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A new type of complex reservoir-matrix system for the controlled delivery of diltiazem hydrochloride was developed. This capsule-type device was designed for oral administration to humans and/or animals. It contained (i) an appropriate amount of the drug in a compartment ; (ii) a swelling-controlled membrane which was prepared by mixing polymeric materials with another appropriate amount of the drug ; and (iii) a water-soluble gelatin capsule as container. The swelling-controlled membranes were prepared from poly(2-hydroxyethyl methacrylate) hydrogels. The effect of pH on the swelling of the hydrogels was studied. In-vitro dissolution testing was carried out to evaluate the release of the drug using a continuous-flow method. Zero-order release kinetics was obtained over a period of 12 h.

A study has been performed in 50 subjects, 25 white and 25 black, measuring skin color (PI), basal skin resistance (SR) and amplitude of the galvanic skin response (GSR), and resting heart rate (HR) and the heart rate response (HRR) induced by a startle tone. A multiple correlation matrix revealed a statistically significant relationship between PI and SR and also GSR; between HR and HRR, and between SR and GSR. Analysis of the group differences revealed that blacks had significantly lower (darker) PI values, higher SR, greater GSR, and a higher HR and HRR. It is unclear from this study whether race or the intensity of skin color influenced the measured physiological responses.

The effect of drug-loaded synthetic dressings on the contraction, epithelialization, and collagen synthesis of deep second-degree burns was followed for 21 days in 44 guinea pigs. Two symmetrical burns were inflicted on the back of each animal; the animals were then divided at random into the following test groups: Group 1 (n = 10), a prefabricated, precut, pliable, and noncracking dressing designated as Dimac (DM), versus Dimac plus 2% silver sulfadiazine (DM+); Group 2 (n = 10), Hydron loaded with 2% silver sulfadiazine (HAgS) one versus fine mesh gauze and 1% silver-sulfadiazine cream (GAgS); Group 3 (n = 12), Hydron (Hyd) versus fine mesh gauze (G); Group 4 (n = 4), fine mesh gauze versus Telfa (Tel); Group 5 (n = 6), Telfa versus Telfa; Group 6 (n = 2), gauze versus gauze. Epithelialization and contraction rates were measured at dressing changes on postburn days 6, 12, 18, and 21, with a computerized sonic digitizer. Collagen biosynthesis was measured from the wound scar on PBD 21 and expressed as relative collagen biosynthesis. Contraction on PBDs 18 to 21 was significantly lower (p less than 0.05) in the DM and DM+ treated burns. Epithelialization of the DM and DM+ treated groups on PBD 21 was significantly (p less than 0.05) higher than in the Hyd, HAgS, GAgS, and Tel treated burns, and did not differ from the G treated wounds. The relative collagen biosynthesis method was inapplicable to this burn wound model.

Repeated daily administration of an oral dose of 1000 mg of alpha-methyl-dopa (methyl dopa) to conscious dogs produced a conditioned adaptive hypertensive systolic and diastolic arterial pressure response along with the direct hypotensive pharmacological effect. The lower dose of 500 mg/day appeared to be devoid of direct or adaptive response effects, while the higher dose of 2000 mg/day only produced a blood pressure lowering response. The abrupt drug withdrawal unmasking the homeostatic state resulted in a marked systolic and diastolic pressor response which endured for about 10-days with peak effect reached at 17-days after termination of drug treatment. Comparable results were obtained whether the dogs were evaluated while in their normal horizontal body position or in a repositional upright condition.

We have developed a method for measuring SR which combines the accuracy of DC measurement of basal SR level with the convenience gained from the AC coupling of SR responses for purposes of separating the total signal into basal SR level and SR responses. Our circuitry accomplishes (1) amplification of total DC signal, (2) post-amplification signal separation and display of SR responses and, on the same display channel, (3) pulse coding of basal SR.

Total fasting as a method for weight reduction has been used successfully in non-mental patients and found to produce an elevation in mood. In the present study, this method was explored in mental patients. Twenty-one patients began the fast. Three refused to co-operate from the start; four manifested an exacerbation of symptoms; four were unmotivated to continue more than four days; and ten completed the ten-day fast. the latter ten became relaxed and pleasant after the first few fasting days. Three patients requested a repeat fast. Weight loss ranged from 2.8 to 1.3 pounds per day.Changes were noted in hemoglobin, hematocrit, plasma unesterified fatty acids, CO2combining power, urinary acetone, and urine specific gravity.This may prove to be a satisfactory approach to weight reduction in mental patients.

