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Biomedical subjects

P N Durrington

Publications and source records attributed to P N Durrington.

At least 73 records · Page 4Linked to original sources
PubMed1998

Can we afford to treat hyperlipidaemia as we should? Strategies for rational treatment.

There is no debate about whether patients with established coronary heart disease (CHD) should receive cholesterol-lowering drug therapy: the great majority should. certainly those whose serum cholesterol exceeds 5 mmol/l. In primary CHD prevention the indication for lipid-lowering drug therapy is largely determined by the absolute risk of CHD. There is considerable disagreement about the level of absolute risk at which such treatment should be commenced. The relative absence of side-effects of the statin drugs and their relatively high cost means that issues of cost-effectiveness are of more concern for state health services than the balance between benefits of therapy and adverse events. Thus, the degree of risk at which they are recommended appears to be largely determined by the type of healthcare system a nation has and the frequency of high risk individuals in that nation. In Britain, which has both state healthcare and numerous high risk patients, the cost of primary prevention with statins except at extreme risk is viewed as prohibitive, whereas the CHD risk at which lipid-lowering drugs are recommended is lower in the USA, where healthcare costs are borne more directly by the patient, and in European countries with lower rates of CHD. Whatever level of risk is recommended for the use of lipid-lowering drugs in primary CHD prevention, the clinician should be in a position to assess CHD risk in an individual with a reasonable degree of accuracy. When recommended algorithms and charts were compared with calculations of risk using the equations derived from the Framingham Study, on which they are based, they were shown to be inaccurate. High density lipoprotein cholesterol emerged as a particularly important risk factor, which when omitted led to underestimation of risk in women and people with multiple risk factors. It is concluded that guidelines should be evaluated in the type of patient for whom they are intended. It is important to redress the balance between the numerous publications on the interpretation of clinical trials and the virtual absence of rigorous assessments of methods for determining CHD risk in clinical practice.

Adult↗
PubMed1998

Triglycerides are more important in atherosclerosis than epidemiology has suggested.

Epidemiology call be a useful guide to risk prediction. If, for example, the value of serum cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides as predictors of future CHD events is considered, then generally the triglyceride level measured on a single occasion will add little to the prognostic information contained in cholesterol and HDL cholesterol. The serum triglyceride concentration is, however, often more strongly correlated with future CHD incidence in univariate analysis than is serum cholesterol. However, in multiple logistic regression analysis, particularly when HDL cholesterol is included, the strength of the apparent independent relationship between triglycerides and CHD incidence is weakened often to the point of insignificance in individual trials, although it is still evident on meta-analysis of all the epidemiological trials in which both HDL cholesterol and triglyceride levels were measured. The erosion of the relationship between triglycerides and CHD incidence when HDL is included in multiple logistic regression analysis is to some extent is an artefact of the greater biological variation of triglyceride concentrations compared with HDL cholesterol. When allowance is made for this triglycerides can have more predictive power than HDL. Important clinical decisions are generally not based on single measurements, but on a series which reduces the effect of biological variation. However, even more importantly epidemiology cannot tell us that lowering cholesterol or raising HDL cholesterol levels will have more therapeutic benefit than decreasing triglyceride levels. That can only be established in clinical trials. An overview of trials involving drugs, which have as their principal action triglyceride-lowering, revealed them to decrease CHD incidence as much as statins. In the trials the drugs, which principally lowered triglycerides, also produced small decreases in serum cholesterol. The decrease in CHD incidence was, however, more than would be predicted from a similar reduction in cholesterol achieved with statins. Epidemiology can thus be a poor guide to clinical decisions. Furthermore the epidemiological relationship between cholesterol, triglycerides, HDL and CHD gives us only limited insight into the mechanisms by which these lipids and lipoproteins are involved in atherogenesis and their relative importance in this process. Thus evidence from clinical studies linking hypertriglyceridaemia with potentially important atherogenic factors such as intermediate density lipoproteins, small dense LDL and increased cholesteryl ester exchange may provide a greater understanding of atherogenesis and potential sites of therapeutic intervention than epidemiology. There is thus evidence for the therapeutic value of lowering triglycerides and an emerging view that triglyceride-rich lipoproteins are frequently crucial in atherogenesis.

