The antidepressant effect of agnmtine in pharmacological depression models

AIM To explore the antidepressant effects and its possible mechanism of agmatine （AGM） in pharmacological depression models. Methods The 5 -hydroxytryptophan potentiation test, yohimbine toxicity potentiation test, apomorphine-induced hypothermia test and reseponie-induced hypothermia test in mice were used in this study. Results Repeated administration with AGM（10,20,40,80mg. kg^-1 ,     

A comparison of some pharmacological actions of morphine and Δ9-tetrahydrocannabinol in the mouse

The effects of morphine and ⁹-tetrahydrocannabinol (THC) on the tail-flick reflex, body temperature, and catecholamine synthesis were examined in the mouse in order to compare their effects in a single species and strain under uniform conditions. Naloxone antagonism of THC and cross-tolerance between morphine and THC were also studied. Both morphine and THC produced antinociception, hypothermia, and increased catecholamine synthesis at 30 min after s.c. injection. Morphine produced greater increases in dopamine synthesis and was a more potent antinociceptive agent, while THC produced greater increases in norepinephrine synthesis and was a more potent hypothermic agent. Naloxone pretreatment (1 mg/kg) partially antagonized the hypothermia and increase in catecholamine synthesis produced by THC. There was also crosstolerance between morphine and THC, but it was asymmetric in that THC-tolerant animals were crosstolerant to only the hypothermic action of morphine and morphine-tolerant animals cross-tolerant to only the antinociceptive action of THC.     

Advances in the pharmacological treatment of Graves’ orbitopathy

Graves’ orbitopathy has a deteriorating effect on patients’ appearance and vision, thus significantly decreases their quality of life. A multidisciplinary team of endocrinologists, ophthalmologists, head and neck surgeons, nuclear medicine physicians, radiologists, and psychologists should constitute a standard health care team for those patients. It is vital that the therapy is based on an individual approach, with patients being well informed and involved in the decision-making process. Generally, traditional therapies include immunosuppression with steroids, orbital irradiation and surgical decompression. Novel treatment modalities include: biological agents, somatostatin analogs, antioxidants, methotrexate. Better insight into pathogenesis of Graves’ orbitopathy is the only chance for targeted therapy development.     

Controversies in the pharmacological treatment of Graves’ disease in children

ABSTRACT

Introduction: Graves’ disease (GD) is a disorder, in which auto-immunity against the thyroid- stimulating hormone (TSH) receptor is the pivotal pathogenetic element. This disease may have different clinical manifestations, the most common being thyrotoxicosis. Treatment of this condition differs according to its etiology, but there is currently no evidence-based therapeutic strategy which is universally adopted in all countries.

Areas covered: a systematic review of the updates on the management of pediatric GD was performed using the Pubmed data base until March 2018. Systematic reviews with or without meta-analysis were analyzed using the following terms: Antithyroid drugs, Childhood, Hyperthyroidism, Radioactive iodine, Thyroidectomy.

Expert commentary: As the best way to manage children with GD remains a matter of debate among pediatric endocrinologists, and there is currently no evidence-based therapeutic strategy which is universally adopted, we confirm that the original and prolonged treatment with anti-thyroid drugs (ATDs) remains the mainstay of treatment for juvenile hyperthyroidism. Alternative treatments include radioiodine (RAI) therapy or surgery (total thyroidectomy). We recommend individualizing the therapeutic approach, without prejudices toward radical therapies that become necessary in case of relapse, adverse effects or poor compliance to ATDs. The optimal approach depends on patient or family preference, and specific patient clinical features.     

Of mouse and man--what is the value of the mouse in predicting gene expression in humans?

The mouse is the most commonly used mammalian species in biomedical research and is widely regarded as a human surrogate species. In this Editorial, Robert Coleman discusses the validity of this assumption and cautions against the unquestioning acceptance of the mouse an experimental model for drug discovery and development.     

