Profound hyperglycemia and metabolic acidosis after verapamil overdose.

Verapamil, a potent calcium antagonist, possesses varied systemic effects, including smooth muscle relaxation leading to both peripheral and coronary artery vasodilation, slowed atrioventricular nodal conduction and decreased insulin release from the pancreatic B cells. Reports concerning the effects of acute intoxication with verapamil are scarce. A case is presented of a 22 year old woman who developed profound hyperglycemia and metabolic acidosis after the inadvertent overdose of thirty 80 mg tablets (2,400 mg) of verapamil. This case illustrates the need for physicians to be aware of verapamil's inhibitory effects on insulin release and to exercise special care when prescribing verapamil in patients with preexisting diabetes mellitus.

Insulin-like growth factor-I (IGF-I) antisense oligodeoxynucleotide mediated inhibition of DNA synthesis by WI-38 cells: evidence for autocrine actions of IGF-I.

Insulin-like growth factor-I (IGF-I) is elaborated into culture medium by WI-38 cells, a human embryonic lung fibroblast cell line, and may participate in the autocrine stimulation of DNA synthesis. We have confirmed the expression of IGF-I by these cells and documented that they express the type 1 IGF receptor and a number of IGF-binding proteins. In situ hybridization histochemistry demonstrated relatively uniform expression of IGF-I and type 1 IGF receptor transcripts among WI-38 cells. To determine whether WI-38-synthesized IGF-I exerted mitogenic effects, a 15-base oligodeoxynucleotide complementary to the 5'IGF-I mRNA sequence (IGF-I AS-Oligo), including the translation start site, was incubated with cultured cells in an attempt to inhibit IGF-I synthesis. The IGF-I AS-Oligo was stable in cell culture, formed intracellular duplexes with IGF-I mRNA, and at 2 microM reduced IGF-I in conditioned medium by 83%. The IGF-I AS-Oligo also inhibited [3H]thymidine incorporation into DNA in a dose-dependent fashion (by 77% at 2 microM and by 95% at 20 microM). This reduction in DNA synthesis was prevented when the medium was supplemented with 100 ng/ml IGF-I. The oligomer also decreased the abundance of IGF-binding proteins in conditioned medium. The IGF-I AS-Oligo appears to exert its effects by blocking IGF-I mRNA translation, rather than blocking transcription or initiating RNase-H activity, because the abundance of IGF-I transcripts was not decreased in its presence. These findings confirm an essential role for IGF-I in WI-38 cell DNA synthesis and are consistent with autocrine actions by WI-38 cell IGF-I.

Gene expression of insulin-like growth factors (IGFs), the type 1 IGF receptor, and IGF-binding proteins in dexamethasone-induced fetal growth retardation.

Altered gene expression and/or actions of the insulin-like growth factors (IGFs) have been implicated in the mediation of both pre- and postnatal growth retardation secondary to glucocorticoid excess. To investigate this possibility, we assessed the gene expression of the IGFs, the type I IGF receptor, and IGF-binding proteins (IGFBPs) in 20-day gestation liver and lung of growth-retarded fetuses whose mothers were treated with dexamethasone (DXM; 100 micrograms, ip, daily) on gestation days 15-19 (gestation = 21-22 days). DXM treatment in dams produced fetal growth retardation without decreasing litter size (32% decrease in fetal body weight). Both fetal liver and lung demonstrated decreased wet weight (48% and 47%, respectively) and DNA content (65% and 51%, respectively) compared to control animals. Our results suggest that increased expression of IGFBP-1, and possibly IGFBP-2, is involved in mediating the marked growth retardation. As assessed by solution hybridization assays and Northern blot analysis, there was an 8.5-fold increase in IGFBP-1 mRNA expression in the livers of DXM-treated fetal animals compared to that in sham-injected controls (P less than 0.002). IGFBP-2 mRNA expression was also increased (60%) in fetal liver, whereas IGFBP-3 was decreased (57%). In fetal lung, IGFBP-1 transcript abundance was also higher in DXM-treated fetal animals. Serum concentrations of IGFBP-1, but not those of IGFBP-2, were increased (approximately 4-fold) in the DXM-treated fetuses, as quantified by [125I]IGF-I ligand blotting and IGFBP-2 immunoblotting. Because hypoinsulinemia increases the expression of IGFBP-1 and -2, serum insulin concentrations were measured and found to be decreased in the DXM-treated fetuses (24 microU/ml) compared to control values (72 microU/ml). Analysis of mRNA expression for IGF-I, IGF-II, and the type 1 receptor transcripts did not support a role for decreased IGF or IGF receptor expression in the etiology of DXM-mediated growth retardation. IGF-I was unchanged in both liver and lung, and IGF-II transcripts were increased by 31% in liver and unchanged in lung of DXM-treated fetal animals. Northern analysis of hepatic and lung poly(A) RNA demonstrated no evidence for independent regulation of specific-sized IGF transcripts. Further, type 1 IGF receptor RNA abundance increased 42% in fetal liver and was unchanged in lung. Because IGFBPs may modulate IGF action, these results suggest that increased IGFBP-1, and possibly IGFBP-2, expression may be of importance in the etiology of DXM-induced fetal growth retardation.

