The eyes have it: cataract surgery and changing patterns of outpatient surgery.
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Age Distribution↗
Biomedical subjects
R G Evans
Publications and source records attributed to R G Evans.
Going for the gold: the redistributive agenda behind market-based health care reform.
Political conflict over the respective roles of the state and the market in health care has a long history. Current interest in market approaches represents the resurgence of ideas and arguments that have been promoted with varying intensity throughout this century. (In practice, advocates have never wanted a truly competitive market, but rather one managed by and for particular private interests). Yet international experience over the last forty years has demonstrated that greater reliance on the market is associated with inferior system performance--inequity, inefficiency, high cost, and public dissatisfaction. The United States is the leading example. So why is this issue back again? Because market mechanisms yield distributional advantages for particular influential groups. (1) A more costly health care system yields higher prices and incomes for suppliers--physicians, drug companies, and private insurers. (2) Private payment distributes overall system costs according to use (or expected use) of services, costing wealthier and healthier people less than finance from (income-related) taxation. (3) Wealthy and unhealthy people can purchase (real or perceived) better access or quality for themselves, without having to support a similar standard for others. Thus there is, and always has been, a natural alliance of economic interest between service providers and upper-income citizens to support shifting health financing from public to private sources. Analytic arguments for the potential superiority of hypothetical competitive markets are simply one of the rhetorical forms through which this permanent conflict of economic interest is expressed in political debate.
Australia↗
Low dose angiotensin II infusions into the renal artery induce chronic hypertension in conscious dogs.
Angiotensin II was infused at 0.5 ng/kg/min either directly into the left renal artery (n = 5) or intravenously (n = 4) for 28 days in conscious dogs. Renal artery infusion of angiotensin II had no significant effect on mean arterial pressure after 1 and 24 h, but pressure had increased by 12 +/- 2, 12 +/- 4, 8 +/- 3 and 13 +/- 3 mmHg on days 7, 14, 21 and 28, respectively, during infusion. Renal blood flow decreased significantly at 24 hours (p = 0.02) but was not significantly reduced subsequently. Over days 7-28, central venous pressure and haematocrit rose significantly but body weight did not change significantly. During intravenous infusion of angiotensin II, arterial pressure increased (5 +/- 4, 7 +/- 5 and 5 +/- 3 mmHg on days 7, 14 and 21, respectively), body weight rose and haematocrit fell significantly, but central venous pressure did not change. Thus, angiotensin II infused into the renal artery, at a dose which had no initial pressor effect, produced chronic, stable hypertension, with equivocal evidence of renal fluid retention. We conclude that elevated levels of angiotensin II in the kidney alone can cause chronic hypertension.
Angiotensin II↗
Mark Pauly on welfare economics: normative rabbits from positive hats.
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Decision Making, Organizational↗
Evidence for a renomedullary vasodepressor hormone.
1. Recent physiological experiments have established that increasing the perfusion pressure of the kidney causes the release of vasodepressor substance from the renal medulla. 2. The substance is not a platelet activating factor, a prostaglandin or nitric oxide and the vasodepressor response to increased renal perfusion is not due simply to inhibition of renin release. 3. The mechanisms by which the renomedullary vasodepressor substance lowers arterial pressure remain to be determined. Sympathoinhibition may account for part of the response, but the hypotension still occurs in autonomic ganglion blocked animals. 4. The source of substance appears to be the renomedullary interstitial cells, though the control of the production and release of the substance remain to be determined. 5. The substance may be a lipid but it is yet to be fully isolated and identified. 6. The threshold for release of the substance appears to be close to normal resting arterial blood pressure. 7. Despite strong evidence that the renal medulla releases a vasodepressor hormone in response to increased renal perfusion pressure, much is still to be determined regarding the physiology of this hormone and its involvement in the aetiology of hypertension.
Kidney Medulla↗
Synthetic inhibitors of endopeptidase EC 3.4.24.15: potency and stability in vitro and in vivo.