Down-regulation of the Notch pathway mediated by a γ-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia

Background and purpose:

γ-Secretase inhibitors (GSIs) block NOTCH receptor cleavage and pathway activation and have been under clinical evaluation for the treatment of malignancies such as T-cell acute lymphoblastic leukaemia (T-ALL). The ability of GSIs to decrease T-ALL cell viability in vitro is a slow process requiring >8 days, however, such treatment durations are not well tolerated in vivo. Here we study GSI''s effect on tumour and normal cellular processes to optimize dosing regimens for anti-tumour efficacy.

Experimental approach:

Inhibition of the Notch pathway in mouse intestinal epithelium was used to evaluate the effect of GSIs and guide the design of dosing regimens for xenograft models. Serum Aβ₄₀ and Notch target gene modulation in tumours were used to evaluate the degree and duration of target inhibition. Pharmacokinetic and pharmacodynamic correlations with biochemical, immunohistochemical and profiling data were used to demonstrate GSI mechanism of action in xenograft tumours.

Key results:

Three days of >70% Notch pathway inhibition was sufficient to provide an anti-tumour effect and was well tolerated. GSI-induced conversion of mouse epithelial cells to a secretory lineage was time- and dose-dependent. Anti-tumour efficacy was associated with cell cycle arrest and apoptosis that was in part due to Notch-dependent regulation of mitochondrial homeostasis.

Conclusions and implications:

Intermittent but potent inhibition of Notch signalling is sufficient for anti-tumour efficacy in these T-ALL models. These findings provide support for the use of GSI in Notch-dependent malignancies and that clinical benefits may be derived from transient but potent inhibition of Notch.     

Recent developments in the pharmacological treatment of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the substantia nigra. The decline of dopamine leads to motor dysfunctions manifested as tremor, rigidity and bradykinesia. The pharmacological treatment of choice for the past 30 years has primarily been the dopamine precursor levodopa. Although it is the most effective treatment available, it is clear that other drugs are needed in order to sustain a therapeutic benefit and to alleviate fluctuations in mobility (i.e., motor fluctuations). Furthermore, there is some evidence that levodopa may hasten the occurrence of motor fluctuations and involuntary movements called dyskinesias. Hence, many clinicians delay the use of levodopa and employ the use of other symptomatic treatments including monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists as first-line therapy in de novo patients. Regardless of treatment, the disease continues to progress as there is still no obvious means of altering disease progression (i.e., no neuroprotective therapy), to restore loss of dopamine (i.e., no restorative therapy) or prevent the disease (i.e. preventative therapy). With disease progression, polypharmacy is common and often employs a combination of antiparkinsonian agents. There have been some key advances in treatment with the advent of MAO-B inhibitors, dopamine agonists and catechol-O-methyltransferase inhibitors; however, the arsenal of drug treatment remains limited. As the mechanism of PD is further elucidated, novel drug treatments will continue to emerge in the areas of preventative, restorative or symptomatic therapy. Despite the purpose of treatment, the ideal pharmacological drug for PD will include the presence of a safe side-effect profile, a simple dosing schedule, the ability to provide symptomatic relief and the potential to alter disease progression. The purpose of this article is to examine upcoming antiparkinsonian drugs in clinical trials based on their pharmacology, safety and efficacy.     

The challenge of pain in the pharmacological management of Parkinson’s disease

ABSTRACT

Introduction: Pain is a common symptom in Parkinson’s disease (PD), impairing quality of life. The clinical appearance and the underlying etiologies are diverse. Different subtypes of pain may occur, with musculoskeletal pain considered to be the most frequent. Often there is also a combination of different causes of pain. There is a lack of controlled studies addressing pain therapy in PD.

Areas covered: In this review the authors analyzed the currently available data, taking into account the available publications in the databases, especially PubMed. The authors further provided their expert perspectives on the challenges of treating pain in PD patients.

Expert opinion: There is both nociceptive and neuropathic pain and in patients with PD, some PD-related pain and some unrelated. Diagnosis requires a thorough and differentiated history and examination, and targeted diagnostics. Therapeutically, many drugs are used, but the data is unfortunately limited and not specific. Medications used include Parkinson-related, mainly dopaminergic drugs, as well as opioids and non-opioid analgetics, anticonvulsives, antidepressants, and more recently cannabinoids. Currently, therapy is performed nonspecifically, without taking into account the special requirements of PD. Unfortunately, in many cases, pain is resistant to these therapies. In the future, both diagnostic and therapeutic efforts should be made to address this issue.     

