Terazosin

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New Cardiovascular Drugs 1986, edited by Alexander Scriabine.

Raven Press, New York 0 1986.

Terazosin

J . Jaroslav Kyncl, Robert C. Sonders, W. David Sperzel, Martin Winn, and John H. Seely

Research & Development Division, Abbott Laboratories, North Chicago, Illinois 60064

Terazosin (Hytrinm; A-45975) was developed in recognition of the antihypertensive potential of the quinazoline vasodilators (13,23). Structurally related to prazosin, terazosin is a selective a, receptor antagonist that has recently been intro- duced in several countries as an oral once-a-day antihypertensive agent. This chapter presents a summary of the preclinical experience with terazosin together with some initially published clinical results.

CHEMISTRY

Terazosin, 2-{4-[(tetrahydro-2-furanyl)carbonyl]-l-piperazinyl}-6,7-dimethoxy- 4-quinazolinamine monohydrochloride dihydrate (molecular weight 459.93), is a congener of prazosin. The chemical structure of terazosin differs from that of prazosin in that the furan ring of the former is saturated.

The saturation of the furan ring dramatically increases the water solubility of the molecule (28.1 m g / d for terazosin versus 1.1 mglml for prazosin), a feature with multiple practical consequences. In addition, the saturated furan moiety provides the molecule with one optically active center so that terazosin, unlike prazosin, can exist in two enantiomeric forms. This property is of theoretical significance since the enantiomers can refine our understanding of the topography of the ^a]

receptor, hitherto delineated solely through the interaction with the prazosin molecule. The configurations of prazosin and terazosin are practically identical except for the furan moiety, which extends in the two enantiomers into different spatial orientations (Fig. 1).

It has been proposed that the saturated furan ring of terazosin enables greater loading with tritium than could be done with prazosin. This could make terazosin an a,-receptor radioligand with specific activity superior to that of prazosin (1 1).

1

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2 TERAZOSIN

PR AZOSIN

4,

^{- 7} ^TERAZOSIN^R,

^s

FIG. 1. Three-dimensional representation of the two enantiomers of terazosin in comparison with prazosin.

PHARMACOLOGY Antihypertensive Activity

Terazosin has been shown to lower blood pressure in spontaneously hypertensive rats (SHR) without a concomitant increase in heart rate (13,23). The hypotensive effect was observed at oral doses ranging from 0.1 mglkg to 30 mg/kg. It occurred as early as 15 min following oral administration, and the maximal decrease in systolic pressure reached was approximately 70 to 80 mm Hg (Fig. 2, top) (13,14,16,23).

The overall blood-pressure-lowering efficacy of terazosin was equal to that of prazosin (14). In contrast to prazosin, however, terazosin exhibited a more gradual onset of action as demonstrated in a potency-comparison analysis throughout the time course of action of the two compounds. Thus, during the initial 1-hr period, prazosin consistently elicited a greater decrease in blood pressure than terazosin, whereas as time elapsed, the potencies of both compounds became equal (Fig. 2, bottom) (14). The duration of the antihypertensive effects in SHR was similar for both compounds. Mathematical analysis of several studies revealed that terazosin repeatedly exhibited a more uniform and linear dose-response curve and a less variable duration of action than prazosin (14). Differences in pharmacokinetics may explain the time response patterns of the two compounds. No tolerance has been observed following repeated oral administration of terazosin (5 days) in S I B rats (14,16).

An antihypertensive effect of terazosin was also demonstrated in DOCA-salt and

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TERAZOSIN 3

one-kidney, one-clip hypertensive rats (16).The compound also lowers blood pressure when given intravenously to anesthetized normotensive rats (1 8).

Hemodynamic Effects in Dogs

The hemodynamic effects of terazosin were studied in anesthetized male beagle dogs at intravenous doses of 0.1 and 0.3 mgkg administered cumulatively (Table 1) (14). In these experiments, terazosin exhibited a dominant effect of decreasing the arterial blood pressure (slightly more pronounced for systolic than diastolic blood pressure, BP), left ventricular blood pressure (LVSP), and total peripheral resistance (SVR). Transient increases in heart rate (HR), cardiac output (CO), and left ventricular dPldt,, were observed immediately following the administration of the drug. These lasted only several minutes and later subsided towards the base lines; in case of LVdPfdt,,, the effects reversed into a mild reduction.

