Acquistion and retention of categorized material in normal aging and senile dementia

The “shopping list task” is a new verbal learning task with a high degree of face validity for elderly subjects. Learning and delayed recall performance were examined for three groups of subjects: young normals (n=63, median age=21), elderly normals (n=44, median age=69) and mild to moderately impaired senile dementia patients (n=60, median age=70). The young normal subjects performed best of the three groups in both initial learning and delayed recall measures. The elderly normals showed significant decrements in learning and recalling the list items (p<.01). The impaired elderly showed much greater performance decrements in both learning and recall. None of the subjects showed a deficit in delayed recognition. These results suggest that both storage and retrieval difficulties occur in normal aging and dementia. The recognition test results suggest that recall deficits evidenced by both elderly groups are in large part due to faulty retrieval mechanisms. Since the shopping list task discriminated well among the three groups, it has potential for memory assessment in clinical settings.     

Aging changes the effects of cocaine on vigilance task performance of rats.

To investigate age-related behavioral changes with the administration of cocaine, young (6-10 mo), middle-aged (12-18 mo), young-old (21-24 mo), and old (25-36 mo) rats that had been trained on a 2-choice, discrete trial vigilance task were tested under different doses of cocaine. The young and middle-aged rats exhibited significantly increased accuracy and decreased choice latencies following 2.5 mg/kg cocaine. A 15.0 mg/kg dose increased variability in these measures and increased food retrieval latencies. The young-old and old rats exhibited no significant changes in accuracy or choice latency to 1.25, 2.5, and 5.0 mg/kg cocaine; however, a dose of 15.0 mg/kg significantly reduced accuracy in both these groups and increased choice latencies in the old animals. Also, doses of 5.0 and 15.0 mg/kg tended to increase food retrieval latencies more in the two older groups than in the two younger groups. These results indicate that, rather than a simple increase or decrease in sensitivity, there is a qualitative change in cocaine's behavioral effects as rats age. These findings may reconcile long-standing discrepancies in the literature regarding age-related changes in the behavioral effects of amphetamine, with actions and effects very similar to those of cocaine.     

Diazepam during endoscopic submucosal dissection of gastric epithelial neoplasias

AIM:To investigate risk factors and adverse events related to high-dose diazepam administration during endoscopic submucosal dissection for gastric neoplasias.METHODS:Between February 2002 and December 2009,a total of 286 patients with gastric epithelial neoplasia underwent endoscopic submucosal dissection in our hospital.To achieve moderate sedation,5-7.5 mg of diazepam was administered intravenously by non-anesthesiologists.Intermittent additional administration of 2.5-5 mg diazepam was performed if uncontrollable body movement of the patient was observed.All patients were classified into groups based on the required diazepam dose:low-dose (≤ 17.5 mg,n=252) and high-dose (> 17.5 mg,n=79).RESULTS:Differences between the low-and highdose diazepam groups were observed in lifetime alcohol consumption (0.30 ± 0.48 vs 0.44 ± 0.52 tons,P=0.032),body weight (58.4 ± 10.3 vs 62.0 ± 9.9 kg,P=0.006),tumor size (15 ± 10 vs 23 ± 18 mm,P < 0.001),lesion location (P < 0.001) and the presence of ulcerative findings (14/238 vs 18/61,P < 0.001).Multivariate analysis identified all five variables as independently related to required diazepam dosage.In terms of adverse reactions to diazepam administration,paradoxical excitement was significantly more frequent in the high-dose diazepam group (P < 0.001).CONCLUSION:Intermittent administration of diazepam enabled safe completion of gastric endoscopic submucosal dissection except in patients who were alcohol abusers or obese,or who showed complicated lesions.     

Diazepam versus midazolam for colonoscopy: a prospective evaluation of predicted versus actual dosing requirements

We performed a prospective, randomized, double-blind study to evaluate the efficacy of the currently recommended low doses of midazolam for conscious sedation compared with diazepam for colonoscopy. Each agent was administered in a fixed ratio dose in combination with meperidine, and titrated incrementally to allow for adequate sedation prior to initiating and during the procedure. The currently recommended starting dose of midazolam (0.03 mg/kg) proved to be very appropriate for pre-medication. In contrast, the currently recommended starting dose of diazepam (0.10 mg/kg) proved excessive in 21% of patients (especially in those aged > 65). The low initial and incremental doses of midazolam compared favorably with diazepam in all efficacy parameters studied and exceeded diazepam in post-procedure amnesia scores (p = 0.01). Moreover, the sedative effects of midazolam at these lower doses were not lost despite long duration procedures (> 40 min). We conclude that midazolam, given in small incremental doses, in combination with meperidine, produces effective conscious sedation for colonoscopy and exceeds diazepam in its amnestic effect.     