Nonpeptide angiotensin II receptor antagonists. Studies with EXP9270 and DuP 753.

A series of nonpeptide angiotensin II (Ang II) receptor antagonists was evaluated in rat adrenal cortical microsomes for their inhibitory effects on the specific binding of [3H]Ang II, in the isolated rabbit aorta bioassay for their functional antagonism of contractile response to Ang II, and in high renin, renal-hypertensive rats for their intravenous antihypertensive effects, expressed as IC50, pA2, and intravenous ED30, respectively. Highly significant linear correlations were found between IC50 and pA2 (r = -0.88), between IC50 and intravenous ED30 (r = 0.79), and between pA2 and intravenous ED30 (r = -0.93). In both in vitro and in vivo functional assays, none of these antagonists exhibited agonistic effects. The orally active nonpeptide Ang II receptor antagonists EXP9270 and DuP 753 (oral ED30 = 3.6 and 0.59 mg/kg, respectively) were selected for further characterization. These antagonists exhibited selective and competitive Ang II antagonism in rabbit aorta and guinea pig ileum. In conscious normotensive rats, DuP 753 abolished the pressor response to saralasin, suggesting that the pressor effect of saralasin is attributed to its Ang II-like activity. In addition, DuP 753 also blocked the Ang II-induced drinking response and aldosterone release in rats. These results suggest that Ang II receptor blockade is the primary mechanism of the antihypertensive effect of these nonpeptide Ang II receptor antagonists. Further, the specificity and lack of partial agonistic effects of these molecules make them potentially useful physiological probes and therapeutic agents.

Nonpeptide angiotensin II receptor antagonists. IV. EXP6155 and EXP6803.

EXP6155 (2-n-butyl-1-[4-carboxybenzyl]-4-chloroimidazole-5-acetic acid) and EXP6803 (methyl 2-n-butyl-1-[4-(2-carboxybenzamido)benzyl]-4-chloroimidazole -5-acetate, sodium salt) are shown to be novel, nonpeptide, antihypertensive, specific angiotensin II receptor antagonists. In rabbit aorta, they competitively inhibited the contractile response to angiotensin II with pA2 values of 6.54 and 7.20 and did not alter the response to norepinephrine or KCl. In guinea pig ileum, both agents blocked the responses to angiotensin I and II and did not alter the responses to bradykinin and acetylcholine. A similar specific angiotensin II antagonism was shown in vivo in the spinal pithed rat model. In renal artery-ligated rats, a high renin hypertensive model, EXP6155 and EXP6803 given intravenously, decreased blood pressure with ED30 of 10 and 11 mg/kg, respectively. Both compounds did not alter blood pressure when given orally at 100 mg/kg. Unlike saralasin, EXP6155 and EXP6803 given intravenously did not cause a transient increase in blood pressure in the renal artery-ligated and normotensive rats. Our results indicate that EXP6155 and EXP6803 are selective angiotensin II receptor antagonists and antihypertensive agents. Since neither compound had partial agonist activities or bradykinin potentiation effects, unlike the existing peptide angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, respectively, they may represent preferred probes for studying the physiological roles of angiotensin II.

Hypotensive action of DuP 753, an angiotensin II antagonist, in spontaneously hypertensive rats. Nonpeptide angiotensin II receptor antagonists: X.

In conscious 18-21-week-old spontaneously hypertensive rats, DuP 753, a nonpeptide angiotensin II receptor antagonist, given orally at 3 and 10 mg/kg or intravenously at 3, 10, and 30 mg/kg, reduced blood pressure dose dependently. It did not alter heart rate at these doses. At 10 mg/kg i.v., DuP 753 decreased blood pressure significantly for at least 24 hours, suggesting a long duration of the antihypertensive effect. Unlike saralasin, DuP 753 did not cause a transient increase in blood pressure. The acute antihypertensive efficacy of DuP 753 was greater than that of captopril. Our data indicate that, for captopril to reduce blood pressure to a similar extent as that of DuP 753, it would need to be supplemented by a diuretic. DuP 753 did not have an acute diuretic effect. Bilateral nephrectomy, but not inhibition of prostaglandin synthesis, abolished the antihypertensive effect of DuP 753, suggesting that the antihypertensive effect of DuP 753 is dependent on an active renin-angiotensin system. Furthermore, DuP 753 inhibited the pressor response to angiotensin II but not the responses to norepinephrine, vasopressin, and Bay K 8644 (a calcium agonist). As neither DuP 753 nor captopril decreased blood pressure acutely in Wistar-Kyoto normotensive rats, our results suggest that the renin-angiotensin system plays a significant role in the control of blood pressure in spontaneously hypertensive rats.