1. The role of the metalloendopeptidase EC 3.4.24.15 (EP 24.15) in peptide metabolism in vivo is unknown, in part reflecting the lack of a stable enzyme inhibitor. The most commonly used inhibitor, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB, Ki = 16 nM), although selective in vitro, is rapidly degraded in the circulation to cFP-Ala-Ala, an angiotensin converting enzyme (ACE) inhibitor. This metabolite is thought to be generated by neutral endopeptidase (NEP; EC 3.4.24.11), as the Ala-Tyr bond of cFP-AAY-pAB is cleaved by NEP in vitro. In the present study, we have examined the role of NEP in the metabolism of cFP-AAY-pAB in vivo, and have tested a series of inhibitor analogues, substituted at the second alanine, for both potency and stability relative to the parent compound. 2. Analogues were screened for inhibition of fluorescent substrate cleavage by recombinant rat testes EP 24.15. D-Ala or Asp substitution abolished inhibitory activity, while Val-, Ser- and Leu-substituted analogues retained activity, albeit at a reduced potency. A relative potency order of Ala (1) > Val (0.3) > Ser (0.16) > Leu (0.06) was observed. Resistance to cleavage by NEP was assessed by incubation of the analogues with rabbit kidney membranes. The parent compound was readily degraded, but the analogues were twice (Ser) and greater than 10 fold (Leu and Val) more resistant to cleavage. 3. Metabolism of cFP-AAY-pAB and the Val-substituted analogue was also examined in conscious rabbits. A bolus injection of cFP-AAY-pAB (5 mg kg-1, i.v.) significantly reduced the blood pressure response to angiotensin I, indicating ACE inhibition. Pretreatment with NEP inhibitors, SCH 39370 or phosphoramidon, slowed the loss of cFP-AAY-pAB from the plasma, but did not prevent inhibition of ACE. Injection of 1 mg kg-1 inhibitor resulted in plasma concentrations at 10 s of 23.5 microM (cFP-AAY-pAB) and 18.0 microM (cFP-AVY-pAB), which fell 100 fold over 5 min. Co-injection of 125I-labelled inhibitor revealed that 80-85% of the radioactivity had disappeared from the circulation within 5 min, and h.p.l.c. analysis demonstrated that only 25-30% of the radiolabel remained as intact inhibitor at this time. Both analogues were cleared from the circulation at the same rate, and both inhibitors blunted the pressor response to angiotensin I, indicative of ACE inhibition. 4. These results suggest that both NEP and other clearance/degradation mechanisms severely limit the usefulness of peptide-based inhibitors such as cFP-AAY-pAB. To examine further EP 24.15 function in vivo, more stable inhibitors, preferably non-peptide, must be developed, for which these peptide-based inhibitors may serve as useful molecular templates.
Analysis of Variance↗
Role of bradykinin receptors in the renal effects of inhibition of angiotensin converting enzyme and endopeptidases 24.11 and 24.15 in conscious rabbits.
1. We tested the effects on systemic haemodynamics and renal function, of inhibition of endopeptidase (EP) 24.15 (E.C. 3.4.24.15), in conscious uninephrectomized rabbits in which the activities of angiotensin converting enzyme (ACE, E.C. 3.4.15.1) and neutral endopeptidase (EP 24.11, E.C. 3.4.24.11) were already inhibited. To test the role of bradykinin B2-receptors in mediating the effects following inhibition of these enzymes, the antagonist Hoe 140 was used. 2. Hoe 140 (0.1 mg kg-1, i.v.) did not affect resting mean arterial pressure or heart rate, but antagonized the depressor effect of right atrial administration of bradykinin. The dose-response curve for bradykinin was shifted more than 1000 fold to the right for more than 4 h. Hoe 140 approximately doubled resting urine flow and increased fractional Na+ excretion from 4.2 to 6.0%; consistent with the hypothesis that it exerts a partial agonist effect on the kidney. 3. Combined inhibition of ACE (captopril; 0.25 mg kg-1 plus 0.2 mg kg-1h-1) and EP 24.11 (SCH 39370; 3 mg kg-1 plus 3 mg kg-1h-1) was followed by a sustained reduction in arterial pressure (-6 +/- 2 mmHg) and increase in heart rate (35 +/- 7 beats min-1). There was a small increase in renal blood flow (by 6.5 +/- 3.2% relative to vehicle-treatment) without a change in glomerular filtration rate, and about a 150% increase in Na+ excretion. Hoe 140 (0.1 mg kg-1, i.v.) pretreatment did not influence the renal effects of captopril and SCH 39370, although it did appear to blunt their hypotensive and tachycardic effects. 4. When EP 24.15 was inhibited with N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB; 5 mg kg-1 plus 3 mg kg-1h-1, i.v.) in rabbits pretreated with captopril and SCH 39370, no changes in systemic haemodynamics or renal function were observed. 5. We concluded that in conscious uninephrectomized rabbits, EP 24.15 does not play a major role in modulating renal function, at least under conditions where ACE and EP 24.11 are already inhibited. In contrast, ACE and/or EP 24.11 do modulate renal function in this model, but their influences are mediated chiefly through metabolism of peptides other than bradykinin.
