[Peculiarities of growth of the monocellular green algae culture after the influence of electromagnetic field in deuterated water-containing media].

Exposing the inoculum of monocellular green algae Dunalialla tertiolecta and Tetraselmis viridis to 50 Hz electromagnetic field for several hours resulted in a reduced growth rate in both cultures. It was ascertained that heavy water inhibited growth of algae Dunaliella tertiolecta. The light water activated growth of the culture in the exponential phase only.

The design and synthesis of novel NK1/NK2 dual antagonists.

Functional probing of the backbone of the Sanofi NK2 antagonist SR 48968 has resulted in the discovery of two new classes of NK1/NK2 dual antagonists: the diamine class and the oxime class. The addition of the amino or the oxime functional group results in the reversal of the stereochemical preference of the NK2 receptor.

Sch 50971, an orally active histamine H3 receptor agonist, inhibits central neurogenic vascular inflammation and produces sedation in the guinea pig.

We studied the actions of Sch 50971, a novel histamine H3 receptor agonist, in an experimental neurogenic model of migraine and characterized its sedative and respiratory actions. Sch 50971 (i.v. and p.o) inhibited plasma protein extravasation in the dura mater of guinea pigs after electrical stimulation of the trigeminal ganglia. The minimum effective doses of Sch 50971 were 3.0 mg/kg i.v. and 10 mg/kg p.o., which produced a 40% and 42% decrease in plasma protein extravasation, respectively. The effects of Sch 50971 (3.0 mg/kg i.v. ) were blocked by the histamine H3 antagonist thioperamide (3.0 mg/kg i.v.). The 5-HT1D agonist, sumatriptan (0.3 mg/kg i.v.), and the histamine H3 agonist, (R)-alpha-methylhistamine (0.3 mg/kg), also inhibited plasma extravasation by 40 and 46%. In sedation studies, Sch 50971 (1-100 mg/kg p.o.) potentiated pentobarbital-induced sleep. The ED40 min for Sch 50971, the benzodiazepines triazolam and diazepam, the histamine H1 antagonist diphenhydramine and the H3 receptor agonist (R)-alpha-methylhistamine were 7.0, 0.5, 2.3, 14.1 and 23.4 mg/kg p. o., respectively. The sedative effects of oral Sch 50971 was blocked by thioperamide (10 microgram i.c.v.). The sedative activity of Sch 50971 was also examined using EEG activity, locomotor activity and sleep. In conscious guinea pigs, Sch 50971 (10 mg/kg p.o.) depressed locomotor activity, increased total sleep time and produced EEG patterns consistent with physiological sleep. Sch 50971 decreased beta wave activity but had no effects on delta wave activity, theta activity or alpha wave activity. In contrast, triazolam (1.0 mg/kg p. o.) depressed delta and theta wave activity and produced large increases in alpha and beta wave activity. In conclusion, Sch 50971 is an orally active, potent and selective agonist of histamine H3 receptors that may act to ameliorate the sequelae of migraine headaches, where activation of histamine H3 receptors may be beneficial. Sch 50971 also decreases motor activity and promotes EEG activity consistent with physiological sleep.

Studies on the pharmacology of the novel histamine H3 receptor agonist Sch 50971.

Experiments were performed to characterize the pharmacology of Sch 50971 ((+)-trans-4-(4(R)-methyl-3(R)-pyrolidinyl)-1H-imidazole dihydrochloride, CAS 167610-28-8), a novel histamine H3 receptor agonist. The activity of Sch 50971 was compared with that of (R)-alpha-methylhistamine (CAS 75614-87-8), a potent and moderately selective agonist of histamine H3 receptors, in a series of in vitro and in vivo assays. Sch 50971 is a high affinity, selective H3 receptor agonist in vitro and in vivo. Sch 50971 inhibits [3H]-N-alpha-methylhistamine (CAS 673-50-7) binding to the histamine H3 receptor in human brain (Ki = 5.0 nmol/l) and guinea pig brain (Ki = 2.5 nmol/l). Sch 50971 also inhibits electric field stimulated guinea pig ileum contractions (pD2 = 7.47) and decreases [3H]-norepinephrine (CAS 51-41-2) release (pD2 = 7.48) from guinea pig pulmonary artery by activation of presynaptic inhibitory H3 receptors. The in vitro effects of Sch 50971 are antagonized by low concentrations of a selective H3 antagonist, thioperamide (CAS 106243-16-7). Sch 50971 has low affinity (IC50's > 10 mumol/l) for histamine H1, dopamine D1 and D2, serotonin 5-HT2 and muscarinic cholinergic receptors. It also does not exhibit histamine H2-antagonist activity. In guinea pigs and cats, Sch 50971 exhibits in vivo H3 agonist activity. Sch 50971 inhibits sympathetic hypertension evoked by stimulation of the medulla oblongata in anesthetized guinea pigs (ED30 = 0.3 mg/kg i.v., ED30 = 1.0 mg/kg i.d.). Sch 50971 also inhibits the effects of sympathetic nerve stimulation on nasal resistance in cats. In these assays, Sch 50971 exhibits an efficacy and potency comparable to H3-agonist (R)-alpha-methylhistamine. However, under in vivo conditions, Sch 50971 does not exhibit histamine H1-mediated responses that are seen with (R)-alpha-methylhistamine at doses close to those that produce H3 effects. Therefore, Sch 50971 is a novel, potent and selective agonist of histamine H3 receptors with an improved in vitro and in vivo receptor profile selectivity compared with (R)-alpha-methylhistamine.

