Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents

A series of dihydropyridines substituted at the 2-position by basic side chains are described and their potencies as calcium antagonists listed. One compound, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine (17, amlodipine) was found to be comparable in potency to nifedipine and to have an elimination half-life of 30 h in dogs. Oral bioavailability approached 100%, and hemodynamic responses were gradual in onset and long-lasting in effect. The two enantiomers have been prepared, and the bulk of the activity was found to reside with the (-) isomer, 18. X-ray crystallographic studies, carried out on a close analogue of 17, suggest the existence of a weak hydrogen bond between the side-chain oxygen and the proton on the ring nitrogen.     

Exchange-transfusion with pyridoxalated polymerized hemoglobin: effects on liver PO2

To examine the efficacy of modified stroma-free hemoglobin in maintaining liver PO2, rats were exchange-transfused to hematocrit 10% using pyridoxalated polymerized hemoglobin (plp-polyHb, 10-12 g/dl) prepared from crystalline Hb. Following hemodilution, plasma Hb was 7.4 g/dl, and rats were normotensive. Mean liver PO2 was 3.4 vs 23.3 mm Hg in sham-exchanged controls. Other rats, hemodiluted similarly with 6% albumin or hydroxyethylstarch, were hypotensive and died. At 24 hours plasma Hb was 2.0 g/dl, indicating an intravascular half-life of approximately 16 hours. Hepatic PO2 was 12.4 vs 26.8 mm Hg in nonhemodiluted controls. Data provided by clearance of low-dose indocyanine green suggested reduced plasma volume and depressed liver blood flow. Scattered foci of midzonal hypoxic damage were observed in liver lobules. The basis for hypoxic injury is considered to be due in part to the acute restriction of oxygen supply induced by exchange-transfusion with plp-polyHb. The rate of loss of intravascular hemoglobin and diminished plasma volume could have contributed to oxygen insufficiency as well. Endotoxin present in the plp-polyHb was not a factor.     

In vivo kinetics of 123I-labelled insulin: studies in normal subjects and patients with diabetes mellitus

Radioactive tracer techniques using 131I- and 125I-insulin have been applied to study insulin metabolism. A simple method to label human insulin with 123I to a high specific activity is described. We have used this radiotracer to study insulin kinetics in vivo in normal subjects and in two groups of diabetic patients. The rate of decline in plasma radioactivity was shown to be significantly reduced in patients with diabetes. There were no significant differences in the time-activity profiles of liver and kidneys between the groups studied. This technique may provide insight into the mechanism of some forms of insulin resistance.     

Role of computed tomography in screening for hepatocellular carcinoma in patients with cirrhosis

One hundred patients with cirrhosis underwent abdominal computed tomography (CT) using a delayed contrast technique to determine liver and spleen volume. These scans were reviewed to screen this "at risk" population for hepatocellular carcinoma (HCC). Fifteen of the 100 screened patients had focal abnormalities suspicious for HCC. On biopsy, only 1 patient was shown to have HCC. The other 14 patients had either fatty infiltration or focal regeneration. In the same time interval, a total of 10 patients had histologically proven HCC. All presented with symptoms and died within 4 months of diagnosis. The results show that focal hepatic lesions can be detected by CT but in this population the lesions may not be due to HCC. The incidence of HCC was approximately 1%, probably reflecting a truly low incidence in this population.     

Petit Mal-Grand Mal ECT: A Method to Induce Seizures Without Barbiturate Anesthesia

Petit mal-grand mal (PM-GM) electroconvulsive therapy (ECT) is a technique developed by Impastato to elicit unconsciousness with a subconvulsive electrical stimulus, rather than with barbiturate anesthesia. Muscle relaxation is produced with succinylcholine chloride before stimulus is applied. The cases reported here illustrate applications of the technique to depressed patients with severe cardiac and pulmonary disease, and the use of PM-GM ECT in a patient in whom seizures could not be elicited by the usual ECT technique is described.     

