Agoraphobia: newer treatment approaches.

Agoraphobia is the commonest and most severe form of phobic disorder. Techniques presently available for its treatment fall into the broad categories of behavior therapy, pharmacotherapy, and psychotherapy. Of the behavioral approaches in current use flooding is probably most effective. Group exposure methods are valuable and have the advantage of conserving therapist time. Pharmacological agents of demonstrated value include monoamine oxidase inhibitors (phenelzine) and tricyclic antidepressants (imipramine). These drugs are capable of preventing the spontaneous panic attacks observed in agoraphobic patients. Psychotherapy, once the mainstay of treatment, has largely become an adjunctive procedure.


A multivariate analysis and modification of a preattentive, perceptual dysfunction in schizophrenia.

Preattentive information processing was examined in matched samples of process nonparanoid schizophrenics, reactive paranoid schizophrenics, and nonschizophrenic psychiatric inpatients. Three measures of visual preattentive processing were administered under standard conditions and also enriched conditions in which preattentive discriminability was enhanced through increased perceptual grouping and segregation. Nonparanoid schizophrenics displayed a differential performance deficit under standard conditions on each measure. Under conditions of enhanced preattentive discriminability, nonparanoid schizophrenics differentially improved to the extent that no significant differences were found between groups on two of the measures. Paranoid schizophrenics and psychiatric controls did not differ significantly across measures or conditions.


Cognitive and evoked response measures of information processing in schizophrenics with and without a family history of schizophrenia.

Twenty-four male schizophrenics, 12 (SFH) with schizophrenia in the immediate family and 12 (SNFH) with no evidence of schizophrenia in the family background, and 24 male control subjects, 12 highly educated (HEC), and 12 minimally educated (MEC), were assessed for premorbid social adjustment and were administered the Digit Symbol Substitution Test, a size estimation task, and the EEG average evoked response (AER) at different levels of stimulus intensity. As predicted from the stimulus redundancy formulation, the SFH patients were poorer in premorbid adjustment, were less often paranoid, functioned at a lower level of cognitive efficiency (poor digit symbol and greater absolute error on size estimation), were more chronic, and, in some respects, had size estimation indices of minimal scanning. Contrary to prediction, the SFH group had the strongest and most sustained augmenting response on AER, while the SNFH group shifted from an augmenting to a reducing pattern of response. The relationship between an absence of AER reducing and the presence of cognitive impairment in the SFH group was a major focus of discussion.


Urinary catecholamines and amphetamine excretion in hyperactive and normal boys.

Urinary catecholamines and metabolites and urinary amphetamine excretion were examined for hyperactive and normal boys following a single dose of dextroamphetamine (0.5 mg/kg) and placebo. Hyperactive children showed a significantly faster rate of excretion of amphetamine which could not be accounted for by previous exposure to drug or by signs of neurological involvement. Urinary norepinephrine (NE) was significantly higher for hyperactive than for normal children, but NE excretion did not correlate with motor activity or any measures of arousal. The single dose of amphetamine produced a significant rise in urinary epinephrine excretion (EP) for the normal children but not for the hyperactive group, supporting the notion of a more sluggish catecholamine response to stimulants for hyperkinetic children.


A method for determining median nerve conduction velocity across the carpal tunnel.

Palmar stimulation was used to assess median nerve conduction across the carpal tunnel. In 50 hands from 25 control subjects, motor and sensory latencies in the wrist-to-palm segment (mean +/- SD: 1.15 +/- 0.21 msec and 1.12 +/- 0.21 msec respectively) were less than half the conventional terminal latencies in the wrist-to-muscle and wrist-to-digit segment (3.01 +/- 0.44 msec and 2.47 +/- 0.39 msec). Motor and sensory conduction velocities (MNCV and SNCV) in the wrist-to-palm segment (56.0 +/- 7.6 m/sec and 58.7 +/- 7.5 m/sec respectively) were comparable to those in the elbow-to-wrist segment (57.0 +/- 4.5 m/sec and 62.4 +/- 5.7 m/sec). In 20 symptomatic hands from 13 patients with mild carpal tunnel syndrome, delay in motor and sensory terminal latencies (3.91 +/- 0.67 msec and 2.90 +/- 0.57 msec) was primarily attributable to increased conduction time in the wrist-to-palm segment (1.96 +/- 0.59 msec and 1.58 +/- 0.49 msec) and not in the remaining more distal portions. Consequently, MNCV and SNCV were significantly (P less than 0.001) slowed when calculated in the segment across the carpal tunnel (36.6 +/- 11.2 m/sec and 44.9 +/- 11.8 m/sec), even though the conventional terminal latencies from the stimulus site at the wrist were often within normal limits.


Altered tissue carnitine levels in animals with hereditary muscular dystrophy.

Low levels of muscle carnitine have been found in patients with Duchenne dystrophy, a case possibly of Becker dystrophy, and limb-girdle syndrome as well as in patients with the recently described muscle carnitine deficiency syndrome. Tissues of the mouse, hamster, and chicken were analyzed to determine whether tissue carnitine levels were altered in the animal models of muscular dystrophy. Significantly higher levels of carnitine were found in dystrophic mouse muscle, but carnitine levels in plasma, liver and heart were normal. Histological changes in the skeletal muscle of dystrophic hamsters were relatively mild, and both skeletal muscle and plasma levels were normal. The liver carnitine level was higher than normal levels. The dystrophic hamster also had an inherited cardiomyopathy, and interestingly its heart carnitine level was much lower than normal. The red muscle of the normal chicken contained 5 times the level of carnitine found in white muscle. The dystrophic chicken had higher than normal levels of carnitine in the white muscle, but normal levels in the red muscle. Although all 3 animal models of muscular dystrophy studied have altered levels of carnitine in some tissue, none of the animal models had the same pattern of altered tissue carnitine levels seen in human patients.


A clinical study of chronic childhood spinal muscular atrophy. A review of 141 cases.

The case histories and clinical details of 141 children (67 males and 74 females) with chronic childhood spinal muscular atrophy (SMA) have been reviewed. Hundred of these children were alive at the time of the study. The cases comprise a consecutive unselected series of all with this disease who presented to two large English neurological centres over a 10-year tracing period. Chronic childhood SMA is defined here as a progressive disease of anterior horn cells with initial proximal selectivity, which does not of itself cause death before 18 months of age. Clinical signs are first manifest between birth and 8 years of age, but in 95% before 3 years. Cumulative frequency tables for motor skills are presented; 46% of children never walked, even with orthopaedic aids; 37.6% were able to walk unaided at some stage. No child was able to run after 12 years of age. Late-presenting sporadic cases retain motor skills longer than do familial cases. A sex influence on the clinical course of the disease has been demonstrated, males being more severely affected. Cumulative frequency curves for age-at-onset and age-at-presentation have been compiled. A sib of an affected index case, still clinically normal at 2 years of age, has passed 90 percent of his risk period; the use of such cumulative frequency curves for studies of carrier-frequency and incidence is discussed. The median age at death for this disease exceeds 10 years. The range encompassed by the clinical spectrum is discussed.


A study of environmental factors in relation to fatal infantile spinal muscular atrophy (SMA type I). An analysis of birth order and parental age effects, social class, seasonal influence, and clustering in time and place.

Major studies of the childhood spinal muscular atrophies have suggested that environmentally-produced phenocopies might occur, and that environmental factors might be important in some clinical features of these diseases. A formal analysis of some possible intra-uterine and post-natal influences has been undertaken in 78 index cases (72 families) of acute infantile SMA (acute Werdnig-Hoffmann disease; SMA Type I). There is no evidence to suggest that social class, parental age, birth order, or season of birth influences this disease or that clustering in time and place occurs.


Morphological evidence for 6-hydroxydopamine-induced sprouting or noradrenergic neurons in the cerebellum.

Intracisternal injection of 6-hydroxydopamine (6-OHDA) into young rats during the first 24 hours after birth resulted in a significant elevation of cerebellar norepinephrine by day 9. This elevation continued through 120 days. Fluorescence microscopy demonstrated an increased fluorescence in all layers of the cerebellar cortex in treated rats from 9 days after treatment through 120 days. This was considerably greater than the normal developmental change observed in control rats and appeared to be due to an increased number of fluorescent terminals. Quantitative electron-microscopic analysis indicated that all layers of the cerebellar cortex of treated rats contained significantly more boutons with small dense-cored vesicles (SGV), a morphologic marker for catecholamines, than controls. No significant difference in the number of SGVs per bouton was observed in 6-OHDA treated rats.


Lipid abnormalities in hereditary neuropathy. Part 3. Plasma and erythrocyte lipids of HMSN-III (Dejerine-Sottas disease).

Plasma glucosylceramide levels of 5 patients with Hereditary Motor and Sensory Neuropathy Type III (Dejerine-Sottas disease) were approximately 50% higher than in controls. Erythrocyte glucosylceramides, however, were within the range of normal values. Elevated plasma glucosylceramide levels provide further evidence that an abnormality of lipid metabolism may underlie this recessively inherited hypertrophic neuropathy. No abnormality was observed among other glycosphingolipid fractions. An altered sphingomyelin fatty acid composition and reduced phosphatidylcholine level was also found, but this may not be disease-specific.


Further observations on myelinated axon numbers in normal and dystrophic mice.

Counts of the number of myelinated axons in the nerves to slow-twitch soleus and fast-twitch plantaris muscles of 129 ReJ dy/dy dystrophic mice at 4, 15 and 24 weeks of age have shown statistically significant reductions when compared to normal values. In addition muscle fibre losses had occurred in both muscles at the earliest age point studied. There was no suggestion of a progressive loss of myelinated axons. There was a greater percentage reduction in the soleus than in the plantaris nerves. The number of myelinated axons in the nerves to the plantaris and soleus muscles of the 129 ReJ +/+ normal animals was approximately the same, in contrast to the C57BL/6J strain where the soleus nerve always contained a greater number. Statistically significant reductions in the number of myelinated axons in the nerves to the medial gastrocnemius muscles of C57BL/6J dy2J/dy2J dystrophic mice have been observed at both 15 and 72 weeks of age. Muscle fibre losses have also been recorded in 72 weeks dystrophic medial gastrocnemius muscles.


The organization of endoneural collegen in peripheral nerves as revealed with the scanning electron microscope.

Transmission electron microscopy of isolated nerve fibers of rat sciatic nerve and scanning microscopy of small groups of fibers reveal that the majority of collagen fibrils form tightly woven cuffs around individual nerve fibers. Only a small fraction of the fibrils is not associated with individual nerve fibers and forms a loose, wide-meshed net between them. These observations reconfirm the pre-electron-microscopic concept of a sheath of Key and Retzius or of Plenk and Laidlaw, respectively.


