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Metformin-associated vitamin B12
ORIGINAL ARTICLE
deficiency in the elderly
KW Liu, DLK Dai, W Ho, E Lau, J Woo
ABSTRACT
Objective. To compare the prevalence of the vitamin B12 deficiency in
geriatric diabetic patients treated with or without metformin.
Methods. Records of 134 patients with diabetes mellitus (DM) aged 61
to 93 (mean, 80) years who were treated with (n=56) or without (n=78)
metformin were reviewed. Patient demographics (age, gender, duration
of DM, smoking status, alcohol consumption), medication parameters
(daily dosage and duration of metformin therapy), and haematological
parameters (haemoglobin level, mean corpuscular volume [both of
which may reflect vitamin B12 deficiency], serum vitamin B12, and
folate level) were recorded. Definite deficiency was defined as serum
vitamin B12 level of <150 pmol/L, whereas possible deficiency as <220
pmol/L.
Results. The mean serum vitamin B12 level was lower in the metformin
group (282.1 vs. 380.1 pmol/L, p=0.023). 15% and 37% of these
patients had definite and possible vitamin B12 deficiency, respectively.
The metformin group had significantly higher prevalence of definite
deficiency (29% vs. 5%, p<0.001) and possible deficiency (52% vs.
27%, p<0.03). Odds ratios of definite and possible deficiency in the
metformin group were 7.40 (95% CI, 2.32-23.62; p=0.001) and 2.92
(95% CI, 1.41-6.02; p=0.004), respectively. Within the metformin group,
the mean serum vitamin B12 level was significantly lower in those on
high dosage (173 vs. 315 pmol/L, p<0.005).
Conclusion. Metformin use was significantly associated with vitamin
B12 deficiency. Physician should check the patient’s baseline vitamin
B12 level, and serially monitor vitamin B12 levels and nutritional status
of those treated with metformin, and prescribe vitamin B12 supplement
if necessary.
Correspondence to: Dr Kin Wah Liu, Geriatric Outpatient Clinic, Prince of Wales Hospital, Hong Kong. E-mail: kwliuhk@ Key words: Diabetes mellitus, type 2; Metformin; Vitamin B 12 deficiency
INTRODUCTION
adults. Annually, approximately 575 000 people aged ≥60 years are diagnosed as having diabetes.3 Metformin may be associated with vitamin B12 According to the World Health Organization, the deficiency in elderly patients with diabetes mellitus number of type-2 DM patients is expected to double (DM),1 which is a common disease among older within the next 25 years. In Hong Kong, diabetes is people. Almost 50% of type-2 diabetic patients are the ninth commonest cause of death and accounts over 60 years old.2 In the United States, more than for 1.6% of all deaths in 2005.4 In a population-based 10 million persons over the age of 60 years have DM. survey in Hong Kong in 1995, the age-adjusted This amounts to a prevalence of about 21% in this prevalence of type-2 diabetes was 8.5%. The crude age group as compared to about 10% in younger prevalence ranged from 1.7% in persons aged 25 to Asian Journal of Gerontology & Geriatrics Vol 6 No 2 December 2011 Metformin-associated vitamin B12 deficiency in the elderly 34 years, compared to >25% in those older than 65 diet (n=7), pernicious anaemia (positive schilling test years.5 Older adults with diabetes are at higher risk result or positive of anti-intrinsic factor antibodies, of incontinence,6 falls,7 cognitive impairment,8 and n=10), pancreatic exocrine insufficiency, and/or a depressive symptoms.9 DM is also a predictor for history of gastrectomy or small bowel resection functional decline in older adults and is associated (n=7). Patients were also excluded if in the previous with increased difficulty in activities of daily living 3 months they had received oral or intramuscular (ADL) and instrumental ADL.10 vitamin B12 supplementation or non-oral feeding that potentially contained vitamin B12 (n=5). Owing The United Kingdom Prospective Diabetes Study to the long half life of vitamin B12 in body stores, demonstrated that the biguanide metformin is as the 3-month exclusion period was selected, thus effective as sulfonylurea for glycaemic control and ensuring an adequate washout period. has additional cardiovascular protective effects.11 The American Diabetes Association suggests using Patient demographics (age, gender, duration metformin as the first-line medical therapy for type-2 of DM, smoking status, alcohol consumption), diabetes.12 When used alone, metformin rarely causes medication parameters (daily dosage and duration of hypoglycaemia in older people. It increases insulin metformin therapy), and haematological parameters sensitivity and improves weight loss and the lipid (haemoglobin level, mean corpuscular volume [both profile. Its side effects include lactic acidosis in patients of which may reflect vitamin B12 deficiency], serum who experience heart failure, renal failure, and among vitamin B12, and folate level) were recorded. Two alcoholic patients, as well as vitamin B12 deficiency. reference levels for the vitamin B12 deficiency were 30% of patients have vitamin B12 malabsorption after used: definite deficiency (<150 pmol/L) and possible biguanide treatment, although it is uncertain whether deficiency (<220 pmol/L).17–22 this is due to DM itself or to biguanides.1 Diabetic older people were routinely screened Metformin does not alter intestinal motility or for diabetic control (Hba1c and spot blood glucose) cause bacterial overgrowth in the gut.13 Biguanide and nephropathy (renal function test). Vitamin B12, interacts with a complex of intrinsic-factor/vitamin folate HbA1c, and renal function testing were also B12 and cubilin, which is an endocytic receptor requested.
