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Iloperidone (HP 873) is a D2 and 5-HT2 receptor-antagonist that is under development as a potential atypical antipsychotic agent. Two studies on iloperidone evaluated its safety and tolerability, made a preliminary pharmacokinetic assessment of single 3- and 5-mg doses, and determined the effect of food on its tolerability and pharmacokinetics in healthy volunteers after single 3-mg doses. Iloperidone was well absorbed orally in fasted subjects. The Cmax occurred approximately 2 to 3 hours after administration of a single 3- or 5-mg dose. The pharmacokinetic parameters increased with the dose between 3 and 5 mg (from 2.2 to 5.2 ng/mL for Cmax, and 16 to 50 ng/mL.h for AUC). Iloperidone was eliminated slowly, with a mean t1/2 of 13.5 to 14.0 hours. Coadministration with food did not significantly affect AUC, tmax, or Cmax. These results indicate that the rate of iloperidone's absorption is decreased, but the overall bioavailability is unchanged, when the drug is taken with food. Orthostatic hypotension, dizziness, and somnolence were the most commonly reported adverse events. Coadministration of food reduced the incidence and severity of these events.

Dehalogenation reactions of selected phenothiazine antipsychotic and tricyclic antidepressant drugs were studied during fast atom bombardment (FAB) mass spectral analysis. All of these halogenated compounds demonstrated the presence of ions corresponding to the loss of a halogen and its replacement by a hydrogen atom. The structure of the dechlorinated ion for chlorpromazine and the source of the hydrogen atoms replacing the chlorine were studied using perdeuterio-glycerol, accurate mass measurement and comparison of the spectrum with its authentic dechlorinated analog. In addition tandem mass spectrometric studies illustrated identical daughter ion spectra for the dechlorinated ion arising during FAB mass spectrometry of chlorpromazine and the analogous ion present in its unhalogenated analog promazine. The dechlorination process once started by exposure to the atom beam during static FAB mass spectrometry demonstrates an accumulation of dechlorinated ion with time. During continuous flow FAB where the sample is refurbished with time the extent of dechlorination remains relatively constant. The extent of dehalogenation was greater for chlorinated compounds as compared to fluorinated derivatives. The percentage exchange of chlorinated compounds ranged from 7.2% to 32.6% while the percentage exchange for triflupromazine was 3.3%. The recognition that such ions can arise during FAB mass spectrometry avoids the possible misinterpretation of such ions as being due to sample contamination or due to in vivo metabolic dehalogenation during metabolism studies.

HP 818 (1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole) exhibits the profile of a potent nonnarcotic analgesic with neuroleptic properties. HP 818 blocks the effects of chemical (phenylquinone), pressure (tail clip), and radiant heat (tail flick) painful stimuli in mice (ED50 values of 0.3, 1.2, and 4.1 mg/kg s.c., respectively). This compound displays antinociceptive activity by the subcutaneous, oral, and intravenous routes of administration. It is also effective in the shock titration assay in squirrel monkeys and in a model of surgically induced pain. The rank order of potency of HP 818 and several other standard compounds in these tests for analgesia was Innovar > fentanyl > HP 818 > codeine > droperidol. In addition to its antinociceptive effects, HP 818 possesses neuroleptic properties. It is active in the climbing mouse, pole climb avoidance, and intracranial self-stimulation assays (ED50 values of 1.8, 1.7, and 2.5 mg/kg i.p., respectively). Moreover, HP 818 inhibits amphetamine- and apomorphine-induced stereotypy, indicative of D2-dopaminergic blocking properties. HP 818, unlike typical neuroleptic agents, does not induce supersensitivity to the effects of apomorphine when administered chronically in mice. In contrast to the clinical standard neuroleptanalgesic Innovar, HP 818 (1.0–3.0 mg/kg i.v.) produces no significant cardiovascular or respiratory changes in the anesthetized dog. Thus, HP 818 is potentially an effective presurgical medication due to its nonnarcotic analgesic activity and sedative neuroleptic effects, along with its lack of limiting cardiorespiratory side effects.

The cardiovascular effects of ascending doses (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg i.v.) of two angiotensin l-converting enzyme (ACE) inhibitors, REV 6207 and enalapril, were assessed in conscious furosemide-treated (3 mg/kg s.c.) monkeys. Both ACE inhibitors produced a dose-related inhibition of the pressor response to angiotensin l (0.66 μ/kg i.v.) with concomitant decreases in mean arterial pressure and no change in heart rate. The calculated ED50 values for REV 6207 (0.316 mg/kg) and enalapril (0.275 mg/kg) were similar and both abolished the pressor response to angiotensin l at a dose of 3 mg/kg. The results of the study show that REV 6207 is a potent nonsulfhydryl-containing ACE-inhibitor with blood-pressure-lowering activity comparable to enalapril in the conscious monkey with high renin activity.

The cardiovascular effects of the calcium antagonists HP 406 and nifedipine were assessed in a series of in vitro and in vivo studies. HP 406 was found to display moderate affinity for dihydropyridine binding sites, as determined by the inhibition of [3H]-nitrendipine binding on rat ventricular membranes. HP 406 was found to have an IC50 of 1.3 × 10−7 M as compared to nifedipine with an IC50 of 7.0 × 10−9 M. Additional in vitro studies were conducted with isolated spontaneously contracting and electrically paced guinea pig atria and rabbit aortic rings. HP 406 was found to have minimal effects on cardiac chronotropic and inotropic activity in isolated guinea pig atria. In contrast, nifedipine caused significant dose-related reductions in heart rate and myocardial contractile force. Rabbit aortic rings were precontracted with potassium chloride (KCI) or norepinephrine (NE), and HP 406 or nifedipine was added to tissue baths in a cumulative dose range. HP 406 and nifedipine both caused dose-related relaxation of KCI- and NE-contracted rings; however, the IC50's against KCI were found to be significantly lower than those against NE for both compounds. The IC50's against NE were found to be 4.8 × 10−8 M and 5.9 × 10−8 M for HP 406 and nifedipine, respectively. The IC50's against NE were 1.9 × 10−5 M for HP 406 and 4.4 × 10−5M for nifedipine. Finally, the antihypertensive activity of HP 406 and nifedipine were compared in the spontaneously hypertensive rat (SHR) and renal hypertensive dog. Both compounds produced significant reductions in mean arterial pressure at 1 mgikg p.o. in the SHR and at 3 mgikg p.o. in the renal hypertensive dog. Nifedipine was also found to cause a significantly greater tachycardia compared to HP 406. The results of this study show that HP 406 is a potent antihypertensive agent with minimal direct or reflex-mediated chronotropic effects. The mechanism of this antihypertensive activity appears to result from calcium-channel antagonism and vascular dilation.