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Beta adrenergic receptor antagonists (beta blockers) differ greatly in their cardioselectivity and intrinsic sympathomimetic activity, and these differences may have important therapeutic consequences. We have therefore studied the effect on blood pressure, heart rate and plasma renin activity of the beta blocking drug oxprenolol (Trasicor) which has considerable intrinsic sympathomimetic activity, both alone and in combination with the benzothiadiazine cyclopenthiazide. Eleven patients with mild to moderate benign essential hypertension were randomly allocated to one of two treatment groups. Oxprenolol was given as the first drug to Group 1, and cyclopenthiazide as the first drug to Group 2. The patients were assessed before the start of treatment, after 2 to 3 weeks of treatment with one drug and after a further 2 to 3 weeks of treatment with both drugs. Heart rate, blood pressure and plasma renin activity were measured with the patients recumbent and after a standardized tilt to 85 degrees to provide a reflection of day to day cardiovascular stress. Oxprenolol reduced arterial blood pressure without inducing significant bradycardia. The addition of cyclopenthiazide had little further effect. Oxprenolol alone suppressed plasma renin activity both at rest and during tilt and also abolished the increase in plasma renin activity after administration of cyclopenthiazide. The combination of (1) moderate reduction of blood pressure. (2) inhibition of the otherwise inevitable increase in plasma renin activity with the use of a diuretic drug, and (3) only moderate inhibition of overall sympathetic activity indicates that it is possible to achieve physiologic balance with the appropriate beta blocking drug.
In a multicenter, prospective study of step II antihypertensive therapy with indoramin, 1,847 hypertensive patients (773 men and 1,074 women) between the ages of 18 and 70 years were treated by 148 general practitioners. Patients whose blood pressure was inadequately controlled after 4 weeks of therapy with cyclopenthiazide (0.25 to 1.0 mg/day) had indoramin (25 to 200 mg/day) added to their treatment regimen. During cyclopenthiazide treatment, mean (+/- SD) blood pressure decreased from 176/105 +/- 20/7 mm Hg at baseline to 164/98 +/- 21/9 mm Hg (p less than 0.001), and only 447 (24%) patients obtained satisfactory blood pressure control. The addition of indoramin produced a further reduction in mean blood pressure from 169/102 +/- 18/6 to 152/89 +/- 18/8 mm Hg during the first 3 months of treatment (p less than 0.001); this response was maintained for up to 2 years. Satisfactory blood pressure reduction was achieved in 79% of the patients who received indoramin (mean dose, 68 mg/day) plus cyclopenthiazide. Only 25 patients (2%) discontinued indoramin treatment because of nonresponse, and 156 (12%) withdrew because of adverse effects, the most common being sedation, dizziness/giddiness, and headache. These results indicate that indoramin provides safe and effective blood pressure control when used as step II treatment for hypertensive patients who fail to respond to single-agent diuretic therapy.
One day after unilateral nephrectomy (uNX), excretion of p-aminohippurate (PAH) reaches 80% of control values in rats. A stimulation of tubular transport by repeated administration of xenobiotics shortened the phase of diminished PAH excretion capacity following. The relative extent of compensation (%) after uNX is not affected significantly by inhibitors of protein synthesis. These inhibitors influence the time course of compensation after uNX. Administration of azauracil, fluorouracil and neomycin, respectively, causes a dose dependent reduction of PAH excretion in nephrectomized and sham operated animals. This effect is also provable following pretreatment with cyclopenthiazide, which can stimulate the PAH elimination. A stimulated renal function after uNX can also be suppressed by high doses of inhibitors of protein synthesis. In contrast to this, small doses of these substances produce a stimulation of renal PAH excretion. The extent of this stimulation reached the same degree as after cyclopenthiazide pretreatment found in preliminary experiments. An additional treatment with cyclopenthiazide does not additionally increase PAH excretion. These results indicate that processes of compensatory growth as well as induction of renal tubular transport are caused by increased protein synthesis.
Nifedipine has been used in hypertension, mainly as a third-line drug for rapid blood pressure reduction, for over 10 years. More recently it has been shown to be effective and safe in reducing mild to moderate blood pressure when used alone in a slow release formulation. A placebo-controlled study investigating the efficacy and safety of nifedipine in comparison with cyclopenthiazide-potassium has now been carried out by 4 general practitioners in the Glasgow area. Ninety-four patients were entered into the study. After a 4-week placebo run-in phase, patients were randomly allocated to receive either slow-release nifedipine 20 mg b.d., or cyclopenthiazide 0.25 mg with 8.1 mmol potassium daily. The dose was doubled at week 8 for non-responders, and at week 12 the alternative drug was added if there was still no response. The patients were studied for up to 28 weeks. Nifedipine was found to have similar blood pressure lowering efficacy to cyclopenthiazide-potassium, but withdrawals from nifedipine due to side-effects at an early stage were more common.