Respective importance of different nerve conduction velocities in leprosy.

Motor and sensory nerve conduction studies were performed in the distal part of the ulnar, median and radial nerves of 12 tuberculoid and 12 lepromatous leprosy patients, compared with 15 normal subjects. Slowing of sensory conduction velocity (SCV) was shown in all nerves with no difference between tuberculoid and lepromatous patients. The radial SCV slowing is correlated (P less than 0.001) with the clinical findings. Impairment of motor distal latencies was observed only in tuberculpoid patients. It is concluded that the radial SCV is the most reliable conduction test and is proposed as an early diagnostic test for leprosy.


Vitamin B-6 absorption in children with acute celiac disease and in control subjects.

The concentration of serum pyridoxal phosphate was determined before and 15, 30, 60, 90, and 120 minutes following an oral load test with 5 mg pyridoxine hydrochloride/kg body weight in 14 children with acute celiac disease and in 15 control subjects. Children with acute celiac disease suffer from a biochemical vitamin B-6 deficiency. The increase in pyridoxal phosphate of children with acute celiac disease after loading was significantly decreased when compared with that of control subjects. In children with celiac disease maximal concentration of serum pyridoxal phosphate appeared later (after 60 minutes) and was decreased in comparison to control subjects (after 30 minutes). A positive correlation existed between the net increase of pyridoxal phosphate 60 minutes following pyridoxine loading and the net increase of blood xylose 60 minutes after oral loading. The results are compatible both with a malabsorption of pyridoxine in childhood celiac disease and a shifting of the site of pyridoxine absorption from the upper part of jejunum into the more distal parts of intestine.


Tryptophan and threonine requirements of fingerling channel catfish.

Growth studies, utilizing a 24% crude protein diet containing an amino acid pattern similar to whole egg protein, indicate that the tryptophan requirement for fingerling channel catfish (Ictalurus punctatus) is about 0.12% of the diet (dry weight basis) or 0.5% of the dietary protein. Similar studies indicate that the threonine requirement for the same fish is about 0.53% of the diet (dry weight basis) or 2.21% of the dietary protein. The dietary requirement of threonine was confirmed by serum free threonine analysis. A marked increase in serum free threonine occurred at a dietary threonine level of approximately 0.5% of the diet. None of the gross pathological changes previously reported for tryptophan deficiency in sockeye salmon and rainbow trout were observed in channel catfish.


Starvation and refeeding in rats: effect on organismic respiration, cytoplasmic constituents of liver, and succinic dehydrogenase activity in liver, kidney, and heart.

An analysis of starvation and starvation followed by refeeding was undertaken to characterize some organismic, organ, and mitochondrial responses to these two circumstances. Body weight, organismic respiration as well as weight protein and succinic dehydrogenase activity for liver, kidney, and heart were determined over the course of 6 days of starvation and 5 days refeeding for adult male rats. Assays of marker enzyme activities for mitochondria (cytochrome oxidase), lysosomes (acid phosphatase), endoplasmic reticulum (glucose-6-phosphatase), and plasma membranes (5'-nucleotidase) were conducted for liver in addition to quantitations of mitochondrial protein. All enzyme determinations were done on whole tissue homogenates and reported as total organ activity. Liver mitochondria were harvested quantitatively directly from whole liver homogenates by zonal centrifugation for determination of mitochondrial protein. Starvation resulted in a major loss of body weight, organ weight, and organ protein; liver greater than kidney greater than heart. These changes were accompanied by a major reduction in organ succinic dehydrogenase activity; liver greater than kidney. In heart, succinic dehydrogenase was doubled in activity at day 2 of starvation and subsequently diminished to values not significantly lower than controls. In liver, mitochondrial mass (protein) was severely diminished. From analysis of marker enzyme activities, it appeared that lysosomes, endoplasmic reticulum, and plasma membrane were also decreased. Refeeding restored the greatest part of these losses within 5 days.


Effect of dietary vitamin E and vitamin C on respiration and swelling of guinea pig liver mitochondria.

The effect of dietary vitamin C on vitamin E status and function was studied with weanling male Hartley guinea pigs. Thirty guinea pigs fed a basal diet free of vitamins E and C were divided into two groups; only one group received 2 mg/100 g body weight/day of vitamin C. Each group was further divided into three subgroups and received 0, 0.2, and 0.4 IU/100 g body weight/day of vitamin E. After 5 weeks the animals were killed. Degree of erythrocyte hemolysis induced by dialuric acid, level of plasma vitamin E and extent of liver lipid peroxidation were determined. Liver mitochondria were isolated and in vitro oxygen uptake was measured. The rate of swelling of mitochondria in two media was also determined. The results showed that the adequate dietary vitamin C supplementation did not affect the extent of erythrocyte hemolysis induced by dialuric acid, but increased the plasma vitamin E level and lowered liver lipid peroxidation. It also maintained the normal respiration and swelling rates of liver mitochondria when vitamin E was inadequate.


Effect of age and dietary fat level on fatty acid oxidation in the neonatal pig.

A total of 35 pigs were obtained by cesarean section, placed in individual sterile isolators, and randomly allotted to treatment groups. Thirty pigs received purified, isoenergetic liquid diets containing 2 or 32% butterfat (dry matter basis) and were killed at 1, 7, or 21 days of age. Five pigs were killed at 2 hours post delivery and received no diet. Twenty-one-day old pigs showed a tendency for higher weight gain and feed consumption when consuming the 32% fat diet although the differences were not significant. The rate of oxidation of [U-14C]palmitate to CO2 and acid soluble products was measured in homogenates of liver, kidney, heart, and leg muscle (biceps femoris) from pigs 0, 1, 7, and 21 days of age. The relative rates of oxidation of [U-14C]myristate, [U-14C]palmitate, and [U-14C]stearate were measured in homogenates of liver from 7-day old pigs. Palmitate oxidation was stimulated by carnitine in all four tissues and the rate of carnitine-stimulated palmitate oxidation to acid soluble products in heart and to CO2 in liver was higher in tissues from pigs consuming the 32% fat diet. The rate of palmitate oxidation increased with age in liver, kidney and leg muscle tissues and was maximum at 21 days in kidney and leg muscle and at 7 days in liver. The rate of palmitate oxidation in heart tended to decrease with animal age. In homogenates of liver from 7-day old pigs, palmitate was oxidized at a faster rate than stearate or myristate. The activities of carnitine palmitoyltransferase (CPT) (EC 2.3.1a) and succinate dehydrogenase (EC 1.3.99.1) in mitochondria isolated from liver, kidney, heart, and leg muscle did not vary considerably with age although CPT activity tended to be higher in those tissues from pigs consuming the high fat diet. Changes in the rate of palmitate oxidation with age tended to parallel changes in the level of mitochondrial protein per g of wet tissue and suggested an increased ability to utilize fat as an energy substrate during early development of the neonatal pig.


Splenic protein synthesis in magnesium deficiency: mechanism of the inhibition.

To investigate the basis for the depressed protein synthesis in vivo in magnesium deficient spleens, the activities of splenic subcellular fractions in polypeptide synthesis were studied in vitro. Splenic ribosomes from Mg deficient animals were normal structurally and functionally. In contrast, supernatant fractions from the deficient spleens had a reduced ability to incorporate labeled amino acids into protein, both in the presence of endogenous mRNA and in the presence of added polyuridylic acid. The specific defects observed in the Mg deficient supernatants were twofold: There was a modest reduction in the rate of acylation of tRNA and a more marked reduction in the activity of the elongation factors, EF-I and EF-II. The reduction in elongation factor activity was quantitatively sufficient to account for the inhibition of protein synthesis in vivo.


Fatty acid composition of submandibular salivary gland lipids in essential fatty acid deficient rats.

Essential fatty acid (EFA) deficiency was induced in young weanling rats by feeding a fat-free diet or a diet containing 7% Hydrogenated coconut oil (HCO). At intervals of 4, 8, and 16 weeks, rats from the deficient and the control groups were killed and their Submandibular Salivary Glands (SMSG) were dissected out and extracted for lipids. The fatty acid composition of total lipids, triglycerides (TG), free fatty acids (FFA), phosphatidyl choline (PC), and phosphatidyl ethanola-mine (PE) fractions was determined. The levels of 16:1 and 18:1 were increased whereas those of 18:2 and 20:4 were decreased in the EFA-deficient groups as compared to the controls. 5,8,11-eicosatrienoic acid (20:3 omega9) accumulated in the total lipids as well as other lipid fractions of the SMSG from the deficient rats. The levels of this fatty acid increased as the EFA-deficiency progressed. Changes in fatty acid composition of SMSG lipids of EFA-deficient rats were associated with a reduction in flow rate of whole saliva. Protein concentration and amylase activity of saliva was the same in the two groups.


Adipose cellularity and body composition in polygenic obese mice as influenced by preweaning nutrition.

Male mice from a line selected for rapid postweaning growth (M16) and an unselected control (ICR) were reared from birth to 3 weeks either in litters of eight (N8) or 14 (N14). Body weight gain and feed intake of M16 mice were greater than ICR. These high rates of gain and feed intake also were extended to an older age in M16 (10 weeks) than in ICR (6 weeks). The M16 line exceeded the ICR line and N8 mice exceeded N14 for fat, lean, ash, and live body weights at 4, 6, 10, 16, and 30 weeks of age. Fat percentage was greater in N8 than N14 for both ICR and M16. The adipose cellularity of the epididymal fat pads of M16 indicated a hypertrophic-hyperplastic form of obesity at 10, 16, and 30 weeks. Within each line, the N14 mice had fewer and slightly smaller fat cells than N8. However, M16-N14 mice still had considerably more and larger fat cells than ICR-N8. Restriction of energy intake from birth to 3 weeks reduced subsequent feed intake and degree of obesity. After 4 weeks, the genetic effect exerted a greater influence on the development of obesity than the preweaning nutritional regimen.


Effect of postweaning feed restriction on adipose cellularity and body compositon in polygenic obese mice.

