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One problem among many: drug use among care leavers in transition to independent living ibuprofen 400mg with mastercard. Newburn T & Person G (2002) The place and meaning of drug use in the lives of young people in care best 600mg ibuprofen. Rugg J (2000) Making connections: tackling youth homelessness through a multi-agency approach generic 400 mg ibuprofen with mastercard. Fountain J, Howes S, Marsden J et al (2003) Drug and alcohol use and the link with homelessness: results from a survey of homeless people in London. Youth homelessness and substance use: report to the drugs and alcohol research unit. In: Kimler B & Hoorens S (eds) Understanding illicit drug markets, supply-reduction efforts, and drug-related crime in the European Union. Cameron L & Williams J (2001) Cannabis, alcohol and cigarettes: substitutes or complements? Office of National Drug Control Policy (2011) National drug control strategy: data supplement 2011. Dave D (2006) The effects of cocaine and heroin price on drug-related emergency department visits. Saxe L, KadushinC, Beveridge A et al (2001) The visibility of illicit drugs: implications for community- based drug control strategies, American Journal of Public Health 91: 1987-94. British Medical Association (2008) Forever cool: the influence of smoking imagery on young people. Anderson P, de Bruijn A, Angus K et al (2009) Impact of alcohol advertising and media exposure on adolescent alcohol use: a systematic review of longitudinal studies. School of Health and Related Research University of Sheffield (2008) independent review of the effects of alcohol pricing and promotion. Smith L & Foxcroft D (2009) The effect of alcohol advertising, marketing and portrayal on drinking behaviour in young people: systematic review of prospective cohort studies. Hunt K, Sweeting H, Sargent J et al (2011) Is there an association between seeing incidents of alcohol or drug use in films and young Scottish adults’ own alcohol or drug use? Padilla-Walker L, Nelson L, Carroll J et al (2010) More than a just a game: video game and internet use during emerging adulthood. Hornik R, Maklan D, Cadell D et al (2006) Evaluation of the national youth antidrug media campagin: 2004 report of findings. Gunasekera H, Chapman S & Campbell S (2005) Sex and drugs in popular movies: an analysis of the top 200 films. British Medical Association (2009) Under the influence: the damaging effect of alcohol marketing on young people. Cumberbatch G & Gauntlett S (2005) Smoking, alcohol and drugs on television: a content analysis. United Nations International Narcotics Control Board (2008) Report of the International Narcotics Control Board for 2007. Berridge V (1984) Drugs and social policy: the establishment of drug control in Britain 1900-1930. Ministry of Health (1926) Report of the Departmental Committee on Morphine and Heroin Addiction (The Rolleston Report). Ministry of Health and Scottish Home and Health Department (1965) Drug addiction: the second report of the Interdepartmental Committee (The Second Brain Report). Medical Working Group on Drug Dependence (1984) Guidelines of good clinical practice in the treatment of drug misuse. Department of Health (England), the Scottish Government, Welsh Assembly Government and Northern Ireland Executive (2007) Drug misuse and dependence. Gruer L, Wilson P, Scott P et al (1997) General practitioner centred scheme for treatment of opiate dependents in Glasgow. Home Office (1998) Statistics of drug seizures and offenders dealt with, United Kingdom, 1996. Her Majesty’s Government (1995) Tackling drugs together: a strategy for England 1995-1998 (Cmd 2846). The Task Force to Review Services for Drug Misusers (1996) Report of an independent review of drug treatment services in England. Budd T, Collier P, Mhlanga B et al (2005) Levels of self-report offending and drug use among offenders: findings from the Criminality Surveys. Reducing demand, restricting supply, building recovery: supporting people to lead a drug free life. Weatherburn D, Topp L, Midford R et al (2000) Drug crime prevention and mitigation: a literature review and research agenda. House of Commons Science and Technology Select Committee Drug classification: making a hash of it: fifth report of session 2005-2006. The Police Foundation (1999) Drugs and the law: report of the independent inquiry into the Misuse of Drugs Act 1971 (The Runciman Report). Kleinman (2009) When brute force fails: how to have less crime and less punishment.

