A pilot study of the beneficial effects of amantadine in the treatment of painful diabetic peripheral neuropathy.

BACKGROUND: Current symptomatic treatments for painful peripheral neuropathy in diabetes have variable efficacy in individual patients. Amongst other chemical transmitters involved in pain reception, the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor is involved in nociception. Amantadine was recently shown to act as a non-competitive antagonist of NMDA and may be effective in the treatment of neuropathic pain in patients with cancer. We have looked at the benefit of amantadine infusion in diabetic patients with painful peripheral neuropathy. METHODS: Seventeen patients with diabetes (nine men) completed this double-blind randomized crossover placebo-controlled trial of intravenous amantadine. The average age was 58.4 (sd 11) years, with duration of diabetes of 21.1 (8.7) years and duration of painful peripheral neuropathy symptoms of 29.1 (24) months. All analgesics except paracetamol were stopped for 4 weeks prior to the study. Infusions were carried out on a weekly basis with amantadine being administered intravenously as a single 200-mg infusion. The Neuropathy Symptom Score (NSS), together with visual analogue scales, were used to assess current pain intensity (VAS-P) pre-therapy and 1 week later VAS-P was repeated together with a visual analogue scale used to assess relief in pain (VAS-R) and the Physicians Global Evaluation (PGE) score used to assess response to therapy. RESULTS: Pre-therapy, the NSS was 6.8 (6.3-7.4) at baseline, remaining unchanged at 6.6 (5.8-7.4) after placebo (P = 0.33), but fell to 4.6 (3.4-5.8) after amantadine (P = 0.003 vs. baseline and P = 0.02 vs. placebo). The baseline perception of pain was scored as 7.8 cm (7.3-8.3), with no difference following placebo, at 8.2 cm (7.7-8.6) (P = 0.34), but following amantadine it fell to 6.2 cm (4.9-7.8) (P = 0.01 compared with pre-therapy, P = 0.003 compared with placebo). The perception of relief from pain following placebo was only 0.2 (-0.2 to +0.6) but following amantadine was 10-fold better at 1.9 (0.8-3.1) (P = 0.016). The PGE assessment of pain relief was -0.3 (-0.5 to 0) for placebo and following amantadine was 0.8 (0.1-1.5) (P = 0.006). CONCLUSIONS: Our study has shown that intravenous amantadine is beneficial in reducing the pain of painful peripheral neuropathy, with an effect sustained for at least 1 week after an infusion.

Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice.

AIMS: To determine whether metformin pretreatment has beneficial effects in clomiphene resistant infertile women with polycystic ovary syndrome (PCOS) in an infertility clinic. METHODS: This was a randomized placebo controlled double-blind crossover study of 3 months metformin (1500 mg day-1)/placebo, followed by 3 months metformin/placebo together with clomiphene (50-100 mg for 5 days) for three cycles in clomiphene resistant women with PCOS. The primary outcomes were restoration of spontaneous menses, ovulation induction (spontaneous or clomiphene induced) and pregnancy. Secondary endpoints were changes in biochemical parameters related to androgens and insulin. RESULTS: Twelve women completed the metformin arm and 14 the placebo arm. Spontaneous menstruation resumed in five metformin treated patients and in six placebo treated women, P=0.63. No women given metformin spontaneously ovulated, although one patient given placebo did, P=0.30. There was no difference in the efficacy of clomiphene between the two groups with ovulation being induced in five (out of 12) metformin treated women and four (out of 14) placebo treated women, P=0.63. Pregnancy occurred in three (out of 12) women given metformin and two (out of 14) women given placebo, P=0.59. CONCLUSIONS: Metformin is not always beneficial when given to clomiphene resistant infertile women with PCOS in clinical practice.

Analysis of 44,279 blood glucose estimations in relation to outcomes in 80 pregnant diabetic women.