Content of the anti-DNA antibody in the serum of BXSB mouse and suppressive effect of BXSB mouse serum on lymphocyte proliferation

The content of the anti-DNA antibody in BXSB mouse serum and the effect of the sere from BXSB mice on lymphocyte proliferation of normal mouse were observed.Enzyme-linked immunosorbent assay (ELISA) and ~3H-thymidine incorporation were used.The content of anti-DNA antibody in male BXSB mouse serum increased from the age of 3 month and reached to the     

Approaches to the pharmacological treatment of obesity

Obesity is a global health crisis resulting in major morbidity and premature death. The need for safe and efficacious drug therapies is great, and presently unmet. The two drugs currently licensed in the USA for the long-term treatment of obesity, orlistat and sibutramine, provide only modest weight-loss benefits and are associated with high attrition rates owing to side effects. This review summarizes current concepts in the neuroendocrine control of energy homeostasis and major pharmacological treatments for obesity in the pipeline.     

Kinetic properties of the in vivo accumulation of 3H-(−)-N-n-propylnorapomorphine in mouse brain

Summary (1) The influence of various dopamine (DA) receptor agonists and antagonists on the kinetic properties of the specific binding of ³H(–)-N-n-propylnorapomorphine (NPA) in the mouse striatum in vivo was studied. The specific binding of ³H-NPA, defined as the difference between the radioactivity in the striatum and cerebellum, was completely antagonized by the selective D-2 receptor antagonist raclopride but not by the selective D-1 antagonist SCH 23390, showing that the binding occurs exclusively to the D2 receptors. (2) The selective D-2 receptor agonists pergolide and quinpirole inhibited the ³H-NPA binding biphasically at low doses, indicating that these DA receptor agonists have high affinities for a subfraction (10 to 30%) of the NPA binding sites. (3) Increasing the synaptic DA concentration by DA release [(+)-amphetamine] or uptake blockade (amfonelic acid and methylphenidate) inhibited the ³HNPA binding in a competitive manner (unchanged B _max, increased K _D). Depletion of the DA in the synapses by -butyrolactone or reserpine decreased the apparent K _D value. (4) The possibility of estimating changes in the synaptic DA concentration from changes in the apparent K _D is discussed. According to the results obtained, the normal concentration of DA in the synaptic cleft in mouse striatum in vivo is about 40 nmol/l and this concentration is increased 2 to 3 times by (+)-amphetamine and amfonelic acid in doses which evoke hyperactivity and stereotypic behaviour.Send offprint requests to S. B. Ross at the above address     

Development of transplant immunosuppressive agents – considerations in the use of animal models

ABSTRACT

Introduction: The development of all immunosuppressant agents to date has involved the experimental use of large and small animal models. Over the last half-century, immunosuppressive drugs have extended the lives of transplant patients worldwide. However, the use of animal models in the development of these drugs is not perfect, and this has brought to light a number of issues including idiosyncratic reactions that are found in animal models but not in humans. The 2006 highly publicized case of the ‘elephant man’ TGN 1412 drug trial highlights the importance of being cogent of the limitations of animal models.

Areas covered: This review covers the utility and limitations of the use of animal models for the development of immunosuppressant agents. This includes both large and small animal models, particularly rodent models in the transplant setting.

Expert opinion: The use of animal models represents a critical stage in the development of immunosuppressive drugs. Limitations include physiological differences to humans; this is especially true of immunologically naïve lab rodents with small memory cell populations. Toxic drug levels may differ widely between species. Animal models are also costly and raise ethical concerns. However, there is currently no way to recreate the complex environment of the human immune system purely in vitro.     

Is the mitochondrial benzodiazepine receptor involved in the control of airway smooth muscle tone?

