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Format ties, “partial repetitions of prior talk” (Goodwin & Goodwin 1987, p. 207), are interesting from an interactional perspective with respect to their functions relating to, for example, (dis-) agreement/alignment or humour, and for scholars of Language Variation and Change because they offer uniquely comparable phonological contexts in naturalistic speech. The present paper investigates the distribution of the sociolinguistic variable ing in format ties in a set of dyadic interviews of six speakers from the North-East of England who were recorded two or three times throughout their twenties – those career-building years during which we often see a change from the predominant use of the alveolar variant (“in’”) to the velar (“ing”). The analysis offers possible interactional and stylistic explanations for the community-level stability and the speaker-level variation and change of ing by focusing on contexts in which speakers format tie. It shows that the use of the highly frequent and thus less marked alveolar variant tends to occur in aligning contexts, while the few velar cases occur in moments where speakers disalign on some level. This argument contributes to work combining interactional and variationist endeavours, in particular with respect to the variable ing.

BackgroundAn understanding vaccine-dependent effects on protective and sustained humoral immune response is crucial to planning future vaccination strategies against coronavirus disease 2019 (COVID-19).MethodsIn this multicenter, population-based, cohort study including 4601 individuals after primary vaccination against COVID-19 ≥ 4 months earlier we compared factors associated with residual antibody levels against severe acute respiratory syndrome coronavirus-2 receptor-binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1).ResultsOur main model including 3787 individuals (2 × BNT162b2, n = 2271; 2 × mRNA-1273, n = 251; 2 × ChAdOx1, n = 1265), predicted significantly lower levels of anti-RBD antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 binding antibody units per milliliter [BAU/mL]) compared with those vaccinated with BNT162b2 (1179.5 BAU/mL) or mRNA-1273 (2098.2 BAU/mL). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (−21.5; 95% confidence interval [CI], −24.7 to −18.3) and no significant association for mRNA-1273 (−4.0; 95% CI, −20.0 to 12.1) or ChAdOx1 (1.7; 95% CI, .2 to 3.1). The predicted decrease over time since full immunization was highest in mRNA-1273 (−23.4; 95% CI, −31.4 to −15.4) compared with BNT162b2 (−5.9; 95% CI, −7 to −4.8).ConclusionsOur study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of individualized vaccine selection, especially in elderly individuals.

Background: Microdialysis sampling after drug microdosing may provide tissue pharmacokinetic data early in clinical drug development. However, low administered doses and small sample volumes pose an analytical challenge, particularly for highly protein-bound drugs. Materials & methods: Carbon-14 [14C]diclofenac was used as a model drug to assess the technical and analytical feasibility of in vivo microdialysis after microdose administration in an in vitro setup. Results: [14C]diclofenac dialysate concentrations were accurately quantified with accelerator MS. [14C]diclofenac dialysate recoveries were similar in the presence and absence of therapeutic diclofenac concentrations but were considerably decreased when albumin was added to the immersion solution, suggesting high protein binding. Conclusion: These results demonstrate the feasibility of combining microdosing and microdialysis to assess tissue pharmacokinetics.

Purpose Clinical research relies on data from patients and volunteers, yet the target sample size is often not achieved. Here, we assessed the perception of clinical research among clinical trial participants to improve the recruitment process for future studies. Methods We conducted a single-center descriptive and exploratory study of 300 current or former participants in various phase I–III clinical trials. Questionnaires were either distributed to current clinical trial participants or emailed to former subjects. Results Subjects strongly agreed or agreed that contributing to improving medical care (> 81%), contributing to scientific research (> 79%), and trusting their treating physicians (> 77%) were motives for study participation. Among healthy volunteers, financial motives positively correlated with the number of clinical trials they had participated in (p p Conclusion Altruistic motives and trust in treating physicians were predominant motives for clinical trial participation. Older patients expected to receive the best available treatment during participation. Healthy volunteers who reported financial motives had participated in more clinical trials. Consistent with great trust in medical staff and government research institutions, little concern was expressed about the misuse of personal data during the trial.

