Biomedical subjects
Publications and source records attributed to D Kyle.
Several N-substituted 11-azaartemisinins were prepared from 11-azaartemisinin in high yield by the DMAP catalyzed addition of terminal acetylenes conjugated with electron-withdrawing groups. Their antimalarial activities against two drug-resistant strains of Plasmodium falciparum were determined.
Smoking is the single biggest preventable cause of death in the UK; killing over 120 000 people each year, contributing to inequalities in health, exacerbating and causing poverty. Smoking has increased steadily among children since 1988 and more recently, among young adults. The current context in the UK is highly favourable for introducing comprehensive tobacco control measures. This paper summarises a regional action plan for tobacco control. Actions at district and regional levels are outlined to establish a comprehensive local tobacco control framework and complement national tobacco control measures. Measures include: a 'SWOT' analysis of current activity; systematic monitoring of smoking prevalence, attitudes to smoking, and the impact of tobacco control interventions; provision of effective smoking cessation support to a minimum standard throughout the health service; increased coverage of smoke-free public places and workplaces; enforcement of legislation on illegal sales to children and against smuggling and selling illegally imported tobacco; paid and unpaid mass media campaigns; and systematic lobbying for fiscal and legislative measures. One of the key components of the plan is the introduction of evidence-based tobacco control strategies at district levels. These should include a performance framework with clear organisational and managerial accountability and employ a co-ordinated, multiagency, partnership approach. Priority groups should be identified. Strategies should seek to engage the public to build support for tobacco control measures. Sufficient time, staff, resources and training must be allocated to tobacco control work and progress towards objectives monitored.
OBJECTIVE: To assess the factors that contribute to impaired quinine clearance in acute falciparum malaria. PATIENTS: Sixteen adult Thai patients with severe or moderately severe falciparum malaria were studied, and 12 were re-studied during convalescence. METHODS: The clearance of quinine, dihydroquinine (an impurity comprising up to 10% of commercial quinine formulations), antipyrine (a measure of hepatic mixed-function oxidase activity), indocyanine green (ICG) (a measure of liver blood flow), and iothalamate (a measure of glomerular filtration rate) were measured simultaneously, and the relationship of these values to the biotransformation of quinine to the active metabolite 3-hydroxyquinine was assessed. RESULTS: During acute malaria infection, the systemic clearance of quinine, antipyrine and ICG and the biotransformation of quinine to 3-hydroxyquinine were all reduced significantly when compared with values during convalescence. Iothalamate clearance was not affected significantly and did not correlate with the clearance of any of the other compounds. The clearance of total and free quinine correlated significantly with antipyrine clearance (rs = 0.70, P = 0.005 and rs = 0.67, P = 0.013, respectively), but not with ICG clearance (rs = 0.39 and 0.43 respectively, P > 0.15). In a multiple regression model, antipyrine clearance and plasma protein binding accounted for 71% of the variance in total quinine clearance in acute malaria. The pharmacokinetic properties of dihydroquinine were generally similar to those of quinine, although dihydroquinine clearance was less affected by acute malaria. The mean ratio of quinine to 3-hydroxyquinine area under the plasma concentration-time curve (AUC) values in acute malaria was 12.03 compared with 6.92 during convalescence P = 0.01. The mean plasma protein binding of 3-hydroxyquinine was 46%, which was significantly lower than that of quinine (90.5%) or dihydroquinine (90.5%). CONCLUSION: The reduction in quinine clearance in acute malaria results predominantly from a disease-induced dysfunction in hepatic mixed-function oxidase activity (principally CYP 3A) which impairs the conversion of quinine to its major metabolite, 3-hydroxyquinine. The metabolite contributes approximately 5% of the antimalarial activity of the parent compound in malaria, but up to 10% during convalescence.
