Vaccination and social distance to prevent COVID-19.

In order to analyze the effect of vaccination in a population with the presence of viruses, a variation of the SIR (Susceptible-Infected-Removed) model is proposed taking into account social distancing and the effect of the vaccine. The equilibrium points of the proposed model are calculated and the stability analysis of the system is carried out. For the proposed model, disease-free equilibrium point and endemic equilibrium point are found and the conditions of existence are discussed. For the disease-free equilibrium point the bifurcation conditions are derived and simulations show that reducing the vaccination effort can lead the disease-free equilibrium to the endemic equilibrium. From the theoretical analysis, a minimum value of effort is obtained to guarantee a disease-free equilibrium point. Simulations were carried out from the value obtained from Rv to validate the theoretical results.

Synergistic effect of a combination of nicarbazin and monensin against coccidiosis in the chicken caused by Eimeria spp.

A clinical study was made into the abilities of nicarbazin and monensin and a nicarbazin + monensin combination to control Eimeria acervulina, E. maxima, and E. tenella in chickens. When included in the feed, at concentrations of 40 ppm nicarbazin or 40 ppm monensin, these products showed partial efficacy evaluated by daily weight gain (DWG) but no activity judged by daily feed intake (DFI) or feed conversion ratio (FCR). By contrast, the combination of 40 ppm nicarbazin + 40 ppm monensin provided complete control of infection judged by greater DWG and DFI, and lower FCR. Monensin at a concentration of 40 ppm was ineffective in preventing lesions caused by all three species. Nicarbazin at a concentration of 40 ppm was unable to suppress lesions of E. acervulina and E. maxima but was able to suppress lesions caused by E. tenella. Nicarbazin 40 ppm + monensin 40 ppm suppressed lesions of all three species. RESEARCH HIGHLIGHTS Nicarbazin or monensin at 40 ppm gave only partial control of Eimeria spp. A combination of 40 ppm nicarbazin + 40 ppm monensin controlled DWG, DFI and FCR. Nicarbazin or monensin at 40 ppm did not suppress all Eimeria spp. lesions. Nicarbazin 40 ppm + monensin 40 ppm suppressed lesions of all three species.

Exploring African Medicinal Plants for Potential Anti-Diabetic Compounds with the DIA-DB Inverse Virtual Screening Web Server.

Medicinal plants containing complex mixtures of several compounds with various potential beneficial biological effects are attractive treatment interventions for a complex multi-faceted disease like diabetes. In this study, compounds identified from African medicinal plants were evaluated for their potential anti-diabetic activity. A total of 867 compounds identified from over 300 medicinal plants were screened in silico with the DIA-DB web server (http://bio-hpc.eu/software/dia-db/) against 17 known anti-diabetic drug targets. Four hundred and thirty compounds were identified as potential inhibitors, with 184 plants being identified as the sources of these compounds. The plants Argemone ochroleuca, Clivia miniata, Crinum bulbispermum, Danais fragans, Dioscorea dregeana, Dodonaea angustifolia, Eucomis autumnalis, Gnidia kraussiana, Melianthus comosus, Mondia whitei, Pelargonium sidoides, Typha capensis, Vinca minor, Voacanga Africana, and Xysmalobium undulatum were identified as new sources rich in compounds with a potential anti-diabetic activity. The major targets identified for the natural compounds were aldose reductase, hydroxysteroid 11-beta dehydrogenase 1, dipeptidyl peptidase 4, and peroxisome proliferator-activated receptor delta. More than 30% of the compounds had five or more potential targets. A hierarchical clustering analysis coupled with a maximum common substructure analysis revealed the importance of the flavonoid backbone for predicting potential activity against aldose reductase and hydroxysteroid 11-beta dehydrogenase 1. Filtering with physiochemical and the absorption, distribution, metabolism, excretion and toxicity (ADMET) descriptors identified 28 compounds with favorable ADMET properties. The six compounds-crotofoline A, erythraline, henningsiine, nauclefidine, vinburnine, and voaphylline-were identified as novel potential multi-targeted anti-diabetic compounds, with favorable ADMET properties for further drug development.