To investigate immunogenicity and safety of BNT162b2 booster vaccination with and without a tetravalent influenza vaccine.A prospective, open-label cohort study on immunogenicity and safety of COVID-19 booster vaccination with or without a tetravalent influenza vaccine was performed. 838 health care workers were included in the following study arms: BNT162b2 booster-only, influenza-vaccine-only or combination of both. Levels of antibodies against SARS-CoV-2 spike receptor binding domain (RBD), and haemagglutinine inhibition (HAI) tested for four different influenza strains (A(H1N1)pdm09, A(H3N2), B/Victoria, B/Yamagata) were measured at time of vaccination and four weeks later.After four weeks, median [IQR] anti-RBD antibody levels and relative change from baseline were higher in individuals who received BNTb162b2 booster vaccination only (absolute: 16,600 [10,980-24,360] vs. 12,630 [8,198-18,750] BAU/mL (p0·0001); relative increase: 49% [23·6-95·3] vs. 40% [21·9-80·6](p = 0·048); booster-only n=521 vs. combination-arm n=229 respectively). Results were confirmed after matching for sex, age, BMI, baseline antibody levels and vaccine compound received for primary immunization (absolute: 13,930 [10,610 - 22,760] vs. 12,520 [8,710 - 17,940]; p = 0·031); relative increase: 55·7% [27·8-98·5] vs. 42·2% [22·9-74·5]; p = 0·045). Adverse events were almost identical in the booster-only and the combination-arm, but numerically lower in the influenza arm (525/536[97·9] % vs.235/240 [97·9%] vs. 26/33 [78·8 %]).While no safety concerns occurred, our study provides evidence on reduced immunogenicity of a BNT162b2 booster vaccination in combination with a tetravalent influenza vaccine. Further studies investigating new influenza variants as well as potential differences vaccine effectiveness are needed.

Objectives The efficacy and quality of generic antibacterial drug formulations are often questioned by both healthcare specialists and patients. Therefore, the present study investigated the interchangeability of generic drugs with their originators by comparing bioequivalence parameters and stability data of generic cefepime, linezolid and piperacillin/tazobactam with their respective originator drugs. Methods In this open-label, randomized, crossover bioequivalence study, three groups of 12 healthy volunteers each received a single intravenous infusion of either 2 g of cefepime or 4.5 g of piperacillin/tazobactam and two generic formulations, or 600 mg of linezolid and one generic formulation. Plasma sampling was performed, with a 5 day washout period between study days. Stability was tested by storing reconstituted generic and originator products according to their own storage specifications and those of the comparator products. All concentrations were measured by LC-MS. Results Similar ratios of generic/originator (90% CI) Cmax were observed for Cefepime-MIP/Maxipime [93.7 (88.4–99.4)], Cefepime Sandoz/Maxipime [95.9 (89.1–103.2)], Linezolid Kabi/Zyvoxid [104.5 (91.1–119.9)], Piperacillin Kabi/Tazobac [95.9 (90.4–101.7)], Piperacillin Aurobindo/Tazobac [99.7 (84.9–104.7)], Tazobactam Kabi/Tazobac [93.4 (87.4–99.8)] and Tazobactam Aurobindo/Tazobac [97.4 (89.7–105.8)]. Accordingly, similar ratios of AUC0–t were observed for Cefepime-MIP/Maxipime [91.1 (87.6–94.8)], Cefepime Sandoz/Maxipime [97.9 (92.5–103.5)], Linezolid Kabi/Zyvoxid [99.7 (93.3–106.6)], Piperacillin Kabi/Tazobac [92.2 (88.3–96.3)], Piperacillin Aurobindo/Tazobac [99.9 (97.0–102.8)], Tazobactam Kabi/Tazobac [91.4 (86.4–96.7)] and Tazobactam Aurobindo/Tazobac [98.8 (94.3–103.6)]. Stable and similar concentrations were measured for all contiguous substances, regardless of storage conditions. Conclusions Compared with their respective originator drugs, generic cefepime, linezolid and piperacillin/tazobactam met the predetermined bioequivalence criteria. All formulations were stable under the storage conditions of their respective comparators.

Spider silk has fascinated mankind for millennia, but it is only in recent decades that scientific research has begun to unravel all its characteristics and applications. The uniqueness of spider silk resides in its versatility, in which a combination of high strength and extensibility results in extraordinary toughness, superior to almost all natural and man-made fibers. Dragline silk consists of proteins with highly repetitive amino acid sequences, which have been correlated with specific secondary structures responsible for its physical properties. The native fiber also shows high cytocompatibility coupled with low immunogenicity, making it a promising natural biomaterial for numerous biomedical applications. Recently, novel technologies have enabled new insights into the material and biomedical properties of silk. Due to the increasing interest in spider silk, as well as the desire to produce synthetic alternatives, we present an update on the current knowledge of silk fibers produced by the spider genus Trichonephila.

