Pharmacokinetics and disposition of CS-8958, a long-acting prodrug of the novel neuraminidase inhibitor laninamivir in rats.

CS-8958, a prodrug of laninamivir (R-125489), is currently under development as an inhaled anti-influenza drug. In this study, the pharmacokinetics and disposition of CS-8958 were characterized in rats. After intratracheal administration of 14C-CS-8958, radioactivity was retained over long periods in the target tissues (trachea and lung) as its active metabolite R-125489 - 19.12% of the dose was retained in the lung at 24 h. After intratracheal administration of CS-8958, plasma R-125489 concentration was slowly eliminated, and its half-life (14.1 h) was considerably longer than that after intravenous administration of R-125489. The radioactivity of intratracheally administered 14C-CS-8958 was mainly excreted into the urine (67.5% of dose), and this excretion lasted over long periods. R-125489 accounted for most of the urinary radioactivity recovered after 24 h. These results demonstrated that CS-8958 administered intratracheally to rats was converted/hydrolysed to R-125489 in the target tissues, and that the R-125489 was slowly excreted into the urine via an absorption rate-limiting process. Such distinctive pharmacokinetics attributed to the slow release of R-125489 suggests the potential for a long-acting anti-influenza drug.

A deterministic genetic model for sympatric speciation by sexual selection.

A deterministic haploid genetic model confirms and explores in more detail the results of our previous individual-based simulation model for sympatric speciation by sexual selection. With the deterministic model, we are able to elucidate parameter dependence by phase plane analysis. We clarify how and why sympatric speciation by sexual selection can happen in a number of ways: (1) Female preferences for or against particular types of males have different effects. Whereas the former affects how readily speciation is invoked, the latter changes the stability of speciation equilibrium. (2) When there is no cost on male ornamentations, speciation is triggered regardless of initial haplotype frequencies if sufficient female preference is provided. (3) There exists a threshold for female initial frequencies for speciation to be invoked, but male initial frequencies have little effect. (4) A small cost on female mate choice does not cancel speciation, but when large, it greatly reduces the possibility of speciation.

Profitability of prey determines the response of population abundances to enrichment.

Theoretical and empirical evidence in a one-predator two-prey system consistently indicates a regular trend that the less profitable (therefore, less vulnerable) prey increases in abundance with enrichment. The response in the abundance of the more profitable (more vulnerable) prey to enrichment has, however, remained unclear. Previous theoretical models have assumed the less profitable prey as inedible, though its actual profitability is unknown. Here, relaxing this assumption, we show that the response of the more profitable prey abundance to enrichment depends critically on the profitability of the less profitable prey. Specifically, the more profitable prey increases in abundance with enrichment if the profitability of the less profitable prey is lower than a critical value so that it cannot support the predator population by itself even at high densities (in this case, the prey is referred to as 'unpalatable') and decreases otherwise. This establishes a more general rule which unifies the previous works and resolves the indeterminacy on the response of the more profitable prey.

Why don't all termite species have a sterile worker caste?

No general theory explains why a sterile worker caste is not found in all species of both Hymenoptera and Isoptera (Insecta). Recent empirical finding show that, in the termites (Isoptera), feeding outside the nest correlates well with the evolution of the sterile (true) worker caste from the non-sterile (false) worker caste. Here we explain the connection between food-nest separation and true worker evolution in termites, providing a general theory on the restricted distribution of the sterile worker caste in the Isoptera. A cost-benefit model suggests that there is a critical level of nest stability above which natural selection favours true workers over false workers, irrespective of genetical relatedness. Because food-nest separation tends to increase nest stability, this theoretical result implies that the less a termite species consumes its nest as food, the more likely is its nest stability to fall above the critical level and a true worker caste will evolve.

Alteration of eicosanoid production in the sensitized guinea pig lung by CS-518.

The effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo [b]thiophene-6-carboxylate), a thromboxane A2 synthase inhibitor, on changes in arachidonic acid metabolism were investigated in the lung of actively sensitized guinea pigs. Antigen challenge enhanced the production of thromboxane A2 as well as histamine and peptide leukotrienes in lung fragments. Exogenous leukotriene D4 also stimulated significant thromboxane A2 production in the non-sensitized lung in vitro. CS-518 was effective in preventing the thromboxane A2 production induced by either antigen or leukotriene D4, and the IC50 values were 90 and 7.5 ng/ml (320 and 27 nM), respectively. CS-518 markedly potentiated the production of prostaglandin E2 and I2 with slight inhibition of leukotriene formation, but indomethacin significantly stimulated leukotriene production. When CS-518 was administered orally, it induced long-lasting inhibition of thromboxane A2 production and potentiation of prostaglandin I2 production in guinea pig lung. Thus, CS-518 not only inhibited thromboxane production but also improved the change in arachidonic acid metabolism in the guinea pig bronchoalveolar tissue during allergic reaction in vivo as well as in vitro, which suggests amelioration of the asthmatic condition.

