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The effects of 4 doses of sodium pentobarbital (10, 20, 40, 80 mg./kg., p.o.) on spontaneous motor activity of mice were tested in photocell cages during a 2-hr. period immediately after drug or saline administration. A total of 480 albino mice was divided among several experimental conditions. Increasing doses produced progressively increasing activity in the last 0.5hr. when normal activity was at a low level. In the first 0.5 hr., the usual intense activity was unchanged by the three lower doses and greatly depressed by the highest dose. Throughout the session, the three lower doses had a stimulant effect on animals tested in a lighted environment in groups of five but not singly, and a small but consistent stimulant effect on both single and grouped animals in a dark environment. Animals fasted for 24hr. prior to the test were greatly stimulated by the lowest dose and were greatly depressed by the highest dose. The results indicate that the stimulant effect of barbiturates requires both inhibitory influences on normal activity and conditions increasing susceptibility to arousal.

Vanillic diethylamide produced central nervous system effects indicative of medullary stimulation when injected into frogs and rats. Vanillic diethylamide administered intravenously to anesthetized dogs and cats produced a marked increase in both the rate and depth of respiration, which was usually accompanied by the return of the corneal reflex and a mild, transient hypotensive effect. The transient hypotensive effect could be eliminated by administering the compound via a slow infusion at rates ranging between 1 and 8 mg./Kg./min. The compound produced identical responses prior to and after bilateral carotid sinus area denervation, and it appears that the compound acts mainly on the medullary centers and that the carotid sinus-body complex is not essential for the stimulatory activity. A 10 mg./Kg. quantity of vanillic diethylamide administered into the arterial inflow to the recipient's head in 2 dog cross-circulation experiments awakened the recipient animal and produced a transient pressor effect in the recipient.

Several compounds which represent classifications of drugs known to have effects on muscular efficiency were administered to dystrophic animals in which atrophy was achieved utilizing a vitamin E-deficient diet. A myopathic mutation of the house mouse (dystrophia muscularis) was also utilized in certain portions of the study. Motor coordination, weight, muscle strength, and urinary creatine and creatinine were measured. The effects of some of the compounds on the isolated diaphragm muscle of normal and dystrophic mice were also studied. Norethandrolone, methimazole, and digoxin increased the ability of vitamin E-deficient rats to perform forced motor activity. The same compounds increased the offspring survival rate of vitamin E-deficient female rats. Potassium chloride (10 mg./Kg./day) temporarily increased the mean rotarod performance time and arrested loss of weight of dystrophic mice. Although there was no statistical difference between the life span of the control and drug-treated groups of strain-129 mice, the group receiving digoxin, 0.05 mg./Kg. subcutaneously, twice a week survived the longest.

4-Hydrazino-1,2,3-benzothiadiazine-1,1 dioxide hydrochloride (EX 4211A) and 6-chloro-3,4-dihydro-3-(β-oxo-n-propyl)-7-sulfamyl-2H-1,2,4-benzothiadiazine 1,1-dioxide phthalazone azine (EX 5004) were studied in the rat and dog to elucidate the mechanism(s) by which these compounds produced hypotensive effects. EX 4211A and EX 5004 were potent hypotensive agents in the anesthetized rat, mildly hypotensive in the anesthetized normotensive dog, and produced a moderate degree of hypotension in unanesthetized renal hypertensive dogs. EX 5004 and EX 4211A appeared to produce their hypotensive effect by the lowering of peripheral resistance through a direct action on vascular smooth muscle.

A three-way crossover experimental design demonstrated that urethan anesthesia enhanced the hypotensive responses of certain diquaternarized ammonium compounds in normotensive rats. The test showed that cardiovascular responses were more significant in hypertensive than in normotensive rats. Barbiturate anesthesia potentiated the hypotensive responses of certain of the compounds in normotensive dogs. Intravenous infusion of two of the compounds into anesthetized normotensive dogs produced a maximum hypotensive effect in 2 minutes with no further lowering of the blood pressure as the infusion was continued.

The hypotensive activity of a series of substituted alkylenediamines was investigated in anesthetized rats and dogs. N,N′-Bis-[α-(2-pyridyl)ethyl]-ethylenediamine dimaleate (JB 5058) produced marked hypotensive effects of long duration in both species of animals. JB 5058 reversed the pressor response to epinephrine, 2 mcg./Kg., and decreased the pressor response to levarterenol, 2 mcg./Kg.; angiotensin II, 1 mcg./Kg.; and bilateral carotid occlusion. The oral administration of the compound to normotensive animals produced a mild transient depression of systolic blood pressure; however, 40mg./Kg. administered orally to renal hypertensive dogs produced a marked decrease in systolic blood pressure which persisted from 34 to 57hours. The data suggest that the primary mechanism of the hypotensive activity of JB 5058 is competitive blockade of the α adrenergic receptors.

