A case of cranial surgery in the Talmud.

The history of Jewish discourse on law and philosophy was transformed from an oral teaching to a written teaching around the beginning of the Common Era. The result of these written laws and commentaries is known today as the Talmud. Many pages of the Talmud discuss illnesses and diseases and their potential treatments, however very few of these potential treatments involve invasive surgery. In one instance, involving a painful skin ailment called ra'aton, the authors of the Talmud suggest cranial surgery as the cure and describe the preparation of a potential anesthetic, the surgery environment, and the removal of a growth. Although this account raises several questions about the ailment itself, it provides us with a rare look at invasive cranial surgery dating back nearly 2,000 years.

Long-term safety of high-dose angiotensin receptor blocker therapy in hypertensive patients with chronic kidney disease.

BACKGROUND: Reducing urinary protein excretion in patients with renal disease is an important therapeutic target to prevent the progression of renal and cardiovascular disease. Drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs), which block the actions of the renin-angiotensin-aldosterone system, are recommended because they reduce blood pressure and proteinuria. Recently, the use of higher doses of ARBs, up to three times the maximal approved dose, resulted in further reductions in protein excretion. Despite the effectiveness of this therapeutic approach, no long-term safety analysis has been conducted in patients receiving high-dose ARB treatment. OBJECTIVE: To study the long-term safety of high-dose ARB treatment. METHODS: We observed 48 patients [44 men and 4 women; ages 64 +/- 15 years (mean +/- SD), weight 88 +/- 28 kg, estimated glomerular filtration rate 53 +/- 23 ml/min] receiving treatment with high doses (1.5-5 times greater than the maximum approved dose) of ARBs, for 40 +/- 24 months (range 6-98 months). RESULTS: The average ARB dose tended to increase over time and was 3.2 +/- 1.2 times greater at the end of the study than that at the start. Systolic blood pressure was similar at the beginning and end of the study period (132 +/- 20 and 125 +/- 20 mmHg, respectively), but diastolic blood pressure showed a decrease throughout the study and was significantly reduced (P < 0.05) in association with 1.5x and 2x the maximum ARB dose (73 +/- 11 and 72 +/- 10 mmHg, respectively) when compared with baseline (78 +/- 11 mm Hg). There was a trend (P > 0.05) for increases in concentrations of serum potassium (0.2 +/- 0.9 mmol/l) and creatinine (0.3 +/- 0.7 mg/dl) with increases in dose from baseline to the end of the study. Serum creatinine concentration was greater (P < 0.05) at the periods of 3x and 4x the maximum dose, but this represented increases of only 12 and 20% from baseline, respectively. CONCLUSIONS: High-dose ARB treatment in patients with chronic renal disease is not associated with any clinically significant long-term negative effects on serum creatinine or potassium and is thus a important therapeutic modality with which to achieve further reductions in urinary protein excretion.

Safety and tolerability of high-dose angiotensin receptor blocker therapy in patients with chronic kidney disease: a pilot study.

BACKGROUND: The progression of renal disease is ameliorated by drugs that inhibit the renin-angiotensin system (RAS). The doses used to slow the progression of renal disease may not completely suppress the RAS for 24 h and may explain why some patients do not obtain optimal renoprotective benefits from therapy. This pilot study was initiated to determine the safety and tolerability of using higher doses, than currently approved by the Food and Drug Administration, for the angiotensin-receptor blocker (ARB) candesartan cilexetil in patients with chronic kidney disease. We hypothesized that higher doses will be safe and well tolerated. Consequently, this should be a viable strategy for larger clinical trials evaluating the preservation of renal function. METHODS: Twelve patients (10 males; age = 57 +/- 14 years) with a history of diabetic or non-diabetic chronic kidney disease were enrolled in an 8-week open-label trial. Patients received candesartan titrated to a targeted dosage of 160 mg/day (5 times above the currently approved maximum dose) and remained at that dosage for the subsequent 4 weeks. The safety and tolerability of the higher doses were determined by measures of blood pressure, serum creatinine and potassium. RESULTS: Candesartan was well tolerated with no serious drug-related adverse events reported. Serum creatinine concentrations throughout the study were not different (p > 0.05) from baseline levels (2.0 +/- 0.5 mg/dl). Plasma potassium concentrations at 160 mg/day candesartan (4.9 +/- 0.7 mEq/l) were similar (p > 0.05) to those at baseline (4.8 +/- 0.5 mEq/l). CONCLUSIONS: The results of this pilot study suggest that supramaximal doses of ARBs are safe and well tolerated in patients with chronic kidney disease, while reducing both blood pressure and proteinuria. This study demonstrates the need to further investigate the optimal dosing strategy for ARBs in reducing the progression of renal disease.

The effect of high-dose angiotensin II receptor blockade beyond maximal recommended doses in reducing urinary protein excretion.

The optimal doses of angiotensin-converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARBs) for maximal reduction in urinary protein excretion are not known. Moreover, beneficial effects from ARBs, such as tissue protection owing to a more complete blockade of the renin-angiotensin-aldosterone system (RAAS), may be independent of blood pressure-lowering by ARBs. In this investigation, we evaluated whether increasing the dose of candesartan cilexetil, in subjects already on the maximally-recommended FDA doses of 32 mg, would induce a further reduction in 24-hour urinary protein excretion in patients with heavy proteinuria (urinary protein excretion >1.5 g/day; mean 4.4±2 g/day). Ten patients were started on 16 or 32 mg of candesartan cilexetil daily. After 1-2 months of therapy, the dose was titrated upwards to 96 mg. In all subjects, there were further reductions in 24-hour urinary protein excretion when the dose was increased beyond the recommended 32 mg maximal dose. Increasing the dose of candesartan cilexetil to 96 mg was safe, as most subjects showed no changes in serum potassium and, as expected, only a slight increase (0.5-0.7 mg/dl) in serum creatinine. These data warrant further investigation, since some subjects may require higher doses of candesartan to achieve optimal regression of proteinuria.