The M16 line of mice, selected for rapid postweaning gain, exhibits polygenically controlled obesity and hyperphagia. The effect of limiting postweaning energy intake on the subsequent growth and development of obesity in M16 mice was investigated. Male mice from M16 and an unselected line (ICR) were provided either ad libitum or limited (congruent to 70% of ad libitum) feed during the rapid postweaning growth period from 4 to 6 weeks of age. Body weights (g) at 6 weeks of age were: ad libitum ICR (31.0 +/- 0.6), restricted ICR (23.8 +/- 0.7), ad libitum M16 (45.0 +/- 0.6) and restricted M16 (30.1 +/- 0.6). In both lines, restricted feed intake severely depressed body fat, lean, ash, and water at 6 weeks. In addition, percent triacylglycerol, fat cell size and number in the epididymal fat pads were lower. Restricted M16 and ICR mice showed a marked compensatory gain in all body components when subsequently fed ad libitum for 10 weeks. All measurements of adiposity at 16 weeks were similar for the restricted and ad libitum regimens within each line. The relative amounts of energy deposited as fat and lean between 4 and 16 weeks were not influenced by restricted feeding, but M16 mice deposited a larger proportion of energy as fat than as lean when compared with ICR mice. The results suggest that fat cell number is determined at a relatively early age in mice and is primarily under genetic control.


Stimulatory effect of 1,25-dihydroxycholecalciferol-like substances from Solanum malacoxylon and Cestrum diurnum on phosphate transport in chick jejunum.

Extracts of the calcinogenic plants Solanum malocoxylon and Cestrum diurnum stimulate phosphate absorption by the jejunum of vitamin D-deficient chicks, as determined by everted gut sac technique. Their action on cellular pathways of transepithelial phosphate transport is indistinguishable thereby from that of cholecalciferol. Increased net absorption from the lumen was due to enhanced uptake of phosphate from the luminal side, while leakage of tissue phosphate in the opposite direction was apparently unaffected. Steep serosa/mucosa concentration gradients were observed as consequence of enhanced levels of transepithelial phosphate flux in the mucosa-to-serosa direction. With respect to their stimulatory action on phosphate absorption, the calcinogenic plant factors retained their biological activity when phosphate transport was depressed by a high strontium diet. Their action in overcoming the strontium inhibition of phosphate absorption, calcium-binding protein synthesis, and alkaline phosphatase activity, was comparable to the effect of 1,25-dihydroxycholecalciferol. On the basis of these biological responses, the action of the plant factors from Solanum malacoxylon and Cestrum diurnum provides further evidence for their close resemblance to the hormonally active sterol.


Effect of malnutrition and rehabilitation on the metabolism of polyamines in rat liver.

In adult male rats the activity of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMD) and the concentration of putrescine and spermidine increased markedly 3 to 4 weeks after feeding the animals a 6% casein diet. Incorporation of [14C]orotic acid into nuclear RNA also increased during this period of time. In contrast, spermine concentration remained unchanged. During the fifth week of protein restriction enzyme activities, putrescine and spermidine concentrations and orotic acid incorporation returned to control levels. After the restricted rats were put on a control diet there was a rapid increase above control levels in ODC activity and a proportionally smaller increase in SAMD activity. Putrescine and spermidine concentration also increase above control levels. Both enzyme activities and polyamine concentrations were within normal levels 96 hours after refeeding. Spermine values were unmodified by refeeding. After a transient rise 12 hours after refeeding, incorporation of labeled orotic acid into RNA decreased significantly for the rest of the experiment.


The effect of dietary fat or cholesterol and cholic acid on the rate of synthesis of rat liver glucose-6-P dehydrogenase.

The effect of dietary fat or cholesterol and cholic acid on the rate of synthesis of rat liver glucose-6-P dehydrogenase was measured by isolating hepatocytes from the livers of rats fed diets containing various amounts and types of lipid. Hepatocyte proteins were labeled with [3H]leucine and glucose-6-P dehydrogenase was immunoprecipitated with a specific antiserum. The immunoprecipitates were electrophoresed on sodium dodecyl sulfate-polyacrylamide gels and the radioactivity in the glucose-6-P dehydrogenase subunit was used to calculate the relative rate of synthesis of the enzyme. It is concluded that the activity of glucose-6-P dehydrogenase is primarily regulated by alterations in the rate at which the enzyme is synthesized. Dietary fat may decrease the rate of degradation of glucose-6-P dehydrogenase.


A hypertension control program based on the workplace. Report on the Chicago Center.

In several large Chicago companies and institutions, workplace screening of 7,151 persons yielded 833 suspect hypertensives. Of these, 91% attended a follow-up verification visit, where for 513 persons high diastolic pressure was confirmed. One-half of these persons were referred to their physicians for treatment and one-half were randomly assigned to be treated directly by HDFP, in a step-wise pharmacologic regimen to normalize diastolic pressure. Of the 257 persons assigned to program treatment, 94% accepted such treatment, and over 90% of these still living in the community were active participants at one year. Average diastolic pressure of these active participants was 83.1 mm Hg at one year, compared to 102.6 at first screen and 98.8 at the second confirmatory screening. A strenuous effort has been made to reduce or eliminate obstacles to treatment, including lack of understanding of the need for long-term therapy, cost barriers and barriers of inconvenience of treatment. The medical team conducting the program combined physicians with nonphysician therapist-health counselors, plus "outreach" staff, to maximize program adherence. Preliminary experiences in the Chicago Center of the Hypertension Detection and Follow-Up Program (HDFP) give encouraging evidence that the workplace is a useful base for successful hypertension control efforts.


Perimetry of contrast detection thresholds of moving spatial sine wave patterns. I. The near peripheral visual field (eccentricity 0 degrees-8 degrees).

Contrast detection thresholds for moving spatial sine wave gratings were obtained, at the fovea, and at eccentricities of 1 degree, 2 degrees, 4 degrees, 6 degrees, and 8 degrees on the nasal horizontal meridan, for two subjects. The target field subtended 30 X 30 minutes of arc. The spatial frequency range extended from 2 cpd up to the spatial resolution limit, the temporal frequency range from 0.1 Hz up to the CFF. Mean retinal illuminance was 10 trolands. We find for these conditions: (i) Contrast detection thresholds are higher, the higher the spatial and/or temporal frequency of the stimulus. (ii) Acuity appears to be independent of the temporal frequency, the CFF appears to be independent of the spatial frequency. (iii) The higher the eccentricity, the higher the contrast detection threshold for any drifting sine wave pattern. The threshold doubles roughly any 2 degrees-3 degrees for spatial frequencies of 2-20 cpd, except that the visual field for a given fineness of grating is blind beyond a certain critical eccentricity. This critical eccentricity is a monotonically decreasing function of the spatial frequency of the grating. These measurements do not support the hypothesis that coarse patterns are preferentially detected at extrafoveal sites in the visual field.


Perimetry of contrast detection thresholds of moving spatial sine patterns. II. The far peripheral visual field (eccentricity 0 degrees-50 degrees).

Contrast detection thresholds for moving sine wave gratings were obtained at the fovea and at eccentricities of 6 degrees, 12 degrees, 21 degrees, 32 degrees, and 50 degrees on the nasal horizontal meridian. The field subtended 4 degrees X 4 degrees. Spatial frequencies ranged from 0.25 cpd up to the resolution limit, temporal frequencies from 0.1 Hz up to the CFF. Mean retinal illuminance was 10 trolands. We find for these conditions: (i) For any eccentricity there exists a unique combination of spatial frequency and velocity for which the threshold is a minimum. (Extremes are 2 cpd and 2 degrees s-1 at the fovea, and 0.5 cpd and 12 degrees s-1 at an eccentricity of 50 degrees. (ii) Acuity depends little on velocity, the CFF only little on spatial frequency. (iii) The higher the eccentricity, the higher the threshold for any drifting sine wave pattern. Except for this the qualitative threshold behavior as a function of spatial and temporal frequency is identical at the fovea and at eccentricities up to 50 degrees. The thresholds double every 12 degrees for spatial frequencies of 0.25-2 cpd. For a given spatial frequency the visual field is blind beyond a certain critical eccentricity. This critical eccentricity is a monotonically decreasing function of spatial frequency.


Perimetry of contrast detection thresholds of moving spatial sine wave patterns. III. The target extent as a sensitivity controlling parameter.

Contrast detection thresholds for moving sine wave gratings were obtained at the fovea and at eccentricities of 6 degrees, 21 degrees, and 50 degrees on the nasal horizontal meridian. The targets subtended from 30 X 30 minutes of arc up to 16 degrees X 16 degrees. We have found that the contrast detection thresholds depend critically on the extent of the target field. If this extent is large enough peripheral detection thresholds are on a par with those measured at the fovea, only the sensitivity range is shifted to lower spatial frequencies. We show that if the just resolvable distance at any eccentricity is taken as a yardstick, and field width and spatial frequency are scaled accordingly, then the spatio-temporal contrast detection thresholds become identical over the whole visual field. It is shown that a smaller area, measuring several just resolvable distances across, has to be stimulated before successive or simultaneous contrast detection is possible at all. Detection performance improves if the stimulated area is enlarged up to diameters of at least 10(2) just resolvable distances. The just resolvable distance correlates well with mean interganglion cell distance, and with the cortical magnification factor.


Perimetry of contrast detection thresholds of moving spatial sine wave patterns. IV. The influence of the mean retinal illuminance.

Contrast detection thresholds for moving sine wave gratings were obtained at the fovea and at eccentricities of 6 degrees, 21 degrees, and 50 degrees on the nasal horizontal meridian. The targets subtended from 30 X 30 minutes of arc up to 16 degrees X 16 degrees. Mean retinal illuminance was varied between 10 and 0.01 trolands. The transition from the de Vries-Rose to the Weber region occurs in the far peripheral visual field at a 2-3 decades lower illuminance level than at the fovea. The spatio-temporal contrast detection thresholds become comparable over the whole visual field if the mean distance between retinal ganglion cells is taken as a yardstick, and field width, spatial frequency, and quantum density are scaled accordingly. This means that at scotopic illuminance levels coarse or medium gratings are preferentially detected at other than foveal locations. (The fine gratings cannot be resolved at all at such levels.) It is argued that both electrophysiological and psychophysical evidence indicates that Weber behavior starts whenever some small fixed number of quantum absorptions occur within an area of 1 mean interganglion cell distance across. Or, equivalently, if a fixed small number of "neural quanta" enters a 100 X 100 micron2 area of the visual cortex.


Revaccination of previous recipients of killed measles vaccine: clinical and immunologic studies.

Clinical and immunologic studies were performed in association with revaccination with live measles vaccine in 75 adolescents 11 to 14 years after immunization with killed measles vaccine. Ten subjects had local pain with swelling or erythema or both at the injection site; in three, the local reactions were severe and disturbing systemic complaints were also noted. These marked reactions were more common in subjects in whom the interval between the last dose of killed vaccine and the dose of live vaccine of the primary immunization series was less than or equal to 2 months, in subjects with prevaccination serum HAI antibody titers of less than or equal to 5, and in subjects with high measles antigen specific lymphocyte stimulation ratios. Serum complement levels could not be correlated with clinical reactions. Measles specific lymphocyte stimulation ratios were significantly higher in recipients of killed vaccine than in three compara,ive groups, in subjects with a killed-live interval in the initial vaccine series of less than or equal to 2 months as compared with greater than or equal to 3 months, and in subjects with prevaccination HAI antibody titers of less than or equal to 5 as compared with titers greater than or equal to 10. Although both low serum antibody and high measles specific lymphocyte reactivity were associated with marked local reactions, and probably indicative of susceptibility to atypical measles, our findings suggest that exaggerated lymphocyte reactivity is of greater importance in the adverse clinical response.