Angiotensin-Converting Enzyme Inhibitors↗
Long term results of a phase I/II study of aggressive chemotherapy and sequential upper and lower hemibody radiation for patients with extensive stage small cell lung cancer.
BACKGROUND: A Phase I/II study of an aggressive six-drug chemotherapy regimen followed by the use of sequential hemibody radiation therapy as a possible non-cross-resistant systemic treatment was undertaken for patients with extensive stage small cell lung cancer. METHODS: The 20 enrolled patients received 7 cycles of cyclophosphamide-based chemotherapy. The first cycle consisted of cyclophosphamide, doxorubicin, etoposide, vincristine, and lomustine. Subsequent cycles used a regimen of doxorubicin alternating with cisplatin. Thoracic radiation was delivered in a split-course fashion during the first week of chemotherapy cycles 5 and 6 (2000 cGy in five fractions during each week). Prophylactic cranial radiation was delivered in a split-course fashion during the first week of chemotherapy cycles 2 and 3 (1700 cGy in 5 fractions during each week). After the 7 cycles, patients received 600 cGy upper hemibody radiation followed by 800 cGy lower hemibody radiation. RESULTS: Nineteen of 20 patients were evaluable for toxicity and response to treatment. Hematologic toxicity accounted for treatment delays or decreased doses in 16 of 19 patients. Thirteen patients completed the initial 7 cycles; progressive disease was the only reason for discontinuing treatment. Two patients had fatal hematologic complications after lower hemibody radiation. Three patients had severe or greater peripheral neurologic toxicity, two had severe central neurologic toxicity, and one had severe cardiac toxicity. Of 19 patients, 9 achieved a complete response; median survival was 11.5 months. Five-year progression free survival and 5-year overall survival were 27% and 16%, respectively. CONCLUSIONS: This aggressive regimen is feasible for patients with extensive stage small cell lung cancer; however, hematologic-related mortality after lower hemibody radiation suggests that future investigations should be initiated at lower initial doses of lower hemibody radiation. Long term survival of the patients suggests that sequential hemibody radiation treatment warrants further investigation.
Adult↗
Alpha 2 adrenoceptor- and imidazoline-preferring binding sites in the dog kidney.
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Adrenergic alpha-2 Receptor Agonists↗
Manufacturing consensus, marketing truth: guidelines for economic evaluation.
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Drug Costs↗
Audit of brachial plexus neuropathy following radiotherapy.
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Brachial Plexus↗
Nitric oxide synthase blockade and renal vascular responses to norepinephrine and endothelin-1 in conscious dogs.
The effects of inhibiting nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NNA) on renal vasoconstrictor responses to intrarenally administered norepinephrine (NE) and endothelin-1 (ET-1) were studied in conscious dogs. NE was infused into the renal artery at 0.02, 0.05, 0.1, and 0.2 micrograms/kg/min (15 min at each rate), with the dogs (n = 5) pretreated with either L-NNA 10 mg/kg intravenously (i.v.) or vehicle (250 mM NaHCO3 solution at 2 ml/kg i.v.) NE produced dose-related decreases in renal blood flow (RBF) and renal vascular conductance that were significantly greater after L-NNA pretreatment than after vehicle. ET-1 was infused intrarenally at 2.7 ng/kg/min for 45 min with the dogs (n = 5) pretreated with either L-NNA 10 mg/kg i.v. or vehicle. ET-1 caused a progressive decrease in RBF and renal vascular conductance. In contrast to the results with NE, RBF and renal vascular conductance decreased significantly less in response to ET when the dogs were pretreated with L-NNA as compared with pretreatment with vehicle. Therefore, blockade of NO synthase augmented NE-induced but not ET-induced renal vasoconstriction. The results therefore suggest that NO may act to lessen the renal vascular effects of NE, but this effect does not appear to be generalised to all vasoconstrictors.
Animals↗
Effects of fenoxycarb on development and reproduction of the oriental cockroach, Blatta orientalis.