Decreasing sensitivity to neuroleptic agents in developing rats; evidence for a pharmacodynamic factor

Developing rats are far more sensitive than adults to the behavioral effects of haloperidol. The present results support the hypothesis that this change may reflect age-related changes in brain responses such as alterations in drug-receptor or drug-effector mechanisms. Dose-response studies of catalepsy and ptosis were conducted in male Sprague-Dawley rats aged 30, 56, or 100 days. Resulting dose-effect curves were approximately parallel and showed rightward shifts with highly significant progressive increases of ED₅₀. Similar developmental decreases in drug sensitivity (3–6 ×) were found following systemic (PO or IP) administration of haloperidol or the phenothiazine neuroleptic perphenazine, which differ markedly in structure, potency, distribution, and metabolism. Age-related decreases in drug sensitivity (3–4 ×) were also found using intracerebroventricular (ICV) administration of both agents in an attempt to bypass potential pharmacokinetic influences. Since the age-dependent decrease in sensitivity to both neuroleptics was found during the rising phase of drug action (1st hour) and ranked: PO>IP>ICV, some change in absorption and distribution of both drugs may occur in addition to the apparently important maturational decrease in target-organ sensitivity indicated by the responses to direct ICV injection and by the similarity of results obtained with dissimilar agents.     

Therapeutic FES: from rehabilitation to neural prosthetics

The purpose of this paper is to review the therapeutic applications of electrical stimulation and to focus on functional neuromuscular electrical stimulation (FES), which is the production of useful muscle contractions for joint stability and limb movement. The use of FES to improve patient function during the recovery period after illness or injury and the transition to FES neural prosthetic systems for patients who do not fully recover will be discussed. Emphasis will be given to the maintenance of posture and the production of purposeful movement from the perspective of technologies and clinical strategies that are available today and from the perspective of those technologies that have the potential for transfer to community health care in the near future.     

Blood platelet uptake of serotonin in episodic aggression

Blood platelet uptake of 3H-serotonin (5HT uptake), a potential marker of serotonergic function, was determined in male outpatients with episodic aggression (n = 15) and in age- and sex-matched nonaggressive controls (n = 15). Correlations with rating scales of "impulsivity" (Barratt Impulsivity Scale, 10th revision) and "anger" (Spielberger Anger Expression Scale) were performed. Mean 5HT uptake was 18% lower in patients with episodic aggression. A significant negative correlation between % difference in platelet 5HT uptake and impulsivity score was observed, but the correlation between 5HT uptake and anger was not significant. These results support the hypothesis of disturbed serotonergic function in aggression and suggest that the primary relationship is in the "control" of aggression. The blood platelet may be useful in identifying impulsive subtypes.     

Detection of clustered gastrointestinal contractions in partial intestinal obstruction by surface vibration analysis.

Gastrointestinal contraction "clusters" with alternating quiescence occur in partial intestinal obstruction and are conventionally detected by intraluminal manometry. Surface Vibration Analysis (SVA), which is a noninvasive test, was evaluated in this study in experimental and clinical situations. In the experimental situation, former SVA was assessed against simultaneous manometry in two volunteers, in whom partial obstruction had been induced by intrajejunal balloon distension. Manometry showed typical contraction "clusters" with alternating quiescence, each of two to four minutes duration, in obstructed jejunum proximal to the balloon. The distal jejunum was inhibited. SVA showed a pattern of hyperactivity and quiescence corresponding to proximal jejunal activity. In the clinical situation, SVA recordings taken after a standard meal in nine patients with suspected chronic obstruction adhesive obstruction, (subsequently proven in seven patients and disproved in two), and 36 volunteers were compared. All patients with proved obstruction showed an SVA pattern of alternating hyperactivity and quiescence. This pattern was not observed in volunteers or nonobstructed patients.     

Plateau potentials evoked by climbing-fibre stimulation are restricted to the Purkinje cell dendrites of the cat

The present study investigated the duration of afterdepolarizations in Purkinje cell somata following climbing-fibre activation. Intracellular recordings revealed that, in cells with membrane potentials more negative than -50 mV and with normal spike-generating capabilities, climbing-fibre activation resulted in somatic responses with short afterdepolarizations. As the cell deteriorated and the resting membrane potential became more positive, the duration and form of the climbing-fibre response resembled the plateau potentials recorded from proximal dendrites. The absence of plateau potentials in undamaged Purkinje cell somata was confirmed by extracellular recording of test spike amplitudes following evoked climbing-fibre responses.