Evaluation of [1-11C]octanoate as a new radiopharmaceutical for assessing liver function using positron emission tomography.

[1-11C]Octanoate was evaluated as a new radiopharmaceutical for the evaluation of liver function using positron emission tomography (PET). In biodistribution studies with normal mice, [1-11C]octanoate was rapidly taken up by the liver. [1-11C]Octanoate in the liver was present in the parenchymal cells and was predominantly metabolized via beta-oxidation followed by its rapid clearance. In the CCl4-treated mice, [1-11C]octanoate showed significantly slower hepatic clearance than that in the controls. In PET studies using rats, the time-radioactivity curves in the liver showed a two-phase decrease, and compared with the normal rat, the CCl4-treated rat showed a slower hepatic half-clearance time for the first phase, which is related to beta-oxidation metabolism. A preliminary PET study of [1-11C]octanoate metabolism in a normal volunteer was consistent with these animal studies. The present study showed that metabolism of [1-11C]octanoate in the liver was influenced by beta-oxidation, and it is advantageous to use [1-11C]octanoate clinically as a regional liver-function diagnostic agent in conjunction with PET.

Evaluation of radioiodinated iodoclorgyline as a SPECT radiopharmaceutical for MAO-A in the brain.

An in vivo estimation of the newly synthesized MAO-A specific inhibitor, [125I]-labeled N-[3(2,4-dichloro-6-iodophenoxy)propyl]-N-methyl-2- propynylamine ([125I]-iodoclorgyline), was performed. Retention of the radioactivity of this radioligand was observed in the brain from 1 h post-injection. Pretreatments with clorgyline and l-deprenyl showed selective binding of [125I]-iodoclorgyline to MAO-A in the brain at 24 h post-injection. Moreover, a good correlation (r = 0.907) between the uptake of [125I]-iodoclorgyline and MAO-A enzyme activity in the cortex was observed in the pretreatment study with several doses of clorgyline. Although improvement to increase the brain/blood ratio is desirable because of slow blood clearance of the radioactivity, radioiodinated iodoclorgyline may serve as a useful SPECT radiopharmaceutical for quantitative analysis of MAO-A in the brain.

Autogenous and anautogenous mosquitoes: a mathematical analysis of reproductive strategies.

A mathematical model is presented to compare the relative advantage of an anautogenous mosquito population (in which females blood feed throughout life) with an obligate autogenous population (in which females do not feed on blood for the first oviposition). The advantage is measured by the intrinsic rate of natural increase. Autogeny was more advantageous than anautogeny when host searching time (ts), the ratio of the fecundity of the first autogenous to anautogenous oviposition (p), the fecundity in one anautogenous oviposition (n), or the instantaneous death rate of the adult population (D) was large, or when the preimaginal period (xo), the instantaneous death rate during the preimaginal period (D'), or survival during blood feeding (s) was low. The parameters most sensitive to the advantage of autogeny were ts, p, and s. The value of n was insensitive, and xo, D, and D' were intermediately sensitive to autogeny. Conditions when autogeny was advantageous were equivalent to conditions conducive to high autogeny rates in facultatively autogenous species, which alter the expression of autogeny depending upon environmental stimuli. Data on several facultatively autogenous species are discussed qualitatively and quantitatively to demonstrate the utility of our model in considering the evolution of autogeny and the autogeny rate.

Cysteine conjugate of methazolamide is metabolized by beta-lyase.

Bovine kidney and liver homogenates degraded a cysteine conjugate of methazolamide, S-(5-acetylimino-4-methyl-Delta2-1,3,4-thiadiazolin-2-yl)cysteine. We isolated the degradation product following incubation with kidney homogenate by high-performance liquid chromatography on reversed-phase columns. The chemical structure was confirmed by proton and carbon-13 nuclear magnetic resonance spectroscopy (1H NMR and 13C NMR, respectively), and elemental analysis by high-resolution mass spectrometry to be N-(3-methyl-5-mercapto-Delta4-1,3,4-thiadiazol-2-yl)acetamide, a thiol compound. The reaction is thought to be catalyzed by a pyridoxal-dependent enzyme(s) as indicated by an inhibition study using aminooxyacetic acid. Possible involvement of the thiol compound in the development of an adverse effect is discussed.