Activity of the alternative pathway of complement in the newborn infant.

Levels of C3, properdin, factor B, and C3 to C9 activity were markedly reduced in cord sera taken from 94 normal newborn infants. Nevertheless, cord serum supported complete activation of its own alternative pathway by zymosan or CoF. Lysis of a target cell, however, was defective; nearly 75% of cord sera had reduced rabbit erythrocyte CH50 titers. These were partially increased by the addition of factor B and properdin, and totally restored by adding factor B, properdin, and C3 to C9. Therefore, although the alternative pathway of the neonate is intact, it appears to be limited in its ability to generate an adequate number of stable and active enzymatic sites on a target cell membrane.


The phenotypic variability of diastrophic dysplasia.

To determine the relationship between so-called "diastrophic variant" and diastrophic dysplasia, four patients considered to have the variant condition were studied in detail and compared to 67 patients (including 17 sets of affected sibs) considered to have classical diastrophic dysplasia. Analysis of the combined clinical, radiographic, histologic, and genetic data indicates that there is wide variability in the phenotypic expression of diastrophic dysplasia, even within sibships, and that those individuals previously labeled as having "diastrophic variant" appear to have mild diastrophic dysplasia.


Randomized trial of early closure of symptomatic patent ductus arteriosus in small preterm infants.

As a result of randomized assignment, 15 preterm infants weighing 1,500 gm or less at birth and who had a symptomatic PDA were treated according to a medical management protocol, and ten according to an early surgical closure protocol. All infants required mechanical ventilation at the time of study entry, which was one week after birth. Birth weight, gestational age, age at onset of congestive failure, age at study entry, and the initial morbidity of members of the two groups were similar. The nine surviving infants managed according to the surgical closure protocol were weaned from mechanical ventilation sooner, had a decreased need for digoxin and furosemide, achieved gastrointestinal function sooner, and had a smaller hospital bill than the 12 survivors of the medical management group. These results indicate that infants with a symptomatic PDA still requiring mechanical ventilation at one week after birth will benefit from surgical closure of the ductus at that time.


Digoxin therapy in low-birth-weight infants with patent ductus arteriosus.

Digoxin therapy was evaluated retrospectively in a group of 30, and prospectively in a group of 16 low-birth-weight, premature infants with cardiorespiratory symptoms due to persistent patency of the ductus arteriosus. The response to decongestive therapy was equivocal. Digoxin levels in serum varied between 1.5 and 13 ng/ml. Digoxin half-life in serum exceeded three days in four patients. Fourteen of the combined group of 46 infants had signs of toxicity of digoxin. High dosage, inadvertent  overadministration, and variable clearance of digoxin, as well as special characteristics of the patients studied, are postulated as explanations for the high incidence of toxicity. This study suggests that digoxin therapy in low-birth-weight, premature infants with patent ductus arteriosus is not without risk.


Surgical resection for pulmonary interstitial emphysema in the newborn infant.

Three patients with pulmonary interstitial emphysema are presented in whom the course was similar and progressive. Eventually all three infants developed respiratory insufficiency and chronic dependence on mechanical ventilation, cardiovascular complications of patent ductus arteriosus with congestive heart failure, and seizures probably secondary to intermittent periods of asphyxia and hypoxemia. All infants underwent lobectomy and recovered rapidly. Follow-up examinations have shown some residual pulmonary abnormalities. All three infants are progressing within the normal range for motor development.


Neonatal transport: a controlled study of skilled assistance. Mortality and morbidity of neonates less than 1.5 kg birth weight.

To attempt to demonstrate the need for skilled care of sick neonates in transport, a modified randomized controlled study of infants being transported to this institution was carried out. Although special equipment was used, ambulances were not modified. Results of the first phase reported here show that infants weighing less than 1.5 kg at birth, transported by a trained physician and nurse, were significantly warmer, less hypotensive, and less acidotic on admission to the NICU. Mortality was significantly reduced, first week morbidity somewhat lessened, and duration of stay in hospital reduced by more than one third (P less than 0.01).


Pulmonary pressure/volume relationships during the last phase of delivery and the first postnatal breaths in human subjects.

Intrathoracic pressure and volume changes during delivery and the first postpartum breaths were measured in 17 term infants. The following findings emerged: (1) Infants were often exposed to high pressures during delivery, when significant volumes of lung fluid were expressed. (2) Despite this, none of the infants' lungs reinflated by passive "elastic recoil." (3) The active inspiratory effort required for reinflation was usually small or moderate, and an "opening pressure" did not appear to be necessary for the initial rise in volume. It is believed that diaphragm and intercostal muscle tone falls or disappears during delivery and returns during the first breath.


Plasma concentrations of phenobarbital in mother and child after combined prenatal and postnatal administration for prophylaxis of hyperbilirubinemia.

Phenobarbital is known to reduce serum bilirubin concentration in the newborn infant, but optimal dosage is unknown. Ten pregnant women and their infants were given a standard regimen including prenatal maternal administration and postnatal administration to the infant during the first week of life. The plasma levels of phenobarbital in the infants were found to increase during the period of administration, and to remain high for many days beyond the period of hyperbilirubinemia. Optimal dose schedules for phenobarbital should be based both upon pharmacologic effects (including those other than bilirubin disposition) and upon the pharmacokinetic profile of the drug in the newborn infant.


Behavioral consequences of congenital rubella.

Psychiatric and behavioral consequences of congenital rubella are reported for 243 children studies during the preschool period, and for 205 of these who were re-examined at ages 8 to 9. At preschool 37% were retarded, with the skew toward severe and profound; 15% had reactive behavior disorder and 7% had autism. At school age retardation diminished to 25%, but neurotic problems and behavioral pathology due to neurologic damage both increased. There were two remissions and three new instances of autism.


Use of the psychological test report in the course of psychotherapy.

Most studies predicting psychotherapy outcome involve the use of a particular test or group of tests. Very little is found concerning the use or usefulness of what is more generally available, the psychological test report. This article discusses the psychological test report not only as a useful instrument to predict outcome of psychotherapy, but also as an objective measure to assist in understanding the progress of psychotherapy and to alert the therapist of potentially very critical and delicate situations. Case examples are included illustrating the use of the psychological test report during the course of psychotherapy.


A reply to Stricker's criteria for insurance reimbursement for psychological assessments.

Stricker (1978) proposes a set of criteria which has been offered as a guideline to determine third party payments for psychological assessments. While the author views these as generally reasonable for adult assessments, he suggests that a different set of criteria be used for child assessments.


Locus of control, learned helplessness, and control of heart rate using biofeedback.

Subjects were 24 male undergraduate students. False biofeedback was provided to give the impression of success or failure (helplessness) on a preliminary task. Authentic biofeedback was then provided for control of heart rate. Subjects were administered pre- and post-locus of control scales using Levenson's multidimensional scales. A significant relationship between locus of control and success or failure conditions added validity to Levenson's approach. Results and future research are discussed.


Cross-situational consistency among problem adolescents: an application of the two-factor model.

A study was conducted to measure cross-situational consistency of the orthogonal dimensions of the two-factor model of social-emotional functioning. According to this model, large proportions of variance in social-emotional functioning can be accounted for by two orthogonal, highly replicable dimensions. The setting was Hawthorne-Cedar Knolls, a long-term institution for emotionally disturbed and delinquent youths; the subjects were 206 residents of varied ethnic and socioeconomic backgrounds. Cross-situational correlations between school and cottage settings were found to be .52 for Factor II (Cooperation-Compliance versus Anger-Defiance) and .42 for Factor I (Interest-Participation versus Apathy-Withdrawal). The results confirm the consistency and discriminant validity hypotheses--specifically, correlations between the corresponding factors of different instruments measuring behavior in different settings were large, whereas correlations between noncorresponding factors were very low. The value of using broad, higher order factors in personality research on the trait versus situation issue is discussed.


Absorption of oral tetracycline in patients with Billroth-II gastrectomy.

The bioavailability of a single 250-mg oral dose of tetracycline hydrochloride was studied in seven patients following Billroth-II gastrectomy in comparison with seven control subjects matched for age and body weight. There were no significance differences between control subjects and gastrectomized patients in the apparent lag time prior to the start of absorption (23.6 vs. 22.8 min), peak serum tetracycline concentration (1.72 vs. 1.75 microgram/ml), the time of attainment of peak concentrations (3.35 vs. 3.42 hr), the apparent first-order absorption half-life (1.8 vs. 1.4 hr), or the apparent first-order elimination half-life (8.0 vs. 8.7 hr). Completeness of tetracycline absorption, as judged by area under the 24-hr serum concentration curve, did not differ significantly between the two groups, nor did 24-hr urinary excretion of tetracycline. Thus the abnormalities of gastrointestinal structure and function produced by Billroth-II gastrectomy do not result in impairment of the rate and completeness of tetracycline absorption.


Enzyme induction following a single dose of amobarbital in dogs.

The elimination of amobarbital in dogs was investigated by injecting various doses of amobarbital into a given animal. At low doses (3 mg/kg) serum levels declined in a first-order fashion. Superficially, at high doses (20 mg/kg) the relationship between serum concentration and time could be quantitatively characterized by simple one-compartment saturable kinetics. Indeed, qualitatively, saturation of the amobarbital-metabolizing enzymes was indicated by a shallower initial slope of the semilogarithmic concentration--time profile at the high than at the low dose. However, in addition, an acute enzyme induction phenomenon was observed which was indicated by a shorter terminal half-life of amobarbital at the high dose than after the low dose and also by a shortening in antipyrine half-life.


Pharmacokinetic analysis of percutaneous absorption: evidence of parallel penetration pathways for methotrexate.

Compartmental models were developed to describe the penetration of a drug from a topically applied vehicle through the skin. Data for in vitro penetration of methotrexate through hairless mouse skin from vehicles varying in pH from 3.5 to 6.5 were computer-fitted to estimate model parameters. Comparison of lag time and the exponential coefficient suggested that parallel penetration pathways exist. The fraction of drug penetrating through the shunt pathway increased as vehicle pH and ionization increased. Penetration curves were quantitatively partitioned into bulk tissue and shunt contributions. At pH 6.5, flux through the shunt pathway predominated.