After single administration of potassium dichromate or glycerol, renal PAH excretion was markedly reduced in adult, but not in newborn and infant rats. As already demonstrated in rats with intact kidney functions, repeated administration of PAH or cyclopenthiazide stimulates also renal PAH excretion in rats with acute renal failure. In detail, after PAH or cyclopenthiazide treatment of rats the duration of injury is shortened whereas the intensity of the nephrotoxic effects is not changed. However, the stimulation depends on the age of animals as well as on the nephrotoxic agent administered.
In immature rats, renal excretion of p-aminohippurate (PAH) can be increased by daily pretreatment with triiodothyronine (T3) or tetraiodothyronine (T4) beginning on the 2nd day after birth (10 micrograms/100 g b.wt. i.p.). The increase of PAH excretion is nearly of the same extent, if 5-, 10-, 20-, 30-, 50-, and 105-day-old rats were pretreated with thyroid hormones (10 micrograms/100 g b.wt. i.p., 3 days, once daily). There is no strongly dose dependent renal effect of T3 and T4, respectively. The time course of stimulation of renal PAH excretion was also characterized in rats of different ages. Simultaneous pretreatment of young and adult rats with cyclopenthiazide and T3 is not distinctly more effective as both components given alone. Particularly the low degree of stimulation in young rats receiving cyclopenthiazide cannot be pronounced by additional T3 administration. Inhibitors of protein biosynthesis (azauracil, neomycin) can antagonize the stimulation of renal p-amino-hippurate excretion in rats receiving T3. The presented data indicate that T3 is effective in young rats. Furthermore, T4 can be converted to T3 in young rats, too. The importance of an intact protein synthesis seems to be a prerequisite to stimulate the kidney function by T3 pretreatment.
Repeated pretreatment with p-aminohippuric acid (PAH), probenecide, cyclopenthiazide, and phenobarbital stimulates the renal excretion of PAH. For an interval of at least 6 hrs following i.p. application pretreated rats excrete more PAH excretion than the controls. All the drugs studied were found to stimulate renal PAH excretion within a period of 3 hrs by 50-60% of the control value. The required duration of pretreatment varies with the substance used. With cyclopenthiazide, the excretion of PAH is demonstrable for 2-3 weeks. Phenobarbital has a brief stimulating action. Correlations of a binding of drugs to structures of their tubular cell and the length of the stimulating action are discussed.
The interaction of three structurally related benzothiadiazine diuretics, viz., hydroflumethiazide, bendrofluazide and cyclopenthiazide wit beta-cyclodextrin was investigated. The study aimed at enhancing the solubility of these poorly soluble drugs via inclusion complexation with beta-cyclodextrin, Solubility measurements revealed that complexes were formed between each of three drugs and beta-cyclodextrin, The complexes were found to have 1:1 stoichiometric ratios and stability constants of 165.4, 55.7 and 27.9 M-1 for cyclopenthiazide, bendrofluazide and hydroflumethiazide, respectively. UV spectrophotometric analysis of the formed complexes agreed with the solubility results. The variation in the extent of binding between each of the three drugs and beta-cyclodextrin was attributed to their variation in molecular volume, partition coefficient and electrostatic properties of the binding sites.
Twenty hours after unilateral nephrectomy (uNX) the PAH excretion of uninephrectomized rats reaches about 80% of the controls. Immediately after removal of one kidney the parenchyma loss can be compensated by an intensification of glomerular filtration. Thereafter the active tubular secretion capacity raises. 24 h after uNX, a significant increase of renal mass could be measured. The specific PAH accumulation capacity per 1 g renal cortical tissue increases significantly 96 h after uNX if the animals had been pretreated with cyclopenthiazide before the operation. Administration of azauracil or fluoruracil or neomycin causes a dose-dependent reduction of PAH elimination in sham operated as well as in uNX-rats. The effect of stimulation by cyclopenthiazide, also occurring after uNX could be reduced significantly by the inhibitors. The relative extent of compensation (80 +/- 10%) was not influenced by the inhibitors of protein synthesis. The compensation after uNX and the stimulation of renal tubular function are mediated by different mechanisms.
Following treatment with cyclopenthiazide, triiodothyronine or dexamethasone the renal excretion of p-aminohippurate (PAH) as well as the accumulation of PAH in renal cortical slices from adult rats and from rats with immature kidney function are increased. There are differences with respect to the age of the rats as well as in dependence on the substance used for treatment. In 10- and 60-day-old rats the [14C]leucine uptake following such a stimulation of kidney function is increased, that means active tubular transport of amino acids can also be stimulated. Furthermore, the [14C]leucine content in the protein fraction of homogenized kidney tissue is increased, indicating a higher degree of incorporation of amino acids in kidney tissue following treatment with cyclopenthiazide, triiodothyronine or dexamethasone.
