Dose-dependent dissociation of pro-cognitive effects of donepezil on attention and cognitive flexibility in rhesus monkeys

BACKGROUND: Donepezil exerts pro-cognitive effects by non-selectively enhancing acetylcholine (ACh) across multiple brain systems. The brain systems that mediate pro-cognitive effects of attentional control and cognitive flexibility are the prefrontal cortex and the anterior striatum which have different pharmacokinetic sensitivities to ACh modulation. We speculated that these area-specific ACh profiles lead to distinct optimal dose-ranges for donepezil to enhance the cognitive domains of attention and flexible learning. METHODS: To test for dose-specific effects of donepezil on different cognitive domains we devised a multi-task paradigm for nonhuman primates (NHPs) that assessed attention and cognitive flexibility. NHPs received either vehicle or variable doses of donepezil prior to task performance. We measured donepezil intracerebral and how strong it prevented the breakdown of ACh within prefrontal cortex and anterior striatum using solid-phase-microextraction neurochemistry. RESULTS: The highest administered donepezil dose improved attention and made subjects more robust against distractor interference, but it did not improve flexible learning. In contrast, only a lower dose range of donepezil improved flexible learning and reduced perseveration, but without distractor-dependent attentional improvement. Neurochemical measurements confirmed a dose-dependent increase of extracellular donepezil and decreases in choline within the prefrontal cortex and the striatum. CONCLUSIONS: The donepezil dose for maximally improving attention functions differed from the dose range that enhanced cognitive flexibility despite the availability of the drug in the major brain systems supporting these cognitive functions. Thus, the non-selective acetylcholine esterase inhibitor donepezil inherently trades improvement in the attention domain for improvement in the cognitive flexibility domain at a given dose range.

Antigenotoxic potential of gel extract of Aloe vera against Sodium azide genotoxicity in Allium cepa cells

Nowadays, the increasing rate of human exposure to various kinds of environmental mutagens has necessitated the search for natural antimutagens /antigenotoxic agents in natural products. In this study, Aloe vera gel extract was tested for its possible antigenotoxicity following the Allium cepa assay. Ten onions (Allium cepa) per dose were grown for 48 and 72 hours on gel extract of A. vera at 6.25%, 12.5%, 25.0%, 50.0% and 100.0% in combination with sodium azide (0.05mg/ml) solution for microscopic and macroscopic evaluations, respectively. Distilled water and sodium azide were the negative and positive controls, respectively. The cell division in the root tips, and root growth in the exposed A. cepa were inhibited in a dose dependent manner by the mixture of A. vera and sodium azide. However, the mixture of absolute (100.0%) dose and sodium azide completely arrested cell division and induced a lower root length than that recorded for sodium azide alone. The genotoxicity of sodium azide was inversely reduced by the doses of A. vera except at 100.0%. These results show that gel extract of A. vera possesses strong antigenotoxic /antimutagenic potency at lower dose range of 6.25% to 25.0% in A. cepa cells, however, its higher doses above 50.0% to 100.0% could be severely toxic when being considered for suppression of environmental mutagens’ mutagenicity or genotoxicity. This suggests that gel extract of A. vera contains phytochemical(s) that can be useful in the development of anticancer drug.

A Novel Oral Syringe for Dosing and Administration of Multiparticulate Formulations: Acceptability Study in Preschool and School Children

The popularity of multiparticulate formulations (MPs) as a paediatric dosage form continues to increase. MPs comprise of multiple small units that are easy-to-swallow. Currently, MPs are commonly manufactured into unit doses that are either swallowed whole or opened prior to administration. While this is an acceptable approach, dosing is envisioned to be optimised with a “standard” paediatric device which can better harness the flexible dosing potential of MPs. We evaluated a novel oral syringe (SympfinyTM, HS Design, Morristown, NJ, USA) that is being developed as a tool to dispense and administer MPs to children. Forty children, 4–12 years old, received 0.5, 1.2, and 2.0 mL doses of placebo MPs using the oral syringe with spring water or a drink of choice to complete sample intake. Acceptability was recorded as those able to completely swallow the dose and participants also rated dose acceptability on a 5-point scale. The ability to completely swallow the dose decreased as dose volume increased; the smallest dose was completely swallowed by 87.5% (35/40) children, and 69.4% (27/39) of children confirmed their willingness to take the sample as a daily medicine. Larger doses, 1.2 and 2.0 mL, gave values of 55% and 57.5% for the doses completely swallowed and 58.8% and 51.72% for willingness to take the sample as a daily medicine, respectively. Use of a drink of choice showed no increase in swallowability as compared with water. The novel oral syringe being developed is an appropriate device for dispensing doses flexibly and administering neutral tasting MPs directly to the mouth in the lower dose range without the need for a co-administration vehicle in children aged 4–12 years.