Renormalization Group Flows of Hamiltonians Using Tensor Networks.

A renormalization group flow of Hamiltonians for two-dimensional classical partition functions is constructed using tensor networks. Similar to tensor network renormalization [G. Evenbly and G. Vidal, Phys. Rev. Lett. 115, 180405 (2015)PRLTAO0031-900710.1103/PhysRevLett.115.180405; S. Yang, Z.-C. Gu, and X.-G. Wen, Phys. Rev. Lett. 118, 110504 (2017)PRLTAO0031-900710.1103/PhysRevLett.118.110504], we obtain approximate fixed point tensor networks at criticality. Our formalism, however, preserves positivity of the tensors at every step and hence yields an interpretation in terms of Hamiltonian flows. We emphasize that the key difference between tensor network approaches and Kadanoff's spin blocking method can be understood in terms of a change of the local basis at every decimation step, a property which is crucial to overcome the area law of mutual information. We derive algebraic relations for fixed point tensors, calculate critical exponents, and benchmark our method on the Ising model and the six-vertex model.

Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety.

Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects.

Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation.

BACKGROUND: In May 2008, the National Institute for Health and Clinical Excellence (NICE) issued an updated guideline [clinical guideline (CG) 66] for the management of all aspects of type 2 diabetes. This report aims to provide information on new drug developments to support a 'new drugs update' to the 2008 guideline. OBJECTIVE: To review the newer agents available for blood glucose control in type 2 diabetes from four classes: the glucagon-like peptide-1 (GLP-1) analogue exenatide; dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin; the long-acting insulin analogues, glargine and detemir; and to review concerns about the safety of the thiazolidinediones. DATA SOURCES: The following databases were searched: MEDLINE (1990-April 2008), EMBASE (1990-April 2008), the Cochrane Library (all sections) Issue 2, 2008, and the Science Citation Index and ISI Proceedings (2000-April 2008). The websites of the American Diabetes Association, the European Association for the Study of Diabetes, the US Food and Drug Administration, the European Medicines Evaluation Agency and the Medicines and Healthcare Products Regulatory Agency were searched, as were manufacturers' websites. REVIEW METHODS: Data extraction was carried out by one person, and checked by a second. Studies were assessed for quality using standard methods for reviews of trials. Meta-analyses were carried out using the Cochrane Review Manager (RevMan) software. Inclusion and exclusion criteria were based on current standard clinical practice in the UK, as outlined in NICE CG 66. The outcomes for the GLP-1 analogues, DPP-4 inhibitors and the long-acting insulin analogues were: glycaemic control, reflected by glycated haemoglobin (HbA1c) level, hypoglycaemic episodes, changes in weight, adverse events, quality of life and costs. Modelling of the cost-effectiveness of the various regimes used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model. RESULTS: Exenatide improved glycaemic control by around 1%, and had the added benefit of weight loss. The gliptins were effective in improving glycaemic control, reducing HbA1c level by about 0.8%. Glargine and detemir were equivalent to Neutral Protamine Hagedorn (NPH) (and to each other) in terms of glycaemic control but had modest advantages in terms of hypoglycaemia, especially nocturnal. Detemir, used only once daily, appeared to cause slightly less weight gain than glargine. The glitazones appeared to have similar effectiveness in controlling hyperglycaemia. Both can cause heart failure and fractures, but rosiglitazone appears to slightly increase the risk of cardiovascular events whereas pioglitazone reduces it. Eight trials examined the benefits of adding pioglitazone to an insulin regimen; in our meta-analysis, the mean reduction in HbA1c level was 0.54% [95% confidence interval (CI) -0.70 to -0.38] and hypoglycaemia was marginally more frequent in the pioglitazone arms [relative risk (RR) 1.27, 95% CI 0.99 to 1.63]. In most studies, those on pioglitazone gained more weight than those who were not. In terms of annual drug acquisition costs among the non-insulin regimes for a representative patient with a body mass index of around 30 kg/m2, the gliptins were the cheapest of the new drugs, with costs of between 386 pounds and 460 pounds. The glitazone costs were similar, with total annual costs for pioglitazone and for rosiglitazone of around 437 pounds and 482 pounds, respectively. Exenatide was more expensive, with an annual cost of around 830 pounds. Regimens containing insulin fell between the gliptins and exenatide in terms of their direct costs, with a NPH-based regimen having an annual cost of around 468 pounds for the representative patient, whereas the glargine and detemir regimens were more expensive, at around 634 pounds and 716 pounds, respectively. Comparisons of sitagliptin and rosiglitazone, and of vidagliptin and pioglitazone slowed clinical equivalence in terms of quality-adjusted life-years (QALYs), but the gliptins were marginally less costly. Exenatide, when compared with glargine, appeared to be cost-effective. Comparing glargine with NPH showed an additional anticipated cost of around 1800 pounds. Within the comparison of detemir and NPH, the overall treatment costs for detemir were slightly higher, at between 2700 pounds and 2600 pounds. LIMITATIONS: The UKPDS Outcomes Model does not directly address aspects of the treatments under consideration, for example the direct utility effects from weight loss or weight gain, severe hypoglycaemic events and the fear of severe hypoglycaemic events. Also, small differences in QALYs among the drugs lead to fluctuations in incremental cost-effectiveness ratios. CONCLUSIONS: Exenatide, the gliptins and detemir were all clinically effective. The long-acting insulin analogues glargine and detemir appeared to have only slight clinical advantages over NPH, but had much higher costs and did not appear to be cost-effective as first-line insulins for type 2 diabetes. Neither did exenatide appear to be cost-effective compared with NPH but, when used as third drug after failure of dual oral combination therapy, exenatide appeared cost-effective relative to glargine in this analysis. The gliptins are similar to the glitazones in glycaemic control and costs, and appeared to have fewer long-term side effects. Therefore, it appears, as supported by recent NICE guidelines, that NPH should be the preferred first-line insulin for the treatment of type 2 diabetes. More economic analysis is required to establish when it becomes cost-effective to switch from NPH to a long-acting analogue. Also, long-term follow-up studies of exenatide and the gliptins, and data on combined insulin and exenatide treatment, would be useful.

