Structure - activity studies with histamine H3 - receptor ligands

Se han sintetizado análogos de tioperamida. Los compuestos han sido ensayados in vitro para explorar los factores que permitan diseñar compuestos derivados de la tioperamida sin grupo tiourea que mejoren la penetración cerebral. Los compuestos más activos como H3-antagonistas contienen un átomo de nitrógeno aromático hetorocíclico sobre la cadena lateral. Estos compuestos se han empleado como cabeza de serie para obtener potentes H3-antagonistas de histarnina con estructura de ariloxietil y ariloxipropilimidazoles. Las relaciones estructura actividad de agonistas se han revisado brevemente. Se han estudiado un grupo de análogos de (S-[2-imidazol-4-il)etil]isotiourea (imetit) con el objeto de explorar la transición entre agonistas y antagonistas. N,N' -dibutil-[S-[3-(imidazol- 4-il)propil]isotiourea es un muy potente antagonistas que tiene Ki=1.5 nM.Analogues of thioperamide have been synthesised and tested in vitro on rat cerebral cortex to explore structure-activity relationships with the intention of designing compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Compounds derived from histamine and having an aromatic nitrogen containing heterocyc1e on the side-chain amino group have been found to act as H3 - antagonists. These have served as leads to provide aryloxyethyl- and aryloxypropylimidazoles which are potent H3 antagonists of histamine. Structure-activity relationships for agonists are brief1y reviewed. Analogues of the very potent and selective agonist, imetit (S-[2-imidazol-4-yl)ethyl]isothiourea) have been studied to explore the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist. N,N' -Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having K¡=1.5 nM

The role of hypothalamic H1 receptor antagonism in antipsychotic-induced weight gain

Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK—carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity

The waking brain: an update

Wakefulness and consciousness depend on perturbation of the cortical soliloquy. Ascending activation of the cerebral cortex is characteristic for both waking and paradoxical (REM) sleep. These evolutionary conserved activating systems build a network in the brainstem, midbrain, and diencephalon that contains the neurotransmitters and neuromodulators glutamate, histamine, acetylcholine, the catecholamines, serotonin, and some neuropeptides orchestrating the different behavioral states. Inhibition of these waking systems by GABAergic neurons allows sleep. Over the past decades, a prominent role became evident for the histaminergic and the orexinergic neurons as a hypothalamic waking center

Histaminergic system in brain disorders: lessons from the translational approach and future perspectives

Histamine and its receptors were first described as part of immune and gastrointestinal systems, but their presence in the central nervous system and importance in behavior are gaining more attention. The histaminergic system modulates different processes including wakefulness, feeding, and learning and memory consolidation. Histamine receptors (H1R, H2R, H3R, and H4R) belong to the rhodopsin-like family of G protein-coupled receptors, present constitutive activity, and are subjected to inverse agonist action. The involvement of the histaminergic system in brain disorders, such as Alzheimer’s disease, schizophrenia, sleep disorders, drug dependence, and Parkinson’s disease, is largely studied. Data obtained from preclinical studies point antagonists of histamine receptors as promising alternatives to treat brain disorders. Thus, clinical trials are currently ongoing to assess the effects of these drugs on humans. This review summarizes the role of histaminergic system in brain disorders, as well as the effects of different histamine antagonists on animal models and humans

Monoaminergic and histaminergic strategies and treatments in brain diseases

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.peer-reviewe

Aplikasi Modified Proctor Pada Roller Compacted No-fines Concrete Dengan Agregat 5-10 Mm