involved in the absorption. The vitamin B12-intrinsic factor complex is taken up by the ileal cell surface The prevalence of vitamin B12 deficiency was by a calcium-dependent process, which is affected by calculated for the metformin and non-metformin metformin via impaired calcium availability.14,15 The groups. Potential factors associated with vitamin B12 hydrophobic tail of biguanides such as metformin, deficiency were examined using the Chi squared extends into the hydrocarbon core of membranes. test or Fisher’s Exact test (for categorical variables) The protonated biguanide group gives a positive or independent sample t tests (for continuous charge to the surface of the membrane, which variables). The binary logistic regression model was displaces divalent cations.16 Thus, the biguanides used for both univariate and multivariate analyses to alter membrane potentials and affect their calcium- calculate the odds ratios (OR). The 95% confidence dependent functions. Metformin also has an effect intervals (CI) were based on likelihood. All p values on the cubilin, which may affect B12-instrinsic factor were 2-sided and considered significant if <0.05.
complex absorption and result in the deficiency.
METHODOLOGY
The mean patient ages of the metformin and This observational, cross-sectional study compared non-metformin groups were 79.3 and 80.5 years,
the prevalence of vitamin B12 deficiency in 134 DM respectively. The 2 groups were not significantly
patients aged 61 to 93 (mean, 80) years who were different in terms of age, gender, smoking status,
treated with (n=56) or without (n=78) metformin alcohol consumption, and serum levels of folate and
from September 2005 to June 2006. Patients were HbA1C (Table 1).
excluded if they had other conditions associated
with vitamin B12 deficiency, including vegetarian The mean serum vitamin B12 level was lower
Asian Journal of Gerontology & Geriatrics Vol 6 No 2 December 2011 83 in the metformin group (282.1 vs. 380.1 pmol/L, patients in the metformin group and 3 in the non-
p=0.023, Table 1). 15% and 37% of these patients metformin group had severe vitamin B12 deficiency
had definite and possible vitamin B12 deficiency, (<100 pmol/L).
respectively (Table 2). The metformin group had
significantly higher prevalence of definite deficiency Within the metformin group, the mean serum
(29% vs. 5%, p<0.001) and possible deficiency (52% vitamin B12 level was significantly lower in those on
vs. 27%, p<0.03) [Table 2]. Odds ratios of definite high dosage (>1500 mg per day) [173 vs. 315 pmol/L,
and possible deficiency in the metformin group were p<0.005, Figure), but not significantly different
7.40 (95% CI, 2.32-23.62; p=0.001) and 2.92 (95% between long-term (>3 years) and short-term users
CI, 1.41-6.02; p=0.004), respectively (Table 3). Eight (p=0.546).
Patient characteristics of metformin and non-metformin groups*
* Data are presented as mean±SD or No. (%) of patients Prevalence of definite and possible vitamin B12 deficiency in metformin and non-metformin groups
Risk factors of vitamin B12 deficiency
Asian Journal of Gerontology & Geriatrics Vol 6 No 2 December 2011 Metformin-associated vitamin B12 deficiency in the elderly We used 3 years as the cut-off point because most of our patients had been treated with metformin for a long period. Thus, we could not evaluate the short-term effect of metformin use on vitamin B12 deficiency. 16 weeks of treatment with metformin is associated with a significant decrease in vitamin B12 in 14% of the subjects.24 Serial monitoring of the vitamin B12 level is required, in particular at the start of metformin treatment. Baseline vitamin B12 level should also be checked prior commencing metformin treatment.