Understanding vaccine-dependent effects on protective and sustained humoral immune response are crucial to plan further vaccination strategies against COVID-19. Population-based data comparing different vaccination strategies are lacking.This multicenter, population-based cohort study included 4,601 individuals ≥18 years of age after primary vaccination against COVID-19 at least four months ago (full immunization). We compared factors associated with residual antibody levels against SARS-CoV-2 receptor binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 [ChAdOx1]).Our main model including 3,787 individuals (2xBNT162b2 n = 2,271, 2xmRNA-1273 n = 251, 2xChAdOx1 n = 1,265) predicted significantly lower levels of anti-RBD-antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 BAU/ml) compared to those vaccinated with BNT162b2 (1179.5 BAU/ml) or mRNA-1273 (2098.2 BAU/ml). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (-21.5 [95%CI -24.7 to -18.3]) and no significant association for mRNA-1273 (-4.0 [95%CI -20.0 to 12.1]) or ChAdOx1 (1.7 [95%CI 0.2 to 3.1]). The predicted decrease over time since full immunization was highest in mRNA-1273 (-23.4 [95%CI -31.4 to -15.4]) compared to BNT162b2 -5.9 [95%CI -7 to -4.8]). Higher antibody levels were observed for individuals with systemic adverse events upon vaccination and current smoking (BNT162b2), for days between first and second vaccination (BNT162b2 and ChAdOx1) and for absence of comorbidities (all).Our study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of an individualized vaccine selection, especially in elderly individuals.

In einem Untersuchungsgebiet am westlichen Bodensee (Halbinsel Mettnau) zeichnet sich zwischen 1976 und 1997 eine deutliche Zunahme fruh ausgeflogener Teichrohrsanger ab, was auf ein fruheres Bruten schliesen last. Weiterhin hat sich die Erstankunft des Teichrohrsangers am Bodensee in den letzten 16 Jahren (1982–1997) im Vergleich zum Zeitraum 1961 bis 1980 um genau eine Woche verfruht (im Mittel vom 26.4. auf den 19.4.). Wahrend sich zwischen der jahrlichen Erstankunft des Teichrohrsangers am Bodensee und der Zahl fruh ausgeflogener Jungvogel kein statistisch gesicherter Zusammenhang finden last, ist die Temperatur in der ersten Maihalfte ein guter (statistisch signifikanter) Indikator fur die Zahl fruh ausgeflogener Teichrohrsanger.

The trichothecenes, simple and Macrocyclic (3–4 rings to which an ethylene oxide ring is attached), are secondary metabolities of a group of fungi, which cause severe toxicoses via damage to eukaryotic cells by interfering with ribosomal structure and/or activity. In the sample trichothecenes, the ethylene oxide ring is protected against premature opening, i.e. against inactivation, by a bridge between the oxygen in ring B and the hydroxyl group at position 3 in ring C. If the latter is absent, as in certain macrocyclics, the trichothecenes are of little toxicity, but in the toxic members of the Macrocyclic series a different, still unknown protective mechanisms is involved.

AbstractThe trichothecene mycotoxins are secondary metabolites, produced by a variety of species of fungi, and are contaminating various agricultural commodities. The toxicity of the trichothecenes has been tested by several methods of systemic applications. The toxic effects of trichothecenes, introduced directly into the rat brain, are much more selective and specific than the toxic actions, evoked by peripheral applications. In vitro, the enzymatic conversion of T-2 toxin by brain homogenate is largely restricted, as compared to the metabolic changes in the mammalian body as a whole. In vivo, slight modifications of the substituents, attached to the fundamental ring system A-C of the trichothecenes, cause marked variations in cerebral toxicity. This is particularly noteworthy for the macrocyclic trichothecenes, where relatively small changes in the large ring D cause more than a hundred fold variation in toxicity.