Correlation between in vitro and in vivo drug metabolism rate: oxidation of ethoxybenzamide in rat.

In vitro and in vivo correlations of the microsomal oxidation of drugs were examined, using ethoxybenzamide as a model drug. Ethoxybenzamide disappearance time course from rat plasma in vivo was analyzed by a two-compartment model assuming a Michaelis-Menten type elimination process. Ethoxybenazmide oxidation in vitro was measured by the appearance rate of salicylamide in rat liver microsomal suspension. Parameters obtained were Vmax = 3.46 and 3.77 mumoles/min/kg body weight and Km = 0.378 and 0.192 mM, in vitro and in vivo, respectively.


Progestin permeation through polymer membranes I: diffusion studies on plasma-soaked membranes.

The potential of several commercially available polymeric materials for use in controlled-release drug delivery devices was investigated. Progesterone was used as a model hydrophobic drug. The progesterone permeation rates through polydimethylsiloxane, two polyether urethanes, a hydroxyethyl methacrylate, a polyether urethan--polydimethylsiloxane blend, and a cellulosic membrane were determined. The permeabilities were obtained on nonsoaked membranes and on membranes soaked in plasma for varying times. The purpose of the plasma soaks was to examine the effects of lipid absorption and degradative processes within the membrane on progesterone permeability. This study identified several polymers that show potential for use in controlled-release drug delivery devices. The plasma treatment studies showed that several polymers may not be acceptable. The plasma soak studies were interpreted in terms of the mechanisms of drug permeation through the membranes.


Progestin permeation through polymer membranes II: diffusion studies on hydrogel membranes.

The potential use of hydrogels in controlled-release drug delivery systems for contraceptive steroids was investigated. The permeabilities, diffusion coefficients, and partition coefficients for progesterone were determined for hydrogels made from hydroxyethyl methacrylate containing varying amounts of ethylene glycol dimethacrylate and tetraethylene glycol dimethacrylate. In addition, copolymers of hydroxyethyl methacrylate with methoxyethyl methacrylate and methoxyethoxyethyl methacrylate were investigated. The results were interpreted in terms of the mechanisms of permeation of progesterone through the hydrogels. This study showed that progesterone permeated these membranes primarily through loose pores in the hydrogel network except at high concentrations of the cross-linker, ethylene glycol dimethacrylate, where dissolution and diffusion of the progesterone in the polymer network was the dominant mechanism.


Comparison of effects of quinidine and dihydroquinidine on canine heart.

Various cardiac effects of quinidine and dihydroquinidine were tested in isolated dog hearts and in vivo in dogs. No significant differences were found in the negative inotropic, chronotropic, and dromotropic effects. Dihydroquinidine was more potent than quinidine in decreasing coronary arterial pressure.


Plasma propranolol levels in beagle dogs after administration of propranolol hemisuccinate ester.

The hemisuccinate ester of propranolol was administered to beagle dogs to test its applicability as a potential prodrug of propranolol. Following oral administration of propranolol hemisuccinate, plasma propranolol levels were eight times higher than after an equivalent dose of propranolol hydrochloride. The hemisuccinate was absorbed rapidly, with peak plasma levels observed at 0.5--1 hr. Following intravenous dosing, the disappearance half-life of the prodrug from the plasma was 0.5 hr while the propranolol half-life was 1.7 hr. This study demonstrated the potential usefulness of the prodrug approach when a highly metabolized drug such as propranolol is protected from first-pass elimination.


Simple procedure for determining octanol--aqueous partition, distribution, and ionization coefficients by reversed-phase high-pressure liquid chromatography.

The described simple, accurate, and precise reversed-phase high-pressure liquid chromatographic procedure is in excellent agreement with 1-octanol shake-flask partition or distribution coefficients over a 3.5 log range. A chemically bonded octadecylsilane support is persilated and coated with 1-octanol. With 1-octanol-saturated buffers as mobile phases, a stable baseline (compared to 1-octanol adsorbed on silica) is obtained rapidly, and the log relative retention times are highly correlated with unit slope to log distribution or partition coefficients obtained from the classical shake-flask procedures. Only relatively basic, unhindered pyridines deviate, probably because of binding with residual silinol sites. In addition, if the apparent pKa or pKab of an ionizable compound lies within the pH operating range of the column support, the apparent pKa or pKab usually can be determined simultaneously with log P by measuring the log distribution coefficient at several pH values. The procedure gives rapid results, requires little material, and can tolerate impurities.


Substituted tetralins VI: Tentative assignment of absolute stereochemistry of 1-methyl-1-phenyl-1,2,3,4-tetrahydro-3-naphthoic acid and N,N,1-trimethyl-1-phenyl-1,2,3,4-tetrahydro-3-naphthylamine isomers.

The absolute configurations of the enantiomers of N,N,1-trimethyl-cis- and trans-1-phenyl-1,2,3,4-tetrahydro-3-naphthylamines (Ia and Ib) were assigned tentatively from the circular dichroism spectrum of a bridged ketone derived by cyclization of optically active 1-methyl-cis-1-phenyl-1,2,3,4-tetrahydro-3-naphthoic acid (IIa). Thus, (--)-IIa and the corresponding amine, (--)-Ia, were assigned the (2S, 4R)-configuration. Epimerization of (--)-IIa through its methyl ester yielded the trans-acid, (--)-IIb, which established the absolute configuration of (--)-IIb and the corresponding amine, (--)-Ib, as (2R, 4R).


Pharmacokinetics of drug permeation through human skin.

Based on sorption and permeation characteristics of scopolamine in human skin in vitro and drug elimination kinetics obtained from pharmacokinetic studies, a mathematical model was developed for estimating and optimizing the temporal pattern of scopolamine delivery from a transdermal therapeutic system through human skin in vivo. Experimentally measured scopolamine delivery in vivo conformed to this model.


Enhancement of bioavailability of a hydrophobic amine antimalarial by formulation with oleic acid in a soft gelatin capsule.

The relative availability of the orally administered hydrophobic antimalarial alpha-(dibutylaminomethyl)-6,8-dichloro-2-(3',4'-dichlorophenyl)-4-quinolinemethanol (I) from two dosage forms was determined in beagle dogs. Compound I was soluble in oleic acid to the extent of 23.5% (w/w), and oleic acid was suitable for encapsulation in soft gelatin capsules. The availability of I formulated as its hydrochloride salt in a standard hard gelatin capsule formulation was significantly lower than that of I formulated in a soft gelatin capsule with oleic acid as the solvent. A 20% solution of I in oleic acid (soft gelatin capsules) maintained at 23 degrees provided 4% of the oleic acid ester of I iwithin 1 month. Further reaction, however, was not seen over 2 years.


Heterocyclic tricycles as potential CNS agents I: 4-aminoalkylindeno[1,2-c]pyrazoles.

Series of 4-(3-dimethylaminopropyl)-4-hydroxyindeno[1,2-c]pyrazoles and 4-(1-methyl-4-piperidyl)-4-hydroxyindeno[1,2-c-]pyrazoles were synthesized and identified. The compounds were evaluated as potential CNS agents using spontaneous and forced motor activity in mice as an initial test. 2-Ethyl-3-methyl-4-(1-methyl-4-piperidyl)-4-hydroxyindeno[1,2-c]pyrazole possessed significant biological activity.


Interactions of caffeine and theophylline with p-cresol: UV studies.

UV absorption studies demonstrated the formation of weakly bonded charge transfer complexes between caffeine and theophylline with p-cresol in chloroform. The transitions involved were detected at wavelengths longer than those of the single pure substances. Equilibrium constants from the Benesi-Hildebrand equation could be measured together with other thermodynamic constants and molar extinction coefficients. In general, the equilibrium constants were very small while the entropies of formation were quite high. Even though the equilibrium constants of caffeine--p-cresol were independent of wavelength over a narrow range, the apparent enthalpies of formation of both complexes indicated wavelength dependence.


Hardness increase induced by partial moisture loss in compressed tablets and its effect on in vitro dissolution.

The hardness increase induced by partial moisture loss in compressed tablets was studied. Several factors such as the type and percentage of the excipient, the water solubility and hygroscopicity of the excipient or drug, and the influence of frequently used binders were investigated. The results indicate that the tablets increased in hardness by the recrystallization of the soluble excipient or the soluble drug in the void spaces This recrystallization occurred because of the moisture loss after expulsion of the solution of the excipient or drug in the void spaces on compression. The large increase in hardness induced by the partial moisture loss did not decrease in vitro dissolution appreciably. This result was clearly different from the hardness increase caused by higher compression loads in the absence of a moisture-induced effect, which showed a decrease in the in vitro dissolution as the hardness was increased.


Hemodynamic alterations in isoproterenol-induced cardiac arrhythmias in corticoid-treated rats.

Hemodynamic alterations were studied to determine their role in isoproterenol-induced cardiac arrhythmias in the desoxycorticosterone acetate--saline-treat rat. Since epinephrine, a catecholamine possessing an alpha-adrenergic receptor agonist component, was considerably less potent as an arrhythmogenic agent, an elevation in blood pressure was thought to be protective against arrhythmias. Both albuterol, a beta2-adrenergic agonist, alone and epinephrine administered following tolazoline, an alpha-adrenergic blocking agent, decreased blood pressure to that of isoproterenol but failed to elicit significant arrhythmias. Phenylephrine administered prior to isoproterenol resulted in significant arrhythmias despite the maintenance of mean blood pressure at normal levels. The study shows that blood pressure alterations are not important in the etiology of isoproterenol-induced arrhythmias in the corticoid-pretreated rat.


Semiautomated system for high-pressure liquid chromatographic determination of dissolution rate of fludrocortisone acetate tablets.

A new semiautomated high-pressure liquid chromatographic (HPLC) system is described to determine the dissolution rate of fludrocortisone acetate tablets. The system uses a miniaturized dissolution basket and shaft assembly having the same geometry as that given in USP XIX. This reduced size permits use of smaller volumes of dissolution medium, allowing most very low dose oral solid dosage forms to be handled. The USP dissolution kettle was also replaced with a new miniaturized vessel that continuously filters the sample solution before it enters the flow system. Volumes of dissolution medium as small as 15 ml can be accommodated, depending on the sensitivity of the assay employed and the solubility of the drug substance under study. The concentration of fludrocortisone acetate in solution was monitored by a new HPLC system employing a reversed-phase column compatible with the aqueous dissolution medium used. A comparative dissolution study of different lots was made using different basket rotation speeds.


Bioavailability of sulfonamide suspensions I: Dissolution profiles of sulfamethizole using paddle method.