The hypotensive activity of a series of 2,2,6,6-tetramethylpiperidine derivatives was investigated in anesthetized rats and dogs. The piperidine compounds were derivatives of pempidine (1,2,2,6,6-pentamethylpiperidine), an orally effective potent ganglionic blocking compound. N-Amino-N-[β-(2,2,6,6-tetramethylpiperidino-)-ethyl]-guanidine sulfate (EX 4510) appeared to be slightly more active than pempidine. All of the active hypotensive compounds in this series which were tested against pressor challengers in anesthetized dogs potentiated the epinephrine and angiotensin II pressor responses and depressed or blocked the bilateral carotid occlusion pressor response. Preliminary data suggest that the active compounds, like pempidine, are ganglionic blockers.

Aqueous extracts of Piper methysticumForst, were tested for pharmacological activity. The roots of this plant have been used by the natives of many of the islands of the South Pacific in a beverage known as Kava to allay anxiety and reduce fatigue. The extracts were shown to have a depressant action on the central nervous system, evidenced by depression of spontaneous motor activity, marked reduction in irritability of rats having bilateral septal lesions, inhibition of the conditioned avoidance response in rats, and blockade of EEG arousal patterns in cats.

N,N′-Bis-[α- (2-pyridyl)ethyl]-ethylenediamine dimaleate (JB 5058), a substituted polymethylene diamine with hypotensive action, was noted to have alpha adrenergic blocking activity, as demonstrated in the cat superior cervical ganglion nictitating membrane preparation. It did not produce a centrally mediated hypotensive response in the dog cross-circulation preparation. JB 5058 produced only a transient decrease in cardiac output while increasing femoral blood flow. The hypotensive activity of JB 5058 appears to be caused by a decrease in peripheral vascular resistance primarily due to alpha adrenergic blockade. It also appears to produce a modest antagonism of angiotensin II on vascular smooth muscle.

A series of 3,6-substituted pyridazine derivatives were tested for central pharmacologic activity. On the basis of their effects on gross behavior, spontaneous, and forced motor activity of albino mice, the alkoxy-pyridazine derivatives were characterized as CNS depressants, while the alkoxy-2-dimethylaminoethoxy-pyridazine derivatives produced initial stimulation followed by a depression of spontaneous activity. The latter compounds also shortened hexobarbital sleeping time in mice and induced a low-voltage fast-wave activity in the electrocorticogram of the cat. None of the compounds produced any alteration of avoidance escape responding in mice or rats or caused a significant inhibition of convulsions produced by chemo- or electrostimulation in rats. A substudy indicated that there was little or no species difference in the learning ability or the response to chlorpromazine of mice and rats in the conditioned avoidance response test (pole climbing).

A total of 384 mice, given 2-hr. tests twice in the photocell activity cage under the same conditions, showed lower activity scores (with square root transformation) in the second test. This behavioral carry-over effect was greater for subgroups given the second test at an interval of 1 or 3, instead of 7 or 14 days, after the first. Chlorpromazine produced a greater decrement in activity in the first 0.5hr. of the second test than of the first. In both tests, aggregations of five, rather than single animals, showed a greater drug decrement in the first hour and some recovery from the drug effect in the Last 0.5hr. The most stable data were obtained in the first 0.5hr. A high correlation between tests, especially with a 1-day interval, indicated that a repeated-test design can provide a sensitive measure of drug effects.

The cardiovascular activities of mecamylamine, pempidine, and several pempidine analogs were investigated. The active compounds produced a significant drop in blood pressure and cardiac output in anesthetized normotensive dogs, markedly inhibited superior cervical ganglionic transmission in the cat, and produced a slight transient decrease in vascular resistance when administered intraarterially into the denervated perfused hind limb of the dog. Pempidine and N-amino-N-[β-(2,2,6,6-tetramethylpiperidino)ethyl]guanidine sulfate (EX 4510) exhibited quantitatively and qualitatively similar hypotensive responses when administered orally to unanesthetized renal hypertensive dogs. The hypotensive activities of hexamethonium, pentolinium, chlorisondamine, mecamylamine, and pempidine were evaluated in the prostigminized rat. Prostigmine antagonized the hypotensive response of only hexamethonium, suggesting that hexamethonium alone produces a competitive type of antagonism at the autonomic ganglia.

