Cyclodextrins: improving the therapeutic response of analgesic drugs: a patent review

Introduction: Cyclodextrins (CDs) are cyclic oligosaccharides that have recently been recognized as useful tools for optimizing the delivery of such problematic drugs. CDs can be found in at least 35 pharmaceutical products, such as anticancer agents, analgesic and anti-inflammatory drugs. Besides, several studies have demonstrated that CD-complexed drugs could provide benefits in solubility, stability and also improve pharmacological response when compared with the drug alone.

Areas covered: The patent search was conducted in the databases WIPO, Espacenet, USPTO, Derwent and INPI, using the keywords cyclodextrin, pain and its related terms (analgesia, hyperalgesia, hypernociception, nociception, antinociception, antinociceptive). We found 442 patents. Criteria such as the complexation of analgesic agents and evidence of improvement of the therapeutic effect were indispensable for the inclusion of the patent. So, 18 patents were selected.

Expert opinion: We noticed that some patents are related to the complexation of opioids, NSAIDs, as well as natural products, in different types of CDs. The use of CDs creates the prospect of developing new therapeutic options for the most effective treatment of painful conditions, allowing a reduction of dosage of analgesic drugs and the occurrence of side effects. Thus, CDs can be an important tool to improve the efficacy and pharmacological profile of analgesic drugs.     

抗抑郁药物的作用机理与研究进展

本文通过查阅国内外有关文献,对抗抑郁症药物的作用机理与研究进展进行阐述,为抗抑郁药物的进一步研究提供参考。     

Cyclodextrins: structure,physicochemical properties and pharmaceutical applications

Since their discovery over 100 years ago cyclodextrins (CDs) have been the subject of numerous scientific publications. In 2016 alone CDs were the subject of over 2200 research articles published in peer-reviewed journals and mentioned in over 2300 patents and patent applications, many of which were on pharmaceutical applications. Natural CDs and their derivatives are used as enabling pharmaceutical excipients that enhance aqueous solubility of poorly soluble drugs, increase drug permeability through biological membranes and improve drug bioavailability. Unlike conventional penetration enhancers, their hydrophilic structure and high molecular weight prevents them from penetrate into lipophilic membranes leaving biological membranes intact. The natural CDs and some of their derivatives have monographs in pharmacopeias and are also commonly used as food additives and in toiletry products. CDs form inclusion complexes with lipophilic moieties of hydrophobic drugs. Furthermore, CDs are able to form non-inclusion complexes and self-assembled aggregates; small and large complex aggregates with micellar-like structures that can enhance drug solubility. Excipients commonly used in pharmaceutical formulations may have additive or inhibiting effect on the CD solubilization. Here various methods used to investigate CD aggregate formation are reviewed as well as techniques that are used to increase the solubilizing effects of CDs; methods that enhance the apparent intrinsic solubility of drugs and/or the complexation efficacy and decrease the amount of CD needed to develop CD-containing pharmaceutical formulations. It will be explained how too much or too little CD can hamper drug bioavailability, and the role of CDs in solid dosage forms and parenteral formulations, and examples given on how CDs can enhance drug delivery after ocular, nasal and pulmonary administration.     