300Serum vitamin B12 concentration (pmol/L) There is no consensus on the cut-off point of vitamin B12 deficiency. We defined definite and possible deficiency as serum vitamin B12 levels of <150 and <220 pmol/L, respectively.17-21 Nonetheless, patients with varying clinical features of vitamin B12 deficiency may be regarded as within normal Figure. Serum vitamin B12 concentrations in patients
with different dosages of metformin: the lower and the
range.17,26 In adults, a vitamin B12 level of 150 pmol/L upper bounds of the boxes represent the 25th and 75th
is considered the lowest level for an adequate state. percentiles, respectively. The horizontal lines in the boxes
correspond to the median values. The lower and upper error
In a developing deficiency, serum concentrations are bars indicate the 10th and 90th percentiles, respectively.
maintained by depleting body storage. Therefore, a concentration of 150 pmol/L might not reflect a sufficient vitamin B12 status,27 and a cut-off value of <220 pmol/L is proposed.21 Patients with subtle DISCUSSION
deficiency (150 to 220 pmol/L) may benefit from vitamin B12 supplement. Metformin has some effects on reducing the level of serum vitamin B12 or its metabolites. Metformin Polypharmacy may also affect the vitamin B12 is involved in 14 to 22% of patients with definite level. Medications that may decrease serum vitamin vitamin B12 deficiency.23,24 Metformin may result in B12 level include acid-suppressive therapy, i.e. cobalamin malabsorption secondary to the impaired histamine-2 receptor antagonist (H-2 blockers) or release of vitamin B12 from food or its binding proton pump inhibitor.28 We intended to examine protein. The protonated biguanide group gives a the effect of polypharmacy on the vitamin B12 positive charge to the surface of the membrane, which deficiency and to determine whether the acid-acts to displace divalent cations.16 Thus, metformin suppressive therapy was a confounder of serum alters membrane potentials and affects divalent vitamin B12 level. However, only a small proportion membrane cations. A higher dosage of metformin of our patients were receiving such therapy, and the might lead to stronger or higher positive charge on association betweeen polypharmacy and vitamin the surface of the cell membrane by the protonated B12 deficiency could not be established. Physicians biguanide group. It affects the cubilin function and should be aware of the problem of polypharmacy or results in impaired vitamin B12 absorption. A daily iatrogenesis in geriatric patients. dose of 1500 mg metformin was considered high in this study, because the clinically significant response Anaemia and excessive mean corpuscular to metformin is generally not seen at a daily dose of volume (MCV) are well-known clinical parameters <1500 mg.25 The serum vitamin B12 level should be indicative of vitamin B12 deficiency. A case of monitored for patients receiving high daily dosage, megaloblastic anaemia secondary to vitamin B12 and dosage should be reduced when patients develop malabsorption and long-term metformin treatment vitamin B12 deficiency. Further studies are required has been reported.29 However, there was no to validate whether dosage reduction improves the significant difference between our metformin and deficiency.
non-metformin groups in terms of the haemoglobin Asian Journal of Gerontology & Geriatrics Vol 6 No 2 December 2011 85 level and MCV. Indeed, haematological indices are considerations. Diabet Med 1998;15(Suppl 4):S41-6.
not a reliable guide for diagnosing subtle vitamin 3. National Centre for Chronic Disease Prevention and Health Promotion. National diabetes fact sheet: general information and B12 deficiency.30,31 Anaemia tends to occur only national estimates on diabetes in United States. Centres for Disease when metabolic deficiency is moderately severe32 Control and Prevention 2005. Available from: http://ww.cdc.gov/ or the deficiency is severe enough to affect the 4. Centre for Health Protection. Available from: http://www.chp.
haematological indices. In addition, macrocytosis can be masked by coexisting microcytic processes 5. Janus ED. Epidemiology of cardiovascular risk factors in Hong including thalassaemia and iron deficiency.33 Kong. Clin Exp Pharmacol Physiol 1997;24:987-8.
6. Blaum CS, Ofstedal MB, Langa KM, Wray LA. Functional status and health outcomes in older Americans with diabetes mellitus. J Limitation
Am Geriatr Soc 2003;51:745-53.