The correlated effects of drugs on coronary flow, heart actions (mechanical and electrical), and potassium movements in the isolated perfused heart (modified Langendorff technic), were investigated. The potassium movements were studied by comparing nonradioactivc (K39) potassium in the perfusing fluids entering the heart and the concentrations of these leaving the heart as collected at short intervals (5 to 10 sec) before and after injections of each drug. It was observed that there is a transient net loss and increased rate of potassium (K42) turnover following injections of epinephrine, norepinephrine, isoproterenol, and aminophylline. Following injections of acetylcholine and nitroglycerin, there was, conversely, a net gain of potassium (K39), but a similar increased rate of potassium (K42) turnover. Characteristic electrical changes progressively leading to ventricular fibrillation were associated, in all cases, with increasing degrees of potassium disequilibrium. It is concluded that under the influence of these agents the observed potassium disequilibrium might induce changes in myocardial permeability, which might possibly act as “trigger mechanisms” responsible for the observed stimulation or depression of heart function. These findings emphasize the importance of a proper assessment of the patient's electrolyte balance in the course of cardiovascular drug therapy.

In the conscious dog, the most apparent oxybutynin effect was a dose-related tachycardia. Associated with this heart rate increase were a very slight, sometimes significant, elevation in diastolic pressure and an insignificant increase in systolic pressure. Under pentobarbital anesthesia, the systolic/diastolic arterial pressure oxybutynin responses were reversed and showed a dose-related systolic and diastolic hypotension. However, the tachycardic response to oxybutynin still appeared. The arterial pressure and heart rate responses produced by the autonomic agents were altered by the oxybutynin treatment in a pattern indicative of an anticholinergic mechanism of action. Differences in many response profiles were observed with either conscious or anesthetized dogs, but the statistically significant inhibition of the acetylcholine-induced systolic and diastolic arterial pressure and bradycardic responses were constant in both conditions. Oxybutynin is an anticholinergic agent with mild to moderate cardiovascular activity.

In a series of 32 conscious and anesthetized paired dogs, pentobarbital anesthesia significantly lowered basal systolic/diastolic arterial pressures, raised basal heart rate, and altered their responses to selected autonomimetic treatments. Pentobarbital anesthesia also significantly increased the effective hypotensive and/or bilateral carotid occlusion pressor response inhibiting dose of cryptenamine. Further examination of the data revealed that the conscious dog systolic depressor response to cryptenamine is the most sensitive and accurate bioassay criterion for the evaluation of cryptenamine potency.

Rats, 21, 120, and 480 days of age, were given acquisition training in a 1-way avoidance task and tested for retention of the response 1 and 30 days later. Whereas the 480-day-old rats showed poorer performance during acquisition, the 21-day-old rats showed the greatest impairment of long term retention. The results suggest that age differences in performance are due to intrinsic maturational processes.

Seven malt essential hypertensives underwent 9 weekly 2-hr biofeedback training sessions in an attempt to produce decreases in blood pressure. Feedback, contingent Upon heart bent by heart beat decreases in systolic pressure, was provided by an automated blood pressure monitoring system. The subjects were administered the Category Test (a subtest of the HaLstead-Reitan Neuropsychological test Battery) both before and after biofeedback training. As controls, 4 male hypertensives underwent 3 weekly sessions in which blood pressure was monitored without feedback being provided. Prior to training, a significant positive correlation was otained between systolic blood pressure and number of errors made on the Category Test, Biofeedback training produced significant decreases in systolic pressure within sessions and in diastolic pressure between sessions, in the control subjects, no significant changes in pressure were observed. For both systolic and diastolic pressures, significant correlations w-ere obtained between magnitude of decrease during biofeedback training and improvement in Category Test scores subsequent to training.

Conscious dogs were given diltiazem hydrochloride (DTZ) orally for 5 successive days at doses of 1, 3, and 10 mg/kg/day. During the 5th day, cardiovascular responses were monitored at various timed intervals after dosing. Arterial blood was sampled concomitantly for drug analysis. DTZ produced a dose-related decrease in blood pressure. The maximum reduction amounted to -30/-33 mm Hg in systolic/diastolic pressure, which occurred 90-150 min after the dose of 10 mg/kg. Heart rate and respiration were not significantly changed. There were dose-related alterations in the electrocardiogram tracing components, ranging from PR interval prolongation to junctional rhythms and ectopic beats. No overt physical responses were apparent. The mean DTZ peak plasma levels were approximately 708 ng/ml after 10 mg/kg, 224 ng/ml after 3 mg/kg, and 98 ng/ml after 1 mg/kg. The estimated t1/2 values for the 3- and 10-mg/kg/day dosings were 142 and 150 min, respectively. Correlations between the DTZ plasma level and the magnitude of the cardiovascular responses were highly significant in terms of blood pressure and PR interval changes. Low levels of DTZ were found 23 h after dosing. These levels were not associated with any meaningful cardiovascular activity.

