Histamine H3-receptor inverse agonists as novel antipsychotics.

Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ.

A metabolic approach to simulating the dynamics of C-14, H-3 and S-35 in sheep tissues.

The results of a study in which groups of sheep were given single oral administrations of 14C, 3H and 35S and then slaughtered over a period of 1 year are reported. The experimental data were used to investigate the potential of metabolically based models for describing the transfer of the three radionuclides to sheep tissues. The structure of these models is based upon a simplified understanding of the transfer of the macro-elements C, H and S by processes such as respiration and protein synthesis/degradation. A consequence of this approach is that the three models have many common parameters. The models reproduced the general trends of the observations, accounting for 74%, 66%, and 58% of the observed variation in the 14C, 3H and 35S data, respectively, suggesting that they may provide a useful alternative approach to modelling the transfer of these radionuclides. The models presented are limited to the particular experimental situation for which they were developed, and further experimental work would be required to extend them. However, such metabolically based models have great potential: for example, they should be able to account for the influence of dietary intake, physiological status or the form of the radionuclide in the animals diet (e.g. tritiated water or organically bound tritium).

Oligoradionuclidetherapy using radiolabelled antisense oligodeoxynucleotide phosphorothioates.

Radiolabelled antisense oligodeoxynucleotides have been used for in vivo biokinetic studies in AIDS and cancer patients. The therapeutic possibilities are still unknown and the major question in therapeutic use of radio-oligonucleotide is the optimal source of radiation. We studied the pharmacokinetics and in vivo tissue distribution for oligodeoxynucleotide phosphorothioates by using the data from three different radionuclides: sulphur-35 (t1/2 = 87.4 days, maximum beta-energy = 167 keV), phosphorus-33 (t1/2 = 24.4 days, maximum beta-energy = 250 keV) and phosphorus-32 (t1/2 = 14.3 days, maximum beta-energy = 2270 keV). The absorbed doses of 32P-, 33P- and 35S-labelled oligonucleotides were estimated using the published biodistribution data for several oligonucleotides in two animal models for both tumour xenografts and AIDS. The local energy absorption of 33P turned out to be higher than that of 32P if the mass was smaller than approximately 300 micrograms, and the local absorption of 35S was higher than that of 32P when the mass was <80 micrograms. In a mouse tumour xenograft model an i.v. injected activity seemed to achieve sufficient radiation doses in the tumour: in a 1 g tumour 4.9 Gy for 32P, 5.1 Gy for 33P and 5.5 Gy for 35S were calculated when the kidney dose was kept as 5 Gy. In the same model in smaller tumours the doses were for a 1 mg tumour 0.73 Gy (32P), 5.1 Gy (33P) and 5.5 Gy (35S), and for a 1 microgram tumour 0.08 Gy (32P), 3.1 Gy (33P) and 3.9 Gy (35S). Thus, 33P and 35S have more beneficial radiotherapeutic characteristics than 32P. Relative advantage factors (33P and 35S versus 32P) for kidney and liver doses using these nuclides varied from 0.997 to 1.001 for a 1 g tumour and there was no difference in the radiation dose to normal organs. Therefore, we conclude that in oligonucleotide radiotherapy tumours >1 g should be treated with 32P, whereas smaller tumours should be treated with 33P or 35S. There is no significant difference between 33P and 35S, and either radionuclide could be selected according to labelling properties.

[Effect of low doses of internal irradiation resulting from the administration of 75Se- and 35S-labeled compounds on the cellular immune response]. / Vliianie malykh doz vnutrennego oblucheniia, formiruiushchikhsia pri vvedenii v organizm soedinenii 75Se i 35S, na kletochnyi immunnyi otvet.

The administration to rats of radioactive preparations. 75Se- selenomethionine, 35S-methionine or sodium 75Se-selenite in the amounts creating the absorbed dose in the body of 0.5 Gy suppressed the delayed hypersensitivity reaction as was registered 1-12 months after the injection. The delayed hypersensitivity was tested in vitro by the method of inhibimacrophage spreding inhibition. The degree of suppression of the cellular immune response depended upon the type of the compound administered, of which the radionuclide was a component, and upon characteristics of radiation spectrum of the radionuclide.

The radiation dose to man following the intravenous injection of radiosulphate (Na2(35)SO4).

An estimation of the radiation dose to mans' testes, the critical organ, for radiosulphate (Na2(35)SO4) has been made by a combination of studies on rats and human volunteers. The radiation dose to rats testes and the rate of disappearance of radiosulphate from the blood and urine of humans have been increased. The calculated radiation dose of 7.7 muGy/MBq to mans' testes is lower than previously reported.

[Lymphocyte migration in internally irradiated animals. Effect of internal beta radiation on the migration of spleen lymphocytes in CBA mice]. / Migratsiia limfotsitov v organizme v usloviiakh vnutrennego oblucheniia. Vliianie vnutrennego beta-izlucheniia na migratsiiu limfotsitov selezenki myshei CBA.

The syngeneic transfer system was used to study migration of 51Cr-labelled spleen lymphocytes in mice after incorporation of beta-emitter, 35S-methionine. Migration of 51Cr-labelled lymphocytes to lymph nodes was stably decreased, and to liver, kidneys and lungs increased. The lymphocyte migration impairment was associated with the influence of beta-radiation on both the migratory properties of cells and the factors of their microenvironment responsible for the lymphocyte migration within the mouse body. No distinctions were observed in the character and manifestation of disturbances of the lymphocyte migration after the injection of 35S-methionine and gamma-emitter, 75Se-selenomethionine.

Iodide and thiocyanate efflux from brain following injection into rat caudate nucleus.

Mechanisms and pathways of 125I and 35SCN efflux from the brain were investigated in anesthetized rats. Tracers were injected into the caudate nucleus through a guide cannula implanted 1 wk previously and concentrations of isotope in brain and cerebrospinal fluid (CSF) were determined at various times after injection. 125I clearance from the brain followed a single exponential curve. In control rats 36.2% of the 125I remained in the brain 30 min after injection and 60.4% in rats pretreated with perchlorate. Comparable values for 35SCN were 25.8% in control rats, 41.0% with perchlorate, and 39.7% with iodide loading. Estimates of 125I and 35SCN effluxes from the brain via the blood-brain barrier and CSF pathways suggest that greater than 95% of efflux crosses the blood-brain barrier. These results indicate that 1)iodide and thiocyanate are transported across the blood-brain barrier by a common mechanism, and 2) this efflux system is an important factor in the control of the distributions of iodide and thiocyanate in the central nervous system.

Monoaminergic influences on the incorporation of 35S in the hypothalamic and neurohypophysial proteins following intracerebroventricular injection of 35S-cysteine in dehydrated rats.

In the rats dehydrated for 48 h the mean specific activity of hypothalamic and neurohypophysial TCA-precipitable proteins following intracerebroventricular injection of L-cysteine-35S-hydrochloride was significantly higher than that found in the dehydrated and reserpinized. Under influence of amphetamine sulfate however, no change of 35S-uptake by TCA-precipitable hypothalamic and neurohypophysial proteins could be detected in rats similarly dehydrated.