Perspectives from the global poliomyelitis eradication initiative.

Ten years after the year 2000 target was set by the World Health Assembly, the global poliomyelitis eradication effort has made significant progress towards that goal. The success of the initiative is built on political commitment within the endemic countries. A partnership of international organizations and donor countries works to support the work of the countries. Interagency coordinating committees are used to ensure that all country needs are met and to avoid duplication of donor effort. Private sector support has greatly expanded the resources available at both the national and international level. At the programmatic level, rapid implementation of surveillance is the key to success, but the difficulty of building effective surveillance programmes is often underestimated. Mass immunization campaigns must be carefully planned with resources mobilized well in advance. Programme strategies should be simple, clear and concise. While improvements in strategy and technology should be continuously sought, changes should be introduced only after careful consideration. Careful consideration should be given in the planning phases of a disease control initiative on how the initiative can be used to support other health initiatives.

Trans-4-methyl-3-imidazoyl pyrrolidine as a potent, highly selective histamine H3 receptor agonist in vivo.

Extensive structural modification of immepyr (+)-2 led to the discovery of trans-4-methyl-3-imidazoyl pyrrolidine (+/-)-3a as a potent and highly selective H3 agonist. The pyrroline (+/-)-3a was resolved, and its (+) enantiomer, Sch 50971 [(+)-3a], showed a greater separation of H3 and H1 activities in vivo (H3/H1 ratio >> 330) than (R)-alpha-methylhistamine (+)-1 (H3/H1 ratio = 17), the standard H3 agonist.

4-[(1H-imidazol-4-yl) methyl] benzamidines and benzylamidines: novel antagonists of the histamine H3 receptor.

A series of amidine substituted phenyl-, benzyl-, and phenethylimidazoles based on the known H3 agonist SK&F 91606 (4) has been synthesized and tested as ligands for the histamine H3 receptor. Insertion of a phenyl ring between the imidazole ring and the amidine moiety produces antagonists. The benzyl series was found to be the most potent and was further investigated. Compounds 9c and 18 (entries 5 and 12, Table 1) are potent ligands for the H3 receptor with K(i) values of 16 nM and 7.2 nM respectively. In vivo, both compounds were shown to be equipotent to thioperamide (2), the standard H3 antagonist.

Progress toward poliomyelitis eradication in the Eastern Mediterranean Region of the World Health Organization.

The Eastern Mediterranean Region (EMR) of the World Health Organization has made substantial progress toward eradicating poliomyelitis. From 1988 to 1995, the number of confirmed cases of polio decreased 66%, from 2342 to 789. National immunization days were conducted in 18 (78%) of the 23 countries in 1995, representing 88% of the regional population. By 1995, 20 countries (87%) in the EMR had established systems for reporting acute flaccid paralysis (AFP), 20 (87%) were investigating AFP or polio cases epidemiologically, 18 (78%) had initiated follow-up at 60 days to confirm or discard suspected polio cases, 7 (30%) had achieved nonpolio AFP rates of > or = 1.0/100,000 children <15 years of age (a measure of the sensitivity of surveillance), and 16 (70%) had made laboratory investigations of polio cases for 1281 (74%) of the 1715 AFP cases reported in the EMR. Despite significant progress, the success of the polio eradication initiative in the EMR will depend on finding solutions to a number of technical, managerial, political, and financial challenges.

Outbreak of paralytic poliomyelitis in a highly immunized population in Jordan.

Between November 1991 and March 1992, 37 cases of paralytic poliomyelitis occurred in Jordan, where none had been reported since 1988. Of these, 17 (50%) of 34 patients had received at least three doses of oral poliovirus vaccine (OPV3). The first and 2 subsequent case-patients were children of Pakistani migrant workers, and the first 8 and a total of 27 (75%) case-patients resided in or near the Jordan Valley. A seroepidemiologic study of 987 children in all regions of Jordan was performed to assess OPV3 coverage and immune response to OPV. Although OPV3 coverage by 12 months of age was high (96%) in the general population, coverage was lower among Pakistani (21%), Bedouin (63%), and Gypsy (9%) children (P < .001). Seroprevalences for poliovirus type 3 were 71% in the Jordan Valley versus 81% in other regions after 3 doses of OPV (P < .06) and 77% in the Jordan Valley versus 98% in other regions after 5 doses of OPV (P < .001). This outbreak demonstrates the importance of achieving high seroimmunity to infection in all geographic areas to prevent the reintroduction and spread of imported strains of wild poliovirus.

Evaluation of oral poliovirus vaccine delivery during the 1994 national immunization days in Pakistan.