Arteriosclerosis↗
PubMed1998

Human serum paraoxonase.

1. Human serum paraoxonase (PON1) is a Ca2+-dependent 45-kDa glycoprotein that is associated with high density lipoprotein (HDL). 2. PON1 hydrolyzes organophosphate (OP) insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals. 3. PON1 has two genetic polymorphisms giving rise to amino acid substitutions at positions 55 and 192. The position-192 polymorphism is the major determinant of the PON1 activity polymorphism. However, the position-55 polymorphism also modulates activity. 4. Genotyping individuals for both PON1 polymorphisms may provide a method for identifying those most at risk of OP poisoning. The effect of the PON1 polymorphisms on activity may explain why some Gulf War veterans have developed Gulf War syndrome and some have not, despite similar OP exposure. 5. PON1 may also be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolyzing phospholipid hydroperoxides. 6. The PON 1 polymorphisms are important in determining the capacity of HDL to protect low density lipoprotein against oxidative modification in vitro, which may explain the relation between the PON1 alleles and coronary heart disease in case-control studies.

Arteriosclerosis↗
PubMed1998

Hypertension, serum insulin, obesity and the metabolic syndrome.

BACKGROUND AND AIMS: In recent years it has been proposed that hypertension is part of a cluster of metabolic risk factors (syndrome X) involving hyperlipidaemia and hyperglycaemia, with hyperinsulinaemia as the common link. This study has investigated: (1) the prevalence of the metabolic syndrome and its component variables and their relationship to body mass index (BMI) and non-fasting insulin levels in a general population; and (2) the distribution and clustering of metabolic variables in normotensives and hypertensives. METHODS: Cross-sectional study of 5222 men aged 40-59 years with no history of coronary heart disease (CHD), diabetes mellitus or stroke drawn from general practices in 18 British towns. The men were a subgroup of the 7735 men in the British Regional Heart Study (BRHS) cohort whose baseline non-fasting serum was analysed for insulin, using a specific ELISA method. MAIN OUTCOME MEASURES: Hyperinsulinaemia, hyperglycaemia, high serum total cholesterol, high triglyceride and hyperuricaemia were defined as the top 20% of the distribution in the 5222 men. Low HDL-cholesterol was defined as the bottom 20%. RESULTS: BMI and non-fasting insulin were both significantly and strongly associated with non-diabetic hyperglycaemia, lipid abnormalities (HDL-cholesterol, triglyceride and total cholesterol) and hyperuricaemia. BMI was strongly associated with hypertension whereas non-fasting insulin showed a much weaker relationship which was abolished after adjustment for BMI. However, only 2.9% of men showed the 'full metabolic syndrome' (hypertension, hyperglycaemia and dyslipidaemia) and a large proportion of these men were hyperinsulinaemic (65%) or obese (47%). Dyslipidaemia (any one of low-HDL-cholesterol, high triglyceride or high cholesterol) was common in both normotensives and hypertensives (40.5% vs 46.4%). Hypertensives showed significantly higher levels of total cholesterol, triglyceride, blood glucose, urate and more clustering of hyperglycaemia and dyslipidaemia than normotensives even after adjustment for BMI. CONCLUSION: Hypertensives were more likely to have lipid abnormalities and clustering of risk factors than normotensives even after adjustment for BMI. The metabolic syndrome is more strongly associated with hyperinsulinaemia than with obesity but it is relatively uncommon in men with no history of cardiovascular disease or diabetes. Given the weak relationship between hypertension and hyperinsulinaemia, the latter is unlikely to explain the higher levels of lipid abnormalities and clustering seen in hypertensives. Overweight/obesity may be primarily involved in the pathways to hypertension and lipid abnormalities but the unravelling of these relationships require more specific measures of adipose tissue distribution, composition and function.

Adult↗
PubMed1998

The effects of low-dose testosterone treatment on lipid metabolism, clotting factors and ultrasonographic ovarian morphology in women.