A comparative bioavailability study was performed using two commercially available, chemically equivalent brands of sulfamethizole suspension. One gram of each suspension was administered to 12 different subjects following a completely randomized crossover design. Serum levels and derived pharmacokinetic parameters were compared statistically. There were no significant differences in the extent of sulfamethizole absorption from the two suspensions as evidenced by the area under the serum level--time curves. Significant differences (p less than 0.05) in the mean serum levels at 0.5 and 0.75 hr and differences in Cmax and tmax indicated that the absorption rate differed for the two products. In vitro tests including particle-size analysis and dissolution studies were performed. The size--frequency distribution of particles in the suspensions was studied using a resistance particle counter. The dissolution characteristics of the two products were studied using the Food and Drug Administration's paddle method and the spin-filter apparatus. Suspension A had a significantly greater amount of drug dissolved at 15 and 30 min using either method. It also had a greater percentage of particles at the smaller size range, indicating that the greater dissolution rate may be related directly to the decreased particle size. A comparison of the in vivo and in vitro results demonstrated a definite rank-order correlation between the dissolution performance of the two suspensions and the in vivo parameters reflecting the absorption rate. Suspension A had a greater amount of drug dissolved at 15 and 30 min and resulted in higher serum levels at 0.5 and 0.75 hr, a higher Cmax, and a shorter tmax.


Disposition of norgestimate in the presence and absence of ethinyl estradiol after oral administration to humans.

The disposition of radioactivity following oral administration of 14C-norgestimate was compared to that following administration of the drug in combination with 3H-ethinyl estradiol in humans. Seven normal, healthy female subjects were each administered one capsule orally containing 14C-norgestimate either alone (74.4 muCi, 0.50 mg) or in combination (73.5 muCi, 0.49 mg) with 3H-ethinyl estradiol (103 muCi, 0.14 mg) in polyethylene glycol 400. Peak levels of radioactivity due to carbon-14 and tritium in plasma occurred within 2 hr after drug administration, followed by distribution and elimination phases. The mean apparent elimination half-life and mean cumulative elimination of radioactivity in the urine and feces following 14C-norgestimate administration were not significantly different than those following administration of the combination dose. Approximately 50% of the administered radioactivity due to carbon-14 was excreted in the urine following administration of 14C-norgestimate both in the presence and absence of coadministered 3H-ethinyl estradiol.


Molecular connectivity study of muscarinic receptor affinity of acetylcholine antagonists.

A correlation between three molecular connectivity indexes and the muscarinic receptor affinity of 104 acetylcholine antagonists was found. Analysis of structure from these indexes reveals not only the importance of the onium and the bulky portions of the molecule but also their virtual independence of each other on the affinity. Analysis of the onium group portion of the molecules indicates that its contribution to the experimental affinity is virtually constant through a variety of structural variations. The influence of the bulky side chains, in contrast, is quite structure dependent. The equation relating connectivity indexes to muscarinic affinity of antagonists is capable of predicting the affinity of other antagonists as well as a number of agonist molecules.


Facile separation of sulfonamides from their degradates by liquid--liquid extraction.

Regulation of acidity for protonation of the free N4-amine can provide for the selective liquid--liquid extraction isolation of a sulfonamide from its degradation products. This principle is applied for the stability-indicating determination of sulfacetamide in the presence of sulfanilamide, sulfaquinoxaline in feed, and sulfabromomethazine in dosage forms. In solution, sulfabromomethazine can exhibit photodecomposition to sulfamethazine. The mean relative errors of the these methods and the precision, represented by relative standard deviations, are each typically less than 2%.


Simultaneous solubilization of steroid hormones I: estrogens and C21 steroids.

The simultaneous solubilization of some estrogens and C21 steroids in aqueous polysorbate 40, tetradecyltrimethylammonium bromide, and sodium lauryl sulfate was studied. The less soluble estrogen estradiol was solubilized independently of the C21 steroids. The micellar solubilities of ethinyl estradiol and both corticosterone and hydrocortisone were independnet of the presence of each other while the solubility of 11alpha-hydroxyprogesterone was enhanced by ethinyl estradiol. The solubilizations of ethinyl estradiol and the two C21 steroids, progesterone and 21-hydroxyprogesterone, were dependent on each other so that a varying amount of the steroid solubilized first was precipitated by an excess of the second steroid. If saturated solutions of the two steroids were mixed, no precipitation occurred. A possible mechanism for the simultaneous solubilization of steroids and its relation to structure are discussed.


Fate of 14C-3-methylamino-1,2,3,4-tetrahydrocarbazole hydrochloride in rats and dogs.

The fate of 14C-3-methylamino-1,2,3,4-tetrahydrocarbazole hydrochloride, a potential psychotherapeutic agent, was studied in rats and dogs. Rats were given a single oral or intraperitoneal dose while dogs received the drug either orally or intravenously. Radioactivity in plasma samples and excreta was determined by liquid scintillation counting. In addition, 14C-levels in various rat tissues were estimated. The drug appeared to be well absorbed in both species. 14C-levels were highest in liver and lung and lowest in plasma. Excretion was primarily urinary and was more complete within the first 96 hr in the rat than in the dog, which suggested a longer 14C-half-life in the dog. No evidence was seen that the drug was demethylated.


Simulated respiratory system for in vitro evaluation of two inhalation delivery systems using selected steroids.

A simulated respiratory system was developed for the in vitro evaluation of two differently designed oral inhalation delivery systems. The deposition properties of a newly designed delivery system used for triamcinolone acetonide were compared to the more conventional, commercially available adapter utilized for an aerosol containing beclomethasone dipropionate. The simulated respiratory system was constructed so that the delivered dose of active ingredient could be classified into two fractions: the fraction that would be deposited in the oral cavity and throat and the fraction that would reach the desired site of activity in the respiratory tract. Based on this method, the newly designed system delivered more than 95% of the labeled dose to the desired site. The beclomethasone dipropionate aerosol system, which was observed to discharge the active ingredient with a greater intensity, delivered approximately 40% of the labeled dose. The particle-size distribution of the dose dispensed from the newly designed delivery system attached to the triamcinolone acetonide aerosol was determined using an impactor technique. No effort was made to correlate these results with an in vivo response.


Thiazole derivatives as potential chemotherapeutic agents: homolytic arylation of thiazole with phenylazotriphenylmethane.

The homolytic arylation of thiazole with phenylazotriphenylmethane (as a free radical source) was carried out to explore the potential chemotherapeutic activity of the resulting triphenylmethyl derivatives. The experimental data differed from similar results on other isosteric heterocycles: one compound only was obtained, having both phenyl and triphenylmethyl groups in the heterocyclic nucleus. The structure of 2-phenyl-5-triphenylmethylthiazole was established by IR, 1H-NMR, and mass spectroscopy. In particular, the mass spectral investigation indicated the cleavage of the 2,3- and 4,5-ring bonds, in contrast with the usual behavior of other thiazole derivatives with no triphenylmethyl substituent.


Improved synthesis of N-(2,6-dimethylphenylcarbamoylmethyl) iminodiacetic acid and analogs.

A new synthesis of N-(2,6-dimethylphenylcarbamoyl-methyl)iminodiacetic acid directly from nitrilotriacetic acid was developed. Six analogs also were synthesized. Their technetium Tc 99m complexes were prepared and characterized. Electrophoresis and chromatography were used to determine the radiochemical purity of each complex.


Dissolution profiles of drugs from tablets.

A theoretical equation to describe the drug dissolution from a tablet was derived by combining and equation for the disintegration rate of a tablet with an equation for the dissolution of particles. The theory is based on the assumptions that: (a) dissolution occurs only from the particles released in a medium by tablet disintegration, (b) the number of particles released into a medium obeys the equation N = NO(T/Td)m, and (c) the dissolution of particles, which are spherical in shape, is represented by the equation previously given by Brooke. Tablet dissolution versus time plots, obtained by calculating the equation with a computer, gave an S-shaped curve between the dissolution curve for particles starting at time zero and the curve for particles starting at the tablet disintegration time. The joint influences of disintegration and particle dissolution on the overall tablet dissolution profile also were examined. When dissolution of powders was rapid, disintegration of a tablet directly influenced its dissolution. When powders intrinsically dissolved slowly, the effect of disintegration on the tablet dissolution profile was slight.


Conductivity of drugs used for iontophoresis.

The electrical conductivities of drugs were measured in vitro using a conductivity MHO-meter. These experiments indicate that local anesthetics, vasoconstrictors, some corticosteroids, several anticancer drugs, and several antiviral agents are suitable for iontophoresis. The contribution to conductivity of buffers and nonspecific ions in the same solution with the drug also was defined.


Pharmacokinetics of oral cephalosporins: cephradine cephalexin.

A crossover experiment was utilized to compare the pharmacokinetics of a 1-g dose of cephalexin tablets, cephalexin capsules, or cephradine capsules in nine normal human volunteers. These antibiotics were administered as three formulations: two 500-mg capsulin every 6 hr for five doses, and one 1000-mg tablet of cephalexin every 6 hr for five doses. Pharmacokinetic parameters in the experimental groups showed no statistical differences (p greater than 0.1), indicating that these drugs are equivalent pharmacokinetically.


Versatile kinetic-approach to analysis of dissolution data.

A new kinetically based dissolution equation is presented that considers dissolution of polydisperse systems and disintegrating solid dosage forms. The equation is applicable under sink as well as nonsink conditions and enables the specific dissolution rate parameter, the dispersion parameter, the disintegration lag time, and a newly introduced parameter, the dissolution availability, to be evaluated simultaneously and directly from percent of label claim dissolved versus time data. The equation showed excellent fit to dissolution data for aminophylline tablets. The kinetic significance of the estimated parameters of the equation is discussed. The method of analysis is compared to an approach employing an empirical equation based on a modified Weibull distribution function.


Bioavailability of three commercial sustained-release tablets of quinidine in maintenance therapy.

The bioavailability of three quinidine formulations was estimated during a dosing interval at steady state following their administration in 12 selected patients in accordance with a Latin-square 3 x 3. Each subject received the three dosage forms as two tablets every 12 hr for 6 days. Blood and urine samples were taken on the 7th day during the regular 12-hr dosing interval. Unchanged quinidine was determined by a reported spectrofluorometric procedure. The total fluorescence of plasma quinidine and metabolites also was monitored. The data obtained indicate that one dosage form gave a high peak level followed by a fall in the concentration. The two other forms presented a relatively lower peak followed by a plateau and then a decline. The differences between the dose-corrected values of Cp,max were statistically significant. Secondary effects were observed particularly with one dosage form and could be related to the high Cp,max value and/or the high percentage of quinidine liberated rapidly in the GI tract. Blood and urinary data indicated an equivalent degree of absorption. The dissolution behavior of the formulations and their absorption data suggest that there is a correlation between the quantity dissolved at 30 min and Cp,max.