Prazosin, tested in parallel experiments, exhibited a similar hemodynamic profile with the exception of LVdPfdt,,, which remained elevated during the entire 2-hr observation period.

Premedication of the dogs with phenoxybenzamine (10 mgkg i.v.) greatly reduced the hypotensive effect of terazosin, whereas propranolol (0.5 mgfkg i.v.) and/or atropine (1 mgkg i.v.) did not affect it significantly. These experiments, together with characteristic modifications of the autonomic challenges, suggested that the a-adrenergic blockade represents a significant component of the hypotensive action of terazosin.

MECHANISM OF ACTION

The mechanism of action of terazosin was shown to be a selective a,-adrenergic inhibition similar to that of prazosin (11,12). The radioligand technology and the norepinephrine overflow technique were employed in these studies.

The binding affinity constants (KI) determined in membrane homogenates pre- pared from rat liver (a, receptor labeled by [3H]prazosin) and rat brain cortex (a2 receptor labeled by [3H]rauwolscine) demonstrated the high a1 selectivity of terazosin. An approximately threefold lower potency of terazosin as compared to prazosin was observed for the a l receptor interaction; the respective KIs (nM) were 2.8620.36 and 1.05 20.27. The affinities for the a2 receptors were extremely low and equal for terazosin and prazosin, the respective KIs (nM) being 452.02 -t 42.46 and 437.52253.52.

In the functional test in the [3H]norepinephrine-preloaded, superfused rabbit pulmonary artery, increasing concentrations of terazosin progressively blocked the contractile response to electrical stimulation mediated by the postsynaptic a, re-

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4 TERAZOSIN

D

(mtlKt1 A . VEHICLE 1 . 1

0 . 1 E . 3 I . 10

c . 30

--G c . 3

Rel. S.E.M.': 1.1 to 4.0%

0 1 5 8 24

TIME (hours)

.S.E.M.

x 100%

MEAN

B

^'0°

r

t

2

4 0 - I

3

30 -

20 10

-

I

F-F Rel. s.E.M.': 2.6 to 8.3%

.-

^S.E*M._MEAN^x^100% TIME (hours)

FIG. 2. Antihypertensive activity in SHR rats. A,B: Following single bolus oral administration of terazosin.

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TERAZOSIN 5

C

I hour D 8 hours

TERAZOSIN

A PRAZOSIN

~~

.03 .1 .3 1 3 10 30

i

.03 Î .I .3 ^c 1 Î 3 10 Î 30 Î LOG DOSE (mg/Kg)

FIG. 2 (continued). C,D: Potency comparison of terazosin and prazosin at 1 hr and 8 hr.

Eight rats were used in each treatment group.

ceptor. Prazosin exhibited comparable although more potent inhibition of the a,- mediated response. In the same tissue, the stimulation-induced tritium overfow, which is governed by the inhibitory (presynaptic) trz receptors, remained unaf- fected by either compound, even at the highest tested concengations (1 FM), at which the contractile responses were completely abolished (Fig. -3).

Of particular note was the time course of the onset and reversibility of the terazosin effect on the superfused tissue in comparison to prazosin (Fig. 4). Although both compounds inhibited the contractile response to electrical stimulation, terazosin reached the equilibrium response much faster than prazosin, and following its withdrawal from the superfusate, the tissue more rapidly recovered to its initial response. It is speculated that the difference in the binding reversibility of these two compounds is determined by their physical chemical differences.

In addition to the abovementioned studies, the a-adrenergic inhibitory properties of terazosin were studied in rabbit aorta in vitro against agonists norepinephrine and phenylephrine (Fig. 5 ) and in vivo, preventing the fatal effect of norepinephrine in mice. Since the selectivity of terazosin for the ^alreceptor, like that of prazosin, reflects primarily its lack of meaningful a2 affinity, the a, affinity of terazosin is in practical terms the determinant of its overall a receptor inhibitory activity in vivo. All of these tests showed terazosin to be a competitive inhibitor with potency approximately one third that of prazosin.

