascular complications, drug compliance is a major problem in the control of hypertension. All antihypertensive medications are associated with side effects; thus, it is a physician''s responsibility to explain to each patient the side effects of the drugs he prescribes to treat hypertension, and to instill in the patient a sense of necessity for the treatment of hypertension. The choice of antihypertensive drug should be made based on each patient''s lifestyle, overall health and ability to tolerate the drug. Ideally, the antihypertensive regimen should be simple, effective, convenient to take and have very few side effects.     

Toward a global view of alcohol, tobacco, cannabis, and cocaine use: findings from the WHO World Mental Health Surveys

Background

Alcohol, tobacco, and illegal drug use cause considerable morbidity and mortality, but good cross-national epidemiological data are limited. This paper describes such data from the first 17 countries participating in the World Health Organization''s (WHO''s) World Mental Health (WMH) Survey Initiative.

Methods and Findings

Household surveys with a combined sample size of 85,052 were carried out in the Americas (Colombia, Mexico, United States), Europe (Belgium, France, Germany, Italy, Netherlands, Spain, Ukraine), Middle East and Africa (Israel, Lebanon, Nigeria, South Africa), Asia (Japan, People''s Republic of China), and Oceania (New Zealand). The WHO Composite International Diagnostic Interview (CIDI) was used to assess the prevalence and correlates of a wide variety of mental and substance disorders. This paper focuses on lifetime use and age of initiation of tobacco, alcohol, cannabis, and cocaine. Alcohol had been used by most in the Americas, Europe, Japan, and New Zealand, with smaller proportions in the Middle East, Africa, and China. Cannabis use in the US and New Zealand (both 42%) was far higher than in any other country. The US was also an outlier in cocaine use (16%). Males were more likely than females to have used drugs; and a sex–cohort interaction was observed, whereby not only were younger cohorts more likely to use all drugs, but the male–female gap was closing in more recent cohorts. The period of risk for drug initiation also appears to be lengthening longer into adulthood among more recent cohorts. Associations with sociodemographic variables were consistent across countries, as were the curves of incidence of lifetime use.

Conclusions

Globally, drug use is not distributed evenly and is not simply related to drug policy, since countries with stringent user-level illegal drug policies did not have lower levels of use than countries with liberal ones. Sex differences were consistently documented, but are decreasing in more recent cohorts, who also have higher levels of illegal drug use and extensions in the period of risk for initiation.     

Combination Chemotherapy in Generalized Hodgkin's Disease

Fifty-two patients with generalized Hodgkin''s disease were treated with a combination of mustine hydrochloride, vinblastine, procarbazine, and prednisolone. Complete remissions were obtained initially in six out of seven patients (86%) who had previously received no treatment, in 15 out of 19 (79%) who had had only radiotherapy in the past, and in 9 out of 26 (35%) who had previously been given chemotherapy with or without radiotherapy. Of these 30 patients in whom a complete remission was obtained 22 have been free of any symptoms or signs of disease for periods ranging from 4 to 22 months. The response to treatment was rapid, and toxicity was not a major problem, except in those who had previously been treated with cytotoxic drugs used continuously and not in courses. A comparative trial of radiotherapy and combination therapy in the treatment of Stage III Hodgkin''s disease is strongly recommended.     

Mitochondria and NMDA Receptor-Dependent Toxicity of Berberine Sensitizes Neurons to Glutamate and Rotenone Injury

The global incidence of metabolic and age-related diseases, including type 2 diabetes and Alzheimer''s disease, is on the rise. In addition to traditional pharmacotherapy, drug candidates from complementary and alternative medicine are actively being pursued for further drug development. Berberine, a nutraceutical traditionally used as an antibiotic, has recently been proposed to act as a multi-target protective agent against type 2 diabetes, dyslipidemias, ischemic brain injury and neurodegenerative diseases, such as Parkinson''s and Alzheimer''s disease. However, the safety profile of berberine remains controversial, as isolated reports suggest risks with acute toxicity, bradycardia and exacerbation of neurodegeneration. We report that low micromolar berberine causes rapid mitochondria-dependent toxicity in primary neurons characterized by mitochondrial swelling, increased oxidative stress, decreased mitochondrial membrane potential and depletion of ATP content. Berberine does not induce caspase-3 activation and the resulting neurotoxicity remains unaffected by pan-caspase inhibitor treatment. Interestingly, inhibition of NMDA receptors by memantine and MK-801 completely blocked berberine-induced neurotoxicity. Additionally, subtoxic nanomolar concentrations of berberine were sufficient to sensitize neurons to glutamate excitotoxicity and rotenone injury. Our study highlights the need for further safety assessment of berberine, especially due to its tendency to accumulate in the CNS and the risk of potential neurotoxicity as a consequence of increasing bioavailability of berberine.     

Immunotherapy of Crohn's disease.

Although the initiating events of Crohn''s disease are unknown, models of experimental colitis have provided new insights in the immunologically mediated pathways of mucosal inflammation. In Crohn''s disease activated mucosal T lymphocytes produce proinflammatory cytokines within the mucosal compartment. With this understanding, there has been a shift in past years from the use of unspecific anti-inflammatory agents (corticosteroids, aminosalicylates) to the use of immunomodulatory drugs (azathioprine, methotrexate). Moreover, novel strategies have been designed for specific targets in Crohn''s disease, in particular T lymphocytes and cytokines. In an open label study treatment of steroid-refractory Crohn''s disease with anti- CD4+ antibodies was well tolerated and showed clinical benefit. However, a sustained depletion of the CD4+ cells precluded further clinical trials. In controlled clinical studies, anti-tumour necrosis factor (TNF-alpha) antibodies induced complete remissions and few side effects were observed. One study suggested efficacy in active Crohn''s disease of recombinant interleukin-10. Long term treatment studies will have to answer questions about the indications for use, benefit and toxicity. Altogether, these results hold promise for future management of Crohn''s disease, where disease-modifying interventions and strategies that effectively maintain disease remission will play a key role.