INTRODUCTION: Low doses of androgen are used in women for the symptomatic treatment of sexual dysfunction and premenstrual syndrome (PMS). However, little is known about the long-term safety of androgen use in women. This study investigated the effects of low dose exogenous testosterone (T) on lipid metabolism, markers of activation of the coagulation system and ultrasonographic ovarian morphology in women. PATIENTS: Twenty-two patients with severe PMS (age 39.6 +/- 3.1 years, mean +/- SD) treated with subcutaneous T implants (100 mg six monthly) for at least two years (mean duration 3.3 (+/- 0.9 years) were compared with 22 age-matched (age 37.7 +/- 2.9 years) control patients with severe PMS who had not previously received T treatment. All women continued to have regular menses. MEASUREMENTS: Fasting blood samples were obtained for measurement of lipids and clotting factors and ovarian ultrasound examination carried out between days 1-4 of the menstrual cycle (2.3 +/- 1.2 months after the T implant in T-treated group). RESULTS: Mean plasma T was 4.5 +/- 2.2 nmol/l, and 1.9 +/- 0.6 nmol/l in the treated and control groups, respectively. In the T-treated group apolipoprotein-A1 (Apo-A1) (treated 99.2 +/- 12 vs controls 116.2 +/- 27.7 g/l, P < 0.01) and high density lipoprotein cholesterol (HDL-C) (treated 1.3 +/- 0.3 vs controls 1.5 +/- 0.4 nmol/l, P < 0.01) were significantly decreased. In addition very low density lipoprotein cholesterol (VLDL-C) (treated 0.4 +/- 0.3 vs controls 0.2 +/- 0.1 nmol/l, P < 0.05) was increased in T-treated patients. There were no differences in total serum cholesterol and triglyceride or low density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo-B), lipoprotein(a), lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein activity. There was no difference in clotting factors between the two groups which included prothrombin time, fibrinogen, antithrombin-III, protein-C, protein-S (total and free), tissue plasminogen activator, plasminogen activator inhibitor, beta-thromboglobulin and prothrombin fragments 1.2. Ultrasound showed normal ovarian architecture with no evidence of polycystic ovarian changes in any patients in the T-treated group. No patient experienced adverse symptoms while on T treatment, in particular, there were no complaints of hirsutism or acne and no one requested termination of treatment. CONCLUSION: Low-dose testosterome administration to women for over two years did not induce changes in ovarian architecture but had small, potentially atherogenic effects on some parameters of lipid and lipoprotein metabolism. However, no differences were detected in markers of activation of the clotting system to indicate an actual increase in the risk of thrombosis. Overall, this study provides largely reassuring data about the safety of low-dose androgen treatment in women. However, caution should be exercised in women with existing or a familial predisposition to lipid abnormalities, because of the small but significant changes found in HDL-C, apo-A1 and VLDL-C.

Adult↗
PubMed1998

Paraoxonase and coronary heart disease.

Paraoxonase (PON1) hydrolyses organophosphate insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals. Human PON1 has two genetic polymorphisms giving rise to amino-acid substitutions at positions 55 and 192. The 192 polymorphism is the major determinant of the PON1 activity polymorphism towards organophosphates. However, the 55 polymorphism also modulates activity. Ex vivo, the PON1 polymorphisms are important in determining the capacity of HDL to protect LDL against oxidative modification in vitro and this may explain the relationship between the PON1 alleles and coronary heart disease in case-control studies. In recent case-control studies serum PON1 concentration and activity were also found to be decreased in coronary heart disease (CHD) independent of the PON1 polymorphism, and in diabetes serum PON1 specific activity decrease is also independent of the PON1 genetic polymorphism. HDL from transgenic mice lacking PON1 fails to protect LDL against oxidative modification. Thus PON1 may be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolysing phospholipid and cholesteryl-ester hydroperoxides.

Animals↗
PubMed1998

Fetal and maternal lipoprotein metabolism in human pregnancy complicated by type I diabetes mellitus.