A retrospective study was conducted to assess glycaemic control in relation to pregnancy outcomes in pre-existing and gestational diabetics. Computerised blood glucose records from 47 pre-existing diabetic patients and 33 gestational diabetics were collected prospectively and then analysed retrospectively in relation to pregnancy outcomes. There were two spontaneous miscarriages from the pre-existing diabetic cohort. A total of 44,279 individual blood glucose estimations were made. The mean fasting glucose for pre-existing diabetic patients fell significantly throughout pregnancy, being 7.7+/-2.1, 7.2+/-3.1 and 6.5+/-2.4 mmol/l, respectively, for trimesters 1,2 and 3 (P<0.01). The mean post-prandial glucose for each trimester were 8.9+/-2.0, 8.6+/-1.6 and 8.2+/-1.2 mmol/l (P<0.01). The HbAlc for pre-existing diabetic patients for each trimester was 7.5+/-1.4%, 6.1+/-1.0% and 5.9+/-0.7%, respectively. Gestational diabetic patients had a mean fasting glucose of 5.6+/-1.5 mmol/l and a mean post-prandial glucose of 8.0+/-2.1 mmol/l during trimester 3. Home glucose monitoring correlated reasonably well with first trimester HbA1c (r2=0.43, P<0.001), but this relationship became less valid as pregnancy progressed. The mean gestation at delivery was 37 weeks, although 30% of women were delivered between 34 and 37 weeks and 8% delivered before 34 weeks. Labour was induced in 49% of patients and the overall caesarean section rate was 58%. The mean birth weight for pre-existing diabetic patients was 3479 g (1410-5000 g) and for women with gestational diabetes was 3605 g (1890-5920 g). For pre-existing diabetic patients HbA1c did not correlate with birth weight; however, home blood glucose data from trimester 2 did correlate (r2=0.15, P <0.005) and there appeared to be stronger relationship with trimester 3 data (r2=0.24, P <0.005). There was no association between trimester 3 glucose data and birth weight in the gestational cohort. The babies born to pre-existing diabetic mothers had a high incidence of admission to a neonatal unit and over 50% of the babies had proven hypoglycaemia. Our present computerised system for home blood glucose monitoring has shown that for pre-existing diabetes patients but not gestational diabetic patients, glycaemic control in the second and third trimester influences birth weight. The current degree of glycaemic control in the mothers did not prevent a high rate of neonatal hypoglycaemia.

Non-dipping circadian blood pressure and renal impairment are associated with increased mortality in diabetes mellitus.

AIMS: To assess the relevance of circadian blood pressure variation to future morbidity and mortality in patients with diabetes mellitus. METHODS: A retrospective descriptive 4 year follow-up study of data collected after ambulatory blood pressure monitoring in a clinic setting. RESULTS: Seventy-five patients (46 male; 29 female) of whom 41 % had Type 1 diabetes and 59% Type 2 were followed up for a median of 42 months (11-56). The median creatinine for the whole group at baseline was 101 (56-501) micromol/l. The median circadian blood pressures for the total study population were 147 (110-194)/87 (66-109) mmHg during daytime and 132 (86-190)/77 (50-122) mmHg during night-time. Half of the patients exhibited a fall in night-time pressures to 10% lower than daytime pressures (dippers). Dippers were younger, 47 (32-75) years, than non-dippers, 57 (35-79) years, P = 0.03. Over time, dippers had a lower mortality than non-dippers, with 8% deaths in the cohort of dippers, 26% deaths in the cohort of non-dippers, P = 0.04. Cox regression analysis revealed significant contributions from age, duration of diabetes and baseline renal function to subsequent mortality in non-dippers. Analysing current degree of renal impairment and original dipper status together revealed that, of those patients whose creatinine remained normal, 7% of patients whose blood pressure dipped had subsequently died and 10% of non-dipping patients had died; of those patients whose creatinine unequivocally rose, 10% of dipping patients had died and 42% of non-dipping patients had died, P = 0.03 CONCLUSIONS: Loss of circadian variation in blood pressure is associated with an increased mortality rate, regardless of diabetes type. The combination of non-dipping and subsequent renal impairment leads to the highest mortality rate. The study suggests a role for ambulatory blood pressure monitoring in day-to-day clinical practice to select patients with nephropathy who are at greatest risk, in an effort to alter outcome.