Arachidonic acid (AA), an n-6 long-chain polyunsaturated fatty acid (LC-PUFA), serves an important role in the body as a structural fatty acid of many tissues including neurological tissues. It is also a precursor of the n-6 class of eicosanoids and is the most abundant n-6 LC-PUFA found in human breast milk. We have optimized the production of a microfungal source of a triglyceride oil (ARASCO) which is enriched in AA to about 40% by weight. To establish the safety of this oil as a food, we evaluated the effect of ARASCO in Sprague-Dawley rats (20/sex/group) gavaged at dose levels of 1.0 and 2.5 g/kg/d for a period of 90 d, paying special attention to any potential neurotoxicity of the oil. Two groups of control animals received either untreated standard laboratory diet (untreated control) or the same diet and vehicle oil at the same dose volume administered to the treated animals (vehicle control). Physical observations, ophthalmoscopic examinations, body weight, food consumption, clinical chemistry, hematology parameters, neurobehavioral assessments, and macroscopic as well as microscopic postmortem evaluations were performed. Tissue fatty acid analyses indicated that the AA levels in the brain, heart, and liver of the high-dose ARASCO-fed animals increased by 8, 59, and 76%, respectively, indicating that the AA in the oil was readily incorporated into tissue lipids. In spite of this high elevation in tissue AA levels, no developmental, histopathological, or neuropathological differences were seen in the animals administered ARASCO compared with the vehicle control animals. Being highly enriched in AA, ARASCO offers the means to study the effect of this fatty acid in experimental settings and in human metabolic studies.
While there are many reports of studies that fed arachidonic acid (AA) to animals, there are very few reports of AA feeding to humans under controlled conditions. This 130-d study was conceived as a controlled, symmetrical crossover design with healthy, adult male volunteers. They lived in the metabolic research unit (MRU) of the Western Human Nutrition Research (WHNRC) for the entire study. All food was prepared by the WHNRC kitchen. The basal (low-AA) diet consisted of natural foods (30 en% fat, 15 en% protein, and 55 en% carbohydrate), containing 210 mg/d of AA, and met the recommended daily allowance for all nutrients. The high-AA (intervention) diet was similar except that 1.5 g/d of AA in the form of a triglyceride containing 50% AA replaced an equal amount of high-oleic safflower oil in the basal diet. The subjects (ages 20 to 39) were within -10 to +20% of ideal body weight, nonsmoking, and not allowed alcohol in the MRU. Their exercise level was constant, and their body weights were maintained within 2% of entry level. Subjects were initially fed the low-AA diet for 15 d. On day 16, half of the subjects (group A) wee placed on the high-AA diet, and the other group (B) remained on the low-AA diets. On day 65, the two groups switched diets. On day 115, group B returned to the low-AA diet. This design, assuming no carryover effect, allowed us to merge the data from the two groups, with the data comparison days being 65 (low-AA) and 115 (high-AA) for group B and 130 (low-AA) and 65 (high-AA) for group A. The main indices studied were the fatty acid composition of the plasma, red blood cells, platelets, and adipose tissue; in vitro platelet aggregation, bleeding times, clotting factors; immune response as measured by delayed hypersensitivity skin tests, cellular proliferation of peripheral blood mononuclear cells in response to various mitogens and antigens, natural killer cell activity, and response to measles/mumps/rubella and influenza vaccines; the metabolic conversion of deuterated linoleic acid to AA and the metabolic fate of deuterated AA in the subjects on and off the high-AA diet; and the production of eicosanoids as measured by excretion of 11-DTXB2 and PGI2-M in urine. The results of these studies will be presented in the next five papers from this symposium.