Serum lipid, apolipoprotein concentration, and lipoprotein composition were determined in maternal and umbilical venous cord blood at delivery by elective Cesarean section (CS) in 10 singleton, full-term pregnancies with maternal insulin-dependent diabetes mellitus (type I DM), which predated pregnancy, and in 22 nondiabetic pregnancies. The objectives of the study were to determine the influence of maternal type I DM, and hence potential fetal overnutrition on fetal lipid metabolism. There were no significant differences in gestational age, fetal weight, or fetal serum insulin concentration between the type I DM group and those with nondiabetic pregnancies, although fetal venous cord blood glucose was 3.4 mmol/L (3.0-4.5 mmol/L) (median and 25th-75th percentiles) and 2.9 mmol/L (2.0-3.4 mmol/L), respectively, and maternal Hemoglobin A1c [9.6% (8.2-10.7%) and 6.8% (6.3-7.8%), respectively], was significantly greater in the type I DM subjects (P < 0.02 and 0.002 respectively). Plasma nonesterified fatty acid (NEFA) concentrations were lower in the type I DM mothers [0.85 mmol/L (0.56-2.31 mmol/L) compared with 1.14 mmol/L (0.88-1.24 mmol/L] in nondiabetic pregnancies; P < 0.0001). Serum high-density lipoprotein phospholipids (HDL-PL) were increased in type I DM mothers because of elevated HDL2 phospholipid [0.39 mmol/L (0.27-0.48 mmol/L) compared with 0.12 mmol/L (0.06-0.21 mmol/L), respectively, P < 0.01). The maternal HDL cholesterol (C) concentration was not significantly different in the uncomplicated and type I DM pregnancies. However, in the umbilical venous cord blood, serum levels of NEFA [0.49 mmol/L (0.33-1.29 mmol/L) in type I DM compared with 0.13 mmol/L (0.06-0.33 mmol/L) in nondiabetics; P < 0.02)], total cholesterol (TC) [2.87 mmol/L (1.65-4.86 mmol/L) in type I DM compared with 1.65 mmol/L (1.46-1.87 mmol/L) in nondiabetics; P < 0.02]; free cholesterol (FC) [0.97 mmol/L (0.60-1.26 mmol/L) in type I DM compared with 0.62 mmol/L (0.37-0.75 mmol/L) in nondiabetics; P < 0.05), and cholesteryl ester (CE) [1.90 mmol/L (1.44-3.33 mmol/L) in type I DM compared with 1.01 mmol/L (0.83-1.24 mmol/L) in nondiabetics; P < 0.02), triglyceride (TG) (1.06 [0.50-1.91) mmol/L in type I DM compared with 0.29 [0.25-0.36] mmol/l in nondiabetics; P < 0.001), phospholipid (PL) (2.52 [1.73-3.03) mmol/L in type I DM compared with 1.34 [1.27-1.48] mmol/L in nondiabetics; P < 0.01], and the apolipoproteins A-I and B had significantly higher concentrations in type I DM. In umbilical venous cord blood, ratios of HDL-TC and HDL-PL to apo AI, reflecting the lipid content of HDL, were reduced when the mother had type I DM during pregnancy (P < 0.02 and P < 0.0001, respectively). These results indicate that maternal type I DM may lead to a fetal serum lipoprotein composition more closely resembling that seen in the adult. In type I DM, maternal TG and PL and fetal TC, TG, PL, CE, and FC were correlated to NEFA levels (P < 0.05), but not to glucose, insulin secretion, or maternal control of type I DM. These data suggest that the enhanced supply of NEFA to the fetus in type I DM pregnancies may drive the synthesis of cholesterol as well as TGs and PLs.

Adult↗
PubMed1997

Presence of paraoxonase in human interstitial fluid.

Human serum paraoxonase (PON1) is postulated to have anti-atherosclerotic properties through its ability to prevent lipid peroxide generation on LDL. However, in order to perform this role it must be present in interstitial fluid, to prevent LDL oxidation which takes place in the sub-intimal space of the artery wall. The PON1 activity in interstitial fluid was 15.7 (2.3-183.0) (median (range)) nmol/min/ml compared to 105.3 (74.6-323.9) nmol/min/ml in serum. The PON1 concentration in interstitial fluid was found to be 20.2 (1.1-78.1) microg/ml (median (range)) compared to 109.6 (11.1-485.7) microg/ml in serum. Interstitial fluid PON1 concentration was dependent on the interstitial fluid apo AI concentration (r = 0.690, P < 0.005) indicating PON1 remained associated with HDL. However, the ratio of PON1 concentration to apo AI was lower in interstitial fluid (0.60 +/- 0.20) than in the serum (0.95 +/- 0.18) (P < 0.001) indicating sequestration of PON1 in the sub-intimal space. Therefore, PON1 is present and active in interstitial fluid where it can perform its anti-atherosclerotic function.