Patient education in thyrotoxicosis.

The aim of the study was to assess the need for a thyrotoxicosis patient education programme and to evaluate a group education session. Patients with thyrotoxicosis were sent questionnaires on knowledge, satisfaction and mood. Patients showed limited knowledge about thyrotoxicosis. Newly diagnosed patients did not differ significantly from those who had been diagnosed more than a year previously. There was no significant relation between knowledge and other measures, but satisfaction was significantly correlated with mood. A further 82 patients were recruited to evaluate a group education session. Patients were randomly allocated either to receive a leaflet about thyrotoxicosis or to attend a group education session in addition to a leaflet. Comparison of the two groups showed a significant difference in anxiety (p = 0.02) but no significant difference in knowledge. Only 9 of 31 patients attended the group education session, and no significant differences were found between those who did and did not attend. Patients in the trial who all received leaflets, were more knowledgeable (p = 0.05) and more satisfied (p < 0.05), than those in the initial survey. Patients with thyrotoxicosis have limited knowledge about their condition. The offer of a group education programme had little effect on that knowledge but was associated with a reduction in anxiety. The provision of leaflets alone seemed to improve knowledge and satisfaction compared with no leaflets, but as this was not a randomised comparison, further evaluation is needed.

Further evidence that chronic perindopril treatment maintains neurohormonal suppression but does not lower blood pressure in chronic cardiac failure.

AIMS: Previous studies in heart failure (CHF) after temporary diuretic withdrawal have suggested that perindopril is associated with no first dose hypotension in comparison with other ACE inhibitors (ACEI) or placebo. The aim of this study was to explore further the profile of perindopril during chronic dosing. METHODS: We report the effects of acute and chronic (8 weeks) treatment with the ACE inhibitor perindopril (Per, 2-->4 mg daily) or placebo (P) in a double-blind parallel group study of 24 diuretic treated patients (17M; 67 +/- 8 years, 80 +/- 17 kg) with ischaemic cardiomyopathy (fractional shortening, 19 +/- 5%; radionuclide ejection fraction, 31 +/- 3%). Baseline biochemical, hormonal (ACE, Ang I, Ang II), isotopic renal function (GFR, ERPF, ECFV), pretreatment diuretic dose and heart failure scores were similar between groups. Concomitant cardiac treatments remained unchanged and diuretic withdrawal was not used to introduce treatment. RESULTS: There were no significant effects on electrolytes, liver function tests, serum or erythrocyte magnesium. There was no significant first dose fall in SBP over 6 h) (P, baseline 137 +/- 18; min 115 +/- 16 mmHg; Per, baseline 137 +/- 15; min 118 +/- 17 mmHg). Neither supine nor erect BP was significantly affected by chronic treatment (P, erect baseline 134 +/- 23/76 +/- 10 to 124 +/- 41/74 +/- 10 mmHg; Per, baseline 135 +/- 21/76 +/- 14 to 128 +/- 22/70 +/- 12 mmHg, P=NS). Active treatment was associated with significant ACE inhibition (P, baseline 47 +/- 17 to 43 +/- 17; Per baseline 49 +/- 15 to 14 +/- 7); aldosterone (P, baseline 337 +/- 179 to 375 +/- 306; Per, baseline 335 +/- 357 to 293 +/- 155 pg ml(-1)) and Ang II suppression (P, baseline 9 +/- 9 to 20 +/- 39; Per baseline 10 +/- 9 to 3 +/- 3 pM). Isotopic renal function was unaffected by either treatment. CONCLUSIONS: At this dose (2-4 mg orally) chronic perindopril therapy has no significant effect on blood pressure or renal function. Sustained neurohormonal suppression of ACE and AII occurred without evidence of AII reactivation. A lack of effect on BP at these doses may make perindopril suitable for study in unstable patients with acute HF or useful in those patients where there are concerns over ACEI induced hypotension.