Verbal fluency in senile dementia: an analysis of search and knowledge

This investigation concerns the ability to decide on superordinate category membership as a determinant of retrieval failure in fluency tasks. Subjects were 24 normal elderly (mean age 83) and 66 senile dementia patients (mean age 80.5). Two tasks were presented. In the recall task subjects were asked to supply instances of articles of clothing and fruits. In a recognition task subjects were tested for their knowledge of category membership. Normative production frequencies of the items in the recognition task were systematically varied from intermediate to very low. Senile dementia patients generated significantly (P less than 0.001) less instances of both categories than normal elderly. In contrast, recognition of category exemplars was not impaired. These results present direct evidence for the hypothesis that senile dementia patients know far more category instances than they are able to produce.     

小剂量倍他乐克对老年急性心肌梗死后心室晚电位干预的研究

目的　探讨小剂量倍他乐克对老年急性心肌梗死 (AMI)后心室晚电位 (VLP)长期干预的作用。方法　将 1 68例老年 AMI后 VLP阳性患者随机分为两组 ,86例干预组患者服倍他乐克 6.2 5～ 2 .5 mg/次 ,2次 /d,82例对照组常规服消心痛。结果　小剂量倍他乐克干预后能使 VLP转阴 (74/86) ,使 SA- ECG的 TD- QRS、LAS较治疗前缩短 ,RMS增加 (P<0 .0 1 ) ,并有效控制室性心律失常发生。结论　小剂量倍他乐克长期干预能使老年 AMI患者 VLP转阴 ,同时又避免大剂量快速用药所致副作用。老年 AMI患者出现 VL P阳性如无明显β-阻滞剂禁忌 ,应首选小剂量倍他乐克长期治疗。     

Determinants of the intravenous diazepam dose required for gastroscopy

Factors influencing the intravenous dose of diazepam required by 100 consecutive outpatients being prepared for peroral endoscopy were evaluated. Eleven patients reported a history of using 2 or more doses of benzodiazepine a week and required 0.48 +/- 0.1 mg/kg of diazepam compared with 0.30 +/- 0.02 mg/kg (P < 0.01) needed by 89 patients who reported less frequent or no use. The log (dose/kg) was negatively correlated with age (r = 0.51, P < 0.01), and the log dose was positively correlated with weight to a lesser degree (r = 0. 31, P < 0.01). In the larger group of patients who reported less than twice-weekly or no benzodiazepine use, no effect of alcohol use on dose was found. The dose was unrelated to sex. The findings emphasize the importance of individualizing intravenous doses of diazepam.     

Cyclosporine A in rheumatoid arthritis: randomized, placebo controlled dose finding study.

OBJECTIVE: To determine the lowest effective starting dose and residual benefit of cyclosporine A (CSA) in patients with rheumatoid arthritis (RA) refractory to other agents. METHODS: In a double blind (masked observer), controlled, multicenter study, patients with RA started CSA 0 (placebo; n = 61), 1.5 (n = 89), or 2.5 (n = 94) mg/kg/day in a 21 week study that permitted dose escalation after 8 weeks, 1 week tapering of dose at 16 weeks, and post-therapy observation for 4 weeks. RESULTS: Patients with RA taking CSA 2.5 mg/kg/day fared better than those in the placebo or CSA 1.5 mg/kg/day groups in Patient Global Assessment, Examiner Global Assessment, Pain/Tender Joint Count and Index, Swollen Joint Count, and the "Ability at this moment" part of a modified Health Assessment Questionnaire. There was no difference in response between CSA 1.5 mg/kg/day and placebo groups. In the CSA 2.5 mg/kg/day group: improvement occurred between 8 and 12 weeks of therapy; average CSA dose escalation resulted in CSA 2.85 mg/kg/day by Week 16; benefit was not maintained during post-therapy observation and 7 patients discontinued the study because of an adverse event. Adverse events were common in all groups and included gastrointestinal discomfort, hypertension, and increased creatinine. Adverse events remitted with adjustment of dose or after washout in most patients. CONCLUSION: In RA, treatment of patients with CSA 2.5 mg/kg/day, but not 1.5 mg/kg/day, resulted in improvement of 4 of 5 primary efficacy variables when compared to placebo. Adverse events were mostly manageable. CSA was an effective therapy for patients with RA who had failed at least one second line agent.     