Rapid and micro high-pressure liquid chromatographic determination of plasma phenytoin levels.

A rapid and simple high-pressure liquid chromatographic microanalytical method was developed for the determination of clinically encountered plasma phenytoin levels. This method is accurate down to about 1 microgram of phenytoin/ml of plasma and requires as little as 10 microliter of sample. Total analysis time is about 10 min. The method involves deproteinizing with acetonitrile followed by monitoring the deproteinized sample at 254 nm. Phenytoin's primary metabolite in humans, 5-(p-hydroxyphenyl)-5-phenylhydantoin, also can be quantitated when present in moderately high clinically encountered concentrations. Plasma profiles of phenytoin and its metabolite were followed with time after an intravenous bolus injection to a rabbit.


Comparison of adsorbed films of a polyvinylpyrrolidone copolymer with spread monolayers.

The adsorption of a polyvinylpyrrolidone-polyvinyl acetate graft copolymer from solution was studied by surface pressure measurement. Adsorption from the dilute solutions was slow, limited, in part, by diffusion of polymer molecules to the surface. When absorbed monolayers were compressed on a surface balance, the resulting surface pressure values paralled those of a spread monolayer, strongly suggesting that the structures of adsorbed and spread monolayers are the same.


Polarographic analysis of cephalexin.

Cephalexin was found to be polarographically reducible after hydrolysis in an acidic medium, producing two polarographic waves. Both waves were diffusion controlled. The concentration-diffusion plot method was used for the analysis of cephalexin in capsules.


Analysis of prazosin in plasma by a sensitive high-performance liquid chromatographic-fluorescence method.

A specific high-performance liquid chromatographic-fluorescence method for the quantitative analysis of prazosin in plasma at concentrations down to 0.2 ng/ml is described. The method involves the coextraction of drug and an internal standard from alkalinized plasma followed by a simple purification step prior to evaporation and high-performance liquid chromatographic-fluorescence analysis. The method is sufficiently sensitive to allow pharmacokinetic analyses of 1-mg doses through five half-lives, with a relative standard deviation of 12%.


Synthesis of 1-methyl-2-phenylcarbamoylpyrazolidines as potential anticonvulsant agents.

Lithium aluminum hydride reduction of 1,4-dimethyl-3-pyrazolidinone yielded 1,4-dimethylpyrazolidine. The latter compound and 1-methylpyrazolidine reacted with aryl isocyanates to produce 1-methyl-2-phenylcarbamoylpyrazolidines. Several of these adducts displayed significant anticonvulsant activity in the maximal electroshock seizure and pentylenetetrazol seizure threshold tests.


Cardiovascular effects of Azadirachta indica extract.

A crude extract of the leaves of Azadirachta indica was studied for its effects on the cardiovascular system of anesthetized guinea pigs and rabbits. These effects include profound hypotension and a minimal negative chronotropic effect, which increased at higher doses. In one rabbit, 200 mg of extract/kg decreased the heart rate from 280 to 150 beats/min. The extract also exhibited a weak antiarrhythmic activity in rabbits against ouabain-induced dysrhythmia.


Use of guinea pigs as model to study galactose-induced cataract formation.

Because the dietary requirement for ascorbic acid is similar in humans and guinea pigs, galactose-induced cataract research with the guinea pig as an experimental model instead of the rat might be appropriate and may represent a closer analogy to galactosemic cataract formation in humans. In this study, dietary ascorbic acid was found in all guinea pigs to have a retarding or delaying effect on the development of galactose-induced cataracts.


Quinazolinylformamidines and quinazolinediylbisformamidines as antihypertensive agents.

Eleven quinazolinylformamidines and quinazolinediylbisformamidines were synthesized and investigated for antihypertensive activity in spontaneous hypertensive rats. Several compounds showed moderate antihypertensive activity at 100 mg/kg po. The same compounds were not hypotensive in the normotensive dog.


Quantitative determination of cephalexin in cephradine by NMR spectroscopy.

An NMR method to determine quantitatively the presence of cephalexin in cephradine was developed. The method is applicable to the chemical itself as well as to capsules and oral suspension formulations. The determination is based on the NMR signal arising from the five aromatic protons of the cephalexin molecule. Integration of this signal relative to a signal from cephradine provides the data necessary to determine the percentage of cephalexin present. The precision at the 2% cephalexin levels is +/- 0.18%. The time required to carry out a single analysis is about 10 min, and five analyses can be done in about 0.5 hr.


Mass fragmentographic determination of methadyl acetate in urine using stable isotope labeled analog as internal standard.

A quantitative GLC-mass spectrometric assay was developed for the determination of methadyl acetate in urine. The assay utilized selective ion focusing to monitor, in a GLC effluent, the M--15 ion generated by electron-impact ionization of methadyl acetate. Methadyl acetate-d4 was used as an internal standard. The assay can measure 10 ng of drug/ml with about 6% precision. The curve relating the amounts of drug added to control urine versus the amounts experimentally found over a large concentration range is a straight line with a slope of 0.98 +/- 0.02 and a nearly zero intercept. Assay specificity was confirmed by complete identity of the mass spectrum of methadyl acetate in the biological extract with that of the authentic material. The method was used for the urinary analysis of methadyl acetate in a rabbit given a single intravenous dose. The animal excreted less than 1% of the intact drug with a half-life of approximately 15 hr. Consequently, the long-acting characteristic of methadyl acetate must be attributed to its metabolism into active metabolites.


Color analysis of dextrose solutions using a color difference meter.

A method for quantitating color measurements in dextrose solutions by using a color difference meter is described. This method was shown to correlate well with standard American Public Health Association (APHA) color measurements. A mathematical relationship was developed relating yellowness index values to APHA numbers as described in the USP for dextrose solutions. This relationship was tested by comparing the results from standard APHA color tests on laboratory samples of autoclaved dextrose solutions to APHA numbers calculated from yellowness index values for the same samples.


Evaluation of commercial ginseng products.

The variation in panaxoside content of roots and commercial products of Panax ginseng and P. quinquefolium was evaluated by a new spectrodensitometric TLC method. The method is rapid and applicable to all commercial products, and it has a relative standard deviation of 6.4%. Panaxoside patterns of slurry-filled capsules and root extracts most closely resembled those of whole roots. Tablets did not contain detectable panaxosides while teas and granules for infusion yielded only low concentrations. The wide variation among these products indicates the need for more rigid control.


Use of a nitrogen detector for GLC determination of fluorouracil in plasma during single- and combined-agent chemotherapy.

A GLC assay for fluorouracil was developed and used to monitor plasma drug levels in patients on both single- and combined-agent chemotherapy. Fluorouracil is extracted from plasma, derivatized by flash methylation, and estimated using a thermionic nitrogen-phosphorus detector. The GLC determination was accurate at concentrations as low as Q.1 microgram/ml of human plasma. Other drugs commonly used in combination with fluorouracil did not interfere with the assay.


Studies on bitolterol, di-p-toluate ester of N-tert.-butylarterenol: a new long-acting bronchodilator with reduced cardiovascular effects.

The bronchodilator activity of bitolterol, the di-p-toluate ester of N-tert.-butylarterenol (N-t-B) was evaluated by comparing it with the activity of the parent compound (N-t-B), isoproterenol and in some experiments with salbutamol in the anesthetized, open-chest dog maintained under artificial respiration. Bronchodilation was expressed as percent inhibition of the control bronchoconstriction induced by intravenous carbachol or histamine. At equiactive intravenous bronchodilator doses, the duration of action of bitolterol was 10 times that of N-t-B or isoproterenol. In the cardiovascular studies in anesthetized dogs, chronotropic, inotropic and blood pressure effects of bitolterol were markedly reduced relative to its bronchodilator effect. The bronchodilator/heart rate ratio for bitolterol was 22 times that of isoproterenol and 6 times that of N-t-B or salbutamol suggesting greater selectivity for beta2 adrenoreceptors for bitolterol. A good intraduodenal bronchodilator activity with a prolonged duration of action was obtained with bitolterol when compared with N-t-B and isoproterenol. The intraduodenal/intravenous bronchodilator dose ratio for bitolterol was 2 compared with 240 and 960 for N-t-B and isoproterenol, respectively. Bitolterol showed a significantly less (P less  than .01) chronotropic effect than salbutamol at equibronchodilator doses (ED60) by intraduodenal or aerosol administration. A similar difference in chronotropic effect was observed in the unanesthetized dog. The prolonged bronchodilator effect of bitolterol was attributed to high concentration of the ester in lung tissues and to its slow hydrolysis, gradually releasing the active catecholamine, N-t-B.


The cardiovascular effects of the antihypertensive drug debrisoquin: A contribution to the pharmacology of chronic treatment. II. Eight-week administration to dogs.

Debrisoquin was administered twice daily at the dose of 2.5 mg/kg p.o. to normotensive mongrel dogs for 8 weeks. Weekly measurements of systolic blood pressure in the conscious animals revealed a drug-induced fall by 10 to 12 mm Hg which was fully developed after 2 weeks and was maintained throughout the treatment period. Body weight, blood volume, hematocrit and plasma sodium and potassium did not change significantly under debrisoquin while there was a slight but just significant increase in plasma volume. No adverse effects were observed. Sixteen hours after the last dose, the animals were anesthetized with chloralose-urethane and subjected to several hemodynamic and biochemical measurements. The following results obtained after prolonged treatment with debrisoquin were not different from those after subacute administration (1-week treatment) reported in the preceding paper: decrease in blood pressure and cardiac output, reduction of the pressor response to bilateral carotid occlusion and of the vasoconstrictor effect of sympathetic nerve stimulation in the perfused hind legs and the isolated perfused mesenteric arteries, decrease in sympathetic tone to the vasculature of the hind leg and depletion of norepinephrine from adrenergic nerve endings. The sensitivity of arterial blood vessels to norepinephrine was not altered. However, the bradycardic effects of debrisoquin did fade in the course of the treatment. The results indicate the absence of the development of tolerance to nearly all cardiovascular effects of debrisoquin during a treatment of 8 weeks.