Patients attending the geriatric clinic were relatively 7. Volpato S, Leveille SG, Blaum C, Fried LP, Guralnik JM. Risk factors for falls in older disabled women with diabetes: the older than the general population, resulting in women’s health and aging study. J Gerontol A Bio Sci Med Sci possible selection bias. Metformin-related vitamin B12 deficiency in younger age-groups needs further 8. Strachan MW, Deary IJ, Ewing FM, Frier BM. Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies. Diabetes Care 1997;20:438-45.
9. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The We used serum vitamin B12 levels only to define prevalence of comorbid depression in adults with diabetes: a deficiency. Metabolites (such as methylmalonic meta-analysis. Diabetes Care 2001;24:1069-78.
10. Gould E. Attitudes about aging. In: Mariano C, editor. Best nursing acid and total homocysteine) were not measured. practices in care for older adults: incorporating essential gerontologic They are considered more sensitive indicators of content into baccalaureate nursing education. 2nd ed. New York: vitamin B12 status than plasma vitamin B12 levels, John A. Hartford Foundation Institute for Geriatric Nursing; 1999:12.
which have limited specificity and controversial 11. UK Prospective Diabetes Study (UKPDS) Group. Effect of sensitivity.34 However, the assay for methylmalonic intensive blood-glucose control with metformin on complications acid is complex, costly, and slow processing, whereas in overweight patients with type 2 diabetes (UKPDS-34). Lancet 1998;352:854-65.
total homocysteine increases in patients with folate 12. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, deficiency.
Sherwin R, et al. Management of hyperglycaemia in type 2 diabetes. A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from American Diabetes The amount of the vitamin B12 intake was not Association and the European Association for the Study of recorded. Daily intake of the vitamin B12 can be Diabetes. Diabetes Care 2006;29:1963-72.
estimated from food recall records, which should 13. Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes have been carried out prior to blood sample taking. mellitus. Diabet Med 1998;15:651-6.
Details of food intake such as beef, pork, chicken, fish 14. Gilligan MA. Metformin and vitamin B12 deficiency. Arch Intern or egg, and milk products should have been recorded 15. Andres E, Goichot B, Schlienger JL. Food cobalamin to estimate the amount of daily vitamin B12 intake. malabsorption: a usual cause of vitamin B12 deficiency. Arch Intern Med 2000;160:2061-2.
CONCLUSION
16. Schafer G. Some new aspects on the interaction of hypoglycemia- producing biguanides with biological membranes. Biochem Pharmacol 1976;25:2015-24.
Metformin use was significantly associated with 17. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of vitamin B12 deficiency. Subjects taking higher cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am dosage tended to have lower serum vitamin B12 levels. Physician should check the patient’s baseline 18. Holleland G, Schneede J, Ueland PM, Lund PK, Refsum vitamin B12 level, and serially monitor vitamin B12 H, Sandberg S. Cobalamin deficiency in general practice. Assessment of the diagnostic utility and cost-benefit analysis levels and nutritional status of those treated with of methylmalonic acid determination in relation to current metformin, and prescribe vitamin B12 supplement if diagnostic strategies. Clin Chem 1999;45:189-98.
19. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med 1999;159:1289-98.
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cobalamin deficiency I: usefulness of serum methylmalonic acid 33. Green R. Cobalamin and folate deficiency: the antecedents and and total homocysteine concentrations. Am J Hematol 1990;34:90- association of anaemia. In: Education Programme of the 26th Congress of the international Society of Haematology; 1996 Aug 27. Carmel R. Pernicious anemia. The expected findings of very low 25-29. Singapore: Internal Society of Haematology; 1996:128- serum cobalamin levels, anemia, and macrocytosis are often lacking. Arch Intern Med 1988;148:1712-4.
34. Miller JW, Garrod MG, Rockwood AL Kushnir MM, Allen 28. Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B(12) deficiency LH, Haan MN, et al. Measurement of total vitamin B12 and associated with histamine(2)-receptor antagonists and a proton- holotranscobalamin, singly and in combination, in screening for pump inhibitor. Ann Pharmacother 2002;36:812-6.
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Asian Journal of Gerontology & Geriatrics Vol 6 No 2 December 2011 87

Source: http://www.ajgg.org/AJGG/V6N2/OA3_KW%20Liu.pdf

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