Francisco López-Muñoz

Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg-1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

Bibliometric Study of Scientific Research on Melatonin During the Last 25 Years

We have carried out a bibliometric analysis of scientific publications related to the the pineal gland and melatonin during the period 1900-2014, to detail its distribution, and to interpret the changes that have affected its development. We selected (EMBASE and MEDLINE databases) documents that contained in their title the descriptors pineal*, epiphys*, melatonin* or agomelatin*. As bibliometric indicators of production, we applied Price’s Law, and others as doubling time and annual growth rate of scientific literature. We also applied Lotka’s Law, Bradford’s Law, and calculated the national Participation Index (PaI) for pineal gland, melatonin, and agomelatine in 20 most productive countries in this topic. We obtained 30,617 original documents (17,046 corresponded to pineal gland, and 14,967 to melatonin). Our results indicate fulfilment of Price’s Law, since scientific production on this topic undergoes exponential growth (correlation coefficient r = 0.9528, vs. r = 0.9139 after linear adjustment). The most used journal in the dissemination of documents is Journal of Pineal Research (the core or first Bradford’s zone), with 2,168 papers. The principal producer country is the United States (PaI = 24.11), followed by Germany (PaI = 6.71), Japan (PaI = 5.78), France (PaI = 5.77), and Spain (PaI = 5.33). Productivity on pineal gland and melatonin has undergone exponential growth in the period 1900–2014, without evidence a saturation point.

History of the Discovery of Antidepressant Drugs

The clinical introduction of the first two specifically antidepressant drugs took place during the 1950s: iproniazid, a monoamine-oxidase inhibitor that had been used in the treatment of tuberculosis, and imipramine, the first drug in the tricyclic antidepressant family. Both antidepressant drugs made two fundamental contributions to the development of psychiatry: one of a social-health nature, consisting in an authentic change in the psychiatric care of depressive patients; and the other of a purely pharmacological nature, since these agents have constituted an indispensable research tool for neurobiology and psychopharmacology, permitting, among other things, the postulation of the first aetiopathogenic hypotheses of depressive disorders. The clinical introduction of fluoxetine, a selective serotonin reuptake inhibitor, in the late 1980s, once again revolutionized therapy for depression, opening the way for new families of antidepressants. All of these antidepressants, like the rest of those currently available for clinical practice, except agomelatine, share the same action mechanism, which involves the modulation of monoaminergic neurotransmission at a synaptic level. However, the future of antidepressant therapy could be directed to the search of extraneuronal non-aminergic mechanisms or mechanisms that modulate the intraneuronal biochemical pathways.

Combination Strategies in Treatment-Resistant Depression

Treatment-resistant depression (TRD) is a serious public health problem: high prevalence (40–50 % of outpatient depression patients fail to respond satisfactorily to treatment with antidepressants in monotherapy, with the correct dose, regime and duration); social significance (high medical cost); individual suffering it causes (poor prognosis, chronicity, increased risk of suicide). The combination strategy is an option being used more and more frequently at the clinical level, and tends to be effective in 50–60 % of cases, though this varies according to the drug employed. This review analyze the state of the evidence on this therapeutic strategy, focusing on the family of antidepressants known as selective noradrenaline reuptake inhibitors (NARIs), particularly reboxetine, one of the antidepressants most widely used in combination therapy for TRD in recent years. The results obtained in combination strategies with reboxetine–especially in conjunction with SSRIs–suggest that it is a potentially useful tool.

History of Pineal Gland as Neuroendocrine Organ and the Discovery of Melatonin

The pineal gland is one of the anatomic organs that have generated most controversy and speculation throughout history. Its anatomical localization in the crossroads of the central nervous system (CNS) and its uneven nature in an environment of double structures together with its morphological appearance have attracted the attention of numerous scientists. Thorough and complex physiological theories have been proposed connecting this structure with the human body functionality, including philosophical postulates that relate to its spiritually, including the anatomic jail of the human soul (Cartesian hypotheses). In the early 20th century the first data were published in the scientific literature on the endocrine aspect of the pineal gland, but its ultimate confirmation took place in 1958, with the isolation of melatonin by the team led by Lerner. Later, the term ‘neuroendocrine transducer’ was introduced to explain the principle of the pineal gland, that is to say, the transformation of information about light from the retina into an endocrine response consisting in the synthesis and release of the hormone melatonin.

Melatonergic Drug Ramelteon in Neurotherapeutics

Melatonin, the hormone secreted by the pineal gland, plays an important role in sleep induction and sleep maintenance. With the advancement of age, there is a decline in melatonin production, and elderly individuals often complain difficulties in sleep onset, maintenance of sleep-wake rhythm, and poor quality of sleep. Melatonin replacement therapy has been used for treating insomnias but it is not uniformly successful. With the synthesis of melatonergic agonist, ramelteon, a chronohypnotic drug with a higher affinity for MT1 and MT2 melatonergic receptors, treatment of insomnias has become easy, and many clinical studies have attested the efficacy of ramelteon in treating primary insomnia and secondary insomnias associated with neurodegenerative and neurodevelopmental disorders like autistic disorder. Melatonin has been implicated in the pathogenesis of delirium and autism spectrum disorders (ASD) and has been tried for treatment of these disorders. Although found successful in treating these disorders, melatonergic agonist ramelteon is used for treating autistic disorder and delirium where the drug has been found effective in not only alleviating the sleep disorders but also the behavioral problems. A low or abnormal level of melatonin is suggested as one of the main reasons for the lack of communication skill and socialization which are the main symptoms of ASD. Ramelteon has been used for treating rapid eye movement (REM) sleep behavior disorder (RBD) also and is found to be effective in increasing sleep efficiency and reducing the intensity of behavioral symptoms of this disorder. As a chronohypnotic drug, ramelteon ameliorated the symptoms of jet lag by improving the nighttime sleep efficiency and daytime alertness.

New Galenic Formulations of Melatonin

Melatonin is a neurohormone that plays an important role in maintaining the body’s internal biological clock (the sleep-wake and thermoregulatory system). Its main role is in relation to circadian rhythms and it also acts as an antioxidant. The pharmacokinetic characteristics of melatonin include a short half-life and extensive metabolism, leading to a short action when exogenous formulations are administered. For this reason, different formulations have been developed to increase and prolong the actions of melatonin.

Antidepressant Drugs in Elderly

In our society, scientific advances and the improvement of the living conditions are causing a “demographic transition” with a significant increase in the number of elderly people. Antidepressant treatment in older depressed patients is efficacious, but differences in the effectiveness of different antidepressants have not been demonstrated. With ageing, a series of changes occur in the elderly that modify both the pharmacokinetics and pharmacodynamics of antidepressants and may influence the efficacy, tolerability and safety of treatment in the elderly. Individualized therapy for each elderly patient is needed to achieve acceptable risk–benefit ratio. ratiobebenefitratio.

The Role of Antiepileptic Drugs in Bipolar Depression

Bipolar depression, underdiagnosed in relation to unipolar depression, affects both the individual’s affective as well as cognitive areas. On the other hand, its manifestation is more frequent than hypomania/mania, despite which there has been less research into its treatment than manic phases.