HT-2 toxin was the sole metabolite formed when T-2 toxin was treated with homogenate from brain without its blood content. Homogenate from brain with its full blood content produced--besides HT-2 toxin--T-2 triol, neosolaniol, 4-deacetylneosolaniol and T-2 tetraol, i.e. the same metabolites formed by incubation of T-2 toxin with whole rat blood.

The tested macrocyclic trichothecenes are produced by Myrothecium fungi and by the plant Baccharis megapotamica. The toxicity of five macrocyclic trichothecenes has been measured by intracerebral and subcutaneous injection into rats. It is assumed that the toxic effects are based on inhibition of protein synthesis. Intoxication of rats by these compounds finds expression in slowly progressing respiratory depression and paralysis of skeletal muscles. The macrocyclics are derived from verrucarol, which lacks ring D and exhibits only low toxicity. The high toxicity of the macrocyclics, established by intracerebral and subcutaneous applications, may thus be attributed to the presence of the large ring D.

The antibiotic cycloheximide inhibits protein synthesis in eukaryotic cells. This overall effect is similar to that of T-2 toxin, but the mechanism of intoxication by these two inhibitors are different. This is shown here by intracerebral injections of mixtures of T-2 toxin and cycloheximide, leading to potentiation of their toxic effects. The histopathology of cerebral intoxication by the two compounds is similar, but after cycloheximide the lesions appear earlier, and repair is faster.

The mass pectra of 5-methylsulfonyl-6-pyridone and its 3,4-dihydro derivative show that the most important fragmentations involve the methylsufonyl substituent, which is eliminated in various forms (CH3SO˙; CH3SO2˙; CH3SO2H or SO2H˙). Other fissions like the removal of CO, which is the predominant event in simple 2-pyridones and in 6-pyridone, appear only after breakdown of the sulfonyl group. Only 5-methylsulfonyl-6-phenyl-2-pyridone eliminates an OH radical from the molecular ion.

Under electron impact, 6-thiotheophyllines eliminate various fragments from the pyrimidine moiety. In a retro Diels-Alder reaction, they lose the fragment XCNCH3 from positions 1 and 2 of the pyrimidine ring. In 6-sulfinyltheophyllines, the sulfinyl group is the main target for fragmentation; it can lose either oxygen or sulfur, and the abundance of [M—16]+ and [M—32]+ is much higher than the abundance of the molecular ion. Elimination of the sulfur atom of the 6-sulfinyl substituent, with retention of its oxygen, may be explained by intermediate formation of a ring. All further fragmentations of the 6-sulfinyl derivatives proceed by a primary loss of oxygen or sulfur, followed by elimination of fragments from the pyrimidine moiety, similar to the primary processes, observed in the mass spectra of the 6-thiotheophyllines.

1. The influence of 8-substituents was studied on the rate of oxidation of hypoxanthine and 6-thioxopurine by bovine milk xanthine oxidase (EC 1.2.3.2). 2. An 8-methyl group does not alter the rate of oxidation of hypoxanthine materially, but an 8-phenyl substituent reduces it markedly. This is ascribed to inhibition of the tautomerisation process, responsible for substrate activation, prior to oxidation. 3. In contrast, the 8-phenyl group in 3-methyl-8-phenylhypoxanthine enhances the rate, presumably by binding to a hydrophobic site near the enzymaic center. 4. An 8-phenyl group in 6-thioxopurine markedly increases the rate of enzymaic oxidation. Probably the aromatic substituent diverts anion formation to the imidazole ring. In contrast, ionisation of 8-methyl-6-thioxopurine involves the pyrimidine moiety, thus rendering enzymic attack at position 2 more difficult.

Flash nystagmus (FN) was evoked in pigmented rabbits by exposing one eye to intermittent photic stimuli, while the second eye was protected from light. Atropine, whether injected intravenously or instilled into the conjunctiva, inhibited flash nystagmus. Maximal inhibition appeared at the optimal rate of flashing. Cyclopentolate and N-methylatropinium cation showed similar actions. Eserine exhibited a biphasic effect: initial enhancement, followed by prolonged inhibition. The enhancement was antagonized by atropine. During the enhancement phase, eserine broadened the range of effective flash rates and displaced flicker fusion to higher frequencies. Carbachol also showed a biphasic effect. Regardless of the route of application, all drugs affect flash nystogmus via the circulation. Albino rabbits are refractory to flashing, even after intravenous eserine, but do respond after instillation of the drug into the conjunctiva. The direction of the eye movements, evoked under these conditions, was not fixed, but changed often during or after monocular flashing.