Effect of antidepressant drugs on serotonergic and adrenergic receptors

Summary We examined eight tricyclic antidepressants (doxepin, amitriptyline, clomipramine, imipramine, trimipramine, nortriptyline, desipramine and protriptyline) and four nontricyclic antidepressants (mianserin, nomifensin, iprindole and zimelidine) in terms of their effects on serotonergic and adrenergic receptors by direct binding assays.³H-WB-4101 (0.22 nM) served as a label for postsynaptic alpha receptors while³H-clonidine (0.2 nM) served to label presynaptic alpha receptors in the frontal cortex of the calf.³H-dihydroalprenolol (³H-DHA) (0.5 nM) was used to label the beta₁ adrenoceptors in the calf frontal cortex and beta₂ adrenoceptors in the calf cerebellar cortex.³H-d-Lysergic acid diethylamide (³H-LSD) (2 nM) and³H-serotonin (³H-5HT) (0.5 nM) were used to label the serotonergic receptors in the calf frontal cortex.The results show that at drug concentrations which occur clinically in the plasma water, most of the tertiary amine tricyclics significantly inhibited³H-WB-4101,³H-LSD and³H-5HT binding. None of the antidepressants tested had any significant effect on³H-DHA binding. The secondary amine tricyclics as a group were not potent in inhibiting the binding of all four radiolabelled ligands. The nontricyclic antidepressant mianserin was potent in inhibiting the binding of³H-WB-4101,³H-clonidine,³H-LSD and³H-5HT. We suggest that the differences between the effects of the antidepressants on adrenergic and serotonergic receptors may be responsible for the differences in their therapeutic efficacies and side effects.Supported by the Canada Medical Research Council and the Ontario Mental Health FoundationA preliminary report of this work was presented at the 9th annual meeting of the Society for Neuroscience, Atlanta, 1979     

The use of antidepressant drugs in general practice

Summary The aim of this study was to examine the antidepressant drug prescribing preferences and habits of a population of general practitioners. The method used was that of a questionnaire survey, including case vignettes. The response rate exceeded 70% Data are presented outlining the attitudes of the respondents to the use of antidepressant drugs in the management of common psychiatric presentations in the primary care setting.The majority of general practitioners (G.P.'s) had received little or no post-graduate education in psychiatry. The antidepressants most frequently prescribed were amitriptyline, clomipramine, trazodone and lofepramine. Despite recognition of the alarming frequency of serious self-poisoning incidents with some of these compounds, 26% of respondents confessed to an inability to make an informed choice of antidepressant drug, with 14% using the same drug with every patient with no attempt to select according to individual patient requirements.The management of depressive neurosis generates considerable clinical confusion with a variety of interventions favoured. The use of a sedating antidepressant is popular. There is greater accord for the management of endogenomorphic depression. The use of the benzodiazepine drugs in the management of anxiety disorders is infrequent, with appropriate recognition of the merits of behavioural approaches. However, the role for antidepressant drugs in the management of anxiety disorders is under-recognized.We conclude that general practitioners are required to undertake a significant body of work for which they may be inadequately trained.     

探讨中成药的不良反应

中成药在临床应用中具有质量稳定、疗效温和可靠、剂量易控,使用方便等优势,被广泛应用于各科疾病。但更多的患者错误的认为“中药无毒”有病治病,无病健身,使社会上长期、大量、盲目、不合理使用中成药的现象非常普遍,导致中成药的治疗效果大不如前,而且不良反应比率不断上升,这就有必要客观辨证地认识中成药的不良反应,纠正人们错误的用药观念,为合理用药提供参考。     

Combination of antidepressant drugs: the case of inositol

Inositol is a second messenger precursor that is effective in depression and obsessive-compulsive disorder via a mechanism different from serotonin reuptake inhibitors. However, controlled trials of inositol combined with serotonin reuptake inhibitors in depression or in reuptake inhibitor resistant depressed patients, or in partially responsive obsessive-compulsive patients, did not reveal added benefit. This is comparable to results with combinations of other antidepressant treatments, such as tricyclics plus monoamine oxidase inhibitors. Copyright 2001 John Wiley & Sons, Ltd.     

抗抑郁药物治疗幽门螺旋杆菌阴性的慢性胃炎临床观察

目的:探讨抗抑郁药物对幽门螺旋杆菌阴性的慢性胃炎的治疗作用.方法:将298例幽门螺旋杆菌阴性的慢性胃炎患者随机分成对照组和治疗组,对照组140例予以奥美拉唑胶囊治疗,治疗组158例予以奥美拉唑胶囊及抗抑郁药物(氟哌噻吨美利曲辛片)联合治疗4周,然后对两组治疗前后的疗效进行分析.结果:两组治疗后患者的症状改善程度差异有显著性.结论:抗抑郁药物联合质子泵抑制剂对改善幽门螺旋杆菌阴性的慢性胃炎的症状有显著效果,可作为幽门螺旋杆菌阴性的慢性胃炎有效治疗途径之一.     