The effect of commonly used anticoccidials and antibiotics in a subclinical necrotic enteritis model.

Necrotic enteritis poses an important health risk to broilers. The ionophore anticoccidials lasalocid, salinomycin, maduramicin, narasin and a combination of narasin and nicarbazin were tested in feed for their prophylactic effect on the incidence of necrotic enteritis in a subclinical experimental infection model that uses coccidia as a predisposing factor. In addition, drinking water medication with the antibiotics amoxicillin, tylosin and lincomycin was evaluated as curative treatment in the same experimental model. The minimal inhibitory concentrations (MICs) of all antibiotics and anticoccidials were determined in vitro against 51 Clostridium perfringens strains isolated from broilers. The strains examined appeared uniformly susceptible to lasalocid, maduramicin, narasin, salinomycin, amoxicillin and tylosin, whereas an extended frequency distribution range of MICs for lincomycin was seen, indicating acquired resistance in 36 isolates in the higher range of MICs. Nicarbazin did not inhibit the in vitro growth of the C. perfringens strains even at a concentration of 128 microg/ml. Supplementation of the diet from day 1 onwards with lasalocid, salinomycin, narasin or maduramicin led to a reduction in birds with necrotic enteritis lesions as compared with the non-medicated infected control group. A combination product of narasin and nicarbazin had no significant protective effect. Treatment with amoxicillin, lincomycin and tylosin completely stopped the development of necrotic lesions.