Adult↗
PubMed1997

Effect of the molecular polymorphisms of human paraoxonase (PON1) on the rate of hydrolysis of paraoxon.

1. The hydrolysis of organophosphate pesticides (OP) and nerve gases by serum paraoxonase (PON1) is an important factor determining their toxicity to mammals including man. The PON1 gene contains 2 polymorphic sites at amino acid positions 55 (L-->M) and 192 (G-->A, classically defined as the A and B genotypes) which result in several alloenzymes of PON1 in human serum. 2. The 192 polymorphism has previously been shown to affect PON1 activity. We have investigated the effect of both polymorphisms on the hydrolysis of paraoxon by serum from 279 healthy human subjects. 3. The 55 polymorphism significantly influenced PON1 activity. MM homozygotes had over 50% less activity towards paraoxon compared to the LL and LM genotypes regardless of the 192 genotype (P < 0.001). 4. Multiple regression analysis indicated that the 192 polymorphism, 55 polymorphism and serum PON1 concentration were responsible for 46, 16 and 13% of the variation in PON1 activity, respectively (all P < 0.001). None of the other parameters investigated significantly affected PON1 activity. 5. Therefore both PON1 polymorphisms affect the hydrolysis of paraoxon. AA/MM and AB/MM individuals may be potentially more susceptible to OP intoxication. 6. Genotyping individuals for both PON1 polymorphisms may provide a method for identifying those individuals at most risk of OP poisoning. The effect of PON1 polymorphisms on activity may also explain why some Gulf War Veterans have developed Gulf War Syndrome and some have not.

Adult↗
PubMed1997

Influence of immunosuppressive therapy on lipoprotein(a) and other lipoproteins following renal transplantation.

Coronary heart disease (CHD) is more common in patients with chronic renal failure and is a major cause of death after renal transplantation. Elevated serum levels of lipoprotein(a) (Lp(a)) are a known risk factor for CHD in the general population and levels have been reported to be increased in renal transplant recipients. It has been suggested that cyclosporin may elevate Lp(a) levels. We therefore measured the serum concentration of Lp(a) in 50 renal transplant recipients who were receiving cyclosporin alone as immunosuppressive therapy and 50 who were treated with azathioprine and prednisolone, but not cyclosporin. The patients attended two renal transplant centres, one where cyclosporin alone was used as immunosuppressive treatment when possible and another where many patients commenced on azathioprine and prednisolone remain on this medication rather than cyclosporin. Patients in each group were matched for age and sex, but the time since transplantation was greater in those not receiving cyclosporin. Transplant function, obesity and the underlying cause of renal disease were similar in both groups of patients. Median Lp(a) concentration in the cyclosporin monotherapy group was 32.0 (range <0.8-140.3) mg/dl and was significantly (p < 0.05) greater than that of the azathioprine and prednisolone group which was 18.3 (range <0.8-167.7) mg/dl. The serum high-density lipoprotein (HDL) cholesterol concentration, which was 1.24 +/- 0.39 mmol/l (mean +/- SD) in patients receiving cyclosporin, was significantly (p < 0.05) less than that of those treated with azathioprine and prednisolone in whom it was 1.41 +/- 0.40 mmol/l. The lower level in those on cyclosporin was due to a decrease in the HDL2 subfraction. Serum lipid and lipoprotein concentrations were otherwise similar in the two groups of patients. The serum level of Lp(a) after renal transplantation may be influenced by the choice of immunosuppressive therapy.

Adolescent↗
PubMed1997

Increased immunolocalization of paraoxonase, clusterin, and apolipoprotein A-I in the human artery wall with the progression of atherosclerosis.