An assessment of blood pressure measurement in a diabetic clinic using random-zero, semi-automated, and 24-hour monitoring.

We have undertaken a randomized, observer-blinded comparison of three different methods of assessing blood pressure in 40 outpatients with hypertension complicating diabetes mellitus: the Hawksley random zero sphygmomanometer (RZS) by two observers using a dual headed stethoscope; the semi-automated Dinamap monitor, and 24-h ambulatory blood pressure monitoring (ABPM) using a Spacelabs 90207. The techniques were compared by plotting the difference against average of readings obtained by combinations of two techniques (RZS observer 1 vs 2; RZS (mean observer 1 and 2) vs Dinamap; RZS (mean observer 1 and 2) vs daytime ABPM; and Dinamap vs daytime ABPM). There was good agreement of readings with RZS, observers 1 and 2 and RZS with Dinamap and daytime ABPM. When the three methods were used to classify blood pressure control according to BDA criteria, it was found that they produced equivalent results and although mean systolic pressures appeared lower with ABPM this did not reach statistical significance. Overall control of systolic blood pressure was classified as unsatisfactory in 82% of patients, diastolic blood pressure was unsatisfactory in 55%. Fifty-five percent were determined to be nocturnal 'non-dippers' by ABPM. They were older: median age 62.9 (range 35.9-83.5) years compared to 48.2 (32.4-70.0) years for 'dippers' (p<0.05). Thirteen of the 18 patients who did dip overnight had creatinines within the normal laboratory range, whereas only 6 of 22 'non-dippers' had normal creatinines (median 91 (56-768) micromol l(-1) for 'dippers' vs 166 (76-479) micromol l(-1) for 'non-dippers', p < 0.001). Nineteen of the 29 males studied were 'non-dippers' compared with only 4 out of 11 females (p < 0.001). There was no association between dipper status, duration or type of diabetes or presence of proteinuria.

A neurological complication of inferior petrosal sinus sampling during investigation for Cushing's disease: a case report.

A 45 year old woman with hirsutism was found to have classic biochemical features of ACTH dependent Cushing's disease, with partial cortisol suppression in response to dexamethasone. As no pituitary adenoma could be visualised by CT or MRI, she proceeded to bilateral simultaneous inferior petrosal sinus sampling before possible surgery. During the course of this procedure she had a stroke affecting the brainstem at the level of the pontocerebellar junction. This complication of petrosal sinus sampling has been previously described but is not widely recognised; the procedure should only be undertaken when results of less invasive tests are equivocal.

Spontaneous hypoglycaemia in a noninsulin-dependent diabetes mellitus patient with disseminated pancreatic carcinoma.

A 52-year-old-woman with non-insulin-dependent diabetes mellitus developed carcinoma of the pancreas and had a Whipple's resection performed. She required pancreatic exocrine supplements and insulin post-operatively. Five years later metastatic disease became apparent, and was accompanied by episodic spontaneous hypoglycaemia necessitating the cessation of insulin therapy. Hormonal analysis was performed, off insulin, at a time of hypoglycaemia (glucose 0.9 mmol l-1) and showed negligible insulin concentrations (< 2 mU l-1) but raised IGF-II together with low IGF-I concentrations (1.85 and 0.1 U ml-1, respectively). The association between diabetes and pancreatic carcinoma, and the pathogenesis of non-islet cell tumour induced hypoglycaemia (NICTH) are discussed.

Long-term follow-up of patients with hyperprolactinaemia.