Caracteristicas sociodemograficas del perpetrador de delitos sexuales contra menores en la Ciudad de La Habana: periodo comprendido de septiembre del año 2005 a septiembre del 2006 / Demographic characteristics of the sexual crime perpetrator on minors (in havana city, from september -2006 to september -2007

Las agresiones sexuales repercuten más allá del hecho violento atentando contra la libertad y la dignidad de las personas y generando una compleja gama de trastornos en la integridad de la víctima y en su entorno familiar, educacional y social, además representan una de las más graves disfunciones de la convivencia humana; todo esto se agrava cuando la víctima es una personalidad en formación. Con nuestro estudio tratamos de darle solución al siguiente problema: ¿Qué factores personológicos y sociales caracterizan a los sujetos que cometen delitos sexuales contra menores? El beneficio mayor de este trabajo es de índole social, pues el descubrir y determinar las características del perpetrador ayudaría con una visión criminológica preventiva, unido a lo que ya sabemos sobre las víctimas, a reducir los índices de estos delitos y por ende las secuelas físicas y psíquicas que dejan y que en la mayoría de los casos dan al traste con la vida de las víctimas o provocan su hospitalización. Por lo tanto este proyecto nace de la necesidad imperiosa de buscar perfiles de los sujetos que cometen estos delitos, perfiles que se realizan desde el punto de vista criminológico. Para esto nos trazamos como objetivo establecer las condiciones sociodemográficas sobre la base de las variables edad, sexo, estado civil, nivel escolar, vinculación. Se realizó un estudio descriptivo, longitudinal prospectivo. El universo de trabajo estuvo comprendido por todos los individuos que fueron acusados formalmente en Ciudad de La Habana de cometer un delito sexual en el período comprendido entre septiembre de 2005 y septiembre de 2006. A cada caso se le realizó uniformemente, según criterios e instrumento preestablecidos, las siguientes investigaciones: cuestionario de recogida de datos, entrevista en profundidad, examen pericial psiquiátrico y prueba de funcionamiento familiar. Los perpetradores de delitos sexuales en su mayoría son hombres jóvenes de 21 a 45 años, ... (AU)

Sexual abuse impacts on victims further than the violent fact. It attempts against the freedom and dignity of the persons causing a complex spectrum of disorders on the victims integrity and on his or her social, educational and family environment, besides it represents one of the most critical dysfunctions of the human coexistence, becoming everything worse when the victim is a developing personality. With this work we try to bring a solution to the following problem: Which are the social and personological factors that characterized the perpetrator of sexual crime on minors? The greatest benefit of this work lies on its social condition, therefore, bringing to the light and determining the characteristics of the perpetrator joined with a preventive criminological vision, and what we have already known about the victims will help to reduce the levels of sexual crimes and resulting physical and psychological consequences. Consequently, this project emerged from the necessity of looking for the individuals profiles that commit these kinds of crimes. These profiles are performed from the criminological point of view. This target was developed having into consideration the social demographical conditions based on the variables of age, sex, marital status, educational level and employment condition. A perspective longitudinal descriptive study was carried out. The work included all the individuals properly accused for committing a sexual crime from September, 2005 to September, 2006 in Havana City. Investigations in each case according to criteria and pre-established instrument as compiled data questionnaire, extensive interview, psychiatric expert test and family functioning test were carried out. Most of the sexual crimes perpetrators are twenty-five to forty-five year men, with middle and higher education, and living with a stable couple. Three fourth of individuals do not present properly criminal records or previous convictions .... (AU)

Caracteristicas sociodemograficas del perpetrador de delitos sexuales contra menores en la Ciudad de La Habana: periodo comprendido de septiembre del año 2005 a septiembre del 2006 / Demographic characteristics of the sexual crime perpetrator on minors (in havana city, from september -2006 to september -2007

