The cosalane pharmacophore has been extended by the attachment of two additional substituted benzoic acid rings through amide and methylene linkers. The resulting compounds display significant ...antiviral activity when tested in vitro for inhibition of the cytopathic effects of HIV-1RF in CEM-SS cells and HIV-1IIIB in MT-4 cells. The compound containing the methylene linker also shows moderate activity versus HIV-2ROD in MT-4 cells. Because cosalane and related compounds containing extended pharmacophores inhibit the binding of gp120 to CD4, the presently described new compounds are assumed to act by a similar mechanism. A hypothetical model is proposed for the binding of the methylene-linked compound to CD4.
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In order to define the role of the cholestane moiety in the anti-HIV agent cosalane, a series of cosalane analogs was synthesized in which the cholestane ring system was replaced by normal alkenyl ...and phosphodiester substituents having varied chain lengths and lipophilicities. The compounds containing simple alkenyl substituents were found to be more potent as inhibitors of the cytopathic effect of HIV-1 in cell culture than the phosphodiesters. In addition, the potencies of the alkene congeners correlated positively with chain length and lipophilicity of the alkene. The results indicate that the cholestane moiety of cosalane functions as a lipophilic accessory appendage to escort the dichlorodisalicylmethane pharmacophore to a lipid environment.
Head injury is the leading cause of serious morbidity and mortality in bicycle accidents. There is good evidence to recommend helmets, yet few children wear them. Following a survey of children ...presenting to the emergency room with a bicycle injury, helmet promotion was evaluated in a randomized trial. The intervention consisted of physician counseling and take-home pamphlets. The study involved 334 children: 161 in the intervention group and 173 in the control group. In a follow-up telephone call, 2 to 3 weeks later, only 9.3% of the intervention group had purchased helmets, compared with 8.0% of the control group. Families in the intervention group received further counseling during the telephone contact, resulting in one additional purchase at 6-week follow-up. Evidence that a bike injury motivates cyclists to purchase helmets, and the influence of the self-administered questionnaire most likely account for the high purchase rate in the control group. Surprisingly, the helmet promotion intervention, including follow-up phone counseling, made no further impact. The results probably are best explained by a "double threshold" effect. Certain families were easily encouraged to buy a helmet, whereas others were far from ready to adapt this fairly recent innovation as routine cycling equipment. The findings suggest that physicians interested in helmet promotion would do better to participate in the design and implementation of multidisciplinary community campaigns.
Introduction of an amido group or an amino moiety into the alkenyl linker chain of cosalane (1) provided a new series of analogues 3-8. The new compounds were evaluated as inhibitors of the ...cytopathic effect of HIV-1 and HIV-2 in cell culture. The replacement of the 1' and 2' carbons in the linker chain of I by an amido group was generally tolerated. The length of the linker chain and the stereochemistry of the substituent at C-3 of the steroidal ring had significant effects on the antiviral activity and potency. Incorporation of an amino moiety into the linker completely abolished the anti-HIV activity. There are several steps in the HIV replication cycle that have been proposed as targets for the development of therapeutic agents (De Clercq, E. J. Med. Chem. 1995, 38, 2491; De Clercq, E. Pure Appl. Chem. 1998, 70, 567). However, currently approved anti-HIV drugs are only directed against the viral enzymes reverse transcriptase or protease (Carpenter. C. C. J.; Fischl, M. A.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S. G.; Richman, D. D.; Saag, M. S.; Schooley, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.; Volberding, P. A. JAMA 1998, 280, 78). Drugs capable of interfering with other steps of the virus life cycle will be highly valuable in the antiretroviral therapy of AIDS, as they will have different patterns of resistance mutations than the drugs currently used clinically. In addition, their utilization in combination with other therapeutic agents could provide more potent drug 'cocktails' capable of completely suppressing virus replication. Consequently, there is an urgent need for the discovery of clinically useful anti-HIV agents possessing novel mechanisms of action.
