Investigation of the antinociceptive efficacy and relative potency of extended duration injectable 3-acylmorphine-6-sulfate prodrugs in rats

This investigation was designed to examine the antinociceptive activity in rats of 3-O-acyl prodrugs of M6S relative to the parent drug, after intravenous and intramuscular injection, using the tail flick latency test of antinociception. M6S, 3-acetylmorphine-6-sulfate (3AcM6S), 3-propionylmorphine-6-sulfate (3PrM6S), 3-butanoylmorphine-6-sulfate (3BuM6S) and 3-heptanoylmorphine-6-sulfate (3HpM6S) were administered by the IV route in a dose of 4.10 mu mol/kg. Relatively high levels of antinociception (>40% Maximum Possible Effect) were achieved following administration of M6S, 3AcM6S and 3PrM6S, whereas insignificant antinociception (<20%MPE) was achieved following administration of 3BuM6S or 3HpM6S. Although the mean duration of action for 3AcM6S (6 h) was longer than for M6S or 3PrM6S (4 h), the mean area (+/- S.E.M.) under the degree of antinociception versus time curve (AUG) for 3AcM6S (151.6 +/- 6.9%MPE h) was not significantly different (p <0.05) from that for M6S (120.8 +/- 32.7%MPE h) or for 3PrM6S (106.0 +/- 21.3%MPE h). The mean ED50 (range) doses for M6S, 3AcM6S and 3PrM6S were calculated to be 4.16 (3.61-4.48), 4.32 (3.55-5.09) and 4.54 (4.21-4.79) mu mol/kg, respectively. Preliminary studies were conducted on potential long-acting formulations containing 8 x ED50 doses of M6S and the 3-acetyl and 3-propionyl esters suspended in soybean oil. These showed that 3PrM6S gave a greater AUC (mean + S.E.M.) (1087.4 +/- 97.4%MPE h) and longer duration of action (20 h) than did M6S (613.1 +/- 155.9%MPE h; 10 h duration) or 3AcM6S (379.3 + 114.2%MPE h: 8 h duration). Further studies are needed to more fully investigate these findings. (C) 1998 Elsevier Science B.V. All rights reserved.

Efficacy of zeta-cypermethrin as pour-on or spray formulations for the control of buffalo fly (Haematobia irritans exigua) in cattle

Objective To determine the efficacy of zeta-cypermethrin in controlling buffalo fly (Haematobia irritans exigua). Design Five field trials in northern and central Queensland. Procedure Zeta-cypermethrin pour-on at 2.5 mg/kg, spray at 62.5 ppm, deltamethrin pour-on and pour-on vehicle were applied to groups of 20 cattle. Buffalo fly counts were conducted three times before treatment and 3, 7, 14, 21, 28 and 35 days after treatment. Results In central Queensland where synthetic pyrethroid resistance in buffalo fly populations was rare, 2.5 mg/kg of zeta-cypermethrin pour-on gave good control of buffalo fly for 4 weeks and was better than a deltamethrin product. A zeta-cypermethrin spray used at 62.5 ppm gave 14 days control. In far-north Queensland where resistance to synthetic pyrethroids and heavy rain was common, the maximum period of efficacy of zeta-cypermethrin pour-on was reduced to 2 weeks. Conclusion In areas where there is low resistance to synthetic pyrethroids among buffalo flies, zeta-cypermethrin pour-on can be expected to give good control for 4 weeks.

Self-efficacy for refusal mediated by outcome expectancies in the prediction of alcohol-dependence amongst young adults

The present study examined the relative importance of outcome expectancies and self-efficacy [1] in the prediction of alcohol dependence [2] and alcohol consumption in a sample of young adult drinkers drawn from a milieu previously reported as supportive of risky drinking. In predicting alcohol dependence, outcome expectancies were found to mediate self-efficacy and the same pattern was found for both males and females. This suggests that male and female drinkers may become more similar as they progress along the drinking continuum from risky drinking to dependent drinking. However, in women, in comparison to men, a greater array of expectancies and self-efficacy scales were found to predict heavy drinking, as measured by quantity and frequency. These results suggest that heavy drinking women are particularly at risk of developing drinking related complications and that preventative education needs to take into account gender differences.