Intersexual conflict over precopula duration in mate guarding crustacea.

Precopulatory guarding in Crustacea is usually analyzed as a male decision problem. We suggest an alternative possibility that precopula is established as a result of intersexual conflict over precopula duration. Such a conflict can be expected when the male optimum for precopula duration exceeds the female optimum. As a result, males should start precopulatory attempts earlier, while females should resist until close to receptivity. Our analysis reveals two potential sources of conflict: (1) sexual differences in survival probabilities before and during the mate-guarding; and (2) sexual differences in the probability of finding a mate. The latter is perhaps a more probable source of intersexual conflict, since male biased operational sex ratios are common in mate-guarding Crustacea. The former requires that female moulting cycle is synchronous, whereas the latter may operate in populations with asynchronous moulting cycles as well. We further studied the expected intensity of behavioural conflicts in terms of expected present and future fitness gains. In the beginning of the female moulting cycle, there is no conflict. Conflict arises as males start the guarding attempts and females are motivated to resist, and ceases with a decrease in the female's motivation to resist. Several assumptions and predictions of the model are discussed and compared with the behavioural patterns observed in the aquatic isopod Idotea baltica.

Pharmacokinetic analysis of 123I-labeled medium chain fatty acid as a radiopharmaceutical for hepatic function based on beta-oxidation.

Beta-oxidation is the most important pathway to provide energy for the liver. Our recent findings indicated that radiolabeled medium chain fatty acid analogs could be used as radiopharmaceuticals in the liver, allowing us to monitor alterations in energy metabolism on the cellular level. In the present study, pharmacokinetical analysis of a radioiodinated medium chain fatty acid analog, 6-[123I]iodophenylenanthic acid ([123I]IPEA), was carried out in normal and hepatitis model rats to investigate the index for the measurement of beta-oxidation activity in hepatocytes. The rate constant for metabolism of [123I]IPEA in the liver showed a strong correlation with the ATP level, which was determined as an indicator of beta-oxidation activity in hepatocytes. The radioactivity profile in the liver after [123I]IPEA administration provided important information regarding hepatic viability, and the metabolic rate constant of [123I]IPEA calculated by a pharmacokinetic method was a useful criterion for hepatic diagnosis based on hepatic cellular energy metabolism.

[Japanese cases of hyperostosis frontalis interna].

Although hyperostosis frontalis interna is common in the western countries, it has been rarely reported in the literature in Japan. We had a chance to observe 5 cases diagnosed as hyperostosis frontalis interna. They were found among 10,902 patients who came to our hospital from August 1, 1993 to September 30, 1995. All the patients in these five cases are females aged 67 to 85 (mean = 74.2 years). Four of the 5 cases had been treated as hypertension, 2 as diabetes mellitus, and 1 as hyperlipoidemia. Two cases were accompanied by unruptured aneurysms. The pathology of one case accompanied by chronic subdural hematoma revealed no apparent development of Haversian systems of bone. It seems that the prevalence of this disease in Japan would increase from now on due to the fact that the life style and the diet among Japanese people has been getting westernized.

[Adult T-cell leukemia with vertebral bone tumor and acute transverse myelopathy].

We describe a case of adult T-cell leukemia (ATL) with vertebral bone invasion, who developed acute paraplegia and responded well to irradiation and combined chemotherapy. A 36-year-old man born in Tsushima Island was admitted to our hospital in May 1987, because of a sudden onset of paraplegia, hypesthesia below the level of 7th thoracic vertebra and vesicorectal disturbance. The white blood cell count was 9,500/microliter with 16% of abnormal lymphocytes showing lobulated nuclei. The surface marker analysis revealed that CD3, CD4, CD8 and CD25 positive cells were 88.1, 83.9, 6.4 and 1.3% of the peripheral mononuclear cells, respectively. Anti-ATLA antibody was positive. Serum calcium level was elevated. Bone scintigraphy showed multiple vertebral bone lesions. Vertebral bone mass and a compressed spinal cord in the 7th thoracic level were confirmed by CT scanning and MR imaging. Cerebral spinal fluid was negative for tumor cells. A diagnosis of ATL was made. Irradiation and combination chemotherapy improved bone lesions and neurological signs and the disease was well controlled by maintenance chemotherapy up to the present (August, 1988).