The selective a1 inhibitory properties of terazosin were confirmed and experi- mentally exploited in numerous laboratories (9,16,18,22). On the other hand, terazosin produced minimal antagonistic effects to BaC12, CaC12, serotonin, acetyl- choline, angiotensin 11, or isoproterenol in a variety of isolated organs in v i m ( 14,16).

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TABLE 1. Hemodynamic effects of terazosin in beagle dogsa Time after first dose af Terazosinb SBP DBP co SVR LVSP HR LVdPldt, (min) (mm Hg) (mm Hg) (literdmin) (dyne~sec.~m-~) (mm Hg) (beatdmin) (mm Hg/sec) Base-line values Control period Terazosin Control period Postphenoxybenzamine (1 0 mg/kg) Terazosin

~ ~~~~ ~ 130.2 96.0 1.50 5,811 132.5 139.0 2,475 Percentage change 60 - 9.0' - 2.9 1.3

-

5.1

-

10.4' 5.1 - 3.0 120 -19.0' -14.8 3.7 - 15.7 - 18.5' 10.0 -12.1' 180 - 20.9' - 16.9' 5.7 - 17.0

-

19.8' 11.5 - 4.0 Base-line values 119.4 79.7 1.79 4,581 125.7 143.2 2,080 99.5 62.9 1.92 3,293 108.0 191.6 2,048 Percentage change 60 - 6.1 - 1.1 - 9.7 4.6 - 5.3' - 6.0 -21.8 120 - 5.4 - 0.3 2.8 - 5.0 - 5.9' - 5.1 - 25.0 180 - 6.4 - 1.5 - 9.9 2.3 - 2.0 - 0.4 -21.0

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Base-line values Control period Postpropranolol (0.5 rng/kg) 128.0 85.0 1.64 5,173 132.5 123.3 2,025 123.9 85.6 1.61 5,530 128.4 120.2 1,600 Percentage change Terazosin 60 - 9.4' - 1.1 8.1 - 10.7* - 9.2' 10.8" - 1.6 120 -18.4' -12.2 8.2 - 24.3 -16.8 25.9' - 4.7 1 80 -18.5* -13.5 17.6 - 33.6 -16.6 28.8" - 7.8 Base-line values Control period Postatropine (1 mg/kg)

~ ~~ ~ ~~ ~ ~~ ~~ 131.2 98.5 1.89 5,064 132.5 183.3 2,275 124.8 98.6 1.76 5,276 126.4 224.8 2,300 Percentage change Terazosin 60 - 5.7' - 2.6 - 1.4 4.4 - 2.8 - 6.7 - 4.3 120 -21.6" -22.9'

-

6.4 - 15.6" -18.6' - 9.3 - 26.1 180 -23.8" -27.6* - 7.0 - 22.3' -21.7* - 7.0 - 30.4 *All substances were injected i.v.; n =4;*p<0.05 (paired f-test). bA dose of 0.1 rng/kg was given following control period, at which baseline values were measured, and/or 30 rnin following prernedication; 0.3 mgkg was given 60 rnin later.

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8 TERAZOSIN

(% OF TOTAL TISSUE

TRITIUM)

VEHICLE PRAZOSIN

0 TERAZOSIN

T r

1 0 9

T T

108 10 7 1 0 6

CONTROL MOLAR CONCENTRATION OF TESTED

PERIOD COMPOUNDS IN SUPERFUSATE

X %

S.E.M.: N = 8

FIG. 3. Presynaptic ([3H]NE overflow) and postsynaptic (contractile response) a-adrenergic inhibition in electrically stimulated superfused rabbit pulmonary artery in vitro.

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TERAZOSIN 9

A RABBIT PULMONARY ARTERY 9/24/81 PRAZOSIN

150

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125

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150

I 125 a

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25

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C CONTROL 1X109M C. 1 X l M M

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l X l 0 7 W

RABBIT PULMONARY ARTERY 9128181 TERAZOSIN

B

.so 210 270 330

superfusion

FIG. 4. Onset and reversibility of prazosin (A) or terazosin (B) inhibitory effects on the contractile response to the stimulation in the superfused rabbit pulmonary artery in vitro.

