Dipyridamole-induced headache and lower recurrence risk in secondary prevention of ischaemic stroke: a post hoc analysis.

BACKGROUND AND PURPOSE: Our objective was to investigate the association between recurrent stroke risk and headache induced by extended-release dipyridamole (ER-DP) when administered alone or with low-dose aspirin (ASA+ER-DP). METHODS: This was a post hoc analysis of prospectively collected data on recurrent stroke risk and headache as an adverse event or reason for treatment discontinuation from the PRoFESS (N = 20,332) and ESPS2 (N = 6602) trials. Hazard ratios (HRs) for recurrent stroke were calculated using the Cox model. RESULTS: In PRoFESS, the 2.5-year recurrent stroke risk in patients receiving ASA+ER-DP was 8.2% in those with headache within 7 days of starting treatment and 9.4% in those without [HR 0.85, 95% confidence interval (CI) 0.73-0.98; P = 0.03]. Recurrent stroke risk was 5.0% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.2% in those who did not (HR 0.52, 95% CI 0.35-0.77; P = 0.001). No such difference was observed in clopidogrel-treated patients. In ESPS2, risk of recurrent stroke was 6.2% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.8% in patients who did not (HR 0.62, 95% CI 0.31-1.27; P = 0.19) and 7.3% in patients who discontinued ER-DP due to headache by day 90 versus 13.2% in those who did not (HR 0.53, 95% CI 0.27-1.04; P = 0.06). CONCLUSIONS: Patients taking ASA+ER-DP in PRoFESS who developed headache had significantly reduced stroke recurrence risk versus those without headache. Similar (non-significant) findings for ASA+ER-DP and ER-DP in ESPS2 suggest that dipyridamole-induced headache may reflect better cerebrovascular function.

Impact of angiotensin receptor blockade in combination with hydrochlorothiazide 25 mg in 2121 patients with stage 1-2 hypertension.

The antihypertensive effects of telmisartan 80 mg versus valsartan 160 mg, both combined with hydrochlorothiazide (HCTZ) 25 mg, were assessed in a pooled analysis from two large trials with identical study designs in patients with stage 1-2 hypertension. The trials were double-blind with a 4:4:1 randomization scheme to compare once-daily telmisartan 80 mg and HCTZ 25 mg versus once-daily valsartan 160 mg and HCTZ 25 mg versus once-daily placebo on reductions in clinic blood pressure (BP). The primary end point was changes from baseline in BP at the end of 8 weeks. In total, 2121 patients were randomized (telmisartan-HCTZ, 942, valsartan-HCTZ, 952, and placebo, 227) and had baseline seated BPs of 154/102 and 155/102 mm Hg in the two studies, respectively. Changes from baseline in BP after administration of telmisartan-HCTZ (-24.5/-18.0 mm Hg) were significantly greater than for both placebo (-4.1/-6.5 mm Hg) and valsartan-HCTZ (-22.3/-16.8 mm Hg) (versus placebo, P<0.0001 for systolic and diastolic BP; versus valsartan-HCTZ, P=0.0004 for systolic BP and P=0.0019 for diastolic BP). Adverse event rates were higher in the placebo group than in the active treatment groups (placebo, 41%, telmisartan-HCTZ, 30%, and valsartan-HCTZ, 30%, P<0.05). These data confirm that telmisartan-HCTZ at doses of 80/25 mg lowered systolic and diastolic BP to a greater extent than valsartan-HCTZ at doses of 160/25 mg in stage 1-2 hypertension. The magnitude of the BP-lowering effect provides support for the use of angiotensin receptor blockers with higher doses of a thiazide diuretic (25 mg) to improve hypertension control.

Telmisartan in migraine prophylaxis: a randomized, placebo-controlled trial.

We evaluated telmisartan 80 mg for migraine prophylaxis. Migraine patients (n = 95) with three to seven migraine attacks in 3 months were randomized, double-blind to telmisartan or placebo. The primary end-point was the reduction in the number of migraine days (i.e. a day with > or = 1 h of symptoms) between the 4-week baseline period and the last 4 weeks of the 12-week treatment period. A responder was recorded when there was a symptom reduction of > or = 50% in these 4-week baseline and treatment periods. The reduction in migraine days was 1.65 with telmisartan and 1.14 with placebo (P > 0.05). Post hoc analyses adjusting for baseline and centre showed a 38% reduction in migraine days with telmisartan vs. 15% with placebo (P = 0.03), and a borderline significant difference in responders (40% vs. 25%, P = 0.07). The incidence of adverse events was similar between treatments. This study indicates that telmisartan might be effective in migraine prophylaxis.