The acute effects of antidepressant drugs on the performance of conditioned avoidance behavior in rats

The effects of acute administration of 10 different antidepressant drugs were examined on the performance of a two-way conditioned avoidance response in rats. The antidepressant drugs impaired avoidance behavior by decreasing avoidance responding and increasing the number of escape failures. The order of effectiveness for increasing overall response latency at a common dose of 10 mg/kg was: desipramine, maprotiline, protriptyline, (+) oxaprotiline, nortriptyline, imipramine, amitriptyline, (-) oxaprotiline, fluoxetine, and chlorimipramine. Avoidance behavior was impaired most by those antidepressant drugs that are also potent inhibitors of norepinephrine uptake.     

儿童用含麝香中成药存在问题分析

目的:通过研究儿童用含麝香中成药的药品标准,分析其存在的问题,为儿童用含麝香中成药的合理用药提出建议。方法:对《新编国家中成药》(第2版)中所收载的儿童用含麝香的中成药进行统计,针对其剂型、处方、用法用量等进行分析。结果与结论:儿童用含麝香中成药处方、剂型、用法用量等存在不同程度的问题,有必要对其进行再评价并统一规范完善药品标准的相应项目。     

Serotonin-mimetic and antidepressant drugs on passive avoidance learning by olfactory bulbectomised rats

Olfactory bulbectomised rats were treated with drugs and their rate of acquisition of a passive avoidance task was measured. The acquisition-rate, which is disturbed by the bilateral ablations, was completely restored by acute administration of fenfluramine or fluoxetine. Partial restoration was found with quipazine. Clonodine was without effect. Repeated treatments with impramine and mianserine improved passive avoidance of bulbectomised rats. Metergoline blocked these effects of imipramine and mianserin. These results indicate a serotonergic mechanism in the effect of antidepressants on olfactory bulbectomised rats.     

Alpha 2-adrenoreceptors on human platelets: selective labelling by [3H]clonidine and [3H]yohimbine and competitive inhibition by antidepressant drugs

[3H]Clonidine and [3H]yohimbine have been used to characterize alpha 2-adrenoreceptors on human platelets. At 25 degrees C binding was rapid (t 1/2 of association, 1.8 and 2.7 min) and reversible (t 1/2 of dissociation, 0.5 and 8.2 min). The binding sites for [3H]clonidine and ]3H]yohimbine showed the specificity required for an alph 2-adrenoreceptor. The rank order of potency of inhibitors of [3h[clonidine binding was clonidine greater than yohimbine greater than phenylephrine greater than prazosin and of [3H]yohimbine binding was yohimbine greater than clonidine greater than phenylephrine greater than prazosin. Scatchard analysis of [3H]yohimbine binding indicated the existence of a single population of noninteracting sites (KD = 3.0 nM; Bmax = 188 fmol/mg protein). The high-affinity binding of [3H-clonidine had a lower affinity and a lower number of sites (KD = 5.0 nM; Bmax = 35 fmol/mg protein). [3H]Clonidine binding also showed evidence of a second site of much lower affinity and greater number (KD = 18.6 nM; Bmax = 77 fmol/mg protein) in 40% of the normal population. In vitro, antidepressant drugs competed with [3H]clonidine and [3H]yohimbine for the platelet alpha 2-adrenoreceptor. The rank order of potency of inhibitors of [3H]clonidine binding was mianserin greater than amitriptyline greater than iprindole greater than desipramine and of [3H]yohimbine binding was mianserin greater than amitriptyline greater than desipramine greater than iprindole. The inhibition constants (Ki) of adrenergic drugs and of various antidepressant drugs in competing with [3H]clonidine were correlated with the inhibition constants of these drugs in competing with [3H]yohimbine (r = 0.970; P less than 0.001) which suggests that both radioligands labelled the same alpha 2-adrenoreceptor on the human platelet. The inhibition of binding induced by all antidepressant drugs was competitive. In contrast, long-term administration of tricyclic antidepressant drugs to patients was recently found to be associated with a decrease in the number of binding sites for [3H]clonidine on platelet membranes. The present results indicate that both [3H]clonidine and [3H]yohimbine are useful tools for the quantification of alpha 2-adrenoreceptors on blood platelets and suggests that the specific binding of radiolabelled alpha 2-adrenoreceptor ligands to human platelet membranes might be used to monitor changes in alpha 2-adrenoreceptors during tricyclic antidepressant drug treatment.     