The effects of linker chain modifications were investigated in a series of cosalane analogues. The modifications investigated included: (1) shortening the three-carbon linker chain between the ...dichlorodisalicylmethane and the cholestane moiety by one carbon atom; (2) lengthening the linker chain by one carbon; (3) hydrogenation of the double bond in the linker chain; (4) changing the point of attachment of the linker chain from C-3 to C-6; (5) insertion of a phosphate between the steroid and the linker chain. With the exception of the phosphate modification, which abolished anti-HIV activity and increased cytotoxicity, the linker chain modifications produced relatively minor changes in anti-HIV potency. The steroid and attached linker chain of cosalane therefore appear only to provide a general lipophilic appendage for the dichlorodisalicylmethane pharmacophore.
The effects of linker chain modifications on anti-HIV activity were investigated in a series of cosalane (
1) analogues. The modifications included shortening and lengthening the linker chain between the steroid and the dichlorodisalicylmethane pharmacophore, as well as changing the point of attachment of the linker chain to the steroid. The results indicate that the linker chain and attached steroid provide a general lipophilic appendage for the pharmacophore.
The number of bicycle-related injuries has risen significantly with the increased popularity of bicycle riding in Canada. The risk of injury is highest among children. To assess the magnitude of the ...problem and to identify the contributing factors we used a questionnaire, injury reports and patient charts to survey bicycle-related injuries among children brought to the emergency department of the Children's Hospital of Eastern Ontario, Ottawa, between May 1 and Sept. 30, 1988. The questionnaire was completed for 517 (91%) of the 568 children; 70% were boys, and the mean age was 9.4 years. Only 2% of the patients had been wearing a helmet at the time of injury, although 13% claimed to own one for cycling. Over 60% of the accidents were attributable to carelessness or poor bicycle control; mechanical failure and environmental hazards were minor factors. Over 80% of the injuries occurred within a kilometre of the child's home. Of the 97 children admitted to hospital 49% had head and skull injuries and 40% had limb fractures. Bicycle-related injuries represented 14.8% of all nonwinter (Apr. 1 to Oct. 31) trauma admissions among children 5 years or older. Our results further document bicycle-related injuries as an important childhood problem and underscore the need for improved safety measures.
OBJECTIVES To determine whether blood pressure is reduced for at least 6 months with an intervention to lower alcohol intake in moderate to heavy drinkers with above optimal to slightly elevated ...diastolic blood pressure, and whether reduction of alcohol intake can be maintained for 2 years. DESIGN A randomized controlled trial. METHODS Six hundred forty-one outpatient veterans with an average intake of 3 or more alcoholic drinks per day in the 6 months before entry into the study and with diastolic blood pressure 80 to 99 mm Hg were randomly assigned to a cognitive-behavioral alcohol reduction intervention program or a control observation group for 15 to 24 months. The goal of the intervention was the lower of 2 or fewer drinks daily or a 50% reduction in intake. A subgroup with hypertension was defined as having a diastolic blood pressure of 90 to 99 mm Hg, or 80 to 99 mm Hg if recently taking medication for hypertension. RESULTS Reduction in average weekly self-reported alcohol intake was significantly greater (P<.001) at every assessment from 3 to 24 months in the intervention group vs the control group: levels declined from 432 g/wk at baseline by 202 g/wk in the intervention group and from 445 g/wk by 78 g/wk in the control group in the first 6 months, with similar reductions after 24 months. The intervention group had a 1.2/0.7–mm Hg greater reduction in blood pressure than the control group (for each, P=.17 and P=.18) for the 6-month primary end point; for the hypertensive stratum the difference was 0.9/0.7 mm Hg (for each, P=.58 and P=.44). CONCLUSIONS The 1.3 drinks per day average difference between changes in self-reported alcohol intake observed in this trial produced only small nonsignificant effects on blood pressure. The results from the Prevention and Treatment of Hypertension Study (PATHS) do not provide strong support for reducing alcohol consumption in nondependent moderate drinkers as a sole method for the prevention or treatment of hypertension.Arch Intern Med. 1998;158:1197-1207-->
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