Acetaminophen in the treatment of headaches associated with dipyridamole-aspirin combination.

The authors assessed the prevalence of headaches following extended-release dipyridamole/aspirin combination (DAC), and the efficacy of acetaminophen in the treatment of these headaches. Following DAC, 38.7% of the participants developed headaches. The headaches were self-limited (69.4% placebo efficacy in 2 hours) and the incidence markedly declined over time. Acetaminophen was no more effective than placebo in the acute and preemptive treatment of these headaches.

Change in trabecular architecture as measured by fractal dimension.

The objective of this work was to expose dried trabecular bone material to a decalcifying environment and to quantify the change in the spatial distribution of the bone with a fractal measure. Digitized radiographic images were produced from four separate slices of human vertebral bone as they dissolved within a solution of nitric acid. Pixel data from a region of interest (ROI) within the trabecular bone were used to estimate the time-dependent change in fractal dimension of the ROI as the bone dissolved. Results demonstrated that a change in the spatial distribution of trabecular material may be expressed in terms of a concurrently changing estimate of the fractal dimension.

Middle cerebral artery velocity correlates with nitroglycerin-induced headache onset.

Headache often accompanies treatment with nitroglycerin, but the cerebral hemodynamic effects and the exact mechanism of the headache are incompletely understood. Transcranial Doppler monitoring allows evaluation and monitoring of changes in blood flow velocity in the large intracranial arteries. The objective of this study was to assess middle cerebral artery (MCA) blood flow velocities with transcranial Doppler monitoring in subjects receiving continuous low-dose nitroglycerin intravenously or by patch, and correlate these with clinical headache. Twenty-eight normal adult men received nitroglycerin (0.12 micrograms/kg/min intravenously [n = 14] or 0.6 mg/min by transdermal patch [n = 14]), for up to 120 minutes, with monitoring of clinical headache status (standard 4-point scale), blood pressure, heart rate, end-expiratory PCO2 (CO2), and right MCA velocity. All subjects developed headache (mean time to onset, 34 min), reaching moderate or severe levels in 20. There were no differences in age, weight, mean blood pressure, mean heart rate, or resting end-tidal CO2 between those whose headache reached a moderate to severe level and those whose headache remained mild. MCA velocity decreased from baseline values at all levels of clinical headache (onset, -17%; moderate, -18%; severe, -16%; nitroglycerin stopped, -19%) (p, 0.0001 by t test for each stage of headache). MCA velocity remained decreased at the time of headache resolution (-14%; p < 0.001). Blood pressure, heart rate, and CO2 did not change significantly. There were no differences related to route of nitroglycerin dosing. These data show that continuous low doses of nitroglycerin by patch or intravenously produce headache in normal male subjects. MCA velocities were significantly decreased at headache onset and at all levels of headache severity. Changes in MCA velocity persisted beyond the clinical headache. These results suggest a direct MCA vasodilatory effect of nitroglycerin. This method may also be used to evaluate the intracranial hemodynamic effects of other vasoactive drugs, even in clinical settings.

Prostaglandin F2 alpha-induced mitogenesis in MC3T3-E1 osteoblasts: role of protein kinase-C-mediated tyrosine phosphorylation.

Prostaglandin F2 alpha (PGF2 alpha) stimulates DNA synthesis in osteoblasts through phospholipase-C-dependent increases in intracellular calcium and protein kinase-C (PKC) activity. We present evidence that stimulation of protein tyrosine phosphorylation by PKC is an additional component of the signaling pathways involved in PGF2 alpha-stimulated DNA synthesis in MC3T3-E1 osteoblast-like cells. Mitogenic doses of PGF2 alpha (42 nM) rapidly induced tyrosine phosphorylation of multiple substrates in these osteoblast-like cells. PGF2 alpha stimulated tyrosine phosphorylation of new proteins with apparent mol wt of 87, 80, 50, 47, 36, and 33 kilodaltons and up-regulated phosphorylation of preexisting tyrosine components with mol wt of 123, 112, 68, and 56 kilodaltons. Stimulation of PKC by 1.6 microM phorbol 12-myristate 13-acetate mimicked the pattern of PGF2 alpha-induced protein tyrosine phosphorylation, whereas PKC-deficient cells (induced by overnight pretreatment with 16 microM phorbol 12-myristate 13-acetate) were refractory to PGF2 alpha-stimulated protein tyrosine phosphorylation and DNA synthesis. The tyrosine kinase inhibitors tyrphostin and genistein blocked PGF2 alpha-stimulated DNA synthesis and protein tyrosine phosphorylation, and the tyrosine phosphatase inhibitor orthovanadate prolonged PGF2 alpha-stimulated tyrosine phosphorylation; these findings are consistent with activation of a putative tyrosine kinase. Calcium/calmodulin antagonists also inhibited PGF2 alpha-stimulated DNA synthesis, but the calcium-signaling pathway played no role in PGF2 alpha-induced tyrosine phosphorylation. Our findings suggest that cross-talk between receptor-mediated activation of PKC and protein tyrosine phosphorylation is an important distal signaling pathway necessary for PGF2 alpha-induced DNA synthesis in osteoblast-like cells.