Unilateral nephrectomy (UNX) is followed by a significant decrease of excreted amount of PAH in rats. In 105 and 240-day-old rats, we characterized the time course of restitution of the PAH transport process., Furthermore, we studied whether or not the regeneration of kidney function can be accelerated by repeated administration of cyclopenthiazide. After stimulation of tubular transport of PAH by repeated administration of cyclopenthiazide, the loss of one kidney after UNX can be compensated more rapidly as in nephrectomized rats without pretreatment. In 105-day-old rats the regeneration and the extent of stimulation are more marked than in 240-day-old rats.
The renal excretion of p-aminohippurate (PAH) can be stimulated by repeated administration of cyclopenthiazide (5 mg/100 g b.w., i.p. for 3 days, twice daily). The reason for this seems to be an increased renal tubular transport capacity for weak organic acids. Inhibitors of protein biosynthesis as azauracil, actinomycin D, neomycin and cycloheximide influence the cyclopenthiazide stimulated p-aminohippurate excretion. Azauracil (5 mg/100 g b.w.), an inhibitor of replication is effective in the same way as inhibitors acting on transcription and translation (actinomycin D 7.5-60 micrograms/100 g b.w.; neomycin 5-10 mg) 100 g b.w.; cycloheximide 0.02-0.05 mg/100 g b.w., i.p. for 4 days, once daily). Probably these substances inhibit the de novo synthesis of carrier proteins, increased by stimulation of renal tubular transport processes.
During the phase of compensation of parenchyma loss two different mechanisms can be stated causing an improvement of renal tubular transport capacity. Besides an increase of tubular transport ratio in kidney slices from nephrectomized rats an increased mass of kidney tissue participated in the augmented transport capacity. 24 h after unilateral nephrectomy TmPAH is elevated from 0.40 +/- 0.10 to 0.61 +/- 0.13 mg/min x g kidney weight. The simultaneous increase in slice-to-medium ratio of renal cortical slices demonstrate the increase in specific transport capacity of regenerating kidney tissue. Furthermore the increase in kidney mass is the reason for an elevated transport capacity. Stimulation of renal PAH excretion by repeated pretreatment with cyclopenthiazide shortened the phase of compensation and raised the extent of tubular transport capacity following partial loss of kidney tissue. The specific accumulation of PAH in renal cortical slices from nephrectomized, cyclopenthiazide pretreated rats is distinctly elevated 96 h after unilateral nephrectomy from 19.4 +/- 2.7 to 24.3 +/- 0.6 micrograms/g kidney weight. Obviously there are different mechanisms for the increased PAH transport caused by stimulation and by regeneration after unilateral nephrectomy, because additional effects can be stated in regenerating rats by additional stimulation of renal tubular transport.
In a prospective study, 41 patients with documented chronic macular edema of various causes were entered into a therapeutic trial of acetazolamide sodium, a carbonic anhydrase inhibitor. Each patient received a five-cycle cross-over regimen of treatment/no treatment with a further two cycles of cross-over with another diuretic, cyclopenthiazide, which does not inhibit carbonic anhydrase. At each cross-over patients were examined for evidence of macular edema. Sixteen of 41 patients showed a reproducible response to acetazolamide with partial or complete resolution of edema and improvement of visual acuity. The therapeutic effect occurred in more than half of the patients with inherited outer retinal disease or uveitis, but in none with primary retinal vascular disorders. There was no correlation between the response to treatment and the extent or duration of the edema. No influence of cyclopenthiazide on macular edema was detected.
Continuous intra-arterial blood pressure recording using the "Oxford" technique has been used to study the antihypertensive effects of oxprenolol taken three times daily in fully ambulatory patients with essential hypertension, outside hospital. During the first 24 h of treatment there was a reduction in daytime heart rate and a small reduction in daytime blood pressure. After 10 weeks treatment there was a more substantial fall in daytime blood pressure from the hour of waking, but no effect on sleeping nighttime blood pressure or heart rate. Twenty-four hour variation, as assessed by the amplitude of a fitted regression curve, showed a reduction in heart rate but not blood pressure variation. In 4 patients restudied after 11 weeks treatment with oxprenolol (tid) and cyclopenthiazide at 9 a.m. there was some evidence of an antihypertensive effect occurring during both the daytime and nighttime.
PAH transport and Na-K-ATPase activity markedly increase during the first month of postnatal life. Pretreatment of rats with PAH or cyclopenthiazide induces a stimulation of in vitro PAH accumulation in renal cortical slices, whereas Na-K-ATPase activity is unchanged in comparison to saline-pretreated controls. 5 mM ouabain in the incubation medium reduces PAH accumulation. Developmental pattern and stimulation effects are pronounced as in controls. The ouabain-insensitive component of net PAH accumulation progressively increases with age and is significantly enhanced following drug pretreatment, whereas the ouabain-sensitive component of net PAH accumulation shows relatively slight modifications. Consequently, Na-K-ATPase seems not to be linked with postnatal maturation or drug-induced stimulation in tubular PAH transport.