Therapeutic efficacy of zeta-cypermethrin pour-on for the treatment of biting and sucking lice in cattle under field conditions

Objective To assess the efficacy of zeta-cypermethrin pour-on to control cattle lice. Design Five field trials in south-eastern Australia. Procedure Zeta-cypermethrin pour-on, deltamethrin pour-on and pour-on vehicle were applied to groups of 10 cattle. Lice were counted before treatment and 14, 28, 42 and 56 days after treatment. Results Zeta-cypermethrin pour-on given at 2.5 mg/kg was equivalent to, or marginally more effective than a deltamethrin pour-on at 0.75 mg/kg. It eliminated B bovis and H eurysternus and gave good control of L vituli and S capillatus. Zeta-cypermethrin at 1 mg/kg gave good control of B bovis and H eurysternus but was not satisfactory against L vituli and S capillatus. Conclusion Zeta-cypermethrin pour-on, given at 2.5 mg/kg, is an effective treatment for cattle lice control. Zeta-cypermethrin, and other synthetic pyrethroid pour-ons, are the treatment of choice to control B bovis.

Employee reactions to behavioural control under conditions of stress: the moderating role of self-efficacy

Extensive research conducted in the occupational stress literature has failed to provide convincing support for the stress-buffering effects of work control on employee adjustment. Drawing on research conducted in the laboratory context, it was proposed that the stress-buffering effects of work control on employee adjustment would be more marked at high, rather than low, levels of self-efficacy. In a sample of 100 customer service representatives, a significant three-way interaction among role conflict, work control and self-efficacy (measured at Time 1) was observed on (low) depersonalization (measured at Time 2). Consistent with expectations, work control reduced the negative effects of work stress on this outcome measure only for employees who perceived high levels of self-efficacy at work. In addition, there was evidence to suggest that self-efficacy moderated the main effects of work control on job satisfaction and somatic health. These findings are discussed hi terms of their theoretical contribution to the job strain model, and also in relation to workplace interventions designed to improve levels of employee adjustment.

The efficacy of a universal school-based program to prevent adolescent depression

Evaluated whether a universal school-based program, designed to prevent depression in adolescents, could be effectively implemented within the constraints of the school environment. Participants were 260 Year 9 secondary school students. Students completed measures of depressive symptoms and hopelessness and were then assigned to 1 of 3 groups: (a) Resourceful Adolescent Program Adolescents (RAP A), an 11-session school-based resilience building program, as part of the school curriculum; (b) Resourceful Adolescent Program-Family (RAP-F), the same program as in RAP A, but in which each student's parents were also invited to participate in a 3-session parent program; and (c) Adolescent Watch, a comparison group in which adolescents simply completed the measures. The program was implemented with a high recruitment (88%), low attrition rate (5.8%), and satisfactory adherence to program protocol. Adolescents in either of the RAP programs reported significantly lower levels of depressive symptomatology and hopelessness at post-intervention and 10-month follow-up, compared with those in the comparison group. Adolescents also reported high satisfaction with the program. The study provides evidence for the efficacy of a school-based universal program designed to prevent depression in adolescence.

Efficacy of Lentivirus-mediated and MUC1 antibody-targeted VP22-TK/GCV suicide gene therapy for ovarian cancer

Transfer of the herpes simplex virus type I thymidine kinase (HSV-TK) gene into tumor cells using virus-based vectors in conjunction with ganciclovir (GCV) exposure provides a potential gene therapy strategy for the treatment of cancer. Effective gene therapy,, depends on the efficient transfer and specific targeting of therapeutic genes and their protein products to target cells. The purpose of this study was to investigate the anti-tumor effect of Lentivirus-mediated and MUC1 antibody-targeted VP22-TK/GCV suicide gene therapy in animal models. Mouse models were generated with intraperitoneal injection of human epithelial ovarian cancer cells 3AO, which are MUC1-positive. HTV-1-based lentiviral vectors carrying VP22-TK or scFv-VP22-TK were prepared. The animals were injected intraperitoneally with lentivirus containing scFv-VP22-TK, VP22-TK followed by GCV treatment. Combined treatment of lentivirus-expressed scFv-VP22-TK or VP22-TK with GCV inhibited the proliferation and prolonged survival times compared with the control vector. The survival time of animals treated with scFv-VP22-TK/GCV was significantly longer than that of animals treated with VP22-TK/GCV (p = 0.006). Conclusion: Our results suggest that MUC1 antibody-targeted VP22-TK/GCV suicide gene therapy can efficiently inhibit ovarian tumor growth and increase survival in a nude mouse model of ovarian carcinoma. These data support the development of this method for human clinical trials.