Rats of the LC-2-HI strain, selected for high rates of self-stimulation, were supplied with a 3 mM saccharin solution. Within 1 week they developed markedly prolonged latencies to painful stimuli on a hot-plate. In contrast, a similar effect became manifest in LC-2-LO rats only after 3 weeks. Both strains of rats were made diabetic by injection of streptozotocin. LO rats showed more polydipsia and hyperglycemia than HI rats and, when drinking saccharin solution, developed cross-tolerance to morphine within about 2 weeks. It is assumed that saccharin consumption stimulates the release of endogenous opioid peptides, probably via stimulation of gustatory sweet receptors. The opioid peptides exert a biphasic effect: initially they raise the pain threshold, but at a later stage they cause chronic cross-tolerance to morphine.

In cats anesthetized with pentobarbitone sodium the effect of two types of antiserotonergic agents on cardiovascular recuperation after acute hemorrhage was examined. Methysergide, a competitive inhibitor for 5-HT receptors and p-chlorophenylalanine (PCPA), an inhibitor of tryptophan-5-hydroxylase, improved blood pressure recovery after bleeding. After extensive hemorrhage (40 ml/kg blood), treatment with methysergide improved survival. It is proposed that serotonin participates in the depressor response and survival of acute hypovolemic hypotension.

Topical applications of various doses of T-2 toxin to rats led to delayed skin reactions. Following a dose-dependent latent period of 12-24 hr, there appeared vascular dilation, stasis, edema and mononuclear cell infiltration, with many degranulating mast cells. These signs were earliest and strongest in the subcutis. Epidermal necrosis occurred 1-2 days later and was probably caused secondarily by ischemia, due to microcirculatory failure. Ultrastructurally, endothelial cells of small vessels were the earliest sites of change. While intercellular junctions remained closed and pinocytosis decreased, the cytoplasm contained many ribosomes, vacuoles, and abnormal mitochondria. Another early effect of topical T-2 toxin was an increase in number and degranulation of mast cells, especially in the subcutis. The resemblance of the skin injury to that produced by irradiation is noted.

1. 1. Pteridin-4-ones, methylated at nitrogen or carbon, N- methylated lumazines and related oxopteridines were studied as substrates of a highly purified bovine milk xanthine oxidase (xanthine: oxygen oxidoreductase, EC 1.2.3.2). 2. 2. The enzyme can oxidise at high rates both uncharged and anionic substrates. Variation of enzymic activity with pH is mainly due to pH-dependent changes in the active enzymic center. 3. 3. Milk xanthine oxidases at different stages of purification convert pteridin-4-one into the 4,7-dione (compound 13 in this article). 4. 4. Methylation at C-6 in the pyrazine moiety enhances enzymic attack at C-2 in the pyrimidine ring. N- Methylation may increase or reduce rates of oxidation. 5. 5. For oxidation at C-2, the most favorable form of the substrate bears a double bond at C(2)  N(3). Attack at C-7 is enhanced strongly in structures bearing a double bond at C(6)  C(7). 6. 6. In general, pteridines react with xanthine oxidase as non-hydrated molecules. However, oxidation of 8-methyllumazine at C-7 may take place by dehydrogenation of the 7-CHOH group of the covalently hydrated molecule.

Cats, anesthetized with sodium pentobarbitone, underwent acute hemorrhagic shock by withdrawal of 15 ml blood/kg of body weight. The cerebral ventricular system was perfused with artificial cerebrospinal fluid (CSF). Blood and CSF samples were collected during 2 h, for the analysis of catecholamines (CA) and Leu-enkephalin-like immunoreactivity (LE-ir). The fall of blood pressure immediately after hemorrhage was accompanied by a rise of LE-ir in the CSF and by a decrease of norepinephrine and dopamine below their control values. About half an hour later, the LE-ir returned to its initial low level, while the CA were now markedly elevated. A similar opposite behavior of peptides and CA was observed during subsequent sampling periods, although blood pressure remained constant. These experiments demonstrate an inverse relationship of LE-ir and CA in the CSF, after acute hemorrhagic shock.