AIM: To determine the frequency with which hyperprolactinaemic illness tends to resolve with time. STUDY DESIGN: A retrospective case-notes review from a specialist endocrine unit in a provincial teaching hospital and tertiary referral centre. PATIENTS: Seventy women with hyperprolactinaemia referred to the unit in the 15 year period between May 1979 and May 1994. All those with a non-pituitary cause or with macroadenoma had been excluded, as were those who did not have high-resolution imaging, or who were on treatment at the time of referral. INTERVENTION: Intermittent course of treatment with dopamine receptor agonists according to individual need. ENDPOINTS: Latest serum PRL concentration in those who had discontinued treatment, and whether serum PRL tended to be lower in any particular group. RESULTS: There was a significant fall in median PRL concentration from 2000 (714-8000) to 1000 mU/l (220-5600) in the 31 women who had discontinued therapy (P < 0.0005), and serum PRL was normal (< 700 mU/l) in 11 of them. Serum PRL also fell to normal in three of ten women who had no treatment at all. Final PRL concentration was normal in 35% of women who had had at least one pregnancy during the period of follow-up compared to 14% who had not (P < 0.05). CONCLUSIONS: These data confirm the findings of others that hyperprolactinaemia will prove self-limiting in up to one-third of women, and that pregnancy may be one factor which triggers a return to normal function.

Age related changes in glycated haemoglobin in patients with insulin-dependent diabetes mellitus.

A computerized diabetes register was used retrospectively to define trends in HbA1 and blood glucose with increasing age, using a population of patients with insulin-dependent diabetes. A total of 1874 patients provided 11,776 results for analysis between 1982 and 1993. Mean HbA1 rose progressively between ages 10 and 16 years from 9.8% +/- 2.4 (SD) to 10.6% +/- 2.7 at 12, 11.7% +/- 3.1 at 14 and 12.2% +/- 3.2 at 16 years. Mean HbA1 then fell steadily until it reached a nadir of 10.2% +/- 2.8 at 27 years. There followed a gradual deterioration in control each decade: 10.2% +/- 2.9 at 30 years, 10.4% +/- 2.8 at 40, 10.9% +/- 2.6 at 50 and 10.8% +/- 2.7 at 60 years (r2 = 0.56). Glycaemic control was worse in females than in males: HbA1 area under curve between the ages of 10 and 70 years being 6.1% higher (p < 0.0001). This study confirms the clinical impression of worsening control during teenage years but provides evidence of previously unrecognized trends in later life. Nevertheless, a continuing improvement in glycaemic control between 1982 and 1993 was evident in all age groups.

Autonomous nodular hyperplasia of the adrenal cortex: tertiary hypercortisolism?

Two cases of Cushing's syndrome are reported in which apparently autonomous adrenal adenomata were associated with the presence of pituitary tumours. In one case the patient was apparently cured by unilateral adrenalectomy, although she was noted to have radiological evidence of an intrasellar tumour; serum cortisol was not suppressed by dexamethasone and ACTH was undetectable. Serum ACTH in the second case was initially 31 ng/l but became undetectable during the course of investigation. Transsphenoidal removal of a corticotroph adenoma did not affect serum cortisol and she proceeded to unilateral adrenalectomy. The pathogenesis of autonomous macronodular hyperplasia is discussed, as well as the options for management.

Cyclosporin-induced renal vasoconstriction is augmented by frusemide and by angiotensin II in humans.