Las agresiones sexuales repercuten más allá del hecho violento atentando contra la libertad y la dignidad de las personas y generando una compleja gama de trastornos en la integridad de la víctima y en su entorno familiar, educacional y social, además representan una de las más graves disfunciones de la convivencia humana; todo esto se agrava cuando la víctima es una personalidad en formación. Con nuestro estudio tratamos de darle solución al siguiente problema: ¿Qué factores personológicos y sociales caracterizan a los sujetos que cometen delitos sexuales contra menores? El beneficio mayor de este trabajo es de índole social, pues el descubrir y determinar las características del perpetrador ayudaría con una visión criminológica preventiva, unido a lo que ya sabemos sobre las víctimas, a reducir los índices de estos delitos y por ende las secuelas físicas y psíquicas que dejan y que en la mayoría de los casos dan al traste con la vida de las víctimas o provocan su hospitalización. Por lo tanto este proyecto nace de la necesidad imperiosa de buscar perfiles de los sujetos que cometen estos delitos, perfiles que se realizan desde el punto de vista criminológico. Para esto nos trazamos como objetivo establecer las condiciones sociodemográficas sobre la base de las variables edad, sexo, estado civil, nivel escolar, vinculación. Se realizó un estudio descriptivo, longitudinal prospectivo. El universo de trabajo estuvo comprendido por todos los individuos que fueron acusados formalmente en Ciudad de La Habana de cometer un delito sexual en el período comprendido entre septiembre de 2005 y septiembre de 2006. A cada caso se le realizó uniformemente, según criterios e instrumento preestablecidos, las siguientes investigaciones: cuestionario de recogida de datos, entrevista en profundidad, examen pericial psiquiátrico y prueba de funcionamiento familiar. Los perpetradores de delitos sexuales en su mayoría son hombres jóvenes de 21 a 45 años...

Sexual abuse impacts on victims further than the violent fact. It attempts against the freedom and dignity of the persons causing a complex spectrum of disorders on the victim’s integrity and on his or her social, educational and family environment, besides it represents one of the most critical dysfunctions of the human coexistence, becoming everything worse when the victim is a developing personality. With this work we try to bring a solution to the following problem: Which are the social and personological factors that characterized the perpetrator of sexual crime on minors? The greatest benefit of this work lies on its social condition, therefore, bringing to the light and determining the characteristics of the perpetrator joined with a preventive criminological vision, and what we have already known about the victims will help to reduce the levels of sexual crimes and resulting physical and psychological consequences. Consequently, this project emerged from the necessity of looking for the individuals’ profiles that commit these kinds of crimes. These profiles are performed from the criminological point of view. This target was developed having into consideration the social demographical conditions based on the variables of age, sex, marital status, educational level and employment condition. A perspective longitudinal descriptive study was carried out. The work included all the individuals properly accused for committing a sexual crime from September, 2005 to September, 2006 in Havana City. Investigations in each case according to criteria and pre-established instrument as compiled data questionnaire, extensive interview, psychiatric expert test and family functioning test were carried out. Most of the sexual crimes perpetrators are twenty-five to forty-five year men, with middle and higher education, and living with a stable couple. Three fourth of individuals do not present properly criminal records or previous convictions....

Square wave voltcoulometry: a tool for the study of strongly adsorbed redox molecules.

A new multipotential pulse technique called square wave voltcoulometry (SWVC), based on the analysis of the difference of converted charge signals obtained between two successive half-cycles when a square wave potential is applied, is developed to study charge-transfer processes taking place in electroactive monolayers. The use of SWVC presents the advantage of giving rise to a peak-shaped response, which evolves to a charge plateau at high square wave pulse amplitudes, from which the total surface excess and the formal potential can be immediately measured for quasi-reversible and reversible processes. This characteristic represents its main advantage versus other multipotential step techniques, which lead to a negligible current under reversible conditions. The formal potential of the electroactive systems can be measured from the peak potential of the SWVC curves, even for quasi-reversible behavior. Moreover, the non-faradic effects on the response can be easily evaluated and avoided as is demonstrated in this paper. Experimental verification of the theoretical predictions is given for reversible and quasi-reversible systems.