Pakistan conducted national immunization days (NIDs) for the first time in 1994. To estimate coverage, to evaluate risk factors for failure to be immunized, and to determine the effectiveness of mass media, parents of 1288 children in 714 households in four districts were surveyed after the first NID round. In each district, a high proportion of children (93%-96%) received oral poliovirus vaccine (OPV) during the NID. In three districts, unimmunized or partially immunized children were less likely to receive NID OPV than were fully immunized children (Kohistan, P < .001; Quetta, P < .001; and Sibi, P = .05). Although a high proportion of children in each age cohort received NID OPV, in three districts children 0-11 months of age were less likely to receive NID OPV than were older children. Television and radio reached a high proportion of survey households, but other mass media were less effectively utilized. Risk factor and media effectiveness surveys provide important information that is useful for planning future NIDs.

A novel pyrrolidine analog of histamine as a potent, highly selective histamine H3 receptor agonist.

Employing classical conformational analysis on a known H3 agonist, (R)-alpha-methylhistamine (1), a series of conformationally constrained H3 agonists were proposed and synthesized. Pyrrolidine (+/-)-4a, a compound proposed to mimic the anti-conformation of (R)-alpha-methylhistamine (1), was found to be a potent and selective H3 agonist. The pyrrolidine (+/-)-4a was resolved, and its (+) enantiomer, immepyr [(+)-4a], showed a greater separation of H3 and H1 activities in vivo (H3/H1 ratio >> 550) than (R)-alpha-methylhistamine (1) (H3/H1 ratio = 17), the standard H3 agonist. In fact, no evidence of H1 activity was detected at doses of immepyr [(+)-4a] as high as 100 mg/kg i.v. This pyrrolidine, immepyr [(2R,3S)-(+)-4a], represents, to our knowledge, the first reported cyclic, conformationally restricted analog of histamine to possess selective in vivo H3 agonist activity.

[Streptomyces spheroides M8-2 strain--a producer of extracellular proteolytic enzymes possessing fibrinolytic and thrombolytic action]. / Shtamm Streptomyces spheroides M8-2--produtsent vnekletochnykh proteoliticheskikh fermentov, okazyvaiushchikh fibrinoliticheskoe i tromboliticheskoe deistvie.

Strain Streptomyces spheroides M8-2 was obtained as a result of ultraviolet light action on the S. spheroides spores strain 35. The mutant is characterized by the considerable increase (in 4-5 times) of the extracellular proteolytic enzymes which are able to dissolve fibrin and thrombs. The description of the morfologic, cultural and physiologic-biochemical properties of the culture is given. The content of GC-pairs in DNK of the mutant and parent strains has been determined.

[An oligosporogenic mutant of Bacillus brevis]. / Oligosporogennyi mutant Bacillus brevis.

The treatment of Bacillus brevis var. G-B by chemical mutagens yielded a mutant similar in the major characteristics to the parent strain of the P+-variant, but producing less spores and synthesizing more gramicidin S. The mutant can be stored in the freeze-dried state.

[Natural variability of Streptomyces spheroides--a producer of extracellular proteolytic enzymes possessing fibrinolytic action]. / Estestvannaia izmenchivost' Streptomyces spheroides--produtsenta vnekletochnykh proteoliticheskikh fermentov, obladaiushchikh fibrinoliticheskim deistviem.

Streptomyces spheroides M 8-2 was obtained using UV irradiation of spores taken from the parent culture. It shows a high activity of exocellular proteases which are capable of fibrin hydrolysis and degradation of blood clots. On certain media, a population of S. spheroides M8-2 was shown to yield three variants differing in their morphologo-biochemical properties. During submerged cultivation, these variants produce different quantities of exocellular proteases (3 to 19 units per 1 mg of biomass) with the fibrinolytic activity. Variants I and III are most active; their proteolytic activity is 10-14 units per 1 mg of biomass, on the average, and can reach 18-19 units per 1 mg of biomass. Variants with a low activity (variant II) are accumulated when the actinomycets is kept as spores on a solid medium with corn extract and on a solid medium with fibrin. The high proteolytic activity of the strain can be preserved by selection on a diagnostic medium with fibrin taking account of the diameter of hydrolytic zones around the colonies and selecting solely the colonies of variants I and III.

[Lyophilization of the spores and vegetative cells of Bacillus brevis var. G-B.--producer of gramicidin S]. / Liofilizatsiia spor i vegetativnykh kletok Bacillus brevis var. G-B.--produtsenta gramitsidina S.

Viability, antibiotic properties and variation of 4 variants of Bac. brevis var. G.-B. were studied after lyophilization and storage for a year in the lyophilized state. It was shown that the spores and vegetative cells of S and P- variants not synthesizing gramicidin S were somewhat more stable than the spores and cells of R and P+ variants producing the antibiotic. The latter dissociated by 10 per cent towards the cells producing and not producing gramicidin. The developmental rate of the lyophilized vegetative cells was higher than that of the lyophilized spores. Under analogous cultivation conditions they produced higher amounts of the biomass and antibiotic. The lyophilization method described may be recommended for the maintenance of viability and stability of the spores and vegetative cells of Bacillus brevis var. G.-B. producing gramicidin S.