T-2 toxin has been found previously to be markedly more toxic upon intracerebral than upon systemic administration. In order to study the generality of this difference, we have applied to brain and liver of albino rats two different types of trichothecenes: T-2 toxin as a representative of ‘simple’ and myrotoxin B as a representative of ‘macrocyclic’ members of this series. Myrotoxin B, when applied intracerebrally, was about 100 times more poisonous than T-2 toxin. In contrast, upon intrahepatic injection both compounds exhibited similar degrees of toxicity. The different behavior of the two trichothecenes in the organs tested may be due to local metabolic factors.

UV and NMR spectra of caffeine and Isocaffeine were measured in three solvents of different polarity. The Information so obtained revealed unique differences in the electronic structure of 7- and 9- alkyl substituted xanthines. 9-Methyl derivatives bear a “soft” nitrogen at position 3; in 7-methylxanthines this nitrogen is rather “hard”. This characteristic distinction is explained on the basis of orbital interactions, which are also responsible for self-association. In the process of self-association. isocaffeine and caffeine share a hydrophobic effect, but in caffeine water bridges play a decisive rote in molecular aggregation. In contrast, in isocaffeine high polarisability makes the most important contribution to self-association. Steric interference between 3- and 9-alkyl substituents or between a 9-methy1 and a 3-NH group, proposed earlier, does not explain satisfactorily the properties of these xanthines.

In the PMR spectrum of 8-phenylpurines, the multiplet of the o-protons appears downfield of the multiplet, characteristic for m,p-protons. The separation of the centres of these two signals (Δ-value) diminishes with increasing steric interference between the phenyl ring and substituents in the imidazole moiety. The contribution of the purine ring current to the chemical shifts of the aromatic protons was calculated according to the theory of Johnson and Bovey, and the torsion angles θ between the phenyl ring and the plane of the purine system were derived. For 8-phenylpurines with an NH-group in the imidazole ring, θ is 10–15°; for compounds with an N-methyl group in this ring, θ ≈ 35–45°; in 3,9-dimethyl derivatives, Δ becomes zero, while θ is about 50°.

Intravenous injection of the synthetic TRH analog, MK-771, to anesthetised cats raised the blood pressure by a central mechanism, i.e. by activating the outflow of sympathetic stimuli from the CNS to the periphery and raising the plasma concentration of adrenaline and noradrenaline. In contrast, noradrenaline in the CSF was lowered by intravenously injected MK-771. The concentration of 5-HT in the CSF was increased and the pressor action of the peptide was correspondingly enhanced by 5-HT antagonists. These findings suggest that the release of 5-HT into the CSF lowers blood pressure and thus reduces the hypertensive effect of MK-771. Methysergide acts synergistically with MK-771 to combat the sudden fall in pressure induced by acute hemorrhage in the anesthetised cat. Combination of the two drugs enhanced and accelerated recovery from this hypotensive state.

1. 1.|Hypoxanthines, bearing at position 8 aryl or pyridyl substituents, are converted by bovine milk xanthine oxidase (xanthine: oxygen oxidoreductase, EC 1.2.3.2) into the corresponding xanthines at low rates. Oxidation is accelerated considerably when the 8-pyridyl substituents are quaternised. 2. 2.|In the enzymic oxidation of quaternary 8-pyridylhypoxanthines a lag phase precedes the attainment of a constant, maximal reaction rate. It is assumed that the delay is due to a relatively slow conformational change in the active enzymic center. 3. 3.|In 8-(3′- N -methylpyridinio)xanthine bethane, also the pyridinium moiety is attacked at high pH (9–11) to yield an N -methyl-2-pyridone. The analogous pyridone is the only oxidation product of 1-ethyl-8-(3′- N -methylpyridinio)hypoxanthine betaine, which is not attacked in the pyrimidine ring. 4. 4.|The cationic substrates are attracted to the enzyme by an anionic group, which probably forms an ion pair with a protonated amino group in or near the active center.

Rats received daily i.p. injections of p-chlorophenylalanine (PCPA) for 3 days, before morphine and related drugs were implanted into the lateral thalamus or injected systemically. PCPA enhanced the stereotyped response to morphine, methadone, and apomorphine, as expressed by compulsive gnawing, but abolished the antagonistic effect of large doses of i.p. morphine. Thus, suppression of gnawing by large doses of systemic morphine and related analgesics may be mediated by a serotoninergic pathway. PCPA also brought to light the ability of pethidine to cause gnawing, which is otherwise suppressed by the strong antagonistic effect of this drug. Morphine and related analgesic drugs exert a dual effect: stimulation of gnawing via a catecholaminergic mechanism and inhibition of gnawing by a serotoninergic mechanism.