Comparison and transferability of the erm (B) genes between human and farm animal streptococci.

To obtain better insights into the possible exchange of resistance genes between human and animal streptococci, the sequences of the erm (B) genes of streptococcal isolates from humans, pigs, pork carcasses, chickens, and calves were compared. Identical erm (B) gene sequences were present in strains from humans, pigs, pork carcasses, and calves. During in vitro mating experiments, the erm (B) gene was exchanged between porcine Streptococcus suis and human S. pneumoniae, S. pyogenes, and S. oralis strains. The presence of different tetracycline resistance genes and the int Tn 1545 gene was determined in animal streptococci carrying the erm (B) gene. Although tet(M) and int Tn 1545 genes were detected in 24% of the porcine and pork carcass streptococcal strains, the tet(O) gene was the predominant tetracycline resistance gene in these strains (81%). The latter gene was co-transferred with the erm (B) gene from porcine S. suis strains to human streptococci in the mating experiments. These results show that, identical erm (B) gene sequences were present in animal and human streptococci and that transfer of the erm (B) gene from porcine S. suis to human streptococci and vice versa is possible, but probably occurs at a low frequency.

In vivo upregulation of endogenous NGF in the rat brain by the alpha2-adrenoreceptor antagonist dexefaroxan: potential role in the protection of the basalocortical cholinergic system during neurodegeneration.

We have previously reported that the alpha2-adrenoceptor antagonist dexefaroxan protects against the degeneration of nucleus basalis magnocellularis (NbM) cholinergic neurons following cortical devascularization in the adult rat. Since nerve growth factor (NGF) is critical to the survival of NbM cholinergic neurons in the adult brain and its synthesis is known to be regulated by noradrenergic mechanisms, we examined whether the protective effect of dexefaroxan in the devascularization model was associated with regional induction of NGF biosynthesis. Dexefaroxan or vehicle was administered to rats via subcutaneous minipumps for 28 days following devascularization or sham operation procedures. In vehicle-treated devascularized rats, NGF protein levels in the cortex were increased at 5 days but had normalized by 2 weeks postoperation; NGF levels in NbM remained unchanged during this time. In dexefaroxan-treated devascularized rats, increases in NGF protein levels (2-fold) and immunoreactivity were maintained in both the cortex and NbM over the entire 28-day postoperation period; these increases were coincident with changes in functional markers characteristic of NGF's actions, including increases in choline acetyltransferase (ChAT), p75 and TrkA immunoreactivities, and a preservation of NbM cholinergic cell numbers. Dexefaroxan also increased NGF protein levels in sham-operated rats, but without any significant consequence to the otherwise normal NbM cholinergic phenotype in these animals. Results indicate that activation of endogenous NGF systems could contribute to the cholinergic protective effect of dexefaroxan in the cortical devascularization model, and provide further support for a potential therapeutic utility of dexefaroxan in neurodegenerative diseases where central cholinergic function is progressively compromised.

Protective effect of the alpha2-adrenoceptor antagonist, dexefaroxan, against spatial memory deficit induced by cortical devascularization in the adult rat.

The alpha2-adrenoceptor antagonist, dexefaroxan, has been shown in the rat to have neuroprotective and plastic effects against degenerative structural changes in elements of the basalocortical cholinergic system that result from cortical devascularization [Neuroscience 115 (2002) 41]. The present study, using the same experimental protocol, examined the functional consequences of cortical devascularization and dexefaroxan treatment in the Morris water maze memory test. Rats were first trained to find the hidden platform in the test, and then subjected to the devascularization procedure. Thirty-one days later, lesioned rats exhibited a significant deficit in recalling the platform location, compared with sham control animals. A 28-day subcutaneous infusion with dexefaroxan (0.63, 2.5, and 10 mg rat(-1) day(-1)), starting from the moment of the devascularization, protected against this spatial memory deficit.

Effects of the alpha 2-adrenoreceptor antagonist dexefaroxan on neurogenesis in the olfactory bulb of the adult rat in vivo: selective protection against neuronal death.