A Novel Oral Syringe for Dosing and Administration of Multiparticulate Formulations: Acceptability Study in Preschool and School Children

The popularity of multiparticulate formulations (MPs) as a paediatric dosage form continues to increase. MPs comprise of multiple small units that are easy-to-swallow. Currently, MPs are commonly manufactured into unit doses that are either swallowed whole or opened prior to administration. While this is an acceptable approach, dosing is envisioned to be optimized with a ‘standard’ paediatric device which can better harness the flexible dosing potential of MPs. We evaluated a novel oral syringe (SympfinyTM) that is being developed as a tool to dispense and administer MPs to children. Forty children, 4-12 years old, received 0.5, 1.2, and 2.0 mL doses of placebo MPs using the oral syringe with spring water or a drink of choice to complete sample intake. Acceptability was recorded as those able to completely swallow the dose and participants also rated dose acceptability on a 5-point scale. The ability to completely swallow the dose decreased as dose volume increased; the smallest dose was completely swallowed by 87.5% (35/40) children, and 69.4% (27/39) of children confirmed their willingness to take the sample as a daily medicine. Larger doses, 1.2 and 2.0 mL, gave values of 55% and 57.5% for the doses completely swallowed and 58.8% and 51.72% for willingness to take the sample as a daily medicine, respectively. Use of a drink of choice showed no increase in swallowability as compared with water. The novel oral syringe being developed is an appropriate device for dispensing doses flexibly and administering neutral tasting MPs directly to the mouth in the lower dose range without the need for a co-administration vehicle in children aged 4-12 years.

Anti-arthritic and gastroprotective activities of Ardisia crispa root partially mediated via its antioxidant effect

BackgroundThunb A.DC (Myrsinaceae), commonly known as “hen’s eyes”, has been traditionally used in treating various inflammatory diseases. The present study evaluated anti-arthritic, gastroprotective and antioxidant activities ofMethodsAnti-arthritic activity was evaluated in complete Freund adjuvant (CFA)-induced adjuvant arthritis and gastroprotective effect was studied in the ethanol-induced ulcer model in rats. ACRH was further isolated to yield quinone-rich fraction (QRF) and both were analyzed for their total phenolic content, total flavonoid content and antioxidant activities in various antioxidant assays. Both ACRH and QRF were also analyzed for the quinone composition via gas chromatography analysis.ResultsACRH exerted significant reduction of IL-1β and TNF-α at a lower dose range in CFA-induced arthritis, as well as exhibited its cytoprotective effect against ethanol-induced ulcer lesion via involvement of mucosal nonprotein sulfhydryl (NP-SH) groups. ACRH also showed higher phenolic and flavonoid contents, as well as better antioxidant activities than QRF.ConclusionsThese findings demonstrated the plant as a potential anti-inflammatory agent, with ACRH succeeded in inhibiting both arthritic and ulcerogenic effect, possibly mediated via its antioxidant effect.

Density-dependent effects on establishment of Necator americanus and Ancylostoma ceylanicum

The relationships between the number of infective larvae (L3s) to which animals were exposed and the establishment of A. ceylanicum and N. americanus in hamsters were examined. There was no evidence of density-dependent constraints on the establishment of A. ceylanicum in the range 10–1000 larvae, but an experiment in which the range was extended to 1500 L3s gave a significant negative correlation between the magnitude of the infecting dose and percentage establishment. Even so the percentage reduction was relatively small, approximating to 0·89% per 100 larvae administered, and in practice density-dependent constraints on establishment are unlikely to affect experiments with this species in which much lower doses (<250 L3) are generally employed. The range of doses for N. americanus L3s was smaller (10–400). Of the four experiments reported, two gave a significant reduction of establishment with increasing dose and two did not. When the data was split into low doses (<100 L3s) and high doses (>100 L3s), falling establishment with increasing dose was only detected in the lower dose range. There was no difference in the establishment when doses of 100 L3s were compared with 250 or 400 L3s. On balance, it was concluded that density-dependent constraints on establishment of N. americanus in hamsters were not marked and would have little significant effect on experiments utilizing fewer than 200 L3s (approximately 7·6% reduction between 10 and 200 L3s). These results are discussed in relation to host regulation of hookworm burdens.

High-dose cisplatin administration without hypertonic saline: observation of disabling neurotoxicity.

Nephrotoxicity of cisplatin can be ameliorated with intravenous (IV) hydration and forced diuresis with mannitol. Cisplatin has recently been used with hypertonic saline which allows administration of higher doses amounting to 40 mg/m2/d for 5 days, without significant nephrotoxicity. In this report we describe our experience with administration of cisplatin in a dose range of 30 to 40 mg/m2/d for 5 days, administered with IV hydration alone. Thirteen patients with recurrent carcinoma of the head and neck region were treated with high-dose cisplatin along with 5-fluorouracil (5-FU) used as a continuous infusion. Eight patients received a total of 21 courses of cisplatin with the higher dose range (40 mg/m2 for 5 days) and the remainder received 11 courses with the lower dose range. The renal toxicity was minimal but the myelo-suppression was intense, frequently requiring hospitalization for the treatment of infections associated with neutropenia. Furthermore, we encountered severe peripheral neuropathy in five patients, four of whom developed major difficulties with ambulation. Six patients achieved objective regression of their tumor, two had minor response, and five failed to respond to chemotherapy. The study was terminated because of serious nonrenal toxicity from the high-dose cisplatin. Based on our limited experience, we believe that IV hydration alone, without the use of hypertonic saline, allows administration of high-dose cisplatin without significant nephrotoxicity. However, cisplatin used in a dose schedule of 40 mg/m2 for 5 days for more than three courses resulted in a disabling form of peripheral neuropathy.

