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Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.

Indapamide (Lozol), an indoline antihypertensive drug with diuretic and vasodilating activities, was evaluated in 195 patients with mild to moderate essential hypertension (sitting DBP between 95 and 110 mmHg) in a multicentre, randomised, double-blind, parallel-group design trial. A four week single-blind placebo wash-out period was followed by an eight week double-blind period. Patients were randomised to indapamide 1.25 mg/day or to placebo. The primary efficacy endpoint was the mean change in sitting DBP from baseline to week 8. Ninety patients in the placebo group (93%) and 82 patients (84%) in the indapamide group completed the eight weeks of double-blind therapy. Indapamide produced a mean (SE) decrease in sitting DBP of 7.4 (0.63) mmHg (from 100.1 to 92.8 mmHg) compared with a decrease of 3.6 (0.75) mmHg (from 99.6 to 95.8 mmHg) produced by placebo (p < 0.0001). Indapamide and placebo also produced mean decreases in standing DBP of 6.8 (0.75) and 2.8 (0.77) mmHg, respectively (p = 0.0002), in sitting SBP of 11.1 (1.18) and 3.2 (1.35) mmHg, respectively (p = 0.0001) and in standing SBP of 11.4 (1.29) and 4.0 (1.43) mmHg, respectively (P = 0.0002). Reduction in BP of > or = 10 mmHg or to a DBP of < or = 90 mmHg was more frequent (P = 0.0005) among indapamide (46.6%) compared with placebo (23.7%) treated patients. During the eight week double-blind treatment period, incidence rates for all adverse experiences and for drug-related adverse experiences were similar between the two treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

One hundred and ten patients (mean age 50.6 years) with moderate to severe essential hypertension (DBP between 105 and 116 mmHg) were randomised to eight weeks of double-blind treatment with lisinopril (n = 56) or diltiazem SR (n = 54). Fourteen patients withdrew from therapy; six patients withdrew because of adverse events (lisinopril, n = 3; diltiazem SR, n = 1) and lack of BP control (lisinopril, n = 1; diltiazem SR, n = 1). Both monotherapies were titrated upward (lisinopril 20-40 mg daily, diltiazem SR 120-180 mg twice daily) to achieve an office DBP < 90 mmHg. Hydrochlorothiazide (HCTZ; 25 mg daily) was added to monotherapy after week 4 if patients did not reach the BP goal (i.e. non-responders). After four weeks of therapy, 72% of patients (74 of 103) were nonresponders. At eight weeks of therapy, 66 patients (lisinopril, n = 32; diltiazem SR, n = 34) had received HCTZ. At week 8, 53% of lisinopril and 36% of diltiazem SR patients met the response criteria. Mean office DBP decreased from baseline -18.1 +/- 8.6 mmHg for lisinopril patients and -15.9 +/- 10.1 mmHg for diltiazem SR patients at week 8. Lisinopril was as effective as diltiazem in reducing systolic and diastolic office BP at week 4 (p > 0.1). Likewise, at weeks 4 and 8, no statistically significant differences were detected between treatments (p > 0.05) for systolic and diastolic ambulatory BP averaged over 24 hours. Both treatments were well tolerated and showed important antihypertensive efficacy in patients with moderate to severe BP elevation.

Sumatriptan, a specific serotonin1-like receptor agonist, was studied in the acute treatment of migraine. Two hundred forty-two adult migraineurs participated in a randomized, double-blind study in which one dose of 1, 2, 3, 4, 6, or 8 mg of subcutaneous sumatriptan succinate was evaluated in sequential ascending fashion. At each dose level, a placebo group was included. Efficacy was defined as reduction of moderate or severe pain to mild or no pain, without the use of rescue medication. Headache relief rates showed an approximate dose-response relationship and at 1 hour were as follows: placebo, 24%; 1 mg, 43%; 2 mg, 57%; 3 mg, 57%; 4 mg, 50%; 6 mg, 73%; and 8 mg, 80%. Relief of nausea and improvement in clinical disability were also approximately dose related. Adverse events were dose related; the most common types were injection site reactions and tingling. The 6-mg dose was as effective as the 8-mg dose but was associated with fewer adverse effects and so is optimal.