Arachidonic acid (AA) is the precursor of thromboxane and prostacyclin, two of the most active compounds related to platelet function. The effect of dietary AA on platelet function in humans is not understood although a previous study suggested dietary AA might have adverse physiological consequences on platelet function. Here normal healthy male volunteers (n = 10) were fed diets containing 1.7 g/d of AA for 50 d. The control diet contained 210 mg/d of AA. Platelet aggregation in the platelet-rich plasma was determined using ADP, collagen, and AA. No statistical differences could be detected between the aggregation before and after consuming the high-AA diet. The prothrombin time, partial thromboplastin time, and the antithrombin III levels in the subjects were determined also. There were no statistically significant differences in these three parameters when the values were compared before and after they consumed the high-AA diet. The in vivo bleeding times also did not show a significant difference before and after the subjects consumed the high-AA diet. Platelets exhibited only small changes in their AA content during the AA feeding period. The results from this study on blood clotting parameters and in vitro platelet aggregation suggest that adding 1.5 g/d of dietary AA for 50 d to a typical Western diet containing about 200 mg of AA produces no observable physiological changes in blood coagulation and thrombotic tendencies in healthy, adult males compared to the unsupplemented diet. Thus, moderate intakes of foods high in AA have few effects on blood coagulation, platelet function, or platelet fatty acid composition.
Normal healthy male volunteers (n = 10) were fed diets (high-AA) containing 1.7 g/d of arachidonic acid (AA) for 50 d. The control (low-AA) diet contained 210 mg/d of AA. Dietary AA had no statistically significant effect on the blood cholesterol levels, lipoprotein distribution, or apoprotein levels. Adipose tissue fatty acid composition was not influenced by AA feeding. The plasma total fatty acid composition was markedly enriched in AA after 50 d (P < 0.005). The fatty acid composition of plasma lipid fractions, cholesterol esters, triglycerides, free fatty acids, and phospholipid (PL) showed marked differences in the degree of enrichment in AA. The PL plasma fraction from the subjects consuming the low-AA diet contained 10.3% AA while the subjects who consumed the high-AA diet had plasma PL fractions containing 19.0% AA. The level of 22:4n-6 also was different (0.67 to 1.06%) in the plasma PL fraction after 50 d of AA feeding. After consuming the high-AA diet, the total red blood cell fatty acid composition was significantly enriched in AA which mainly replaced linoleic acid. These results indicate that dietary AA is incorporated into tissue lipids, but selectively into different tissues and lipid classes. Perhaps more importantly, the results demonstrate that dietary AA does not alter blood lipids or lipoprotein levels or have obvious adverse health effects at this level and duration of feeding.
Arachidonic acid (AA) is a precursor of eicosanoids, which influence human health and the in vitro activity of immune cells. We therefore examined the effects of dietary AA on the immune response (IR) of 10 healthy men living at our metabolic suite for 130 d. All subjects were fed a basal diet containing 27 energy percentage (en%) fat, 57 en% carbohydrate, and 16 en% protein (AA, 200 mg/d) for the first and last 15 d of the study. Additional AA (1.5 g/d) was incorporated into the diet of six men from day 16 to 65 while the remaining four subjects continued to eat the basal diet. The diets of the two groups were crossed-over from day 66 to 115. In vitro indexes of IR were examined using the blood samples drawn on days 15, 58, 65, 108, 115, and 127. The subjects were immunized with the measles/mumps/rubella vaccine on day 35 and with the influenza vaccine on day 92. Dietary AA did not influence many indexes of IR (peripheral blood mononuclear cell proliferation in response to phytohemagglutinin, Concanavalin A, pokeweed, measles/mumps/rubella, and influenza vaccines prior to immunization, and natural killer cell activity). The post-immunization proliferation in response to influenza vaccine was about fourfold higher in the group receiving high-AA diet compared to the group receiving low-AA diet (P = 0.02). Analysis of variance of the data pooled from both groups showed that the number of circulating granulocytes was significantly (P = 0.03) more when the subjects were fed the high-AA diet than when they were fed the low-AA diet. The small increases in granulocyte count and the in vitro proliferation in response to influenza vaccine caused by dietary AA may not be of clinical significance. However, the lack of any adverse effects on IR indicates that supplementation with AA may be done safely when needed for other health reasons.