TRANSLOCATIONS, THE PREDOMINANT CAUSE OF TOTAL STERILITY IN SONS OF MICE TREATED WITH MUTAGENS

ABSTRACT Histological and cytological analyses of the testes were carried out in 42 sterile sons of males treated in the spermatozoal or spermatid stage with 250 mg/kg ethyl methanesulfonate (EMS) alone or after prefeeding with butylated hydroxytoluene (BHT); or treated with 200 R X-rays. Of the 42 sterile males, 17 had some mature spermatids, nine were blocked at diakinesis, 15 were blocked in pachytene, and one lacked spermatogenic cells altogether, having Sertoli cells only. Mitotic (spermatogonial) metaphases could therefore be analyzed in 41 of the males and meiotic configurations in 26.—(1) None of the males showed abnormalities in chromosome number, such as monosomy, trisomy, or mosaicism for either of these conditions. Certain classes of chromosome abnormalities that have been found associated with male sterility in other investigations, namely trisomies, XXY's, and X-autosome translocations, are not expected from treatment of 19A + Y cells when F1 males are studied. (2) A very high percentage of the sterile males carried translocations. Direct meiotic evidence for this was found in 22 of the animals. In addition, 11 of the 16 that were blocked (or virtually blocked) in pachytene, and thus could be analyzed in mitosis only, consistently showed one abnormally short chromosome (or, one short plus one long), which presumably had resulted from unequal exchange (or sizable deficiency). Of the meiotically detected translocation males, 1 carried a T(A;Y), 17 had single autosomal translocations, and 4 had multiple autosomal rearrangements involving three, four, four, and six breaks, respectively. In addition, three males showed failure of X-Y pairing. (3) Translocations that cause sterility, rather than partial sterility, in males appear to be those in which at least one of the breaks occurs close to one end of a chromosome. The mitotic and meiotic evidences for this were found to be correlated. (4) It is proposed that many cases of induced F1 male sterility may be the result of position effects produced when paracentromeric regions are translocated to euchromatic regions of certain other chromosomes. Since many translocations that produce partial sterility in the female cause complete sterility in the male, the male must be assumed to be more susceptible to disturbances of fertility by the postulated mechanism. (5) There is evidence that EMS, especially in the lower dose range, more often breaks chromosomes near one of their ends than does X-irradiation.

SENSITIVITY OF THE RAT TO INCREASING DOSES OF DEXTRAN

Increasing doses of dextran, a commercial 6% solution, were injected intravenously into both intact and adrenalectomized rats to evaluate the dose–response relationship. The minimum dose capable of producing an edema with 100% incidence was approximately 30 mg/kg in intact and only 4 mg/kg in adrenalectomized rats. Lower doses produced responses of decreasing intensity and incidence with a longer period of onset. Conversely, higher doses resulted in a shorter period of onset and a more intense reaction until a toxic dose was reached, beyond which cyanosis and shock appeared. Adrenalectomized rats reacted similarly to intact ones except that their response occurred at a lower dose range; they could not withstand the toxic effect of higher doses and died of circulatory failure. The fact reported by other workers that the edema is more intense and appears more rapidly after intravenous injection of minute rather than large quantities of dextran was not confirmed; the existence of a "critical dose" that does not produce any edema was not substantiated.

Inaktivierungsversuche mit homozygoten Hefestämmen verschiedenen Ploidiegrades

A series of extensively homozygous and isogenic Saccharomyces strains of different ploidy (haploid —hexaploid) was developed by controlled matings. The degree of ploidy was further checked by analysis of the segregation of mating type alleles and in case of the hexaploid strain also of two other markers. The genetic analysis was consistent with previous findings. Measurements of linear dimensions of the various strains indicated an increase of cellular volume proportional with ploidy. Radiation inactivation studies on the different strains with UV showed a maximum of resistance of the triploid strains and a decrease of resistance with further increase of ploidy from triploid to hexaploid. In X-ray and Po-a-ray inactivation, diploid strains heterozygous in the mating type alleles showed a maximum of resistance, whereas diploids homozygous in the mating type alleles proved to be less resistant than triploids. Additional to the effect of the mating type alleles on the resistance to X-rays and Po-α-rays (aa-effect) there could be shown an effect of alleles controlling the dependence on the aminoacids serine and valine-isoleucine (AS-effect). Strains dependent on serine or valine-isoleucine proved to be more X-ray and Po-a-ray resistant than related prototrophic strains. There is, however, no difference in the UV resistance. This AS effect is not present in haploid strains but only in strains of higher ploidy. The dose effect curves of strains exhibiting an AS effect or an aa effect show a characteristic difference. The AS effect is expressed by a constant dose reduction factor. The aa effect, however, produces dose effect curves that have a more expressed shoulder in the lower dose range than comparable curves of aa or αα strains but run parallel to these curves in the higher dose ranges. Possible meanings of these findings are discussed.