The usage of no-fines concrete as pavement currently was being utilized. It was constituted by diversity effort of concrete cement pavement construction material, besides no-fines concrete pavement having benefit that reduce water pond on pavement surface rapidly because of its pervious. Permeability character of no-fines concrete will recharge groundwater deposit therefore more environmental friendly. Problem faced is low strength of no-fines concrete as compared to conventional concrete. Therefore it is required the effort of increasing the strength of no-fines concrete by increase concrete density that is done by roller machine. No-fines concrete that is compacted by roller machine is called Roller Compacted No-fines Concrete (RCNC). This research analyzed the increase of concrete properties especially compression strength and split tensile strength effected by external compaction using modified proctor in creating the laboratory specimen. Materials of no-fines concrete utilized Clereng coarse aggregate with size 5-10 mm, Gresik Portland cement and the aggregate cement ratio is 4 and 6. To accelerating the hardening concrete utilized admixture type C which is sikaset accelerator with 20% of total water volume. The blow variation of modified Proctor per layer is 28, 42 and 56. Compression test and split tensile test been done at the age of  1 and 28 days. Result of research showed the increase of concrete specific gravity and compression strength in line with the increase of blow variation. RCNC specific gravity acquired ranging between 1,544 and 1,788. Compression strength at the age of 28 days acquired were (1) aggregate cement ratio 4 with 28, 42, 56 blows per layer were 21,47 MPa, 22,92 MPa, 26,55 MPa (2) aggregate cement  ratio 6 each were 8,48 MPa, 10,51 MPa, 14,82 MPa. Split tensile strength at the age of 28 days were (1) aggregate cement ratio 4 with 28, 42, 56 blows per layer each were 2,27 MPa, 2,92 MPa, 3,13 MPa (2) aggregate cement ratio 6 each were 1,63 MPa, 1,83 MPa, 2,08 MPa

Hubungan Kecepatan, Volume dan Kepadatan Lalulintas di Jalan Dr. Ratulangi (Depan City Market Palopo) Menggunakan Model Greenshields

Terbangunnya City Market Palopo sebagai salah satu pusat perbelanjaan di Kota Palopo memberikan dampak pada bertambahnya volume lalulintas di Jalan Dr. Ratulangi, di mana jalan tersebut merupakan salah satu jalan utama yang menjadi penghubung antara Makassar sebagai ibu kota Propinsi Sulawesi Selatan ke daerah seperti Luwu Utara, Luwu Timur bahkan ke Propinsi Sulawesi Tengah, dan Sulawesi Tenggara. Adanya peningkatan volume lalu lintas akan menyebabkan berubahnya perilaku lalu lintas. Secara teoritis terdapat hubungan yang mendasar antara volume (flow) dengan kecepatan (speed) serta kepadatan (density). Penelitian dilakukan dengan survey arus, kecepatan dan mengambil data geometrik pada lokasi penelitian. Data kemudian diolah dan dianalisis dengan metode Greeshields. Dari analisis tersebut diperoleh persamaan hubungan antara volume dan kepadatan adalah Q = 30.766 D – 0.081 D2, sementara persamaan hubungan antara kecepatan dan kepadatan adalah S =3 0.766 – 0.081 D dan persamaan hubungan antara kecepatan dan volume adalah Q = 377.144 – 12.258 S2. Analisis menunjukkan bahwa grafik hubungan antara arus, kecepatan dan kepadatan sesuai dengan model Greenshield

Evaluasi Tingkat Pelayanan Jalan Perkerasan Kaku dengan Metode Pci (Pavement Condition Index) – Studi Kasus Jl. Ahmad Razak, Jl. Tandipau & Jl. Khm. Kasim Kota Palopo

Beban lalu lintas yang berulang-ulang seiring dengan berjalannya waktu akan menimbulkan kerusakan yang berdampak pada menurunnya tingkat pelayanan jalan. Hal ini terjadi bukan hanya pada struktur perkerasan lentur tapi juga pada perkerasan kaku. Salah satu cara yang dapat digunakan untuk menilai tingkat pelayanan jalan adalah metode PCI (Pavement Condition Index). Penelitian ini dilakukan dengan melakukan survey dengan mengamati secara visual jenis-jenis kerusakan dan tingkat kerusakan yang ada di sepanjang Jl. Ahmad Razak, Tandipau dan KHM Kasim di Kota Palopo. Data survey pengamatan kemudian diolah yang akan menghasilkan nilai numerik PCI yang dapat mengindikasikan tingkat pelayanan pada jalan yang diteliti. Hasil penelitian menunjukkan bahwa Jl. Ahmad Razak memiliki nilai PCI 87 dengan ratingGood, sementara Jl. Tandipau nilai PCI 85 dengan rating satisfactory dan Jl. KHM Kasim nilai PCI 91 dengan rating Good