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i

loo

1 RABBIT AORTA

w lo-' lo-' 10-5 lo-' 10-3 M PHENYLEPHRINE NOREPINEPHRINE POTENCY POTENCY PA2 SLOPE RATIO' PA2 SLOPE RATIO' TERAZOSIN 7.80 f 0.09 -1.16 f 0.03 1 7.34 0.40 -0.80 f 0.51 1 PRAZOSIN 8.40 f 0.07 -1.16 f 0.02 3.98 8.17 f 0.44 -0.74 f 0.33 6.76 *antilog [PA. Prazosln - pAt Terazosln] FIG. 5. a-Adrenergic inhibition in isolated rabbit aorta h vjm. Four strips were used for determination of each PA, value, P9 12 0

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TERAZOSIN ANCILLARY STUDIES

Acute Toxicity Studies

The LDso values for terazosin (tested in solution) in rats and mice via mtrave- nous (i.v.) and oral (p.0.) routes of administration are summarized in Table 2.

Prazosin values (tested in suspension) are indicated for comparison. Signs of toxicity were similar for both compounds and included decreased activity, dyspnea, ataxia, twitches, convulsions, and mucoid discharges from the nose and eye.

Deaths, when they occurred, were within 5 min following administration. When the drugs were given orally to rats, significant deviation from parallelism was observed between terazosin and prazosin. When tested i.v. in mice, prazosin, unlike terazosin, was shown to double its toxicity when aged 24 hr in solution, possibly reflecting a slow partial solubilization of prazosin.

Based on the p.0. activity in SHR rats and the p.0. acute toxicity in normotensive rats, the therapeutichafety ratio of terazosin was comparable to that of prazosin; the LDS0 values were several thousand times the effective doses.

Chronic Intravenous Toxicity in Rats

When terazosin was administered daily for 1 month at doses of 10, 40, and 150 mgkg per day, the no-toxic-effect dosage was 40 mglkg per day. Toxicity at 150 mgkg included hypothermia and death and reflected exaggerated pharmacologic effects (7).

Mutagenicity Studies

Terazosin, when tested in vitro in microbial assays employing Salmonella, was devoid of any mutagenic activity in the Ames test.

TABLE 2. LDm values for terazosin and prazosin

Terazosinb PrazosinC Approximate

Route of toxicity

Species administration d P d P ratioa

Rat Rat Mouse

Oral 5.5 6.0 8.9 9.0 1

intravenous 0.255 0.270 0.073 0.075 3.5'

(24 hr) 0.240 0.264 0.045 0.048 5*

Intravenous 0.249 0.270 0.103 0.092 2.6*

Aged formulation

Tlatio terazosin/prazosin; 'p<0.05.

bSolution.

cSuspension.

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12 TERAZOSIN

Effect on Plasma Lipoproteins in Gerbils

The effects of terazosin and prazosin on the plasma lipoproteins in gerbils were compared following 15 days of oral administration of equivalent doses (Fig. 6).

Compared to control, both prazosin, 6.3 and 20 mgkg, and terazosin, 6.9 and 22 mg/kg

,

caused significant decreases in total plasma cholesterol. With prazosin, the high-density lipoprotein cholesterol (HDL-C) was significantly lower than that of control only in the 20 mgkg group. Terazosin decreased the HDL-C at the dose of 6.9 mgkg. There were no significant effects on LDL-C plus VLDL-C or the ratio of HDL-C to LDL-C plus VLDL-C with any of the experimental groups.

Gastrointestinal Irritation Studies in Rats

Neither terazosin nor prazosin produced any visible lesions in the GI tract of rats following oral administration of 30 mgkg (more than 30 times the antihypertensive dose).

TOTAL CHOLESTEROL

90 i i i i

801 _m

- ³

₇₀ ^HDL-C

60 60

5

⁵⁰ ⁵⁰

40 40

30 30

20 20

10 10

0 0

c5

- -

6.3 20 6.9 22 DOSE 6.3 20 6.9 22

LDL-C

+

^VLDL-C

90 1

H D L-C LDL-C

+

^VLDL-C

1.6 1.4 1.2 1 80

70 60

9 50

A

-

40 0.8

30 0.6

20 0.4

10 0.2

0 0

-

6.3 20 6.9 22 DOSE 6.3 20 6.9 22

CONTROL

0

^PRAZOSIN ^TERAZOSIN

FIG. 6. Effect of prazosin and terazosin on plasma cholesterol in gerbils. ('):psO.Ol.