Reduced sensitivity of neurons to noradrenamine after chronic treatment with antidepressant drugs

The sensitivity of cingulate cortical neurons to microiontophoretically administered noradrenaline (NE) and GABA was investigated in groups of rats treated either chronically or acutely with various antidepressant drugs or with the tricyclic antiepileptic carbamazepine. The chronically treated animals received one daily intraperitoneal injection of either desipramine (10 mg/kg), clomipramine (10 mg/kg), maprotiline (25 mg/kg), tranylcypromine (1 mg/kg) or carbamazepine (30 mg/kg p.o) for 4 weeks. The acutely treated rats received one daily injection of the vehicle for 4 weeks, followed by one single injection of one of the five drugs 24 h before the experiment. NE and γ-aminobutyric acid (GABA) were administered microiontophoretically during periods of 60 sec with various ejection currents. In chronically treated rats a statistically significant reduction in the sensitivity of cortical cells to NE was observed with all four antidepressants. However, in rats treated chronically with carbamazepine, no desensitisation was observed.Desensitization to NE following chronic treatment with desipramine developed within the first 10 days of treatment. Following a ten-day treatment, there was a 33 percent and by the end of the fourth week a 43 percent reduction in sensitivity to NE. The sensitivity of these cingulate neurons to GABA was unchanged after chronic treatment with the antidepressant drugs. In conclusion, the present study demonstrates that chronic treatment with antidepressant drugs leads to a postsynaptic subsensitivity of cortical neurons to NE.     

Neurochemical and pharmacological studies on a new 5HT-uptake inhibitor,FG4963, with potential antidepressant properties

A new phenylpiperidine derivative, FG4963, and several tricyclic antidepressants were compared in various in vitro and in vivo tests for central 5HT- and NA-uptake inhibition. FG4963 was found to be a 5HT-pump blocker with activity similar to that of chlorimipramine. FG4963 inhibited NA-uptake less than the most potent tricyclic thymoleptics.In contrast to imipramine derivatives FG4963 was a weak inhibitor of peripheral NA-uptake.FG4963 seems to produce central 5HT-potentiation without affecting organ functions regulated by the autonomic nervous system as much as tricyclic antidepressants.     

Acylhydrazone derivatives: a patent review

Introduction: The N-acylhydrazone (NAH) moiety has been characterized as a privileged structure, capable of providing ligands points for more than one type of bioreceptor. Modifications of the subunits bonded to its acyl and imine functions resulted in several derivatives, which modulate a great diversity of molecular targets. In this context, this patent review reflects the use of the NAH moiety in different compounds.

Areas covered: In this review, the authors perform an analysis of the therapeutic profile of NAH compounds together with their perspective of its usability. The Espacenet and Delphion databases were used as main sources of search, and ‘N-acylhydrazone,’, ‘Acylhydrazone’ and ‘hydrazone’ were used as keywords. From a total of 117 patents retrieved, 22 presented pharmacological activities described in the document, thus being chosen for this review.

Expert opinion: In the last century, only six patents disclosing NAH derivatives for therapeutic purposes were published, and only in 2010, this subunit started receiving some real attention regarding its therapeutic potential. In this review, the Brazilian and Chinese Universities were identified as the major patent applicants, especially for drug candidates for the treatment of chronic pain, inflammatory disorders and cancer. The NAH subunit is very versatile both from synthetic and medicinal chemistry point of view. This feature is a direct result from the conformational diversity that this framework presents, achievable by subtle and simple chemical changes. Therefore, our opinion is that this moiety suits a lot more drug discovery projects than it seems to at first glance. In conclusion, we strongly support and encourage a raise in the use of this unique subunit.     