Intravenous administration of diazepam in patients with chronic liver disease.

The EEG response and drug kinetics after intravenous infusion of diazepam at 1-0 mg/min until nystagmus, dysarthria, and moderate sedation developed, has been investigated in five normal subjects and 17 patients with chronic liver disease. Diazepam induced adequate premedication with a similar clinical response in all subjects with no adverse reactions. Maximal response was during or within five minutes of infusion. The dose of diazepam required in liver chronic disease was 17-9 +/- 1-4 mg (M +/- SEM) compared with 27 +/- 5-4 mg in controls (p less than 0-01). Dose correlated significantly with serum albumin (p less than 0-05). Baseline mean dominant frequency (MDF) and slow wave index (SWI) significantly correlated with albumin (p less than 0-01). After diazepam, the MDF decreased and SWI increased. The change was greatest at the time of maximal clinical response. It was greater in liverdisease and was greatest in patients with previous hepaticencephalopathy. In spite of reduced dose requirements in liver disease, there was no significant difference in plasma concentration at the end of drug infusion...     

Misuse and abuse of diazepam: an increasingly common medical problem.

Misuse and abuse of diazepam among addiction-prone individuals is reported. The most common pattern of abuse appears to be periodic ingestion of 30 to 80 mg of diazepam in one dose, either alone or in conjunction with methadone or other narcotics. Two cases of physical dependency to diazepam have been observed. Many addict patients using diazepam are buying it on "the streets". All physicians should know that diazepam abuse and misuse is occurring, and careful attention should be given to prescribing, transporting and storing this drug.     

Spironolactone therapy in older patients--the impact of renal dysfunction

Low dose spironolactone reduces the risk of death from heart failure. We examined the effects of spironolactone on potassium homeostasis in a cohort of elderly patients with congestive heart failure (CHF). Eighteen patients >70 years, mean 80.5 (+/- SD 6.3) with New York Heart Association CHF Grade II-IV were enrolled. All patients were commenced on 25 mg spironolactone daily. The dose was reduced to 12.5 mg daily when hyperkalemia (potassium>5.0) occurred. A serum creatinine of >150 micromol/l was defined as indicating renal impairment (RI). Blood pressure, pulse rate, urea, creatinine, Na+ and K+ were measured at baseline, day 2-5, day 28 and more often if clinically indicated. Nine of those recruited had RI. Baseline serum potassium was significantly higher in those with RI, mean 4.56 (+/- 0.30) vs. 4.04 (+/- 0.30) mmol/l (P<0.01). Six patients with RI developed hyperkalemia versus one of those with serum creatinine <150 micromol/l (P<0.05). Serum K+ returned to normal in all patients when the dose of spironolactone was reduced to 12.5 mg daily with one exception in whom the medication was withdrawn. When spironolactone is prescribed to older patients with CHF, hyperkalemia appears more likely in those with RI. Halving the dose to 12.5 mg daily results in normalisation of serum potassium. Older patients commencing spironolactone therapy should have serum potassium monitored frequently, particularly in the presence of RI.     

Short-term effect of captopril on microalbuminuria in children with glycogen storage disease type Ia

Early signs of renal dysfunction in glycogen storage disease type Ia (GSD Ia) are glomerular hyperfiltration and proteinuria. In a non-randomized study, the effect of captopril on the improvement of proteinuria in GSD Ia patients with microalbuminuria was investigated. A positive effect has been shown for the insulin-dependent diabetes mellitus patients. Microalbuminuria was defined as albumin/creatinine ratio (mg/mmol) more than 2.5 in spot urine. Nineteen (52.7%) out of 36 patients had microalbuminuria, and 8 patients received captopril at a dose of 1mg/kg per day. Microalbuminuria was evaluated periodically during the follow-up period. Of the captopril-treated patients, one was lost to follow-up. In the remaining 7 patients, urinary albumin excretion normalized in 3 patients (42.9%) and decreased at least by 50% in another 3 patients (42.8%) after 6 months of treatment. One patient, who was the oldest, did not have any benefit. In untreated patients, only two patients had a decrease in microalbuminuria of more than 50%. Patients with microalbuminuria had significantly higher blood lactate (p<0.05) and plasma triglyceride (p<0.01) concentrations and significantly lower blood bicarbonate concentration (p<0.05) than those patients without it. Additionally, the patients with microalbuminuria had been diagnosed earlier than those without microalbuminuria (p<0.05). Patients with microalbuminuria have more severe clinical and laboratory findings than those without microalbuminuria. Captopril at a dose of 1 mg/kg per day seems to be effective in at least 50% of GSD Ia patients with microalbuminuria.     

Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: a placebo controlled study.

OBJECTIVE--To compare the first dose responses to low dose angiotensin converting enzyme inhibitors (captopril, enalapril, and perindopril) in elderly patients with stable chronic heart failure. DESIGN--Double blind, randomised, placebo controlled, parallel, group prospective study of elderly patients with stable chronic heart failure. SETTING--General hospital in-patient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of angiotensin converting enzyme inhibitor therapy. PATIENTS--48 unselected elderly (58-85 years) patients with symptomatic but stable chronic heart failure (New York Heart Association grades II-IV) confirmed by clinical history, examination, and cardiological investigations. Patients gave their written and informed consent to receive their initial treatment under double blind conditions; blood pressure was monitored and blood samples taken to measure the pharmacokinetic and neurohormonal responses. INTERVENTION--Patients were randomised to receive a daily oral dose of placebo, captopril (6.25 mg), enalapril (2.5 mg), or perindopril (2 mg). MAIN OUTCOME MEASURES--Blood pressure and heart rate responses, drug concentration, and plasma renin and ACE activities. Differences between treatment groups were analysed by analysis of variance. RESULTS--The four randomised groups of patients had similar age, severity of heart failure (NYHA class), pretreatment diuretic dosage, plasma renin activity, and serum electrolyte state. Placebo treatment caused a modest but significant diurnal fall in blood pressure. Captopril produced a significant early (1.5 hours) and brief fall in blood pressure. The blood pressure fall with enalapril was later (4-10 hours), longer lasting, and was associated with significant slowing of supine heart rate. Though perindopril produced a similar plasma ACE inhibition to that produced by enalapril, it only caused changes in blood pressure that were similar to those caused by placebo. CONCLUSIONS--This controlled study is the first to indicate a qualitative difference in the acute response to angiotensin converting enzyme inhibitors with similar structure and metabolism (that is, enalapril and perindopril). Low dose perindopril seems to be less likely to cause hypotension in patients with heart failure. The explanation for the differences is unclear but may reflect differential effects on local tissue angiotensin generation.     

Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: a placebo controlled study.

OBJECTIVE--To compare the first dose responses to low dose angiotensin converting enzyme inhibitors (captopril, enalapril, and perindopril) in elderly patients with stable chronic heart failure. DESIGN--Double blind, randomised, placebo controlled, parallel, group prospective study of elderly patients with stable chronic heart failure. SETTING--General hospital in-patient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of angiotensin converting enzyme inhibitor therapy. PATIENTS--48 unselected elderly (58-85 years) patients with symptomatic but stable chronic heart failure (New York Heart Association grades II-IV) confirmed by clinical history, examination, and cardiological investigations. Patients gave their written and informed consent to receive their initial treatment under double blind conditions; blood pressure was monitored and blood samples taken to measure the pharmacokinetic and neurohormonal responses. INTERVENTION--Patients were randomised to receive a daily oral dose of placebo, captopril (6.25 mg), enalapril (2.5 mg), or perindopril (2 mg). MAIN OUTCOME MEASURES--Blood pressure and heart rate responses, drug concentration, and plasma renin and ACE activities. Differences between treatment groups were analysed by analysis of variance. RESULTS--The four randomised groups of patients had similar age, severity of heart failure (NYHA class), pretreatment diuretic dosage, plasma renin activity, and serum electrolyte state. Placebo treatment caused a modest but significant diurnal fall in blood pressure. Captopril produced a significant early (1.5 hours) and brief fall in blood pressure. The blood pressure fall with enalapril was later (4-10 hours), longer lasting, and was associated with significant slowing of supine heart rate. Though perindopril produced a similar plasma ACE inhibition to that produced by enalapril, it only caused changes in blood pressure that were similar to those caused by placebo. CONCLUSIONS--This controlled study is the first to indicate a qualitative difference in the acute response to angiotensin converting enzyme inhibitors with similar structure and metabolism (that is, enalapril and perindopril). Low dose perindopril seems to be less likely to cause hypotension in patients with heart failure. The explanation for the differences is unclear but may reflect differential effects on local tissue angiotensin generation.     