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TERAZOSIN 13

Spontaneous Motor Activity in Rats

Terazosin and prazosin produced comparable biologically insignificant decreases in rat spontaneous motor activity at an oral dose of 80 mgkg (more than 80 times the antihypertensive dose).

METABOLISM

After oral administration of a 0.33 mglkg dose of [14C]terazosin, the levels of radioactivity in the plasma peaked at 10 ng equivalentslml by 4 hr in rats and at 59 ng equivalentslml by 1 hr in dogs. The unchanged parent drug accounted for most of the radioactivity in the plasma of both species, and the half-lives of terazosin were estimated to be 5.5 hr in rats and 8.8 hr in dogs. The I4C levels in whole blood were consistently higher than those in plasma, with cell-to-plasma ratios averaging 1.6 in rats and 2.1 in dogs.

During the 3-day period after oral administration of ['4C]terazosin to rats, 28%

of the I4C dose was excreted in the urine, and 70% was eliminated in the feces.

Following intravenous administration, urinary and fecal excretion averaged 44%

and 56%, respectively. In dogs given [I4C]terazosin orally and intravenously, 38 to 41% of the administered radioactivity was excreted in the urine within 5 days, and 54 to 56% was eliminated in the feces. Based on the excretion data, it was estimated that about 65% of the I4C dose was absorbed in rats, but the absorption was somewhat greater in dogs (range 77-100%).

The importance of biliary secretion in the elimination of [14C]terazosin was demonstrated in additional studies. Within 2 days after intragastric or intravenous administration of [I4C]terazosin (0.33 mg/kg), rats excreted 35% or 59%, respectively, of the I4C dose in the bile. In dogs given the same dose of [I4C]terazosin intravenously, biliary excretion averaged 13% in 6 hr.

Metabolic patterns were determined in the urine and bile of the rats and dogs by thin-layer chromatography. Unchanged terazosin was the predominant radioactive compound in the urine, accounting for 16% of the oral dose and 26% of the intravenous dose in rats and about 16 to 17% of either the intravenous or oral dose in dogs. In addition to the parent drug, at least nine metabolites were detected in the urine and bile of both species. The biotransformation of terazosin appeared to in- volve primarily 0-demethylation and conjugation, hydrolysis of the amide linkage to yield the piperazine derivative, and, to a lesser extent, piperazine ring opening and N-dealkylation (see Fig. 7).

Tissue distribution studies were conducted in rats given single or daily oral doses of [I4C]terazosin (0.33 mg/kg per day). At 1 hr after the single dose, the tissue levels were higher than the plasma concentrations in all organs except the brain and testes. Among the tissues with the highest concentrations were the liver and kidneys, followed by the pancreas, thyroid, pituitary, adrenal glands, and spleen. A comparison of the levels of radioactivity in the tissues 24 hr after the

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o=v I

o=v

Q /

\

o=v I

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TERAZOSIN 1s

single dose and the fifth daily dose of ['4C]terazosin gave little indication of accu- mulation with repeated administration of the drug.

Following oral administration of the 14C-labeled compounds in rats, terazosin displayed more gradual onset of the plasma levels and held higher levels at later intervals (8, 12, and 16 hr) than prazosin, suggesting a potential for more pro- tracted therapeutic effect (Fig. 8).

Absorption, Metabolism, and Excretion of [14C]Terazosin in Humans The metabolic fate of terazosin was studied in man following oral administration of ['4C]terazosin to four male subjects at a dose of 1.0 mg as a capsule. The peak levels of radioactivity in the plasma occurred 0.5 to 1 .O hr after dosing and ranged from 11 to 29 ng/ml. Most of the radioactivity in the plasma during the first day was attributable to the unchanged parent drug (half-life 12 hr), but two minor, un- identified polar metabolites were also detected in the plasma.