In a laboratory study, groups of third-instar Blatta orientalis nymphs were reared to adulthood in arenas containing fenoxycarb (48 mg a.i./m2) treated ceramic or plywood tiles. The reproductive capacity of the emergent adults was assessed by pairing each individual with two untreated individuals of the opposite sex. Oothecal production, oothecal hatch and the numbers of nymphs emergent from each hatched ootheca were monitored. Exposure to 1-day-old deposits of fenoxycarb reduced adult emergence by 45-75% in comparison with an untreated control treatment. Substantial (> 40%) mortality also resulted when nymphs were exposed to deposits up to 3 months old on plywood and up to 6 months old on ceramic. Exposure to fenoxycarb significantly extended the time taken to reach adulthood of males contacting 6-month-old deposits on both surfaces, and of females contacting 1-year-old deposits on ceramic. Adult females exposed as nymphs to fenoxycarb were unable to produce oothecae, except one female laid a non-viable ootheca. Untreated females paired with treated males produced large numbers of oothecae of normal appearance but very low viability, with only 0-7.1% hatching. With marked effects on both development and reproduction in B.orientalis, fenoxycarb is a promising agent for control of this species.
Animals↗
Effects of NG-nitro-L-arginine on pressure natriuresis in anaesthetized rabbits.
1. We tested the effects of blockade of nitric oxide synthesis on renal function under conditions of controlled renal artery pressure. Our hypothesis was that endogenous nitric oxides plays a role in the natriuresis that accompanies increased renal perfusion pressure. We used a novel technique which employed an extracorporeal circuit to produce step changes over a wide range of renal artery pressures in pentobarbitone-anaesthetized rabbits. 2. Rabbits were treated with either NG-nitro-L-arginine (NOLA, 20 mg/kg, i.v.; n = 8) or its vehicle (n = 8). Renal artery pressure was set (by adjusting the extracorporeal circuit) at 65, 80, 95, 110 and then 130 mmHg respectively, at the beginning of each of five 30 min experimental periods. 3. NOLA treatment caused profound renal vasoconstriction that was largely independent of the level of renal artery pressure, renal blood flow being 35-43% lower in NOLA-treated than in vehicle-treated rabbits across the range of renal artery pressures tested (P = 0.002). NOLA treatment increased filtration fraction (P = 0.02), and tended to reduce glomerular filtration rate (P = 0.09). 4. NOLA-treatment affected sodium excretion in a manner dependent on the legel of renal artery pressure, with the slope of the relationship between sodium excretion and renal artery pressure being lower in NOLA-treated than in vehicle-treated rabbits (P = 0.006). 5. These data provide direct evidence that in anaesthetized rabbits endogenous nitric oxide (i) tonically dilates the renal vasculature across a wide range of renal perfusion pressures, and (ii) enhances sodium excretion to a progressively greater degree as renal artery pressure is increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Renal medullary antihypertensive mechanisms.
1. Increasing renal perfusion pressure, using an extracorporeal circuit in rabbits and dogs, causes release from the kidney of a vasodepressor substance. 2. The hypotensive response occurs in denervated kidneys, and it is not due to platelet activating factor, nitric oxide, prostanoids or suppression of renin release. 3. In the rabbit, the pressure threshold for release of the hypotensive substance appears to be slightly above normal resting pressures. 4. The source of the hypotensive substance is medullary, since the hypotensive response to increased renal perfusion pressure is abolished in dogs and rabbits whose medullae are damaged by bromoethylamine treatment. 5. The chemical nature of the hypotensive substance remains unknown. 6. Thus the renal medulla appears to possess a hypotensive hormone, released in response to elevation of renal perfusion pressure. Many aspects of the physiology and pathology of the substance and its significance in blood pressure regulation remain to be determined.
Animals↗
Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor.
1. We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2. In conscious rabbits, cFP (5 mg kg-1, i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-1), and inhibited the pressor response to right atrial angiotensin I (10-100 ng kg-1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg-1h-1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3. In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg-1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 micrograms kg-1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4. CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 microM respectively), and inhibited rat plasma ACE activity (KI = 2.4 microM). Addition of phosphoramidon (10 microM), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems. 5. Taken together these findings suggest that the actions of cFP in vivo are attributable to inhibition of ACE rather than EP 24.15. Given that cFP is a poor inhibitor of ACE in the presence of phosphoramidon in vitro, it is likely that cFP is cleaved by a phosphoramidon-sensitive metallopeptidase in vivo to liberate N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala, a potent ACE inhibitor.
