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alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (20%) and half-life (6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

The binding properties of reduced and carbamidomethylated hGH (RCAM-hGH) were compared to those of native hGH. The time course of binding to rabbit liver plasma membranes and the response of binding to temperature of both RCAM-hGH and hGH were similar. RCAM-hGH binding exhibited a broad pH optimum for binding which was approximately 50% of the peak of hGH binding at pH 6. RCAM-hGH binding was not enhanced by divalent cations to the same extent as hGH binding, but monovalent cations affected the binding of both hormones similarly. The most striking difference in binding between RCAM-hGH and hGH was observed in the displacement curves of the hormones. Half-maximal displacement of 125I-hGH occurred at 19 and 38 pmoles⁄ml hGH and RCAM-hGH, respectively. In comparison, half-maximal displacement of 125IRCAM- hGH occurred at 26 and 46 pmoles⁄ml RCAM-hGH, respectively. Approximately 30–40% of l25I-RCAM-hGH was nondisplaceable by both RCAM-hGH and hGH compared to 10% for 125I-hGH. Scatchard plots of 125I-hGH bindi...

By measuring [125I]hGH binding in the plasma of human GH (hGH)-deficient children at 3- to 4-month intervals during hGH therapy with hGH prepared by Raben's method, we have defined three patterns of antibody formation. One group of patients developed antibodies by 3 months of therapy that persisted despite the length or type of hGH therapy. Their antibodies were characterized by a low affinity (1.49 × 109 M−1) and a high capacity (29 nmol/liter plasma). The development or presence of antibodies adversely affected the growth rate in only one patient in this group. This patient's antibodies were characterized by the highest capacity (1235 nmol/liter plasma) and lowest affinity (0.044 × 109 M−1). The capacity decreased to 134 nmol/liter plasma upon switching to a hGH preparation without aggregated hGH. The second group developed antibodies to hGH by 6–9 months of therapy, but [125I]hGH binding by the plasma returned to control levels by 20 months of therapy. The antibodies of this group were characterized by...

The bioavailability of L-dopa following rectal administration of a series of short-chain alkyl esters of L-dopa was determined in rats and dogs. The esters were stable (>360 min) to hydrolysis in physiological buffer. In vitro enzymatic hydrolysis of the esters in plasma was species dependent, with the hydrolytic rate being faster in rat plasma (t1/2 600 mg/ml) esters of L-dopa are potential candidates for controlled-release rectal delivery systems designed to provide more constant plasma L-dopa levels.

In an attempt to define alterations in cellular metabolism associated with growth hormone deficiency, we have studied the alkaline RNAase activity in the liver subcellular fractions from normal and hypophysectomized (hypox) adult and weanling rats. The total RNAase activity of the liver and kidney subcellular fractions was determined in adult and weanling rats maintained in a fed or fasted (15-hr) state. In the adult rat, RNAase activity/g tissue increased following hypox in each of the liver subcellular fractions with the soluble fraction exhibiting an approximate two-fold increase. Part of the increased activity was real due to an increase in the specific activity of the enzyme and part was apparent due to decreased liver weight following hypophysectomy. RNAase activity of the microsomal fraction of the adult rat kidney increased following both hypox and fasting; however, the largest increase appeared secondary to hypophysectomy. In the weanling rat, RNAase activity was increased only in the nuclear and soluble fraction of the fasted hypox rat liver. The nuclear and soluble fraction exhibited a two-fold increase in activity over comparable fractions from normal and normal fasted rat liver. The increased activity was real due to increased specific activity of the enzyme and apparent due to decreased liver weight. RNAase activity of the soluble fraction of weanling rat kidney increased in the normal fasted, hypox, and hypox fasted rat. This increase in the kidney was only apparent secondary to decreased renal weight following fasting and/or hypox. Liver RNAase activity returned to normal levels in the nuclear and soluble fraction from fasted weanling hypox rat liver following treatment with hGH but not with thyroxine or estradiol. It is concluded: (a) hGH deficiency results in real and apparent alterations of liver RNAase activity, (b) alterations in RNAase activity may be important in the mechanism of action of hGH but factors such as age and fasting are important modifiers of the system.

Significant increases in basal, and glucagon and fluoride stimulated adenylate cyclase activity were observed in liver plasma membranes of hypophysectomized rats compared to normal adult and weanling rats. The fluoride stimulated adenylate cyclase activity was 2-3 fold greater in the membranes from hypophysectomized animals while the glucagon stimulated activity was 5-7 fold greater, and the basal activity was approximately double that of membranes from normal adult animals. Administration of growth hormone to hypophysectomized rats by an intramuscular or intravenous route decreased adenylate cyclase activity to levels equivalent to those in normal adult rats. Estradiol and thyroxine replacement did not alter the adenylate cyclase activity of the membranes from hypophysectomized animals. The fluoride or epinephrine stimulated adenylate cyclase activity of rat diaphragm homogenates was not affected by hypophysectomy.