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Thus the rate- limiting step for systemic absorption of drugs from intravaginal creams cheap 400mg ibuprofen mastercard, inserts and tablets is often dissolution within the vaginal fluid cheap ibuprofen 400 mg otc, particularly for poorly soluble drugs purchase 400mg ibuprofen fast delivery. Obviously, the type of dosage form affects the rate of dissolution; for example, a drug which is already dissolved in an aqueous vaginal gel will be more rapidly absorbed than a drug which is in solid form within a vaginal tablet preparation. The effective area of contact Although the area of the vaginal cavity is approximately 60 cm , the formulation will influence the size2 of the area over which the drug is deposited. The vehicle should facilitate even distribution of the drug throughout the vagina, rather than concentrating it in one spot. Factors such as the hydrophilicity and viscosity of the vehicle will determine how well it spreads through the vagina. Contact time The formulation will also influence the extent of the contact time the drug has with the absorbing surface of the vaginal epithelium. Typical delivery systems such as foams, gels and tablets are removed in a relatively short period of time by the self- cleansing action of the vaginal tract. New bioadhesive gel delivery systems are being developed to prolong contact time with the absorbing surface and are described below. Concentration The rate of absorption via passive diffusion processes (transcellular and paracellular) can be increased by increasing the drug concentration in solution at the absorbing surface (see Section 1. For systems intended for prolonged administration, a highly saturated formulation will also ensure that sufficient drug is present to ensure sustained drug delivery throughout the intended time of application. However, care must be taken, as high local drug concentrations over extended periods of time may also cause severe local irritation or adverse tissue reactions. A brief overview of both the advantages and disadvantages of vaginal drug delivery is given below. However, it2 is much smaller than that offered by the nasal (150 cm ), rectal (200–400 m ), pulmonary (75–700 m ) and3 2 2 intestinal (200 m ) routes. In contrast to the oral route, this route also avoids degradation in the intestinal wall or the liver, prior to the drug reaching the systemic circulation. Reduced first-pass effects after vaginal application of estrogens, progestogens and prostaglandins have all been reported in a number of studies. Permeability The vagina demonstrates a relatively high permeability to many drugs, particularly during the late luteal and early follicular phases of the menstrual cycle. Ease of administration Intravaginal dosage forms are relatively easy to administer and offer the feasibility of self-administration. Patient compliance is generally good, particularly if no leakage or staining occurs. Prolonged retention Prolonged retention of the drug is possible, if the appropriate delivery system such as vaginal silicone ring is used, thereby allowing a reduction in the dosing frequency. Alternative when the oral route is unfeasible The vaginal route may be appropriate in certain situations where the oral route is unfeasible, such as: • patients with nausea and vomiting; • patients with swallowing difficulties; • drugs that cause gastric irritation; • drugs that are unstable in the gastrointestinal fluids; • drugs that undergo extensive first-pass effects in the gut wall or liver. Zero-order controlled release Vaginal drug delivery offers the potential to achieve zero-order controlled release over a controlled period. Adverse effects The relatively low amount of fluids bathing the vaginal mucous membranes means the tissue is prone to adverse reactions, such as local irritation, caused by vaginal devices. Similarly, locally irritating or sensitizing drugs must be used with caution in this route. Furthermore, materials used in vaginal preparations should be sterilized and not act as a growth medium for the proliferation of pathogenic microorganisms, bacteria, fungi, and protozoa. Hormone-dependent changes Cyclic changes in the reproductive system mean that large fluctuations in vaginal bioavilability can occur. Cyclical changes in the vaginal epithelium include changes in the thickness and porosity of the vaginal epithelium, the amount and pH of the vaginal fluids and the degree of enzymatic activity present. Furthermore, estrogen therapy and steroidal contraceptives influence the vaginal fluid, epithelial thickness and vascularity, which also