In the total population of 75 subjects, the skin albedo correlated significantly with skin resistance, a relationship which was not maintained when the total population was separated into its component subgroups of whites, blacks and Indians. The Indians, "anthropologically Caucasians" but skin color more akin to the blacks, exhibited mean skin reflectance and skin resistance intermediate to that obtained in the black and white groups respectively. Other differences and significant correlations between the autonomic functions in the three groups indicated a higher level of sympathetic tone in the Indians, although this could be attributed to the older age of this group. It was suggested from the results that skin color rather than race has a greater influence on skin resistance.

The influence of body position change on the arterial pressure and heart rate responses produced by acute short‐acting and sustained‐release dosage forms of nitroglycerin was evaluated in a series of chronically prepared, conscious beagle dogs. The upright repositioning of the dog to 60° from horizontal markedly enhanced the hypotensive and bradycardic responses produced by both dosage forms. Since it has been suggested that the lowering of arterial pressure is an essential component resulting in the therapeutic usefulness of nitroglycerin in angina pectoris, the experimental orthostatic model could be a sensitive procedure for the laboratory assessment of drugs of this class.

A modification in the design of the Goldblatt renal artery clamp and a description of a new single unit applicator-adjuster are presented. Detailed construction diagrams as well as a description of operative technique are given. The new clamp and applicator were used extensively in preparing a colony of renal hypertensive dogs in our laboratories. The results were excellent and the operative time and difficulties were reduced. Submitted on February 14, 1963

In conscious, unrestrained dogs, equivalent doses of atropine sulfate and Ditran produced a conditioned paradoxic salivary response and a classical conditioned response of mydriasis when the animals were placed into the experimental chamber. The onset and extinction rates for these responses were almost identical for both drug groups and onset appeared after as few as six treatment sessions. Although these drugs arc parasympatholytic agents, a possible explanation of the responses implicates a sympathetic nervous system activation.

From a total of 238 anesthetized dogs, a series of regression analyses was performed examining the relationship between the variables (sex of the animal, date on which the experiment was performed, effect of the three veratrum alkaloidal drug preparations studied, and the number of days the dogs were stored in the animal house) on the arterial pressure pressor amplitudes of the predrug and postdrug carotid occlusion response and on the blood pressure-lowering effects of the drug treatments. The seasonal date of the experiment and the drug treatments significantly influenced the arterial pressure responses, while sex of the animal or days stored prior to use did not consistently alter the slope constants or arterial pressure responses for the drug subgroups.

Pimetine, 1-dimethylaminoethyl-4-benzylpiperidine, was investigated for activity in two experimental models using conscious dogs which have demonstrated high predictive ability in discerning psychotropic agents and categorizing them into tranquilizer or antidepressant classes. Pimetine treatment produced a dose-related reversal of the Ditran Rating Scale score at dose levels devoid of apparent direct behavioral effects. This drug also produced a moderate pressor effect associated with a potentiated acetylcholine arterial pressure response and inhibited responses to serotonin, bilateral carotid occlusion, tyramine and histamine. A clinical study of the antidepressant effects of pimetine is indicated by the results.

THE twenty-one subjects participating in this study were serial admissions to the St Louis Detoxification Center during the period of December 2–21, 1971. Their ages ranged from 29 to 72 yr and they comprised twenty males and one female. A blood sample (10 ml) was obtained from the patient on admission, when a symptom intensity rating evaluation was carried out1,2. Blood concentrations of ethanol, methanol, acetaldehyde and formaldehyde-formate were determined by gas-liquid chromatography3,4. This procedure was repeated on four consecutive days (total of five samples), after which the patient was discharged from the Center.

PARALLEL preclinical and clinical investigations were performed on the compound α, α-diphenyl-2-(4-pyridyl)-cyclopropylmethanol hydrochloride (IN-1060), with the following structure

A surgical procedure is described for the permanent externalization of the common carotid artery in dogs. This preparation has been utilized for repeated direct continuous measurement of systolic and diastolic arterial pressures and for other procedures such as blood sampling, induction of the bilateral carotid occlusion response and for the intraarterial administration of drugs.