Angiotensin II receptor antagonists. From discovery to antihypertensive drugs.

Some simple N-benzylimidazoles, originally described by Takeda Chemical Industries (Osaka, Japan), were characterized to be very weak but selective nonpeptide angiotensin II (Ang II) receptor antagonists with a competitive mode of action. Chemical modifications of these led to EXP6155 and EXP6803, which showed approximately 10- and 100-fold higher affinity, respectively, but were orally ineffective. Oral activity was obtained for the biphenyl carboxylic acid derivatives EXP7711 and especially EXP9654. A further advance in the design of nonpeptide Ang II receptor antagonists was provided by DuP 753, an analogue of EXP7711 in which the carboxylic acid function is replaced by its tetrazol-5-yl equivalent. DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bi phe nyl-4- yl)methyl]imidazole, potassium salt) displaces radiolabeled Ang II from its specific binding sites in various tissues, affording IC50 values of approximately 20 nM. DuP 753 competitively antagonizes Ang II-induced responses in various in vitro and in vivo preparations but does not influence those to KCl, norepinephrine, vasopressin, and others, nor does it affect converting enzyme and renin. In high renin animal models of elevated arterial blood pressure, intravenous and oral administrations of DuP 753 produce a sustained decrease in pressure without influencing heart rate. Marked antihypertensive effects are observed in spontaneously hypertensive rats, but no efficacy is noticed in deoxycorticosterone acetate hypertensive animals. DuP 753 showed no agonistic properties in any of the above test systems and has been chosen to undergo clinical trials for the treatment of hypertension. In rats, the 5-carboxylic acid (EXP3174) represents a major metabolite of DuP 753.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of mitral valve prolapse in bipolar affective disorder.

Of 32 patients with unipolar or bipolar affective disorder, significantly more bipolar patients had mitral valve prolapse. The prevalence of mitral valve prolapse among bipolar patients was also significantly greater than that in the general population.

Antimanic effects of verapamil.

When the authors compared the antimanic effects of verapamil, lithium carbonate, and placebo, no differences were seen between lithium and verapamil and both were more effective than placebo in reducing symptoms. No major side effects emerged during the study.

Comparison of clonidine and lithium in the treatment of mania.

The authors compared the antimanic effects of clonidine with lithium carbonate in a double-blind crossover design with 24 volunteers. Lithium was observed to be more effective than clonidine. Some patients reported experiencing hypotension (N=8) and depression (N=7) while taking clonidine.

Synthesis and pharmacology of the potent angiotensin-converting enzyme inhibitor N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanyl-(S)-pyroglutamic acid.

Structure 3a, a potent angiotensin-converting enzyme inhibitor, was prepared in five steps from L-(+)-alpha-amino-4-phenylbutyric acid by construction of the activated side-chain ester 16, displacement with L-pyroglutamate ester anion, and deblocking. Diastereomer separation was accomplished by chromatography at the diester stage, 17. Pharmacological assays established that 3a parallels enalapril in its ability to inhibit converting enzyme and lower blood pressure.

Nonpeptide angiotensin II receptor antagonists: N-[(benzyloxy)benzyl]imidazoles and related compounds as potent antihypertensives.

A series of compounds has been synthesized and demonstrated to be antagonists of the angiotensin II (AII) receptor. These compounds are structurally related to the N-(benzamidobenzyl)imidazoles and extend the scope of this new class of nonpeptide AII antagonists. It has been found that the amide linkage (X = NHCO) in the N-(benzamidobenzyl)imidazoles can be replaced successfully by a variety of groups (X = single bond, O, S, CO, OCH2, CH = CH, NHCONH); linkers of 0-1 atoms in length are most effective. When administered intravenously to awake renal hypertensive rats, these compounds are potent antihypertensives.

Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives.

A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared. These N-(biphenylyl-methyl)imidazoles, e.g. 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5- (hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously. It has been found that the acidic group at the 2'-position of the biphenyl is essential. Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency. The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective. The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension.

The discovery of potent nonpeptide angiotensin II receptor antagonists: a new class of potent antihypertensives.