An average of 38.8% of the 14C dose was excreted in the urine during the 7-day study period. Approximately 69% of the urinary radioactivity was eliminated during the first 24 hr, and 94% was excreted within 3 days. Fecal excretion accounted for 55.6% of the I4C dose, and the total recovery of the administered radioactivity averaged 94.4%.

The metabolic pathways of terazosin in man were similar to those observed in

nglml

HOURS AFTER DOSE

FIG. 8. Average plasma levels of parent drug (in ng/ml) after oral administration of ['4C]tera- zosin and [14C]prazosin, each to four fasting Sprague-Dawley rats.

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16 TERAZOSIN

rat and dog. Unchanged parent drug accounted for 28.5% of the I4C dose, with 10.4% excreted in the urine and 18.1% eliminated in the stools.

The in vitro protein binding of ['4C]terazosin in human plasma averaged 90 to 94% at 10 to 100 ng/ml. Considerably less [I4C]terazosin was protein bound in the plasma of rats (5143%) and dogs (4045%).

Comparison with Prazosin

In contrast to terazosin, which is almost completely absorbed in man, prazosin has variable absorption ranging from 44 to 69%, with a mean of 57% (10). In addition, prazosin may be affected by first-pass hepatic metabolism (20). Most significantly perhaps, terazosin has an approximate 12-hr half-life, which is three to four times that reported for prazosin (8).

CLINICAL STUDIES

The antihypertensive effects of orally administered terazosin in man have been reported in several clinical studies (4,5,15,17). Terazosin has been administered to hypertensive patients once daily, alone and in combination with other antihypertensive agents, in doses ranging from 1 to 40 mg. Mean reductions in blood pressure from baseline levels to the end of treatment were significantly greater for patients receiving terazosin as monotherapy than for patients receiving placebo (2).

Terazosin was also significantly more effective than placebo when used in combination with other antihypertensive medications ( l), including thiazide diuretics (21).

The 24-hr blood pressure profile of terazosin was investigated in a placebo-con- trolled, dose-titration study in which patients received terazosin as once-daily monotherapy (5). Five patients in the terazosin group underwent 24-hr blood pressure monitoring prior to treatment, after approximately 1 week of therapy (8 2 1 days), and when they finished the study (85 k 14 days). Four patients receiving placebo in the same study also underwent 24-hr blood pressure monitoring. At the end of the study, the circadian blood pressure pattern was shifted downward in the terazosin-treated patients but not in the placebo-treated patients; whole-day blood pressure averages were significantly reduced for the patients receiving terazosin but not for the patients receiving placebo.

The safety profile of terazosin, including side effects such as dizziness and as- thenia, is consistent with what might be expected for an al-adrenergic blocking agent. Terazosin treatment has been associated with favorable changes in plasma lipids (19). Analysis of combined data from three monotherapy studies revealed that both the mean serum cholesterol and the low density lipoprotein plus very low density lipoprotein cholesterol fraction (LDL

+

VLDL) were significantly lower in patients treated with terazosin than in patients receiving placebo. The high-density lipoprotein fraction (HDL), on the other hand, increased in the terazosin group (3).

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TERAZOSIN 17

Data supporting the clinical efficacy and safety of terazosin in the treatment of hypertension have been described elsewhere in more detail (6).

CONCLUSION

Terazosin is a novel quinazoline antihypertensive agent. It has been shown to lower blood pressure when administered orally to experimental animal models as well as to normotensive and hypertensive man. A once-a-day oral regimen with terazosin produces adequate clinical results.

Although overall equally efficacious as prazosin in SHR, terazosin was shown to produce only approximately one-third of the a-adrenergic inhibition associated with prazosin. Like prazosin, terazosin displayed minimal interaction with a2 receptor and should be considered primarily an al-selective agent.

Reflecting structural similarity with prazosin, terazosin exhibited, in general, a similar pharmacological profile, decreasing the arterial blood pressure primarily by lowering peripheral vascular resistance.

The differences between terazosin and prazosin seem to manifest primarily in their pharmacokinetics, perhaps ultimately related to the differences in their water solubility.

In conclusion, the pharmacological profile of terazosin suggests that this drug is a new antihypertensive agent with a salutary effect on plasma lipid profile. Tera- zosin might offer certain advantages over prazosin in its duration of action, homo- geneity, and predictability of the response. In addition, the water solubility of terazosin opens the option of its use by the parenteral route.