Studies were undertaken to examine the relationship between renal morphologic and functional alterations during the development of cis-diamminedichloroplatinum (II) (CDDP)-induced acute renal failure (ARF). Control and CDDP-treated rats (10 mg/kg, intraperitoneally) were housed in metabolic cages for the purpose of renal function determinations. Renal morphology was studied by light and electron microscopy at 6, 24, 48, 72, and 96 hours following treatment. Six hours following CDDP administration, morphologic alterations consisting of nucleolar segregation, ribosome dispersion, and the formation of aggregates of smooth endoplasmic reticulum were observed throughout the P3 portion of the proximal tubule located in the outer stripe of the outer medulla and medullary rays. These changes became more frequently observed throughout P3 during the course of the study. At 24 and 48 hours, focal changes were also observed involving the P1 and P2 segments of the proximal tubule which make up the pars convoluta. ARF, indicated by a reduced creatinine clearance, was first apparent 48 hours following CDDP administration. The development of ARF was associated with focal, primarily sublethal, cell injury throughout the proximal tubule. By 72 and 96 hours necrosis primarily affecting P3 became widespread, and renal function progressively worsened. The establishment of ARF prior to the development of tubular necrosis suggests that the processes of tubular obstruction and/or tubular fluid backleak are not involved in the initiation of ARF in this model. Instead, the alterations involving P1 and P2 appear to be most important during the early stages of CDDP-induced ARF. The severity of the convoluted tubular injury at 48 hours showed a significant correlation with the degree of renal function impairment. The tubular injury affecting P3 did not correlate with the loss of renal function at any of the time points studied. However, tubular injury in P3 did appear responsible for some degree of renal function impairment at 72 and 96 hours, probably as a result of tubular obstruction and/or tubular fluid backleak.

A 27 year old man with nephrotic syndrome due to membranoproliferative glomerulonephritis had multifocal stenoses of the renal and intestinal arteries. The arterial lesions demonstrated by angiograhy closely resembled those of medial fibromuscular dysplasia. The dysplasia progressed over a five year period to involve both renal arteries from their extrarenal segments through their interlobar branches. Low serum levels of complement components C3 and C4, focal reduplication of the glomerular basement membrane on light microscopy, and the patterns of glomerular localization of IgG and C3 by immunofluorescence were characteristic of type I membranoproliferative glomerulonephritis. The development of the arterial dysplasia in a patient with chronic glomerulonephritis suggests a common immunologic pathogenesis of both disorders.

Bumetanide is a recently developed natriuretic and diuretic agent, belonging to the "loop" class of diuretics. Since it is rapidly and almost completely absorbed after oral administration, oral and parenteral formulations have a similar pharmacokinetic profile. Peak plasma levels are achieved approximately 30 min after oral administration. The apparent half-life is 1.2-1.5 hr, and the volume of distribution is about 25 liters. Plasma clearance is 228-255 ml/min. Bumetanide is promptly and almost completely eliminated by metabolism of the butyl side chain and urinary excretion of the parent drug and its metabolites. The principle renal site of action is the ascending limb of the loop of Henle, with a minor effect on the proximal tubule. The drug causes decreases in both free water clearance (during water diuresis) and solute free water reabsorption (during hydropenia), increased fractional delivery of sodium chloride to the distal tubule and a natriuresis approaching 20% of the filtered load of sodium, calciuria, phosphaturia, and minimal bicarbonaturia. Extensive clinical studies have been conducted with both oral and parenteral bumetanide in patients with a variety of edematous conditions. The agent has been clearly demonstrated to be an effective diuretic in the treatment of edema due to cardiac disease (congestive heart failure) and edema, with or without ascites, due to hepatic disease. Bumetanide has also been shown effective in treating edema due to renal disease, even when modest to severe renal insufficiency is present, and it may be useful in the treatment of edema refractory to other loop diuretics. As would be predicted for any potent diuretic, bumetanide administration has been associated with hypokalemia, hypochloremia, metabolic aklalosis, hyperuricemia, and prerenal azotemia. Alterations in glucose metabolism are an inconsistent finding. Transient thrombocytopenia and granulocytopenia have been noted, but no consistent or important alterations in biochemical parameters have been observed. In some patients, especially those with renal failure receiving high doses, myalgias and muscle tenderness have been described. To date only a very limited potential for ototoxicity has been observed. Bumetanide has been administered without difficulty to patients having side effects from other loop diuretics.