The effect of dietary docosahexaenoic acid (DHA) in the absence of eicosapentaenoic acid (EPA) has been studied infrequently in humans under controlled conditions. This 120-d study followed healthy, adult male volunteers who lived in the metabolic research unit (MRU) of the Western Human Nutrition Research Center for the entire study. The basal (low-DHA) diet consisted of natural foods (30 en% fat, 15 en% protein, and 55 en% carbohydrate), containing < 50 mg/d of DHA, and met the recommended daily intake for all essential nutrients. The high-DHA (intervention) diet was similar except that 6 g/d of DHA in the form of a triglyceride containing 40% DHA replaced an equal amount of safflower oil in the basal diet. The subjects (ages 20 to 39) were within -10 to +20% of ideal body weight, nonsmoking, and not allowed alcohol in the MRU. Their exercise level was constant, and their body weights were maintained within 2% of entry level. They were initially fed the low-DHA diet for 30 d. On day 31, six subjects (intervention, group A) were placed on the high-DHA diet; the other four subjects (controls, group B) remained on the low-DHA diet. Platelet aggregation in platelet-rich plasma was determined using ADP, collagen, and arachidonic acid. No statistical differences could be detected between the amount of agonist required to produce 50% aggregation of platelet-rich plasma before and after the subjects consumed the high-DHA diet. The prothrombin time, activated partial thromboplastin time, and the antithrombin-III levels in the subjects were determined, and, again, there were no statistically significant differences in these three parameters when their values were compared before and after the subjects consumed the high-DHA diet. In addition, the in vivo bleeding times did not show any significant difference before and after the subjects consumed the high-DHA diet (9.4 +/- 3.1 min before and 8.0 +/- 3.4 min after). Platelets from the volunteers exhibited more than a threefold increase in their DHA content from 1.54 +/- 0.16 to 5.48 +/- 1.21 (wt%) during the DHA feeding period. The EPA content of the subjects' platelets increased from 0.34 +/- 0.12 to 2.67 +/- 0.91 (wt%) during the high-DHA diet despite the absence of EPA in the subjects' diets. The results from this study on blood clotting parameters and in vitro platelet aggregation suggest that adding 6 g/d of dietary DHA for 90 d to a typical Western diet containing less than 50 mg/d of DHA produces no observable physiological changes in blood coagulation, platelet function, or thrombotic tendencies in healthy, adult males.
Normal, healthy male volunteers (n = 6) were fed diets [high docosahexaenoic acid-DHA] containing 6 g/d of DHA for 90 d. The stabilization (low-DHA) diet contained less than 50 mg/d of DHA. A control group (n = 4) remained on the low-DHA diet for the duration of the study (120 d). Blood samples were drawn on study days 30 (end of the stabilization period), 75 (midpoint of the intervention period), and 120 (end of the intervention period). Adipose tissue (AT) samples were taken on days 30 and 120. The plasma cholesterol (C), low density lipoprotein (LDL)-C and apolipoproteins (apo) [Al, B, and lipoprotein (a)] were unchanged after 90 d, but the triglycerides (TAG) were reduced from a mean value of 76.67 +/- 24.32 to 63.83 +/- 16.99 mg/dL (n = 6, P < 0.007 using a paired t-test) and the high density lipoprotein (HDL)-C increased from 34.83 +/- 4.38 mg/dL to 37.83 +/- 3.32 mg/dL (n = 6, P < 0.017 using a paired t-test). The control group showed no significant reduction in plasma TAG levels. Apo-E, however, showed a marked increase in the volunteers' plasma after 90 d on the high-DHA diet, from 7.06 +/- 4.47 mg/dL on study day 30 to 12.01 +/- 4.96 mg/dL on study day 120 (P < 0.002 using a paired t-test). The control subjects showed no significant change in the apo-E in their plasma (8.46 +/- 2.90 on day 30 vs. 8.59 +/- 2.97 on day 120). The weight percentage of plasma DHA rose from 1.83 +/- 0.22 to 8.12 +/- 0.76 after 90 d on the high-DHA diet. Although these volunteers were eating a diet free of eicosapentaenoic acid (EPA), plasma EPA levels rose from 0.38 +/- 0.05 to 3.39 +/- 0.52 (wt%) after consuming the high-DHA diet. The fatty acid composition of plasma lipid fractions--cholesterol esters, TAG, and phospholipid--showed marked similarity in the enrichment of DHA, about 10%, after the subjects consumed the high-DHA diet. The DHA content of these plasma lipid fractions varied from less than 1% (TAG) to 3.5% (phospholipids) at baseline, study day 30. EPA also increased in all plasma lipid fractions after the subjects consumed the high-DHA diet. There were no changes in the plasma DHA or EPA levels in the control group. Consumption of DHA also caused an increase in AT levels of DHA, from 0.10 +/- 0.02 to 0.31 +/- 0.07 (wt%) (n = 6, P < 0.001 using a paired t-test), but the amount of EPA in their AT did not change. Thus, dietary DHA will lower plasma TAG without EPA, and DHA is retroconverted to EPA in significant amounts. Dietary DHA appears to enhance apo-E synthesis in the liver. It appears that DHA can be a safe and perhaps beneficial supplement to human diets.