contributes to a lack of reproducibility in the vaginal absorption of drugs. This lack of reproducibility constitutes a major problem associated with vaginal drug delivery and, for drugs with a narrow therapeutic index, such variations may be unacceptable. Leakage The bulbocavernosus muscles which surround the orifice of the vagina are not usually strong enough to retain vaginal preparations in the same way as the anal sphincter retains rectal suppositories. Slipping-out or leakage may occur, particularly in the case of preparations involving a relatively large volume of liquid or semisolid. Life-cycle constraints The vagina is the final part of the internal female genitalia, the parturient canal, and also serves as a passage for the outflow of cervical fluids and the menstrual flow. Menstruation, intercourse, pregnancy and delivery, and other anatomical or physiological changes in the life cycle of women must also be taken into account when the timing and effectiveness of drug application are being considered. Applicability constraints No matter what degree of optimization can actually be achieved via this route, it must be remembered that vaginal delivery is only applicable to approximately 50% of the population. Thus it may be that the true potential of this route lies in the treatment of female-specific conditions, such as in the treatment of climacteric symptoms of the menopause etc. However more recently, the vaginal delivery of estrogens, progesterones and prostaglandins has been considered in term of their systemic, as opposed to merely local, delivery. Current technologies in vaginal drug delivery are increasingly concerned with the systemic delivery of these agents and commercial preparations are now available: 11. This risk can be eliminated by treatment with a progestational agent for up to 14 days a month.

Cohen and Cadwallader (20) studied the effects of uniform visual stimulation utilizing a different apparatus buy cheap ibuprofen 600 mg online. The findings showed that under both monocular and binocular conditions purchase 600 mg ibuprofen fast delivery, subjects reported a temporary cessation of ordinary visual experience after prolonged exposure to a uniform visual field generic ibuprofen 400 mg overnight delivery. With increased exposure to these conditions the initial reports of the field as being "foglike" changed to an experience of "blanking out. Factors that facilitated "white-out" were found to include both extensive prior stimulation and scotopic (rather than photopic) stimulation. A similar finding is reported by Ditchburn, cited by Bruner (12), who showed that if a visual pattern is stabilized on the retina so that it is not even displaced by the natural tremor of the eye, it disappears from view within about six seconds. They were told to lie on a comfortable bed in a lighted cubicle, and they wore translucent goggles, cuffs, and gloves. Upon leaving, after two or three days in the experimental situation, subjects had difficulty in focusing; objects appeared fuzzy and did not stand out from their backgrounds; the environment seemed two-dimensional; and colors appeared to be more saturated than usual. The experimenters also found deteriora- -60- tion in visual motor coordination as measured by such tasks as the Wechsler Digit Symbol test, handwriting specimens, and the copying of prose paragraphs. Another study by the same group (69) showed that performance on the Thurstone-Gottschaldt Embedded Figures test declined, whereas no change was manifest in a mirror tracing task. The deterioration of performance on the digit symbol test has since been confirmed by Davis, McCourt, and Solomon (21), who studied ten paid volunteer subjects under different experimental conditions of perceptual deprivation. These investigators failed to find deterioration in the Witkin Embedded Figures test. Vernon and Hoffman (76), after conditions of sensory deprivation lasting twenty-four and forty-eight hours, questioned four subjects about difficulty in focusing, increased saturation of hues, and lack of three-dimensional perception, and reported negative findings for all three phenomena. Heron, Doane, and Scott (41) extended the duration of their experimental procedure to six days and served as their own subjects. They described the disturbances in visual perception as unexpectedly profound and prolonged, with similar manifestations for all three participants. These effects included apparent movement phenomena (with and without head and eye movements by the observers), distortions of shape, accentuation of afterimages, perceptual lag, and increases in color