The hypotensive activity of four tetramethylpiperidine and four benzothiadiazinate derivatives was investigated in anesthetized rats and dogs. The active tetramethylpiperidine derivatives exerted their effects by ganglionic blockade. EX 4922, 1-hydrazinophthalazine 3,4-dihydro-6-nitro-7-sulfamoyl-1, 1,3-trioxo-2H-1,2,4-benzothiadiazinate, was hypotensive in rats, cats, and dogs, the rat being the most sensitive species. The data obtained suggest that the response is due to α adrenergic blockade and a direct depressant action on vascular smooth muscle. EX 4526, 2,2,6,6-tetramethylpiperidine 3,4-dihydro-6-nitro-7-sulfamoyl-1,1,3-trioxo-2H-1,2,4-benzothiadiazinate, was also hypotensive in rats, cats, and dogs. Pre- and postganglionic conduction along sympathetic nerves was depressed, but the pressor effects to exogenous epinephrine were potentiated. A direct relaxation of vascular smooth muscle was also observed.

An extract of Piper methysticumForst. prepared by steam distillation was separated by means of differential solubility into two fractions, F1and F2. These fractions had different physical and chemical characteristics, and known α-pyrones were identified only in subfraction F2. Both fractions decreased spontaneous motor activity in doses which did not alter forced motor activity of mice. Fraction F2, dihydromethysticin, desmethoxy-yangonin, and kawain exhibited potent antiserotonin activity on the isolated rat uterus, whereas F1appeared to be devoid of antiserotonin activity. F1, F2, and dihydromethysticin did not alter serotonin brain levels in mice.

The hypotensive activity of [l-methyl-3-(2′5′6′-trimethyl-1′-cyclohexenyl)propyl] [3-morpholinopropyl] dimethyl ammonium bromide methobromide (RO 2-7832), (+) - 6 - methyl - 9 - diethylaminomethyl - 10 - hydroxy - 1,2,3,3a,5,6,6a,7,11b,11c-decahydro-4H-dibenzo [de,g] quinoline dihydrobromide (RO 2-9618), and 8,8′-bis(2-dimethylaminoethoxy)-6,6′-bithiachroman-4,4′-dione dihydrochloride (RO 2-9811) were investigated in anesthetized rats and dogs. Central and peripheral hypotensive activities were studied utilizing dog cross circulation preparations; and included trimethidinium methosulfate and beta-dimethyl-aminoethyl-N-methylpipe-colinate dimethobromide (JB-591) as well as the previously mentioned compounds. RO 2-7832 and trimethidinium appeared to act as potent ganglionic blockers. The hypotensive activity of RO 2-9618 was due to both ganglionic blockade and mild adrenolytic activity. JB-591 was the only compound that demonstrated any central hypotensive activity.

Sodium pentobarbital, 20mg./Kg. per osdaily, and acetylsalicylic acid (ASA), 100mg./Kg. per osdaily, failed to prevent the development of hypertension in rats subjected to experimental stress. ASA enhanced the lethal effects of the stressors and potentiated the effects of the stress conditions on gastric mucosa. Reserpine phosphate, 0.1mg./Kg. (base) i.p. daily, administered after the animals had been subjected to the stress conditions for 6weeks, did lower the blood pressure to control levels.

Specialty credentialing has been discussed extensively and debated within pharmacy for more than ten years. Within the profession, there now appears to be a consensus on the need for and appropriateness of acknowledging professional practice areas as unique, defined entities. However, there remain substantive differences on how the definition of specialty practice should be constructed. One approach is to identify practice areas by functional activity (e.g., nuclear pharmacy, drug information) and/or therapeutic focus (e.g., psychopharmacy, clinical pharmacokinetics). A second approach is to define clinical pharmacy as a specialty practice that would, at least initially, coalesce clinical practitioners with the common denominator of an active role in the therapeutic decision-making process. The following document was developed by the Committee on Clinical Pharmacy as a Specialty (CCPS). The CCPS is independent of any formal organizational affiliations. It will serve as the preface to a petition that will be submitted to the Board of Pharmaceutical Specialties requesting recognition of clinical pharmacy as a specialty. The intention of the committee is to resolve the question of specialty status for clinical pharmacy through the Board of Pharmaceutical Specialties' review process. It is then hoped that pharmacy can move forward on the important issue of specialty credentialing.