This study investigated the effects of varying dietary levels of very long-chain polyunsaturated fatty acids on growth, brain fatty acid composition and behavior in mice. Five groups of pregnant and lactating B6D2F1 mice were fed diets with either a very high (n-6):(n-3) ratio of 49 [(n-3) deficient)], a normal ratio of 4.0 or a low ratio of 0.32. The (n-6) fatty acids (FA) were provided either entirely as linoleic acid (LA) or as LA in combination with arachidonic acid (ARA), and the (n-6):(n-3) ratios were adjusted by partial replacement of the (n-6) FA with docosahexaenoic acid (DHA). Offspring were maintained on these diets after weaning. The diets with the low (n-6): (n-3) ratio had no effect on the birth weights of the pups, but after 15 d resulted in a significant 12% reduction in body weights. This effect persisted to adulthood and was apparent in both brain and body weights unless ARA was substituted partially for LA as the source of (n-6) FA. There were significant effects of diet on brain fatty acid composition. Increasing levels of DHA in the diet increased brain DHA and decreased ARA, and there was also retroconversion of DHA in EPA in the mice fed high levels of DHA. Addition of ARA to the diet increased brain ARA, and, at high levels only, decreased DHA. There were no effects of this wide variation in dietary (n-6):(n-3) ratio on the ability of the mice to learn the place of the hidden platform in the Morris water maze. However, in both the cued and the place learning, the mice fed the low (n-6):(n-3) diet swam more slowly, unless ARA substituted partially for LA as the source of (n-6) FA. There were no effects of diet on activity in the spatial open field. These findings show that the effects of a diet with a low (n-6):(n-3) ratio and (n-3) FA provided as DHA, can be overcome if LA is partially replaced by ARA as the source of (n-6) FA.
Mature sheep fitted with a rumen cannula and an abomasal catheter were used to evaluate whether sheep maintained by intragastric infusion could be used as a model for studying minimum endogenous phosporus loss in ruminants. In control periods the sheep received 1.29 g phosphorus day-1 by infusion and maintained phosphorus balance. The withdrawal of phosphorus from the infusate led to a reduction in the excretion of phosphorus to 6.4 mg kg liveweight-1 day-1, a level lower than that currently used to estimate maintenance phosphorus requirements. However, salivary phosphorus secretion, based on rumen phosphorus outflow, averaged only about 1.2 g day-1, a level which would be considered insufficient to meet rumen microbial requirements in a normally fed animal. Allowing the sheep access to a small amount of roughage, although contributing little additional phosphorus, greatly increased salivary phosphorus flow and increased their endogenous excretion of phosphorus to levels close to those used to estimate maintenance requirements. These results suggest that this technique may offer an alternative way of measuring minimum endogenous mineral loss to those currently in use.