saturation and contrast. Further work from the same laboratory (28) described the fluctuating curvature of surfaces and lines, and disturbances in size constancy. In addition, these investigators observed that autokinetic effects were harder to abolish, larger figural aftereffects were obtained, and spiral aftereffects were more persistent. Freedman, Grunebaum, and Greenblatt (30) studied the effects of isolation and reduced patterning of visual and auditory input upon visual perception. As controls they employed paid male volunteers, who received only social isolation. Each of the eight experimental subjects was placed on a bed in a lighted room and was instructed not to move about. The control group of six subjects was similarly treated without the additional restrictions to visual, auditory, and tactile input. Both groups remained in the situation for eight hours and had no contact with the experimenters during this time. Their report describes measurable perceptual "aberrations" found -61- in every experimental subject, but none in the control subjects. In some subjects these aberrations persisted for over one hour, and consisted of two-dimensional forms changing shape and size and of straight lines moving and curving. Comparing pre- and postisolation performance, they observed a decrement in size constancy and changes in the Müller-Lyer illusion. In both instances, changes consisted of increased variability of judgment rather than unidirectional effects. Visual-motor coordination, as seen in the copying of Bender-Gestalt figures, was significantly impaired following exposure to the experimental conditions. An increase in apparent movement phenomena through perceptual deprivation has been demonstrated in a study designed specifically to test this relationship. Ormiston (59) compared thirty minutes of perceptual deprivation, sensory bombardment, and a neutral condition for their effects on the perception of the phi phenomenon with thirty subjects serving in each condition. The deprivation condition was realized through having subjects sit in a bare room wearing translucent goggles, ear plugs, and ear muffs. The sensory bombardment condition exposed subjects to motor tasks, a tape with varied sound effects, taste and smell stimuli, and a variety of colored goggles. The neutral condition consisted of having subjects sit on a couch in a waiting room. A comparison of pre- and posttests showed a statistically significant increase in the perception of phi for the deprived group, whereas the bombardment group showed a trend toward decrease in phi perception. Vernon, McGill, Gulick, and Candland (78) studied the effects of sensory deprivation upon a variety of perceptual and motor skills.

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Three other cases have been reported: one woman received a single dose of 8 g of hydroxyurea at about 12 weeks of pregnancy and had an elective termination four weeks later of an apparently normal fetus (Doney et al purchase 600 mg ibuprofen mastercard. Another woman was treated with an unspecified dose of hydroxyurea for six months before pregnancy and from mid-second trimester to near term discount 600 mg ibuprofen overnight delivery, and delivered a healthy infant who developed normally during one year of follow- up (Fitzgerald & McCann purchase 400mg ibuprofen with visa, 1993). The third case involved a woman who had been treated with an unspecified dose of hydroxyurea two years before conception. She deliv- ered a normal infant, who had normal physical and mental development at seven years of age (Pajor et al. The cytotoxicity could be partially prevented by simul- taneous injection of 700 mg/kg bw deoxycytidine monophosphate (Herken, 1984) and completely prevented by simultaneous injection of 1 mg/kg bw colchicine (Herken, 1985). A dose-related increase in the frequency of multiple malformations of the viscera and skeleton and reduced fetal weight were observed at doses ≥ 500 mg/kg bw, but embryolethality was seen only at 1000 mg/kg bw. Hydroxyurea was shown to pass into the embryo and to persist there longer than in maternal blood. Studies from the same laboratory with the same strain of rat showed that intraperi- toneal injection of 375 or 500 mg/kg bw hydroxyurea on day 12 of pregnancy produced microscopic evidence of cytotoxicity in the neural tube, but no malformations were observed when the dams were allowed to deliver their pups at term. Nevertheless, observation of the offspring at 30–50 days of age showed locomotor and behavioural deficits at both doses (Butcher et al. Further studies from the same laboratory with