A study of the effect of delta 9-tetrahydrocannabinol (delta 9-THC) on mammalian salivary flow.

delta 9-Tetrahydrocannabinol (delta 9-THC) caused no change in either pilocarpine or acetylcholine (ACh)-stimulated salivary flow of the cat but significantly decreased salivary flow from the submaxillary gland of the car and dog during electrical stimulation of the chorda tympani. In contributing to this effect, delta 9-THC significantly decreased (47%) basal arterial blood flow to the submaxillary gland of the dog and markedly reduced (51%) the stimulated blood flow to the gland produced by electrical stimulation of the chorda tympani. The decrease in stimulated blood flow by delta 9-THC suggested an effect on the ACh of the gland. No decrease in the synthesis of ACh could be demonstrated in the submaxillary gland of the dog. A significant decrease (37%) in the release of ACh from transmurally stimulated guinea-pig ileum, a model tissue, was produced by delta 9-THC. These data suggest that delta 9-THC decreases electrically stimulated salivary flow by a mechanism involving the decrease in release of ACh which results in a reduction of blood flow to the submaxillary gland, and, also, less ACh for stimulation of the secretory cells of the gland.


Hepatotoxicity and metabolism of iproniazid and isopropylhydrazine.

Iproniazid (1-isonicotinoyl-2-isopropylhydrazine), an antidepressant drug removed from clinical use because of hepatic injury, and isopropylhydrazine, a metabolite of iproniazid, were found to be potent hepatotoxins in rats. This animal model was used in studies in vivo and in vitro to define better the biochemical and chemical mechanism(s) by which iproniazid and isopropylhydrazine mediate hepatotoxicity. Phenobarbital, an inducer of a class of hepatic microsomal cytochrome P-450 enzymes, greatly potentiated the necrosis, whereas inhibitors of these microsomal enzymes such as cobalt chloride, piperonyl butoxide and alpha-naphthylisothiocyanate, prevented the necrosis. Bis-para-nitrophenyl phosphate, an inhibitor of esterase and amidase enzymes, prevented the necrosis caused by iproniazid but had no effect on the necrosis caused by isopropylhydrazine. Iproniazid and isopropylhydrazine labeled with tritium or carbon-14 in the isopropyl group were found to bind covalently to hepatic tissue macromolecules, and those pretreatments that increased hepatic necrosis significantly increased covalent binding, whereas those pretreatments which prevented necrosis significantly decreased covalent binding. Iproniazid labeled with tritium in the pyridine ring or carbon-14 in the carbonyl group did not bind significantly to hepatic tissue. Rats that were given iproniazid or isopropylhydrazine, labeled specifically with tritium and carbon-14 on the c-2 methine position of the isopropyl group, expired acetone and carbon dioxide labeled with carbon-14. More importantly, propane was expired and contained a ratio of 3H/14C that was identical to that in the administered iproniazid or isopropylhydrazine and also identical to the 3H/14C ratio of the metabolite that was covalently bound to hepatic tissue macromolecules. Experiments carried out with rat liver microsomes and isopropylhydrazine specifically labeled with deuterium, tritium and carbon-14 support the view that isopropylhydrazine is the metabolite of iproniazid that is oxidized by a microsomal P-450 enzyme to a species that alkylates tissue macromolecules. Some of the urinary metabolites excreted by rats that were administered hepatotoxic doses of iproniazid and isopropylhydrazine have been identified by cochromatography and isotope dilution with synthetic standards and by comparative mass spectra. Compounds excreted into the urine of rats dosed with iproniazid include iproniazid, iproniazid-1-oxide, isonicotinic acid, isonicotinoyl glycine, acetylisoniazid, isopropylhydrazine, 1-acetyl-2-isopropylhydrazine and acetone. Isopropylhydrazine, 1-acetyl-2-isopropylhydrazine, and acetone have been found in the urine of animals administered toxic doses of isopropylhydrazine.


Brain and plasma concentrations of amphetamine isomers in mice.

Brain and plasma concentrations of (+)- and (-)-amphetamine were compared as a function of dose and time after administration to mice. Doses of an amphetamine isomer contained 12 muCi of [14C]-(+) or (-)-amphetamine. Thirty minutes after administration of 2.5, 5 or 10 mg/kg i.p., (+)-amphetamine/(-)-amphetamine concentration ratios in the brain were significantly greater than 1; this ratio was less than 1 for the 15 mg/kg dose. Plasma concentration ratios were significantly greater than 1 for all doses. The ratios of +/-isomers were consistently greater than 1 in brain and plasma when determined at various times (7.5--120 min) after 2.5 and 10 mg/kg i.p. By contrast, i.v. administration of these doses resulted in no isomeric differences in brain amphetamine, alhough plasma (+)-amphetamine/(-)-amphetamine ratios remained somewhat elevated. After SKF 525-A pretreatment, the i.p. and i.v. routes resulted in similar (+)-amphetamince/(-)-amphetamine concentration ratios. These results suggest that (-)-amphetamine has a higher apparent volume of distribution (Vd) than (+)-amphetamine [Vd for (+)- and (-)-amphetamine, 2.5 mg/kg i.v. = 3.35 and 4.61 liters/kg, respectively; Vd for (+)- and (-)-amphetamine 10 mg/kg i.v. = 2.36 and 4.61 liters/kg, respectively] and that the (-)-isomer may be extracted more efficiently by the liver [plasma clearance (V) for (+)- and (-)-amphetamine 2.5 mg/kg i.v. = 6.91 and 9.09 liters/hr/kg respectively; V for (+)- and (-)-amphetamine 10 mg/kg i.v. = 2.85 and 4.33 liters/hr/kg, respectively] resulting in lower plasma and brain concentrations after i.p. administration.


Carrier-mediated transport of the organic cation procaine amide ethobromide by isolated rat liver parenchymal cells.

Using hepatocytes isolated by collagenase perfusion, we studied the kinetic characteristics of the uptake process for procaine amide ethobromide (PAEB). Determination of initial uptake velocities (Vo) at substrate concentrations from 30 to 400 micrometer demonstrated a saturable process with a Km of 54 +/- 10 micrometer and a Vmax of 0.13 +/- 0.01 nmol/min/mg of protein. Pretreatment of cells with metabolic inhibitors and reduction of the incubation temperature significantly reduced the Vo of 100 micrometer PAEB. Replacement of sodium ions with lithium had no effect, while replacement with choline decreased Vo by 75%. The intracellular concentration of PAEB was 18 times the medium concentration after 90 min, but 33% of that was in the acetylated form. Uptake of N4-acetyl PAEB occurred at a much lower rate and reached a cell/medium ratio of only 6 after 90 min. Only one of seven quaternary amines tested inhibited PAEB uptake at an inhibitor/substrate ratio (I/S) of 7.5, while four out of five tertiary amines significantly decreased Vo at an I/S of 0.75 and all five decreased it at a ratio of 7.5. Some organic acids and steroidal compounds also significantly decreased PAEB Vo at an I/S of 0.75, while others from each group had no effect at an I/S of 7.5. Because uptake is saturable, requires metabolic energy, and occurs against an electrochemical gradient, it is suggested that the hepatic accumulation of PAEB occurs via an active, carrier-medicated transport process.


Choleresis associated with metabolism and biliary excretion of diethyl maleate in the rat and dog.

Diethyl maleate (DEM) induces a choleresis in the rat and dog that appears to be canalicular in origin (bile flow and erythritol clearance increase equally) and occurs in the absence of an increase in bile salt excretion. Increased bile flow is probably accounted for by the osmotic activity of DEM compounds excreted into bile. These compounds represent the glutathione conjugate of DEM (DEM-GSH) and its subsequent metabolic products. Conjugation of DEM largely accounts for the depletion of hepatic GSH.


Electroencephalographic and behavioral effects of D-ala2-methionine-enkephalinamide and morphine in the rat.

Rats were prepared with chronic cortical and temporalis muscle electrodes and bilateral intraventricular (i.vt.) cannulae. The direct and voltage integrated electroencephalogram (EEG) and integrated electromyogram as well as gross behavior were monitored after the i.vt. injection of D-enkephalin (10--240 microgram), morphine (2.5--40 microgram), naloxone (25--50 microgram) or sterile water (10 microliter). EEG high-amplitude slow-frequency waves (EEG slow bursts) occurred after i.vt. morphine or D-enkephalin and were associated with behavioral stupor. The behavioral depressant effect was followed by behavioral arousal and EEG activation. The EEG voltage output during morphine or D-enkephalin-induced EEG slow-wave activity was dose-dependent and was correlated with the behavioral state of the rat. D-Enkephalin was less potent and shorter-acting than morphine but produced a greater maximal response with respect to increasing the EEG voltage output. The effects of D-enkephalin and morphine were antagonized by pretreatment with naloxone (10 mg/kg s.c.). On the other hand, the i.vt. injection of naloxone alone or sterile water had no disruptive effect of the EEG or behavior of the rat. The results of this study established a dose-response relationship for the i.vt. administration of morphine and D-enkephalin using the direct and voltage integrated EEG. The demonstrated difference in maximal EEG response between morphine and D-enkephalin supports the contention that heterogenous opiate receptors in the brain may mediate their effects.


Central cholinergic and noradrenergic stimulation in spontaneously hypertensive rats.

In order to test the integrity of central receptors, spontaneously hypertensive rats (SHR) of the Okamoto strain and weight-matched control rats of the Wistar Kyoto (WKY) strain were given intracerebroventricular (i.vt.) injections of carbachol and norepinephrine. The rats, in an unanesthetized, unrestrained state, were tested for drinking, antidiuretic and pressor responses. Antidiuretic hormone release was determined by using water loaded, diuresing rats as their own antidiuretic hormone bioassay. Blood pressure was measured directly from a femoral artery catheter. Drinking responses to i.vt. carbachol and antidiuretic responses to i.vt. carbachol and norepinephrine infusions were not different between SHR and WKY while pressor responses were potentiated in SHR. The potentiated pressor responses to central carbachol and norepinephrine injections were the result of increased vascular responsiveness to the antidiuretic hormone released by these drugs. A second, neurally mediated, factor was also apparent to i.vt. carbachol injections. This additional factor could be increased sympathetic outflow to central drug stimulation, increased vascular reactivity to sympathetic outflow, decreased baroreflex responses or a combination of the above.


Handling of triamterene by the isolated perfused rat kidney.

Quantitative studies on the renal handling of [3H]triamterene were performed in an isolated perfused rat kidney with near normal function and in an isolated kidney with negligible filtration rate, but preserved perfusate flow rate. The excretory pattern for [3H]triamterene is compatible with that of other weak bases such as quinine and quinacrine. Tubular secretion of [3H]triamterene is strongly inhibited by anoxia and iodoacetate. Tubular reabsorption of [3H]triamterene becomes pronounced when the urine is alkaline. Clearances were reported with and without correction for perfusate albumin binding which is about 75%. Bidirectional transport processes are operative in that [3H]triamterene is secreted by the renal tubule and passively diffuses back across the tubular epithelium by a pH-dependent mechanism.