Inhibition effects of some antidepressant drugs on pentose phosphate pathway enzymes

The glucose metabolism in the pentose cycle is essential to the source of NADPH. Deficiency of these enzymes have been linked to depression and psychotic disorders. Depression is an increasingly prevalent mental disorder which may cause loss of labor. Antidepressant drugs are commonly employed in treatments of mood disorders and anxiety treatment. The purpose of this study is to investigate the effects of aripiprazole, mirtazapine, risperidone, escitalopram and haloperidol on the activity of 6-phosphogluconate dehydrogenase (6PGD) and glucose-6-phosphate dehydrogenase (G6PD) enzymes purified from human erythrocytes. It was found that aripiprazole, mirtazapine, risperidone, escitalopram and haloperidol show effective inhibitor properties on purified G6PD and 6PGD enzymes. The IC₅₀ values of these drugs were found in the range of 26.34 μM-5.78 mM for 6PGD and 16.26 μM-3.85 mM for G6PD. The K_i values of the drugs were found in the range of 30.21 ± 4.31 μM-4.51 ± 1.83 mM for 6PGD and 14.12 ± 3.48 μM-4.98 ± 1.14 mM for G6PD. Usage of drugs with significant biological effects may be a hazard in some conditions.     

Crosstalk between contact hypersensitivity reaction and antidepressant drugs

Allergic contact dermatitis is a delayed-type hypersensitivity reaction mediated by hapten-specific T cells. Many cell types, inflammatory mediators and cytokines are involved in this reaction. Contact hypersensitivity is a self-limited reaction and can be regulated at different levels. Because it is known that disturbances in the immune system underpin the onset of depression and that antidepressant drugs have immunomodulatory effects, it can be hypothesized that antidepressants may have some efficacy in the treatment of contact hypersensitivity. There are some reports on the effectiveness of antidepressants in the inhibition of cutaneous sensitization in mice, and the aim of this narrative review is to assess the evidence for the effectiveness of antidepressant drugs in reducing the recurrence of contact hypersensitivity reactions.     

Acute effects of antidepressant drugs on long-term potentiation (LTP) in rat hippocampal slices

Summary The actions of three clinically effective antidepressant drugs with different pharmacological profiles were investigated in the CAI area of rat hippocampal slices. Imipramine and (+) or (–)-oxaprotiline had negligible effects on population spikes evoked by stratum radiatum stimulation, but reduced postsynaptic excitability in low Ca high Mg medium after an exposure of more than 15 min. Imipramine and (+)-oxaprotiline at 10 mol/l enhanced long-term potentiation (LTP) when a lower stimulation strength was applied while (+)-oxaprotiline reduced UP when a higher stimulus amplitude was used to evoke population spikes. (–)-oxaprotiline (levoprotiline) had a similar effect which was, however, not significant in either stimulation paradigm at the P<0.05 level. Imipramine actions were also studied on epileptiform discharges in Mg²⁺-free medium: a facilitation-inhibition sequence with a slow time course was seen with 50 mol/l but no effect with 10 mol/l. An involvement of N-methyl-D-aspartate (NMDA)-receptors in acute actions of antidepressants is unlikely but long-term potentiation in the hippocampus is modulated by these drugs. Send offprint requests to H.L. Haas, Düsseldorf     

On the classification of antidepressant drugs

Clinical, pharmacologic, and biochemical profiles of antidepressant drugs have been analyzed statistically. A method derived from multivariate statistics separates mere drug potency from the spectral information contained in the profiles. The dimensionality of the spectra is also reduced and this results in a diagram of associations and dissociations between the antidepressants and their scales of observation.The spectra of antidepressants show three poles which have been labeled as D (desipraminelike), A (amitriptylinelike), and M (MAOI).Clinical spectra agree better between one another than various pharmacologic spectra do. Monoamine oxidase inhibitors are readily differentiated from the tricyclic compounds. The latter appear in the sequence: desipramine, nortriptyline, imipramine, and amitriptyline. This sequence can also be reproduced from biochemical spectra of central and peripheral blockade of norepinephrine and serotonin reuptake.