Acetylcholine↗
Renal effects of infusion of rilmenidine and guanabenz in conscious dogs: contribution of peripheral and central nervous system alpha 2-adrenoceptors.
1. We tested the renal effects of the alpha 2-adrenoceptor agonists, rilmenidine and guanabenz and the antagonists, 2-methoxyidazoxan and idazoxan, in conscious dogs. Our aim was to test the hypothesis that putative imidazoline (I) receptors influence renal function. We reasoned that since rilmenidine and guanabenz are selective for I1- and I2-binding sites respectively, an influence of one of these receptive sites on renal function would be reflected in qualitative differences between the effects of these agents. Moreover, effects mediated by putative I-receptors should be relatively resistant to antagonism by the selective alpha 2-adrenoceptor antagonist, 2-methoxyidazoxan. Since the effects of these drugs on renal function could be mediated in the central nervous system or periphery, the dogs were studied under both normal and ganglion-blocked conditions. 2. In dogs with intact autonomic reflexes, 2-methoxyidazoxan (15 micrograms kg-1 plus 0.6 micrograms kg-1 min-1) produced effects consistent with a generalized increase in sympathetic drive, including increases in mean arterial pressure and plasma renin activity, and a reduction in sodium excretion. In ganglion-blocked dogs, 2-methoxyidazoxan reduced sodium excretion but had no discernible effect on systemic or renal haemodynamics. We conclude that an alpha 2-adrenoceptor-mediated mechanism in the central nervous system tonically inhibits sympathetic drive in the conscious dog. 3. In ganglion-blocked dogs idazoxan (3-300 micrograms kg-1) dose-dependently increased arterial pressure. This was not abolished by concomitant administration of 2-methoxyidazoxan (0.3-30 micrograms kg-1). The pressor effect of idazoxan is therefore probably mediated by an agonist action at alpha 1-adrenoceptors. 4. The effects of infusions of rilmenidine (0.1-1.0 mg kg-1) and guanabenz (10-100 micrograms kg-1) were indistinguishable. They comprised dose-dependent increases in mean arterial pressure, urine excretion, and glomerular filtration rate (the latter in ganglion blocked dogs only), and dose-dependent reductions in heart rate, renal blood flow and sodium excretion (only in dogs with intact autonomic reflexes). All of these effects were antagonized by 2-methoxyidazoxan. 5. We conclude that the renal effects of rilmenidine and guanabenz infusions in conscious dogs are predominantly, if not completely, attributable to activation of alpha 2-adrenoceptors. Our results do not support the hypothesis that putative I-receptors contribute towards the renal effects of these agents.
Adrenergic alpha-Agonists↗
Effects of ovarian steroids on hypothalamic opioid receptor subtypes in ovariectomized ewes: regional changes in density and affinity.
The negative feedback regulation by ovarian steroids of luteinizing hormone secretion may be partially mediated by a hypothalamic endogenous opioid mechanism. This could be affected by ovarian steroid-regulated changes in hypothalamic opioid receptor binding mechanisms. In this report we show that in the presence of blocking concentrations of site-selective opioid analogues, [3H] diprenorphin homogeneously labelled mu, delta or kappa receptor subtypes respectively. Using this receptor binding model, we characterized each opioid receptor subtype in the hypothalamic preoptic area and medio-basal hypothalamus of ovariectomized (OVX) and OVX plus progesterone- or oestradiol-17 beta (OE2)-treated ewes. In the preoptic area, progesterone treatment did not influence the affinity or capacity of delta or kappa receptor binding sites, but significantly reduced mu receptor subtype content (20% less than control) with no statistically significant change in affinity. There was no effect of OE2 on either the affinity or capacity of each opioid receptor subtype in this area. In the mediobasal hypothalamus, progesterone treatment significantly decreased delta subtype receptor affinity (22 +/- 11 nM vs control 7 +/- 2 nM) and increased binding capacity (78 +/- 9 fmol/mg protein vs control 37 +/- 16 fmol/mg protein). OE2 treatment had a similar, though more profound effect on affinity (51 +/- 17 nM) and binding capacity (139 +/- 26 fmol/mg protein) at the delta receptor binding site. There were no significant changes in the affinity or capacity of mu or kappa binding sites in the medio-basal hypothalamus. These results indicate that steroid hormones modulate hypothalamic opioid receptors in the OVX ewe in a receptor subtype- and region-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