PDGF induces tyrosine phosphorylation in osteoblast-like cells: relevance to mitogenesis.

We have studied the association between protein tyrosine phosphorylation and the mitogenic effect induced by platelet-derived growth factor (PDGF) in the osteoblast-like cell line MC3T3-E1. PDGF caused a dose-dependent increase in [3H]thymidine incorporation in MC3T3-E1 cells, reaching a plateau at 10 ng/ml. Vanadate, a potent phosphatase inhibitor, induced a twofold increase in thymidine incorporation. The combination of vanadate and PDGF resulted in a dose-dependent synergistic effect on thymidine incorporation. Genistein, a tyrosine kinase inhibitor, inhibited in a dose-related manner (2-20 microM) the mitogenic effect induced by either PDGF or the combination of vanadate and PDGF. These observations suggest that tyrosine kinases are involved in mediating the mitogenic effect of PDGF in these cells. PDGF treatment of MC3T3-E1 cells and subsequent immunoblotting with antiphosphotyrosine antibodies resulted in a marked phosphorylation of the PDGF receptor. Vanadate had a lesser effect on PDGF receptor phosphorylation, but given together with PDGF it induced a significant increase in the intensity of receptor phosphorylation. Preincubation with genistein abrogated these effects. Taken together, these findings indicate a direct correlation between thymidine incorporation and tyrosine phosphorylation in MC3T3-E1 cells and suggest that tyrosine phosphorylation plays a role in PDGF-induced mitogenic activity in osteoblast-like cells.

Endothelin rapidly stimulates tyrosine phosphorylation in osteoblast-like cells.

The mitogenic activity of endothelin (ET) was studied in osteoblast-like cells, MC3T3-E1. [3H] Thymidine incorporation induced by ET was markedly lower than that of platelet-derived growth factor (PDGF). ET synergistically stimulated [3H] thymidine incorporation induced by PDGF with an apparent ED50 value of 2.5 nM. Treatment of MC3T3-E1 cells with ET and subsequent immunoblotting of the cell extracts with antiphosphotyrosine antibodies followed by labeling with [125I] protein A resulted in the identification of several phosphotyrosine-containing proteins. The intensity of these labeled phosphoproteins significantly increased when the cells were treated with a combination of ET and PDGF. Genistein, an inhibitor of tyrosine kinases, blocked [3H] thymidine incorporation as well as protein tyrosine phosphorylation stimulated by either ET, PDGF or the combination of ET and PDGF. These findings suggest that tyrosine phosphorylation could play a role in the comitogenic activity of ET in osteoblast-like cells.

Variable phosphate-mediated regulation of vitamin D metabolism in the murine hypophosphatemic rachitic/osteomalacic disorders.