• 1.1. In addition to binding to GABA_A receptors in the central nervous system, benzodiazepines have also been reported to recognize high affinity binding sites in several different peripheral tissues.
• 2.2. These peripheral benzodiazepine receptors likely consist of distinct integral membrane proteins, which are predominantly localized in the outer mitochondrial membrane and may be associated to form a heteropolymeric receptor complex. One such protein, identified for its ability to bind a class of benzodiazepines and isoquinolines, has been purified and the corresponding complementary DNA (cDNA) has been cloned and characterized. Furthermore, the structure of the rat gene encoding this protein has been clarified, thus potentially opening new insights into the molecular mechanisms responsible for receptor regulation.
• 3.3. Although the exact physiologic and/or pharmacologic role of peripheral benzodiazepine receptors is still unknown, their wide tissue distribution suggests an involvement in many cellular phenomena.
• 4.4. In particular, several lines of investigation indicate that these receptors, densely expressed on airway smooth muscle of various species, may contribute to the modulation of bronchomotor tone and perhaps to the pathogenesis of asthma and airway hyperresponsiveness.

     

Mechanism of activation of mouse liver microsomal glutations S—transferase by paracetamol treatment

Microsomal glutathion S-transferase(mGST) is one of the important detoxifcation enzymes in vivo,its modifying activation by drugs has been paid more attention to in pertinent field recently.This study was to explore the influence of paracetamol(Par) on mGST and its possible mechanism in vivo,and to further reveal the biological significance.Par is metabolized to N-acetyl-p-benzoquinone imine(NAPQI) by CYP2E1 and mGST is activated by sulfhydryl modification.     

In vitro and in vivo pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in rats

To investigate the pharmacological properties of mirabegron in in vitro and in vivo, the effects on cAMP accumulation in Chinese hamster ovary (CHO) cells expressing rat β-adrenoceptors, the relaxant activity in isolated rat bladder smooth muscle, and the voiding effects in cerebral infarcted rats were evaluated. Mirabegron increased cAMP accumulation with EC₅₀ value and intrinsic activity of 19 nmol/L and 1.0, respectively, in CHO cells expressing rat β₃-adrenoceptors. The EC₅₀ values and the intrinsic activities of mirabegron were 610 nmol/L and 0.6 for rat β₁-adrenoceptors and were sumless and 0.1 for β₂-adrenoceptors, respectively. Mirabegron showed concentration-dependent relaxant and full agonistic effects in rat bladder strips under passive tension with EC₅₀ value of 290 nmol/L. The concentration–response curve of mirabegron was affected neither by the β₁-adrenoceptor selective antagonist CGP-20712A nor by the β₂-adrenoceptor selective antagonist ICI-118,551. In in vivo studies with cerebral infarcted rats, a significant decrease in the volume voided per micturition compared with sham-operated rats was observed. Mirabegron dose-dependently increased the volume voided per micturition. In conclusion, we have extended the selectivity profile of mirabegron to rats and demonstrated that it is effective via stimulation of β₃-adrenoceptors in a rat cerebral infarction model of detrusor overactivity.     

Anti-coagulation effect of Fc fragment against anti-β2-GP1 antibodies in mouse models with APS

Anti-beta (2)-glycoprotein I (anti-β2-GP1) is one of the important pathogenesis factors responsible for thrombosis formation in patients with antiphospholipid syndrome (APS). Administration of intravenous immunoglobulin (IVIg) is a common method used to inhibit the abnormal antibody levels and decrease the mortality of APS in emergency situations. We hypothesize that the Fc fragment of IgG is the molecular structure responsible for these effects. The present study investigates the beneficial effects of both recombinant and natural human Fc fragments of heterogeneous IgG against human anti-β2-GP1 antibodies in mouse models with APS. Results showed that both recombinant and natural human Fc fragments moderately but significantly decreased the levels of serum anti-β2-GP1 antibodies and had anti-coagulation effects in human β2-GP1-immunized mice. Furthermore, both recombinant and natural human Fc fragments inhibited thrombosis formation and decreased mortality in mouse models infused intravenously with human anti-β2GP1 antibodies from patients with APS. Findings suggest that the Fc fragment might be one of the active structural units of heterogeneous IgG. Thus, recombinant human Fc fragment administration may be a useful treatment for individuals with APS.