Using immunolocalization techniques, we have shown that paraoxonase (Pon), clusterin, and apolipoprotein (apo) A-I accumulate in the artery wall during the development of atherosclerosis. In normal aortas (n = 6) there were low levels of extracellular Pon, clusterin, and apoA-I, immunoreactivity. The cytoplasm of smooth muscle cells in the media showed granular positivity for both Pon and apoA-I, indicating that these proteins were undergoing lysosomal degradation. This activity was also indicated by the presence of both intact and degradation products of Pon in smooth muscle cells as shown by Western blotting. With the progression of disease from fatty streaks (n = 3) to advanced atherosclerosis (n = 8) there was an increase in Pon, apoA-I, and clusterin immunoreactivity, indicating the increasing presence of these proteins with disease progression. These proteins are the components of a specific HDL subspecies that has been implicated in the prevention of peroxidative damage to phospholipids in LDL and membranes. The increase in Pon, clusterin, and apoA-I during the development of atherosclerosis may therefore represent a protective response to the oxidative stress associated with the development of atherosclerosis.

Adult↗
PubMed1996

Plasma lipoprotein composition and cholesteryl ester transfer from high density lipoproteins to very low density and low density lipoproteins in patients with non-insulin-dependent diabetes mellitus.

We have examined cholesteryl ester transfer (CET) from HDL to low density and very low density lipoproteins (LDL and VLDL) and lecithin: cholesterol acyl transferase (LCAT) activity in plasma from 28 men with non-insulin-dependent diabetes mellitus (NIDDM) treated with diet alone or diet and sulphonylurea drugs and in 27 healthy non-diabetic controls. Patients and healthy subjects had similar LCAT activity, but CET was significantly higher in NIDDM 26.1 +/- 11.5 mumol l-1 h-1) than in healthy men (17.8 +/- 6.5 mumol l-1 h-1) (p = 0.001). Diabetic men also had higher CET compared to 15 healthy non-diabetic men (18.7 +/- 5.6 mumol l-1 h-1) (p = 0.001) with similar serum lipids. CET activity was similar in patients treated with diet alone (24.8 +/- mumol l-1 h-1) or with sulphonylureas (27.7 +/- 15.8 mumol l-1 h-1). The Sf 0-12 fraction was significantly enriched with total cholesterol (p = 0.0001) and free cholesterol (p = 0.0006) in diabetic subjects whether treated with diet alone or on sulphonylureas compared to the 15 non-diabetic controls matched for serum triglycerides. The free cholesterol/phospholipid, the free cholesterol/total protein and the free cholesterol/mass ratios were increased in the Sf 0-12 fraction in diabetic subjects (p < 0.01). These findings indicate that CET is accelerated in patients with NIDDM and that this may be due to the altered composition of acceptor lipoproteins.

Adult↗
PubMed1996

Treatment of dyslipoproteinaemia in diabetes mellitus.

Coronary heart disease (CHD) is the most common cause of premature death in diabetes. Hypercholesterolaemia occurs in diabetes with about the same frequency as in the general population, but it confers a greater risk of CHD in diabetes. Hypertriglyceridaemia and low serum high density lipoprotein (HDL) cholesterol levels are more common in diabetes, particularly non-insulin-dependent diabetes. Nephropathy increases the severity of dyslipoproteinaemia. There remains a reluctance to apply the results of cholesterol-lowering trials to diabetes. No trial has been specifically in diabetes, but this should not constrain the treatment of diabetic patients at clearly high CHD risk. It is suggested that fasting lipids should be measured in all diabetic patients aged less than 70 years with established CHD or whose non-fasting cholesterol is >6.00 mmol I(-1) or triglycerides >3.00 mmol I(-1). For those with raised lipids glycaemic control should be improved, if possible, and dietary therapy aimed at a decrease in fat intake, particularly saturated fat, and weight reduction in the obese. Lipid-lowering drugs are required in patients with CHD and serum cholesterol >5.5 mmol I(-1) with the aim of decreasing non-HDL to <4.00 mmol I(-1). In patients without CHD lipid-lowering drugs should be considered when serum cholesterol exceeds 6.5 mmol I(-1) and the risk of CHD is greater than 20 % over the next 10 years. There is no evidence that pursuing this policy beyond the age of 70 years is beneficial. Diabetic women with dyslipoproteinaemia should, however, be treated in the same way as men. The knowledge that hypertriglyceridaemia and low serum HDL cholesterol are present helps in the assessment of CHD risk and the choice of medication to decrease non-HDL cholesterol, but there is no evidence that their treatment in the absence of raised cholesterol is of benefit.

Administration, Oral↗