A new class of potent antihypertensives has been discovered that exert their effect through blockade of the angiotensin II (AII) receptor. Most AII antagonists reported so far are peptide mimics of the endogenous vasoconstrictor octapeptide angiotensin II. The compounds of this paper are nonpeptides and therefore constitute a new class of potent AII receptor antagonists. Based on the overlap of a conformation of AII with literature lead 3, a hypothesis was developed suggesting the need for an additional acidic functionality to increase the lead's potency. The substitution of an additional carboxylic acid resulted in a 10-fold increase in binding affinity observed for diacid 4. The binding affinities for subsequent compounds were eventually increased 1000-fold over that of the literature leads through a systematic SAR study. Thus the AII receptor binding affinity [IC50 (microM)] of 15 microM for literature lead 1, for example, was increased to 0.018 and 0.012 microM for compounds 33 and 53. A structure-affinity relationship has been found requiring the presence of four key elements for good activity: (1) an additional phenyl ring at the N-benzyl para position of the benzylimidazole nucleus, (2) an acidic functionality at the ortho position of the terminal aromatic ring, (3) a lipophilic side chain at the imidazole 2-position of three to five carbon atoms in length, and (4) a group at the imidazole 5-position capable of hydrogen bonding. The synthesis as well as the pharmacological activity of the compounds in this new series of AII receptor antagonists are presented.

Premenstrual tension syndrome in rapid-cycling bipolar affective disorder.

Premenstrual tension syndrome (PMS) and rapid-cycling bipolar affective disorder have similarities of symptoms, cyclical mood swings, and putative neurotransmitter dysfunction. The possible relationship between these disorders was assessed by evaluating 25 patients with rapid-cycling disorders and 25 normal controls for PMS symptoms. Patients with rapid-cycling affective disorder had an increased tendency to have more severe forms of PMS. In addition, patients with rapid-cycling disorders and more severe forms of PMS tended to cycle more frequently. The significance of this finding and its clinical implications are discussed.

Amoxapine-induced seizures: case reports.

Two patients are described who experienced seizures while on therapeutic doses of amoxapine. It is suggested that the structural similarities of amoxapine to the neuroleptics may account for side effects similar to the neuroleptic compounds, including seizures. Caution is encouraged in prescribing amoxapine to patients with a history of seizure disorder.

Antidepressant effects of estrogen.

PIP: The authors present a case report that provides support for a relationship between estrogen and the menstrual cycle on the 1 hand and affective disorders on the other. The patient in this case, a 35-year old woman, suffered from a rapid cycling affective disorder that was severely affected by her menstrual cycle and responded positively to oral contraceptives (OCs). The patient had a 24-year history of numerous manic and depressive episodes, the 1st of which coincided with menarche. She had noted that, 4 days before menses, she would experience symptoms of premenstrual tension syndrome (PMS) and often the onset of an affective episode. Treatment with a series of psychotropic agents had not been effective in controlling the number of episodes. However, the patient reported that there had been an 8-9-month period in the past when she had taken OCs and had fewer symptoms. Thus, the patient was placed on Ortho-Novum as well as imipramine. At the 9-month follow-up, she reported there had been no further episodes of depression or mania. The exact mechanism behind estrogen's psychotropic effect is unclear, although it increases the central availability of norepinephrine and induces changes in dopaminergic, noradrenergic, and serotonergic receptors. Beta-endorphin levels covary with estrogen levels, and estrogen seems to affect every major neurotransmitter system. The fact that estrogen has not consistently been shown to be effective in this regard may only signify the existence of a distinct subclass of affective disorders closely linked to the menstrual cycle. This subclass may have some type of dysfunction within the hypothalamic-pituitary-gonadal axis that contributes to mood swings.^ieng

Verapamil in the treatment of premenstrual syndrome: case report.

A woman with a long history of premenstrual tension syndrome (PMS) received verapamil for treatment of mitral valve prolapse. Associated with verapamil therapy was a decreased severity in many symptoms of PMS, including agitation, depression, emotional outbursts, and irritability. A possible mechanism is discussed.

Chlorpromazine vs. meperidine in the treatment of phencyclidine psychosis.

Patients with phencyclidine psychosis were treated with two 50 mg injections of either chlorpromazine (N = 10) or meperidine (N = 10). The chlorpromazine-treated group responded more rapidly, but the meperidine-treated group had greater overall improvement. It is suggested that meperidine may have a role in the emergency treatment of phencyclidine psychosis. These findings may provide support for the hypothesis that dopaminergic psychosis is mediated by opioids.

Hyperphagia in premenstrual tension syndrome.

The relationship between premenstrual tension syndrome and dietary intake was studied in a population of 20 young adult women. Caloric intake was measured during the 10 days preceding and following the menstrual cycle. Those women with more severe symptoms recorded a greater increase in caloric intake. Caloric intake during the premenstrual period also increased with age. It is hypothesized that this caloric intake may be due to increased beta-endorphin levels.