Nephrotoxicity is a dose limiting feature of cis-diamminedichloroplatinum (DDP) cancer chemotherapy. We have previously developed a model of DDP induced acute renal failure in the rat, which is characterized by non oliguric progressive azotemia. Protocols have been established in humans to prevent or diminish DDP associated renal alterations during the course of cancer chemotherapy. The present studies were designed to evaluate the effect of prior diuretic therapy, with furosemide, and enhanced solute diuresis, using dextrose and water as the sole source of drinking fluid, on DDP induced acute renal failure in the rat. As compared to water drinking controls neither the diuretic nor the enhancement of osmotic excretion effected DDP associated mortality. The courses of the acute renal failure observed in all three study groups were similar; however, there was a suggestion in the surviving animals that these maneuvers may have contributed to a more rapid return in renal function among rats not dying of DDP induced acute renal failure.

The ontogeny of single nephron filtration distribution was studied in 29 canine puppies two hr to 42 days old using the [14C] ferrocyanide method as modified by Coehlo (9). The ratio of 14C counts in outer cortical nephrons (OC) to counts in juxtamedullary nephrons (JM) were plotted against age for each puppy. This ratio (OC:JM) provided an index for comparing the single nephron glomerular filtration between regions. A four-fold increase in OC:JM occurred from two days to four wk. The youngest puppy, two hr old, showed a ratio of zero because no counts were detected in OC at that age. The most rapid increase occurred in the first 8 days of life. By the fourth wk, the mean OC:JM ratio was 0.72 +/- 0.06, approaching values reported by other laboratories for adult dogs. In contrast to age-related changes in OC:JM ratio, the ratio of middle cortical to JM counts showed no age-related increase. Cortical blood flow distribution was determined by the microsphere method. The ratio of blood flow to outer and inner cortex increased from 0.43 at one-half a day to a mean of 2.93 after one wk. The ratio of OC:JM single nephron filtration of OC/inner cortical nephron renal blood flow was 0.36 from 3 days to 26 days (n = 12) and did not change significantly with age, indicating that changes in zonal filtraion matched the alterations in cortical blood flow distribution.

The safety and efficacy of orally administered celiprolol, a new beta 1-selective adrenergic blocking drug with peripheral beta 2-agonist properties, were assessed in 91 patients with mild to moderate systemic hypertension (supine diastolic blood pressure [BP] 95 to 114 mm Hg without medication) using a placebo-controlled, double-blind, randomized, titration-to-effect study design. All patients received placebo for 4 weeks and were then randomized to receive placebo (n = 46) or once-daily celiprolol (n = 45), which was titrated every 2 weeks (200, 400, 600 mg/day) over a 6-week period to achieve a reduction in supine diastolic BP to less than or equal to 90 mm Hg. Plasma lipids and lipoproteins were also assessed at baseline, during placebo and after randomization to active therapy in a subgroup of patients. Compared with placebo, celiprolol reduced supine and standing BP (reduction of supine BP -0.4/-2.1 mm Hg with placebo, -5.7/-6.4 with celiprolol, p less than 0.05; reduction of standing BP -1.7/-1.0 with placebo, -7.2/-4.9 with celiprolol, p less than 0.05). Supine heart rate was reduced by 6.8 beats/min with celiprolol compared with 2.0 beats/min with placebo (p less than 0.05). No differences were seen when the effects of placebo and celiprolol on plasma lipoproteins were compared. Celiprolol is a safe, effective and well tolerated once-daily antihypertensive drug and has no detrimental effects on plasma lipids.