Analisis Kinerja Pendapatan Asli Daerah (PAD) Provinsi Papua 2009-2017

Penelitian ini bertujuan untuk mengetahui kinerja pendapatan Provinsi Papua tahun 2009-2017 dan Strategi Peningkatan pendapatan asli daerah di Provinsi Papua. Jenis data yang digunakan dalam penelitian ini adalah menggunakan data runtun waktu selama sembilan tahun yaitu tahun 2009-2017. Objek yang diteliti adalah hasil laporan realisasi pendapatan daerah Provinsi Papua selama sembilan tahun. Metode analisis data yang digunakan adalah rasio kemandirian, rasio ketergantungan dan rasio efektivitas pendapatan. Hasil penelitian ini menunjukkan secara deskriptif Kinerja Pendapatan Asli Daerah Provinsi Papua dilihat dari tingkat kemandirian keuangan berkisar antara 6,14 persen – 8.67 persen, nilai ini menunjukkan bahwa kriteria penilaian pada tahun 2009-2017 berada diposisi instruktif yaitu pola hubungan dimana peranan pemerintah pusat dari sisi fiskal lebih dominan dari pada kemandirian pemerintah daerah dalam menghasilkan atau menciptakan pendapatannya sendiri atau dalam kata lain bahwa pemerintah daerah belum mampu melakukan otonomi daerah atau masih bergantung pada pemerintah pusat. Ketergantungan pemerintah daerah selama tahun 2009-2017 terhadap pemerintah pusat masih sangat tinggi, hal ini dapat dilihat dari rata-rata rasio ketergantungan sebesar 83.33%. Efektivitas Pendapatan Asli Daerah Provinsi Papua yang diperoleh selama tahun 2009-2017 secara umum dikatakan sangat efektif. Hal ini ditunjukkan dengan rata-rata efektivitas pendapatan sebesar 106.61%.Kata Kunci: Kinerja Keuangan, Pendapatan Asli Daera

Arus Lalu Lintas, Kapasitas dan Tingkat Pelayanan Ruas Jalan dalam Kota Rantepao

Transportasi mempunyai hubungan yang erat dengan pembangunan. Lancarnya arus lalu lintas akan mendukung arus distribusi barang serta meningkatkan mobilitas masyarkat dalam usaha pemenuhan kebutuhan. Salah satu parameter yang penting untuk diketahui dalam perencanaan lalu lintas perkotaan adalah kapasitas jalan. Kapasitas adalah daya tampung maksimum jalan. Tingkat pelayanan jalan akan menurun seiring dengan meningkatnya rasio volume per kapasitas jalan. Penelitian ini dilakukan dengan survey kondisi geometrik, konfigurasi lajur, hambatan samping dan jumlah kendaraan dalam berbagai jenis pada beberapa ruas jalan dalam Kota Rantepao. Data kemudian diolah berdasarkan MKJI 1997 sehingga diperoleh kapasitas masing-masing jalan, sementara untuk tingkat pelayanan jalan diperoleh dengan membandingkan kondisi arus lalu-lintas dengan kapasitas jalan.  Hasil penelitian menunjukkan bahwa arus maksimum tertinggi terjadi di Jl. Pongtiku yaitu sebesar 1.423,4 SMP/Jam pada pagi hari Pukul 07.00 – 08.00. Sementara kapasitas ruas Jl. Mongsidi sebesar 2.225,65 SMP/Jam; Jl. Pongtiku 2.612,71 SMP/Jam; Jl. A. Mappanyuki 1.355,85 SMP/Jam per lajur; Jl. Ahmad Yani 1.333,86 SMP/Jam per lajur; dan Jl. Poros Rantepao – Bolu sebesar 2.534,33 SMP/Jam. Ratio V/C saat kondisi arus maksimum untuk Jl. Mongsidi 0,36; Jl. Pongtiku 0,54;  Jl. A. Mappanyuki arah selatan dan utara masin-masing 0,35 dan 0,26;Jl. A. Yani arah utara dan selatan  0,51 dan 0,52; sementara Jl. Poros Rantepao – Bolu 0,42; Semuanya dalam tingkat pelayanan tipe