A dysfunction of noradrenergic mechanisms originating in the locus coeruleus has been hypothesised to be the critical factor underlying the evolution of central neurodegenerative diseases [Colpaert FC (1994) Noradrenergic mechanism Parkinson's disease: a theory. In: Noradrenergic mechanisms in Parkinson's disease (Briley M, Marien M, eds) pp 225-254. Boca Raton, FL, USA: CRC Press Inc.]. alpha(2)-Adrenoceptor antagonists, presumably in part by facilitating central noradrenergic transmission, afford neuroprotection in vivo in models of cerebral ischaemia, excitotoxicity and devascularization-induced neurodegeneration. The present study utilised the rat olfactory bulb as a model system for examining the effects of the selective alpha(2)-adrenoceptor antagonist dexefaroxan upon determinants of neurogenesis (proliferation, survival and death) in the adult brain in vivo. Cell proliferation (5-bromo-2'-deoxyuridine labelling) and cell death associated with DNA fragmentation (terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling assay) were quantified following a 7-day treatment with either vehicle or dexefaroxan (0.63 mg/kg i.p., three times daily), followed by a 3-day washout period. The number of terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling-positive nuclei in the olfactory bulb was lower in dexefaroxan-treated rats, this difference being greatest and significant in the subependymal layer (-52%). In contrast, 5-bromo-2'-deoxyuridine-immunoreactive nuclei were more numerous (+68%) in the bulbs of dexefaroxan-treated rats whilst no differences were detected in the proliferating region of the subventricular zone. Terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling combination with glial fibrillary acidic protein or neuronal-specific antigen immunohistochemistry revealed that terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling-positive nuclei were associated primarily with a neuronal cell phenotype. These findings suggest that dexefaroxan increases neuron survival in the olfactory bulb of the adult rat in vivo, putatively as a result of reducing the apoptotic fate of telencephalic stem cell progenies.

Protective effects of the alpha 2-adrenoceptor antagonist, dexefaroxan, against degeneration of the basalocortical cholinergic system induced by cortical devascularization in the adult rat.

It has been hypothesized [Colpaert, F.C., 1994. In: Briley, M., Marien, M. (Eds.), Noradrenergic Mechanisms in Parkinson's Disease. CRC Press, Boca Raton, FL, pp. 225-254] that a deficiency in the noradrenergic system originating from the locus coeruleus is a decisive factor in the progression of central neurodegenerative disorders including Alzheimer's disease, and that treatments which boost noradrenergic transmission (e.g. via blockade of alpha(2)-adrenoceptors) could provide both symptomatic and trophic benefits against the disease. Studies in the rat in vivo demonstrating that the selective alpha(2)-adrenoceptor antagonist dexefaroxan increases acetylcholine release in the cortex, improves measures of cognitive performance and protects against excitotoxin lesions, support this concept. As a further test of the hypothesis, we investigated the effect of dexefaroxan in a rat model of unilateral cortical devascularization that induces a loss of the cortical cholinergic terminal network and a retrograde degeneration of the cholinergic projections that originate in the nucleus basalis magnocellularis. Lesioned and sham-operated rats received a 28-day subcutaneous infusion of dexefaroxan (0.63 mg/rat/day) or vehicle, delivered by osmotic minipumps implanted on the day of the cortical devascularization procedure. In lesioned rats, the dexefaroxan treatment was associated with a significantly higher number and size of vesicular acetylcholine transporter-immunoreactive boutons in comparison to the vehicle treatment; this effect was most marked within cortical layer V. Dexefaroxan also significantly reduced the atrophy of cholinergic neurons within the nucleus basalis magnocellularis. Dexefaroxan had no observable effect on any of these parameters in sham-operated cohorts. These results show that systemically administered dexefaroxan mitigates cholinergic neuronal degeneration in vivo, and provide further evidence for a therapeutic potential of the drug in neurodegenerative diseases such as Alzheimer's disease, where central cholinergic function is progressively compromised.