The familial hypophosphatemic (vitamin D-resistant) disorders are a variety of genetic and acquired syndromes that exhibit unexpected biochemical heterogeneity, manifest as variably abnormal or apparently normal regulation of 1,25-dihydroxyvitamin D [1,25-(OH)2D] production. Recently, we observed that Hyp and Gy mice, murine homologs of X-linked hypophosphatemic rickets, exhibit similarly disparate regulation of vitamin D metabolism. While Gy mice under basal conditions maintain an appropriate elevation (relative to hypophosphatemia) of renal 25-hydroxyvitamin D (25OHD)-1 alpha-hydroxylase, Hyp mice manifest only normal, not increased, enzyme activity. Whether such diversity results from maintenance of phosphate (P)-regulated 1,25-(OH)2D production in Gy mice and loss of this function in Hyp mice or from other variations remains unknown. Therefore, we examined the integrity of P-regulated enzyme activity in the Gy and Hyp mice by testing the effects of enzyme inhibition and alteration of the serum phosphorus concentration on 1,25-(OH)2D production. Initially, we discovered that inhibition of renal 25OHD-1 alpha-hydroxylase suppressed enzyme function in Hyp mice, but did not prevent expression of P-mediated activity in Gy mice. In this regard, while administration of a high calcium diet or 1,25-(OH)2D (0.4 ng/h, sc, for 48 h) resulted in a comparable inhibition of enzyme activity in Hyp (5.9 +/- 0.5 vs. 2.8 +/- 0.7 fmol/mg.min) and normal mice (4.4 +/- 0.6 vs. 2.0 +/- 0.2 fmol/mg.min), similar treatment did not effect complete inhibition of 25OHD-1 alpha-hydroxylase in Gy (10.3 +/- 0.6 vs. 4.9 +/- 0.3 fmol/mg.min) or P-depleted mice (10.2 +/- 0.5 vs. 5.1 +/- 0.4 fmol/mg.min). In accord with the apparent persistence of P-mediated stimulation of enzyme function in Gy mice, dietary P repletion in this mutant resulted in a serum phosphorus concentration similar to that of normal mice and decreased enzyme activity (4.0 +/- 0.8 fmol/mg.min) to a level no different from that expressed in controls (3.4 +/- 0.3 fmol/mg.min). However, in the absence of apparent P-mediated stimulation of enzyme activity, identical treatment of Hyp mice increased the serum phosphorus level comparably, but paradoxically enhanced 25OHD-1 alpha-hydroxylase (3.1 +/- 0.4 vs. 11.7 +/- 2.0 fmol/mg.min). Collectively, these data indicate that enhanced renal 25OHD-1 alpha-hydroxylase expressed in Gy mice and probably in related human diseases results from normally maintained P regulation of enzyme activity, an action absent or mutated in the genetically distinct Hyp mouse.

[Platelet hypoactivity in hypocholesterolemia].

A 6-year-old girl with severe malabsorption resulting from pancreatic insufficiency, and with hypocholesterolemia is described. 57% of her plasma cholesterol was found in high density lipoprotein (HDL), 95 mg/dl, while only 25 mg/dl was in the low density lipoprotein (LDL) fraction. Platelet aggregation in platelet-rich plasma, in response to both collagen and ADP, were substantially reduced (by 54 and 33%, respectively) in comparison with normal controls. However, after removal of plasma and washing the isolated platelets, they were not hypoactive. These results suggest that the plasma environment affects platelet activity, and confirms our in vitro results on the enhancing and inhibiting effects of LDL and HDL, respectively, on platelet activity.

Normal regulation of calcitriol production in Gy mice. Evidence for biochemical heterogeneity in the X-linked hypophosphatemic diseases.

Phenotypic heterogeneity in X-linked hypophosphatemic rickets (XLH) is ascribed to variable penetrance of the genetic abnormality. However, studies of hypophosphatemic (Hyp) and gyrorotary (Gy) mice indicate that mutations at different loci along the X chromosome may underlie the genetically transmitted hypophosphatemic disorders. Thus, genetic heterogeneity may be a determinant of the phenotypic variability in XLH. To determine if such variance includes biochemical diversity, we examined whether Gy mice, similar to Hyp mice, exhibit abnormal regulation of renal 25-hydroxyvitamin D (25[OH]D)-1 alpha-hydroxylase. Serum phosphorus in Gy (4.7 +/- 0.3 mg/dl) and phosphate (P)-depleted mice (4.9 +/- 0.4) was significantly less than normal (8.4 +/- 0.5). Consistent with P depletion, the Gy mice exhibited enhanced renal 25(OH)D-1 alpha-hydroxylase activity (9.3 +/- 0.6 fmol/mg kidney per min), similar to that of P-depleted normals (9.1 +/- 1.5), but significantly greater than that of controls (3.1 +/- 0.3). Such normal enzyme responsiveness was confirmed upon PTH stimulation (1 IU/h s.c.), which revealed that Gy mice increased renal 1-hydroxylase (59 +/- 7.7) similarly to normals (65 +/- 7.7) and P-depleted animals (58.4 +/- 7.8). Calcitonin administration also enhanced enzyme function comparably in the animal models. Evidence confirming normally responsive calcitriol production in untreated Gy mice included increased serum 1,25-dihydroxyvitamin D levels, gastrointestinal calcium absorption, and urinary calcium. The normally regulated vitamin D metabolism in Gy mice indicates that biochemically diverse disease may result from mutations in the gene family regulating renal P transport and underlying X-linked hypophosphatemia. We suspect such heterogeneity is due to altered P transport at variable segments of the proximal convoluted tubule.