A controlled trial comparing the efficacy of rice-based and hypotonic glucose oral rehydration solutions in infants and young children with gastroenteritis

A prospective randomized trial was conducted to compare the efficacy of a rice-based oral rehydration solution (ORS) with glucose ORS in infants and children under 5 years of age with acute diarrhoea and mild to moderate dehydration (<10%). One hundred children presenting to a large metropolitan teaching hospital were eligible for entry to the study and were randomized to receive rice ORS or glucose ORS. Outcome measures were stool output (SO), duration of illness (DD) and recovery time to introduction of other fluids (RTF) and diet (RTD). Significant differences were found for all outcome measures in favour of the rice ORS group. Mean SO was lower (160 vs 213 mt; P<0.02), mean DD was reduced (17.3 vs 24.3 h; P = 0.03) and median RTF was decreased (12.7 vs 18.1 h; P< 0.001) in the rice ORS group compared with the glucose ORS group. The median rime to introduction of diet and mean length of hospital stay showed similar significant reductions. Our study has shown rice ORS to be an acceptable alternative to glucose ORS in young children and have shown that it is significantly more effective in reducing the course of diarrhoeal illness and the time taken to return to normal drinking and eating habits.

Efficacy of praziquantel against Schistosoma japonicum: field evaluation in an area with repeated chemotherapy compared with a newly identified endemic focus in Hunan, China

This study conducted in 1999/2000 was designed to evaluate the efficacy of praziquantel against Schistosoma japonicum in an area with repeated chemotherapy (Area A) compared with a newly identified endemic focus (Area B) in Hunan Province, China. The population size was 2015 and 2180 in Areas A and B, respectively, of which 1129 and 1298 subjects received stool examination. A total of 230 subjects were identified by the Kato-Katz technique (4 smears per person) as being infected with S. japonicum, 124 in Area A (prevalence 11 %) and 106 in Area B (prevalence 8.2%). They were treated with a single oral dose of praziquantel (40 mg/kg) in the non-transmission season. A follow-up stool examination was made 50 days after treatment. Among the 220 cases followed, 22 were found stool-egg-positive, with an overall cure rate of 90 %, and 99 % reduction of infection intensity (eggs per gram stool). No significant difference was found in cure rates between the 2 areas (89.7% vs 90.3%). The efficacy of the drug in the area with repeated chemotherapy was not significantly different from that in the newly identified endemic focus. This study, therefore, suggests that the efficacy of praziquantel against S. japonicum has not changed in the Dongting Lake region after more than 14 years of mass chemotherapy, and there is no evidence of tolerance or resistance of S. japonicum against praziquantel.

Unprecedented oxidation of a biologically active aroylhydrazone chelator catalysed by iron(III): serendipitous identification of diacylhydrazine ligands with high iron chelation efficacy

Ligands of the 2-pyridylcarbaldehyde isonicotinoylhydrazone class show high iron (Fe) sequestering efficacy and have potential as agents for the treatment of Fe overload disease. We have investigated the mechanisms responsible for their high activity. X-ray crystallography studies show that the tridentate chelate 2-pyridylcarbaldehyde isonicotinoylhydrazone undergoes an unexpected oxidation to isonicotinoyl(picolinoyl)hydrazine when complexed with Fe-III. In contrast, in the absence of Fel the parent hydrazone is not oxidized in aerobic aqueous solution. To examine whether the diacylhydrazine could be responsible for the biological effects of 2-pyridylcarbaldehyde isonicotinoylhydrazone, their Fe chelation efficacy was compared. In contrast to its parent hydrazone, the diacylhydrazine showed little Fe chelation activity. Potentiometric titrations suggested that this might be because the diacylhydrazine was charged at physiological pH, hindering its access across membranes to intracellular Fe pools. In contrast, the Fe complex of this diacylhydrazine was charge neutral, which may allow facile movement through membranes. These data allow a model of Fe chelation for this compound to be proposed: the parent aroylhydrazone diffuses through cell membranes to bind Fe and is subsequently oxidized to the diacylhydrazine complex which then diffuses from the cell. Other diacylhydrazine analogues that were charge neutral at physiological pH demonstrated high Fe chelation efficacy. Thus, for this class of ligands, the charge of the chelator appears to be an important factor for determining their ability to access intracellular Fe. The results of this study are significant for understanding the biological activity of 2-pyridylcarbaldehyde isonicotinoylhydrazone and for the design of novel diacylhydrazine chelators for clinical use.