Noradrenaline provides long-term protection to dopaminergic neurons by reducing oxidative stress.

To better understand the neurotrophic function of the neurotransmitter noradrenaline, we have developed a model of mesencephalic cultures in which we find low concentrations (0.3-10 microM) of noradrenaline to be remarkably effective in promoting long-term survival and function of dopaminergic neurons. This protective action reproduced the effect of caspase inhibition. It was atypical in that it occurred independently of adrenoceptor activation and was mimicked by some antioxidants, redox metal chelators and the hydroxyl radical detoxifying enzyme catalase. Interestingly, intracellular reactive oxygen species (ROS) were drastically reduced by treatment with noradrenaline, indicating that the neurotransmitter itself acted as an antioxidant. Prevention of oxidative stress was, however, independent of the glutathione antioxidant defense system. Chemical analogues of noradrenaline bearing two free hydroxyl groups in the ortho position of the aromatic ring (o-catechols), as well as o-catechol itself, mimicked the survival promoting effects of the neurotransmitter, suggesting that this diphenolic structure was critical for both neuroprotection and reduction of ROS production. Paradoxically, the autoxidation of noradrenaline and the ensuing production of quinone metabolites may be required for both effects, as the neurotransmitter was spontaneously and rapidly degraded over time in the culture medium. These results support the concept that central noradrenergic mechanisms have a neuroprotective role, perhaps in part by reducing oxidative stress.

Synthesis and SAR of new 5-phenyl-3-ureido-1,5-benzodiazepines as cholecystokinin-B receptor antagonists.

A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition of substituents at the urea side chain provided in some cases more potent compounds. Moreover the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the racemic ureas resulted in our lead compound GV150013.

New substituted 1-(2,3-dihydrobenzo[1, 4]dioxin-2-ylmethyl)piperidin-4-yl derivatives with alpha(2)-adrenoceptor antagonist activity.

The emergence of a novel theory concerning the role of noradrenaline in the progression and the treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases has provided a new impetus toward the discovery of novel compounds acting at alpha(2)-adrenoceptors. A series of substituted 1-(2, 3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-4-yl derivatives bearing an amide, urea, or imidazolidinone moiety was studied. Some members of this series of compounds proved to be potent alpha(2)-adrenoceptor antagonists with good selectivity versus alpha(1)-adrenergic and D(2)-dopamine receptors. Particular emphasis is given to compound 33g which displays potent alpha(2)-adrenoceptor binding affinity in vitro and central effects in vivo following oral administration.

Drug treatments to reduce excitotoxicity in vivo: a potential for alpha2-adrenoceptor antagonists?

It is hypothesized that the locus coeruleus-noradrenergic system controls compensatory and repair mechanisms in the CNS, and that its dysfunction is a critical factor in the progression of central neurodegenerative diseases. Pharmacological activation of locus coeruleus neurons can be achieved with alpha2-adrenoceptor antagonists, and such compounds are protective in vivo in some models of brain injury where excitotoxicity is thought to be a causative factor. To further explore this neuroprotective potential, the effects of a 7-day treatment with the alpha2-antagonists, (+)-efaroxan and (+/-)-idazoxan, were evaluated in rats undergoing a unilateral lesioning of the striatum with the excitotoxin, quinolinic acid. The alpha2-antagonist treatments reduced both the ipsiversive circling response to apomorphine and the deficit of choline acetyltransferase in the lesioned animals. To elucidate the mechanisms underlying this neuroprotective effect, a modulation of the extracellular levels of amino acids within the striatum was investigated using in vivo microdialysis. Intrastriatal injection of quinolinic acid increased taurine and tyrosine levels by 2-2.5 fold, while most other amino acids were not significantly altered; the effect of (+)-efaroxan on these changes is being investigated. Further research is required to identify which of several possible mechanisms is involved in the neuroprotective action of alpha2-antagonists in vivo.