OBJECTIVE: To investigate the role of the renin-angiotensin-aldosterone system as a homoeostatic mechanism by examining whether mild activation of the renin-angiotensin-aldosterone system could enhance cyclosporin-induced renal vasoconstriction and hypertension. METHODS: We artificially activated the renin-angiotensin-aldosterone system by two means: by pretreatment with frusemide (40 mg/day orally for 2 days) and by administering exogenous angiotensin II (1 ng/kg per min intravenously). In both cases the levels of renin-angiotensin-aldosterone system activation achieved did not by themselves alter renal blood flow, glomerular filtration rate or blood pressure. We then examined the effect of cyclosporin (10 mg/kg twice a day orally) in the presence of the activated renin-angiotensin-aldosterone system in normal humans. RESULTS: Cyclosporin alone acutely altered neither glomerular filtration rate (760 versus 734ml, NS; area under the curve for placebo versus cyclosporin) nor effective renal plasma flow (4,163 versus 3,915 ml, NS; area under the curve for placebo versus cyclosporin). Co-administration of exogenous angiotensin II with cyclosporin induced a fall in effective renal plasma flow from baseline but no change in glomerular filtration rate. Frusemide pretreatment together with cyclosporin administration induced a fall in glomerular filtration rate and a fall in effective renal plasma flow. Neither exogenous angiotensin II nor frusemide pretreatment influenced the blood pressure rise induced by cyclosporin. The present findings demonstrate that renin-angiotensin-aldosterone system activation augments cyclosporin-induced renal vasoconstriction but not cyclosporin-induced systemic vasoconstriction. We suggest that the renin-angiotensin-aldosterone system suppression, which normally occurs with cyclosporin, may be a homoeostatic mechanism to help prevent cyclosporin-induced renal vasoconstriction. The renin-angiotensin-aldosterone system appears, however, to play little or no role in mediating or preventing the initial increase in blood pressure caused by cyclosporin. Furthermore, frusemide is commonly prescribed together with cyclosporin even though this combination has the potential to cause a marked increase in renal dysfunction.

Serial changes in blood pressure, renal function, endothelin and lipoprotein (a) during the first 9 days of cyclosporin therapy in males.

OBJECTIVE: To elucidate the sequential mechanisms underlying cyclosporin-induced hypertension and nephrotoxicity. DESIGN: A study of healthy males over the first 9 days of drug ingestion to permit the detection of serial changes in renal function and blood pressure in a situation free from the confounding variables of concomitant disease or drugs. METHODS: Double-blind, placebo-controlled, randomized crossover study with cyclosporin (5 mg/kg twice a day) or placebo. Blood pressure and urinary sodium excretion were measured each day, and glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured on days 1, 4, 7 and 9. Cholesterol, lipoprotein (a) and endothelin were measured on days 1 and 9. RESULTS: GFR decreased by 9% with cyclosporin and was significantly lower than with placebo on day 4 of therapy. ERPF fell by 24%. The fall in GFR correlated significantly with suppressed plasma renin activity (P < 0.0001). Cyclosporin-induced hypertension occurred in the absence of any change in urinary sodium output or in plasma endothelin. Cyclosporin did not affect lipoprotein (a) levels during 9 days of cyclosporin therapy. CONCLUSIONS: Cyclosporin-induced hypertension and renal vasoconstriction are well established after 9 days of cyclosporin 5 mg/kg twice a day. We found no evidence to implicate either circulating endothelin or renal sodium retention in the onset of cyclosporin-induced hypertension. Cyclosporin-induced renal vasoconstriction appeared to occur when the protective mechanism of plasma renin activity suppression became exhausted.

A reproducibility study of technetium-99m macroaggregated albumin foot perfusion imaging in patients with diabetes mellitus.

The reproducibility of Technetium-99m macroaggregated albumin (99mTc-MAA) foot perfusion imaging was assessed in 14 diabetic patients with foot ulcers. Bilateral femoral intra-arterial injections of 99mTc-MAA were administered and the feet imaged with a gamma camera. Patients returned 1 week later for a repeat study. The scans of 10 patients including one unilateral amputee were evaluated. Of these 19 limbs there were 4 failed injections (21%). The remaining 15 completed repeat studies were analysed both subjectively and semiquantitatively by 2 different observers who were blind to the patient's name and scan date. Subjectively the images of each individual were similar with reports highlighting the same abnormalities. Semiquantitatively areas of increased uptake on both images were significantly correlated for each individual (Pearson's Rho correlation coefficient = 0.96, r2 = 0.92, p < 0.0001) as were areas of poor uptake reported, reflecting decreased tissue perfusion (Pearson's Rho = 0.93, r2 = 0.86, p < 0.0001). There were no side-effects. 99mTc-MAA has proven to be a safe, generally acceptable, and reproducible technique for assessing tissue perfusion in the extremities which provides an accurate means of differentiating viable from non-viable tissue in patients with foot ulcers.