Low-dose cytosine arabinoside for treating hypocellular acute leukemia in the elderly.

Ten previously untreated elderly patients with hypocellular acute leukemia received a low dose of cytosine arabinoside (Ara-C), 10 mg/m2 injected subcutaneously every 12 hours for 14-28 days. Six patients achieved a complete remission (CR) for periods ranging for 6-23 months (median 8.5 months) and the others had a partial remission (PR). Relapse has occurred in three patients to date. The median survival ranged from 10-24 months (median 14.5 months). Only two of the six patients, in whom bone marrow biopsy was performed at CR, had a normal cellularity. This change, however, did not appear to be a significant prognostic factor in those patients. In seven patients who achieved a CR or PR low-dose Ara-C was administrated as maintenance therapy at the same low dose for 10 days each month. Treatment was well tolerated in all patients despite for myelosuppression. There were no drug-related deaths. These observations suggest that low-dose Ara-C is effective in treating elderly patients with hypocellular acute leukemia.     

Beta-blocker therapy in heart failure in the elderly

Chronic heart failure (CHF) is a common and disabling condition with morbidity and mortality that increase dramatically with advancing age. There is some evidence available about beta-blocker therapy in the elderly. The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) and retrospective subgroup (elderly) analyses of landmark clinical trials in stable systolic heart failure have provided data supporting the use of beta-blocker as baseline therapy in heart failure in the elderly. However, beta-blocker is still less frequently used in elderly compared to younger patients. There are many reasons, one of which is that available data on elderly patients are not as convincing as those pertaining to their younger counterparts. There is uncertainty or disagreement about whether beta-blockers are equally beneficial and well tolerated in elderly heart failure patients as in younger ones. In other words, the level of evidence regarding beta-blocker therapy in the elderly is not regarded as high as that in younger patients. Indeed, the senior heart failure population, which in fact comprises the majority of all heart failure patients, is in general less well studied, both experimentally and clinically, than younger populations. Both clinical studies and experience indicate good tolerability in the use of beta-blocker in the elderly. Although beta-blockers are well tolerated by the elderly, target doses (based on previous clinical trials) may be difficult to achieve. The question is whether we should use the same target dose in the elderly as that in younger patients. Theoretically, the most effective dose is the highest dose tolerated, which may differ across different age groups. Is it time to abandon the "target dose" for the "highest dose tolerated"? The time has come to carry out active research to achieve better documentation of evidence based heart failure management in the elderly for the benefit of a large number of elderly patients with heart failure. We need clinical trial data that show definite improvement in outcomes as well as a clear-cut, favourable benefit-risk analysis involving beta-blockers in typical older heart failure patients irrespective of comorbidity and polypharmacy. Until the above is available, it may be wiser to adhere to beta-blocker therapy, which at present is better documented than other heart failure therapies in the elderly.     

Influence of acoustic stress by noise on gastrointestinal motility in dogs

The effects of acoustic stress (AS) on gastrointestinal motility and their prevention by previous treatment with naloxone, phentolamine, propranolol, muscimol, and diazepam were investigated in intact and vagotomized fasted dogs fitted with chronically implanted strain gauges on the antrum at 10 cm from pylorus and on the jejunum at 70 and 140 cm from the pylorus. These effects were compared to those produced by intracerebroventricular administration of ovine corticotropin releasing factor (oCRF). Beginning 40–50 min after the occurrence of a gastric migrating motor complex (MMC), a 1-hr hearing of prerecorded intense music through earpieces (<100 dB) delayed the occurrence of the next gastric MMC observed after 2.8±1.2 hr, while jejunal MMC were still present at a normal frequency. During AS, heart rate and plasma cortisol were significantly increased by 32.7 and 215%, respectively, 10–15 min after the beginning of hearing. The AS-induced lengthening of the gastric MMC cycle as well as cortisol increase were abolished after previous administration of diazepam (0.5 mg/kg intramuscular) or muscimol (10 g/kg intravenous), while they were still present after naloxone (0.1 mg/kg intravenous), phentolamine (0.2 mg/kg intravenous), or propranolol (0.1 mg/kg intravenous). CRF administered intracerebroventricularly (100 ng/kg) also delayed the occurrence of gastric MMC without affecting jejunal motility, and this effect was not antagonized by previous treatment with diazepam or muscimol. Both the effects of AS and CRF were abolished after bilateral thoracic vagotomy. These results suggest that the selective inhibition of gastric motility induced by noise in dog is due to the CNS release of CRF which affects, in turn, the vagal output to the stomach. The suppressive action of diazepam or GABA agonist on noise-induced gastric hypomotility may be related to blockade of the AS-induced CRF release.     