Between 1990 and 1994, a series of prospective studies were conducted to optimize the treatment of multidrug-resistant falciparum malaria on the borders of Thailand. The tolerance of various treatment regimens containing either mefloquine 15 mg/kg (M15) or 25 mg/kg (M25) was evaluated in 3673 patients aged between 6 months and 88 years. Early vomiting (within 1 hour) is an important determinant of treatment outcome in these areas, despite re-administration of the dose. Overall, 7 % of the patients vomited within an hour. Significant risk factors were age < or = 6 years (relative risk (RR), 3.9) or > or 50 years (RR, 2.7), the higher mefloquine dose (M25) (RRm 2.7), vomiting < 24 hours before enrolment (RR, 2.5), axillary temperature > 38.0 degrees C (RR, 1.6), and parasitaemia > 10,000/microliter (RR, 1.3). In children < or = 2 years, 30% vomited with M25, and 13% did not tolerate a repeat dose. Vomiting was reduced 40% by splitting the higher dose (RR, 0.6; 95% CI, 0.4-0.8), and 50% by giving mefloquine on the second day in combination with artesunate (RR, 0.5; CI, 0.3-0.9). Anorexia, nausea, vomiting, dizziness, and sleeping disorders were 1.1-1.4 times more frequent with M25 than M15 in the three days following treatment, but were similar in the single or split-dose M25 groups, despite twofold higher mefloquine concentrations obtained with the latter. There was no evidence that diarrhoea, headache, and abdominal pain were associated with mefloquine use. High-dose mefloquine is well tolerated but should be given as a split dose.
Two variants of the circumsporozoite (CS) protein of Plasmodium vivax (VK210 and VK247) have been identified. Recently, a putative third CS variant of P. vivax, referred to as causing P. vivax-like malaria, has been reported from Papua New Guinea. The objective of this study was to confirm and extend findings on the global distribution of the P. vivax-like parasite. Blood samples were obtained from 126 untreated patients with P. vivax infection acquired in Central America, South America, Africa, Southeast Asia, and the Indian subcontinent. The P. vivax CS gene was amplified by polymerase chain reaction and hybridized with probes specific for the VK210, VK247, and P. vivax-like CS variants. All samples were positive for VK210, VK247, or both. No sample was positive for P. vivax-like DNA. Therefore, the existence of a third variant of P. vivax cannot be confirmed in the geographic areas studied.
A 20-year-old nulligravida woman presented with bilateral cystic nodules of the vulva, diagnosed after simple excision as benign phyllodes tumor. Breast tissue, which also displayed fibrocystic changes, was also recognized. Follow-up at 2 months revealed no evidence of disease; however, 8 months after surgery she returned with a new mass in the vulva. This was excised and found to be recurrent phyllodes tumor. Although somewhat more cellular than the first lesions, it also was deemed to be benign based on histological features supported by flow cytometric DNA studies.
The increasing frequency of therapeutic failures in falciparum malaria in Thailand shows an urgent need for effective drugs or drug combinations. Artesunate, a qinghaosu derivative, is effective in clearing parasitaemia rapidly, but the recrudescence rate can be as high as 50%. We have compared artesunate followed by mefloquine with each drug alone in acute, uncomplicated falciparum malaria. 127 patients were randomly assigned treatment with artesunate (600 mg over 5 days), mefloquine (750 mg then 500 mg 6 h later), or artesunate followed by mefloquine. All patients were admitted to hospital for 28 days to exclude reinfection. Cure was defined as no recrudescence during the 28 days' follow-up. The cure rates for mefloquine and artesunate alone were 81% (30/37 patients) and 88% (35/40); the combination was effective in all of 39 patients. Fever and parasite clearance times were significantly shorter in the groups that received artesunate than in the mefloquine-only group. The frequency of nausea and vomiting was slightly, but not significantly, higher among patients who received both drugs than in the other groups. The combination of artesunate followed by mefloquine is highly effective and well tolerated in patients with acute, uncomplicated falciparum malaria in Thailand.
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