REFERENCES

1. Chrysant, S.G., et al. (1986): Experience with terazosin administered in combination with other 2. Dauer, A .D ., et al. (1986): Terazosin: An effective once-daily monotherapy for the treatment of 3. Deger, G. (1986): Cumulative experience with terazosin administered in combination with diuret- 4. Dietz, A.J., Magarian, E., Freeman, D., and Carlson, J. (1984): Terazosin: Safety and efficacy 5 . Drayer, J. I.M., Weber, M. A , , DeYoung, J.L., and Brewer, O.D. (1983): Long-term BP moni- 6. Focus on a new a,-adrenergic antagonist: terazosin (1986). Am. J. Med., 8(Suppl SC).

7. Fort, F.L., Tekeli, S., Majors, K., Heyman, I. A., Cusick, P.K., and Kesterson, J. W. (1984):

Terazosin: Intravenous safety evaluation in rats. Drug Chem. Toxicol., 7:435-449.

8. Hobbs, D.C., Twomey, T.M., and Palmer, R.F. (1978): Pharmacokinetics of prazosin in man.

J. Clin. Pharmacol., 18:402-406.

9. Itoh, H., Kohli, J.D., and Rajfer, S.I. (1984): Alpha adrenoceptor subtypes in canine mesenteric arteries and veins. Fed. Proc., 43:353.

antihypertensive agents. Am. J. Med., 8(Suppl 5C).

hypertension. Am. J. Med., 8(Suppl 5C).

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in essential hypertension, and effects on serum lipids. J. CIin. Pharmacof., 24(8-9):416.

toring in the evaluation of antihypertensive therapy. Arch. Intern. Med., 143:898.

10. Jaillon, P. (1980): Clinical pharmacokinetics of prazosin. Clin. Pharmacokinet., 5:365-376.

11. Kyncl, J . J . , Bush, E.N., and Buckner, S.A. (1982): Alpha-adrenergic blocking properties of terazosin. Fed. Proc., 41:1648.

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I8 _TERAZOSiN

12. Kyncl, J.J.. Bush, E.N., and Buckner, S. (1986): Terazosin, a new quinazoline antihypertensive agent. 11. Alpha-adrenergic blocking properties. In: Focus on Alpha Blockade and Terazosin, ed- ited by J. Rosenthal. Zuckschwerdt Verlag, Munich.

13. Kyncl, J.J., Hollinger, R.E., Oheim, K.W., and Winn, M. (1980): (ABBO’IT-45975), 2-[4- (tetrahydro-2-furany1)carbonyl- ₁-piperazinyl]-6,7dimethoxy-4-a-quinazolinamide HC 1, a new antihypertensive agent of the quinazoline type. Pharmacologist, 22:3.

14. Kyncl, J.J., Winn, M., Stein, H.H., Dodge, P.W., Anderson, D.J., Hollinger, R.E., and Oheim, K. W. (1985): Terazosin, a new quinazoline antihypertensive agent. I. General phannacol- ogy. In: Focus on Alpha Blockade and Terazosin, edited by J. Rosenthal, Zuckschwerdt Verlag, Munich.

15. Mersey, J.H., and Elkayarn, U. (1984): Effect of Terazosin on blood pressure and lipids in hypertension. Clin. Res., 32(3):688A.

16. Mmgami, S., and Hanazuka, M. (1982): Antihypertensive effect of 2-[4-[{(tetrahydm-2-furanyl)- carbonyl}]- 1 -piperazinyl]-6,7-dimethoxy-4quinazolinamine hydrochloride dihydrate [termsin].

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17. Nelson, E. H.B., Pool, J.L., Taylor, A. A., and Mitchell, J.R. (1982): Evaluation of terazosin in the treatment of essential hypertension. Clin. Pharmacol. Ther.. 31(2):255.

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changes plasma lipids in man. Clin. Res., 30(2):213A.

hepatic extraction in the dog. J . Cardiovarc. Pharmacol., 1:641-647.

diuretics. Am. J. Med., 8(Suppl 5C).

myocardial cells is an alphal adrenergic response. J. Clin. Invest., 72:732-738.