Prenatal Ethanol Exposure Affects Temperature Responses of Adult Rats to Pentobarbital and Diazepam Alone and in Combination with Ethanol

Long-term effects of prenatal alcohol exposure on body temperature responses to pentobarbital and diazepam and to either drug in combination with ethanol were studied in adult rats who were the offspring of dams fed a 5.0% w/v ethanol-containing liquid diet during the last 2 weeks of gestation. Adult offspring of pair-fed and chow-fed dams served as nutritional and normal controls, respectively. Pentobarbital (6.25-25.0 mg/kg) and diazepam (2.5-10.0 mg/kg) produced significantly greater dose-related hypothermic responses in females than males. Following either pentobarbital or diazepam administration female prenatally ethanol-exposed (E) rats responded with a greater fall in body temperature than the controls. Significantly greater hypothermia occurred in both male and female E rats than in controls when ethanol (1.5 g/kg) was administered together with pentobarbital or diazepam. However, the drug combinations did not produce additive effects on body temperature in any prenatal treatment group. Pentobarbital produced acute cross-tolerance to ethanol while diazepam potentiated ethanol's effect. These studies confirm and extend our previous findings of enhanced hypothermic responses to ethanol in adult rats exposed to ethanol in utero and indicate that maternal alcohol consumption produces long-term effects on the central thermoregulatory systems of offspring.     

Age and efficacy of new long acting calcium blocker, nisoldipine, is essential hypertension

The relationship between the age and the clinical efficacy of a new long acting calcium entry blocker, nisoldipine, was investigated in essential hypertension using two double blind group studies, in which nifedipine or atenolol was used as a control drug. Following 4 weeks of the observation period, nisoldipine was administered 2.5 mg once a day and an increase in dose was available up to 5 to 10 mg per day for 12 weeks of the treatment period. One hundred fourty nine cases who received nisoldipine were divided into the following two groups; 97 cases of the middle aged patients under 59 years old (mean age of 49.5 years) and 62 cases of the elderly patients more than 60 years old (mean age of 64.8 years). Average dose of nisoldipine at 12 weeks of treatment period was 4.8 mg in middle age and 5.8 mg in elderly group. The positive antihypertensive effect was observed in 82.2% in the middle aged patients and in 83.6% in the elderly patients; there was no significant difference between the two groups. In each group, significant fall in blood pressure was observed after the treatment, although no significant difference in the fall of systolic and diastolic blood pressure in the treatment period was observed between the two age groups. The side effect was observed in 16 cases (16.5%) of the middle aged patients and in 7 cases (11.3%) of the elderly patients, but no significant difference in the incidence was observed. The significant deterioration of the clinical laboratory findings was not observed in both groups. The rate of usefulness (useful or above) was 74.7% in the middle aged patients and 81.5% in the elderly patients, and there was no significant difference between the two groups. These results indicate that a new long acting calcium entry blocker, nisoldipine, is effective and safe antihypertensive drug for the elderly as well as for the middle aged patients.     

Management and dosing of warfarin therapy

When initiating warfarin therapy, clinicians should avoid loading doses that can raise the International Normalized Ratio (INR) excessively; instead, warfarin should be initiated with a 5-mg dose (or 2 to 4 mg in the very elderly). With a 5-mg initial dose, the INR will not rise appreciably in the first 24 hours, except in rare patients who will ultimately require a very small daily dose (0.5 to 2.0 mg). Adjusting a steady-state warfarin dose depends on the measured INR values and clinical factors: the dose does not need to be adjusted for a single INR that is slightly out of range, and most changes should alter the total weekly dose by 5% to 20%. The INR should be monitored frequently (eg, 2 to 4 times per week) immediately after initiation of warfarin; subsequently, the interval between INR tests can be lengthened gradually (up to a maximum of 4 to 6 weeks) in patients with stable INR values. Patients who have an elevated INR will need more frequent testing and may also require vitamin K1. For example, a nonbleeding patient with an INR of 9 can be given low-dose vitamin K1 (eg, 2.5 mg phytonadione, by mouth). Patients who have an excessive INR with clinically important bleeding require clotting factors (eg, fresh-frozen plasma) as well as vitamin K1.