T-2 toxin was given to rats in three ways: Subcutaneous or intracerebral injection of a solution in dimethyl sulfoxide (DMSO) and by implantation of toxin, adsorbed on talc, into various regions of diencephalon and brain stem. The latter method proved to be most effective. Within a few hours after administration of 10-20 micrograms toxin, the animals became restless, ataxic and dyspneic. These early symptoms were followed by depression and immobility. Prior to death, tachypnea and/or convulsions developed. The rats succumbed to implantation of toxin within 1 - 7 days; no fatalities occurred at later dates. Histologically, the toxin pellets caused necrosis a few days after implantation; at a later stage, the necrotic areas were surrounded by inflammatory infiltrates around small blood vessels. These morphological changes were limited to the application site and were insufficient to explain the lethal effect of intracerebral administration. After intracerebral injections of toxin solutions, the animals died within 24 h. No marked histological changes could be seen after such rapid fatalities.

1. 1. Bovine milk xanthine oxidase (xanthine:oxygen oxidoreductase, EC 1.2.3.2) oxidises 3-hydroxyxanthine slowly to 3-hydroxyuric acid; the 1-methyl derivative of 3-hydroxyxanthine is attacked about twice as fast. 2. 2. The pH optimum for the reaction of 2-hydroxyxanthine is near 5, i.e. the neutral form of this substrate is attacked much faster than the anion. Probably in the ‘active’ form of the latter, the negative charge is located mainly in the imidazole ring, thus inhibiting nucleophilic attack at C-8.

Binding studies using the enantiomers of the synthetic cannabinoid 7-hydroxy-delta 6-tetrahydrocannabinol 1,1-dimethylheptyl homolog in preparations of rat brain cortical membranes reveal that the (+)-(3S,4S) enantiomer HU-211 blocks N-methyl-D-aspartate (NMDA) receptors in a stereospecific manner and that the interaction occurs at binding sites distinct from those of other noncompetitive NMDA antagonists or of glutamate and glycine. Moreover, HU-211 induces stereotype and locomotor hyperactivity in mice and tachycardia in rat, effects typically caused by NMDA receptor antagonists. HU-211 is also a potent blocker of NMDA-induced tremor, seizures, and lethality in mice. This compound may therefore prove useful as a nonpsychoactive drug that protects against NMDA-receptor-mediated neurotoxicity.

1. 1. All available N- mono - and N,N′- dimethylallopurinols and the corresponding- 4-thioxo derivatives have been tested as substrates or inibitors of bovine milk xanthine oxidase (xanthine: oxygen oxidoreductase, EC 1.2.3.2). 2. 2. None of the compounds tested revealed any inhibitory activity towards the enzyme. 3. 3. All compounds were resistant to enzymic oxidation, with the exception of 7-methylallopurinol and its 4-thioxo analog. Both these compounds were attached at position 6. 7-Methylallopurinol was oxidised nearly ten times faster than the isomeric 3-methylhypoxanthine. 4. 4. These observations can be explained by assuming that for attack at C-6, the enzyme must bind both to N-1 and N-2 in the pyrazole ring and causes tautomerisation, which places a double bond at posiiton 5,6 in the pyrimidine ring. This activation process resembles the activation of hypoxanthine.

The neutral molecules of 6-thioxopurin-8-ones are present in aqueous solution as lactams-thiolactams. However, 6-SH-tautomers may be present in the anions of the 1- and 9-methyl derivatives. The sequence of dissociation of the NH-groups is 1 9 7. Ionisation of the 9-NH-group is greatly facilitated in the 3-methyl derivatives, leading to pK values of about 5. Protonation of the 3-methyl derivatives takes place predominantly at N-1 with the formation of “fixed”, amidinium-like, cations. In all other members of the series, protonation involves mainly the 8-oxo group. In 3,9-dimethyl derivatives, the NMR signals of both methyl substituents are markedly deshielded. The behavior of 6-thioxopurin-8-ones resembles that of 6-thiopurines and 6-thioxanthines.