The effects on the renal actions of bumetanide of two inhibitors of prostaglandin synthetase, acetylsalicylic acid (ASA) and indomethacin, were studied in eight normal adults. Indomethacin alone resulted in a significant decrease in FENa compared to the control period. Bumetanide alone resulted in increases in urine volume, FENa, and plasma renin activity. Both ASA and indomethacin blunted the increases in urine volume and sodium excretion, although the inhibition by indomethacin was greater than that of ASA. In addition, indomethacin completely inhibited the bumetanide-induced increase in plasma renin activity. No consistent relationship between these effects and urinary prostaglandin E2 or F excretion was noted. These studies indicate that prostaglandin synthetase inhibitors may interfere with the effects of bumetanide.

Plasma renin activity (PRA) was measured in conscious Brattleboro strain, vasopressin (AVP)-deficient diabetes insipidus (DI) and heterozygous rats with the aid of chronically implanted catheters. Baseline, dehydration-stimulated, and hemorrhage-stimulated levels of PRA were elevated in DI rats, as compared to levels in heterozygous controls. Replacement therapy with either AVP or the nonpressor AVP analog dDAVP reduced PRA to control levels. The high level of PRA in DI rats was associated with the lack of endogenous antidiuretic activity per se and not the pressor activity associated with the vasopressin molecule. Thus, elevated PRA in the chronic absence of AVP (in DI rats) most probably results indirectly from the chronically reduced plasma volume reported associated with hypothalamic diabetes insipidus.

The effect of propranolol therapy on plasma renin activity and blood pressure control was evaluated in 35 uremic patients receiving intermittent center-based outpatient hemodialysis. Patients were determined to be either compliant or noncompliant with therapy based on the steady-state predialysis plasma propranolol concentration. Noncompliance occurred with remarkable frequency and was associated with persistent hyperreninemia and poorly controlled hypertension. Blood pressure control was significantly better in compliant patients, in whom plasma renin activity was generally, but not universally, suppressed. Propranolol can be effectively used in the management of hypertensive dialysis patients, but steady-state plasma propranolol levels should be measured to assess compliance in patients apparently refractory to treatment.

The frequency of hemodialysis-associated hemorrhage was studied prospectively in two successive, parallel, heparin-controlled studies using epoprostenol (PGI2; average dose, 4.1 ng/kg.min) as the sole antithrombotic agent. Sixty-three patients with active or recently active bleeding underwent 163 hemodialysis treatments in each of which prospective bleeding risk was assessed. PGI2 was associated with up to 50% overall reduction in the frequency of bleeding, particularly in the highest risk circumstances. PGI2 also allowed successful completion of the full, prospectively prescribed hemodialysis time in the most treatments (82% versus 93% with heparin). Furthermore, the efficiency of hemodialysis using PGI2, as indicated by the reduction in concentration of blood urea nitrogen and serum creatinine, was equal to that using heparin, even though there was a tendency toward modest reduction in residual volume of the hollow fiber dialyzer and slightly more frequent early termination of treatment from dialyzer clotting with PGI2. No severe vasodilatory side effects of PGI2 were observed during these studies. Hypotension was equally frequent during hemodialysis with heparin as with PGI2. The current results suggest that PGI2 should be considered as a substitute for heparin during high-risk hemodialysis because PGI2 may reduce the incidence of dialysis-associated bleeding without severe adverse side effects.