the same strain of rat showed that teratogenic and embryolethal effects could be induced by a dose as low as 137 mg/kg bw, but not by 100 mg/kg bw, administered intraperitoneally on days 9–12 of gestation (Wilson et al. Behavioural effects were also observed in the offspring of Sprague-Dawley dams treated with a single intraperitoneal dose of 150 mg/kg bw hydroxyurea on various days of pregnancy (Brunner et al. The wide range of malformations induced in rats by hydroxyurea has led to its use as a positive control substance in standard testing for both terato- genicity (Aliverti et al. Comparisons of the teratogenic responses in various stocks and strains of rats showed differences in the type of malformation and the time of sensitivity in two stocks of Wistar rats (Barr & Beaudoin, 1981) and in Wistar and Fischer 344 rats (DePass & Weaver, 1982). A group of 27 pregnant golden hamsters received an intravenous injection of 50 mg/kg bw hydroxyurea on day 8 of pregnancy. A high rate of fetal death and malformations, especially of the central nervous system, was observed (Ferm, 1966). The teratogenicity of hydroxyurea in pregnant New Zealand white rabbits was demonstrated by subcutaneous injection of 750 mg/kg bw once on day 12 of gestation, with embryo and fetal examination 15 min to 32 h later by histology and on day 29 for malformations. Treatment produced marked cytotoxicity and a high percentage of resorptions (61%), reduced fetal weight and malformations in all surviving fetuses affecting most organ systems and the skeleton, as observed in rats (DeSesso & Jordan, 1977; DeSesso, 1981a). Inhibition of the cytotoxicity and teratogenicity of hydroxyurea by D-mannitol, a potent scavenger of hydroxyl free radicals, suggests that these radicals are the proximate cytotoxins and teratogens (DeSesso et al. Groups of 17 mated cats of European and Persian breeds were dosed orally with 50 or 100 mg/kg bw hydroxyurea on days 10–22 of gestation, and the fetuses were exam- ined on day 43. At 50 mg/kg bw, fetal weight and survival were not affected, but a high proportion of the fetuses were malformed, with a wide range of malformations similar to those seen in other species. At 100 mg/kg bw, a large proportion of the cats were not pregnant, but maternal and fetal weights were reduced, the frequency of resorptions increased and one of two live fetuses was malformed (cyclopia) (Khera, 1979). Of 22 pregnant female rhesus monkeys (Macaca mulatta) dosed intravenously with 50–500 mg/kg bw hydroxyurea for various times between days 18 and 45 of gestation, eight aborted or had intrauterine deaths; 10 had fetuses with multiple malformations mostly of the axial skeleton, but also genitourinary, cardiac, brain, eye and intestinal defects; and the infants of three were growth retarded and one was normal (Theisen et al. The embryos of untreated mice were removed on day 9 and cultured in vitro in various concentrations of hydroxyurea for various lengths of time, followed by culture in drug- free medium up to 48 h. In vivo, 45% of the embryos showed malformations, including exencephaly and phocomelia, and the peak plasma concentration of hydroxyurea was 311 ± 22 μg/mL 7 min after injection, with a half-time of 30 min. Culture in vitro with hydroxyurea at 300 μg/mL for 30 min resulted in malformations in 41% of the embryos that were similar to those found in vivo. Culture at a concentration of 500 μg/mL for 30 min or at 250 μg/mL for 1 h resulted in 100% malformed embryos, but culture at 125 μg/mL for 1 h resulted in no malformations (Warner et al. Malformations were also produced in chicks injected in ovo on day 4 with 800 μg of hydroxyurea (Iwama et al. The epididymides and testes were exam- ined eight and 29 days after the last injection. Body weight was not affected in any of the animals, but the testis weight was reduced in a dose-related manner at all doses except the lowest. Spermatogonial stem cells were not affected, and showed repopu- lation of cell stages with normal differentiation kinetics (Evenson & Jost, 1993). In seven cases of leukaemia treated with hydroxyurea, including three given the drug alone, there were rearrangements of chromosome 17, including unbalanced translocations, partial or complete deletions and isochromosome 17q, which resulted in 17p deletion in the leukaemic cells. P53 mutation was observed in six cases, including two treated with hydroxyurea alone. Karyotypic findings in the bone marrow of patients with essential thrombocythaemia treated with hydroxyurea Treatment Leukaemia or myelodysplastic No Total no.

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