Indomethacin and cyclosporin together produce marked renal vasoconstriction in humans.

OBJECTIVE: To test the hypothesis that an imbalance in intrarenal prostaglandins plays a role in cyclosporin-induced nephrotoxicity. METHODS AND RESULTS: Indomethacin was given in combination with cyclosporin to healthy volunteers. Cyclosporin alone (10 mg/kg twice a day) for 4 days had no effect on effective renal plasma flow (ERPF) and glomerular filtration rate but 4 days of therapy with cyclosporin (10 mg/kg twice a day) and indomethacin (50 mg twice a day) in combination resulted in a 37% fall in glomerular filtration rate and a 32% fall in ERPF. This suggests that autoregulatory mechanisms, possibly involving renal prostaglandins, may participate in counteracting the tendency for cyclosporin-induced renal vasoconstriction in humans. Cyclosporin increased systemic blood pressure acutely, and this was not influenced by indomethacin even though indomethacin on its own caused sodium retention. This suggests that, in contrast to the renal vasculature, the systemic vascular response to cyclosporin is neither augmented nor buffered by prostaglandins. CONCLUSION: The reduction in intrarenal prostaglandins clearly played a key role in the development of cyclosporin-induced renal vasoconstriction, but we could not demonstrate a role for prostaglandins or for sodium retention in the initiation of cyclosporin-induced hypertension.

Sequential effects of cyclosporine therapy on blood pressure, renal function and neurohormones.

We have studied the sequential effects of cyclosporine during the first four days after its initiation in an effort to elucidate the primary and secondary events in the pathogenesis of cyclosporine induced nephrotoxicity and hypertension. Knowledge about the earliest effects of cyclosporine provides a more logical approach for devising therapeutic strategies to counteract nephrotoxicity and hypertension. On day 1, cyclosporine acutely increased systemic BP and decreased urine volume. Plasma renin activity was suppressed by day 2 and remained so thereafter. Renal sodium excretion was not affected until day 4 at which point a natriuresis occurred. Cyclosporine exerted a more marked antidiuretic effect on day 4 compared to day 1, which was augmented by a physiological infusion of vasopressin. Over the first four days of therapy, glomerular filtration rate and effective renal plasma flow were unchanged. Our data show that cyclosporine induced hypertension in the initial stages is not sodium dependent, and that changes in renal water handling were not dependent on alterations in the glomerular filtration rate or effective renal plasma flow. In fact, a natriuresis occurred which was most likely due to a combination of pressure natriuresis and angiotensin II suppression. The cyclosporine induced antidiuresis may indicate a distal nephron effect since cyclosporine augmented the antidiuretic effect of vasopressin, although vasopressin levels per se were not increased by cyclosporine alone.

Acute haemodynamic and renal effects of cyclosporin and indomethacin in man.

A single oral dose of cyclosporin (12 mg/kg) was given to healthy volunteers (n = 9) on day 2 with or without indomethacin pretreatment (100 mg day 1 + 100 mg day 2). All parameters reported were analysed after a water-loading protocol on day 2. As a peak drug effect within 4 h of drug ingestion on day 2 cyclosporin on its own increased mean arterial pressure by 13% (P < 0.05) without causing any sodium retention or renal vasoconstriction. Indomethacin pretreatment did not accentuate this hypertensive effect of cyclosporin. The earliest renal effect observed with cyclosporin on day 2 was on water handling with a marked antidiuretic effect. Free-water clearance decreased by a maximum of 48% (P < 0.05) following cyclosporin. Indomethacin pretreatment induced a similar antidiuresis on day 2 but cyclosporin did not augment this antidiuresis any further. This suggests that inhibition of vasodilator prostaglandins within the kidneys may mediate the antidiuretic effect of cyclosporin such that in the presence of indomethacin, cyclosporin had no additional effect. The inhibition of intrarenal prostaglandins by a single dose of indomethacin did not, however, produce any acute cyclosporin-induced change in glomerular filtration rate or renal blood flow.