Abnormal adenosine 3'.5'-monophosphate stimulation of renal 1,25-dihydroxyvitamin D production in hyp mice: evidence that 25-hydroxyvitamin D-1 alpha-hydroxylase dysfunction results from aberrant intracellular function.

Previously we have established that abnormal regulation of renal 25-hydroxyvitamin D (25OHD)-1 alpha-hydroxylase in Hyp mice involves the PTH-adenylate cyclase component of enzyme activation. However, it remains unknown if the muted effects of PTH result from 1) abnormal second messenger production or 2) an intracellular defect limiting enzyme activation. To distinguish between these possibilities, we compared cAMP stimulation of renal 25OHD-1 alpha-hydroxylase in normal, phosphate-depleted normal, and Hyp mice. Administration of N6-monobutyryl cAMP iv (200 mg/kg/day) increased enzyme activity in normal (4.1 +/- 1.7 vs. 40.7 +/- 7.0 fmol/mg kidney.min) and phosphate-depleted mice (13.3 +/- 1.8 vs. 78.2 +/- 10.4) to a level significantly greater than that achieved in Hyp mice (7.4 +/- 1.1 vs. 22.7 +/- 3.6). Moreover, similar to our observations after PTH stimulation, the apparent abnormal cAMP effect did not result from an altered time course of enzyme activation or a rightward shift in the dose response. Collectively, these data indicate that abnormal regulation of 1,25-dihydroxyvitamin D production in Hyp mice results from aberrant intracellular regulation of 25OHD-1 alpha-hydroxylase, a defect probably related to deranged phosphate transport in the renal tubule.

Effect of cyclophosphamide and levan treatment on bone marrow and peripheral blood cells in B16-F10 melanoma-bearing mice.

Immunotherapeutic agents have often been found to provoke opposite effects on tumor growth--inhibitory or stimulatory--depending on dose, timing or route of administration. The reason for these opposite effects is not yet known. Levan (polyfructose), an immunomodulatory polysaccharide, has been found to exert opposite effects on the growth of the F10 variant of B16 melanoma. Low doses inhibit and high doses enhance the growth of this tumor. Cyclophosphamide (CY) augments the inhibitory effect of the polysaccharide. In order to elucidate the mechanism of these opposite effects, we tried to determine the changes induced by levan at inhibitory and stimulatory doses, alone or in conjunction with CY, on the lymphatic and hematopoietic systems of B16-F10 melanoma-bearing mice. In a previous study we reported the effect of these treatments on the morphology of spleen and lymph nodes (Leibovici, Kopel, Siegal & Gal-Mor (1986). Int. J. Immunopharmac., 8, 391). In the present study, we examined the effect of the treatments on bone marrow and peripheral blood composition. The growth of the tumor itself, as well as the various treatments, induced very marked changes in both bone marrow and blood. Tumor inoculation produced a sharp leukopenia and anemia followed by a restoration of both white and red blood cells. In the bone marrow, the tumor caused a gradual decrease in lymphocyte number. CY accentuated the severe leukopenia caused by the tumor. Lymphocyte depletion was prolonged, while restoration of granulocytes was achieved by day 7. A similar pattern of changes was observed in the bone marrow. With levan, opposite effects were observed in blood and bone marrow with the two doses in relation to the number of the cells of the lymphoid and myeloid lines: while 0.1 mg (tumor inhibitory) doses caused a more active restoration of lymphocytes as compared to 10 mg (tumor stimulatory) doses, an opposite effect was seen on the myeloid series--the high dose induced a more pronounced granulocytosis than the low dose. In the combined treatment, the low levan dose accelerated lymphocyte restoration in bone marrow compared to CY, while the high dose delayed the recovery of these cells. The results of the present study in conjunction with our previous study may explain the basis of the intriguing tumor inhibitory-stimulatory effects of some immunomodulators. Moderate increases in myeloid cell series appear to favor tumor inhibition and high increases favor tumor stimulation. In addition, the results of this study suggest that a regulatory relation might exist between the proliferation of the lymphoid and myeloid cell series.

Oral calcitriol and calcium: efficient therapy for uremic hyperparathyroidism.

Therapy with orally administered calcitriol often does not adequately control the biochemical manifestations of secondary hyperparathyroidism in uremic patients. This may be due to inadequate serum concentrations of 1.25(OH)2 vitamin D and/or to insufficient dietary calcium supplementation. In the present study, therefore, we examined the effect on parathyroid function of calcitriol and calcium carbonate, administered orally, in doses sufficient to normalize the serum 1.25(OH)2 vitamin D and calcium concentrations. After nine months of combined therapy, marked suppression of immunoreactive PTH occurred in the absence of hypercalcemia. Furthermore, prolonged therapy resulted in additional suppression of the PTH concentrations comparable in magnitude to that reported following intravenous calcitriol therapy and was associated with a mild degree of hypercalcemia similar to that which occurs with intravenous therapy. Euparathyroidism was achieved in 25% of the patients by 15 months of treatment. In conclusion, secondary hyperparathyroidism can be effectively controlled with combined oral therapy without significant hypercalcemia in selected patients with end-stage renal failure. This salutary effect may result from direct actions of 1.25(OH)2D on the parathyroid gland and/or gastrointestinal tract, or from an overall action of combined treatment to restore calcium homeostasis.

Bone marrow and peripheral blood modifications in C57BL mice administered with cyclophosphamide and levan.

The effects of cyclophosphamide (CY) and levan at low (0.1 mg) and high (10 mg) doses (previously found to inhibit and stimulate, respectively, B16 melanoma growth) were studied. in single and combined administration, on the blood and bone marrow of C57BL mice. Very marked changes in the cellular composition of blood and bone marrow were induced by the various treatments. CY caused a sharp depletion of leukocytes in blood and bone marrow followed by a restoration of granulocytes while lymphocytes remained low. Levan caused a sharp dose-dependent depletion in bone marrow lymphocytes. Blood lymphocytes were not affected, however, by the polysaccharide. With the high levan dose, after a temporary granulocytopenia and monocytopenia, prominent granulocytosis was observed. While CY affected equally the different types of cells, levan decreased the number of lymphocytes and erythroblasts to a greater degree than the number of granulocytes. In the combined CY-levan treatments, the low levan dose generally attenuated the suppressive effect of CY, while the high concentration aggravated it.

Role of renal prostaglandins in bile-induced diuresis in the dog.

To clarify the possible role of renal prostaglandins (PGs) in the phenomenon of bile-induced diuresis in the dog, we studied the effect of in situ unilateral infusion of bile on kidney function and PGs excretion, before and after PG-synthetase inhibitor administration in anesthetized dogs. The contralateral intact kidney served as control. In the first group of 6 dogs, infusion of bile diluted 1:20 resulted in a significant increase in urinary flow (117%; p less than 0.05), sodium (61%; p less than 0.01), potassium (26%; p less than 0.05), PGE2 (240%; p less than 0.05) and PGF2 alpha (137%; p less than 0.05) excretion rates. Further significant increases in urinary flow, sodium and PGE2 excretion rates were noted with infusion of bile diluted 1:10. All parameters returned to basal levels upon cessation of bile infusion. Significant linear correlation coefficients (p less than 0.005) were found between PGE2 excretion rates and urinary flow (r = 0.72), sodium (r = 0.91) and potassium (r = 0.88) excretion rates. In a second group of 6 dogs, intravenous administration of PG-synthetase inhibitor abolished the increase in renal PGs excretion and the increments in the rates of urinary flow and solute excretion in response to bile infusion. These findings support the notion that the acute diuretic and natriuretic effect of bile, and presumably that of cholemia is mediated, in part, through stimulation of renal PGs synthesis.

Post-obstructive urinary concentrating defect. A case study in the role of prostaglandins.

A child with post-obstructive urinary concentrating defect was studied for the possible pathophysiological role of prostaglandins and an eventual therapeutic approach. Increased urinary excretion of prostaglandins was corrected by indomethacin, with resultant increased nephrogenous cyclic AMP and partial improvement in the concentrating defect. The addition of a thiazide restored urinary concentration. These results add clinical support to the conception of the important role of prostaglandins in the mechanism of post-obstructive hyposthenuria. This therapeutic regimen is advocated for prolonged post-obstructive concentrating defect.