Intestinal lymphangiectasia and colonic polyps: surgical intervention.

A 36-mo-old boy with Milroy's Disease, intestinal lymphangiectasia, and an exudative enteropathy (EE), was shown to have four colonic polyps. A large adenomatous polyp was excised from the transverse colon in an effort to control his EE and hypoalbuminemia (1.95 g/dl). His clinical status then stabilized until age 50 mo when there was a marked exacerbation of his EE. Medical management resulted in a temporary stabilization of his condition. A partial resection (40 cm) of the visually worse affected jejunum was performed. There was no improvement in the EE as measured by 51Cr-tagged albumin study; however, his clinical response was dramatic. In the 10 mo since surgery, he has been well and has shown catchup in linear growth.


Anorectal manometry in premature infants.

Twenty-eight unselected premature infants were subjected to anorectal pressure studies, using an infusion manometric technique, with a view to establishing normal parameters in this age group. Satisfactory rectal and sphincter pressure readings were obtained in all but one case. In all of these there was a normal anorectal reflex. Low birth weight and prematurity do no preclude a normal anorectal reflex as measured by this technique.


Posterior tenectomy of the superior oblique.

Modifications of the original technique for posterior tenectomy of the superior oblique are presented and the results obtained in 23 patients with a follow-up of two or more years are reported. The simplicity of the procedure and the lack of intra- and post-operative complications make it useful for surgical treatment of moderate A-pattern deviations.


Juvenile polyposis coli: a case treated with ileoendorectal pullthrough.

Juvenile polyposis coli in a 6-yr-old girl produced such severe chronic complications that total colectomy was required. In what we believe to be the first application of the Soave-Bolley technique of ileoendorectal pullthrough to this condition, symptoms were relieved completely and rectal continence preserved.


A clinical and manometric correlation for assessment of postoperative continence in imperforate anus.

Functional results after surgical correction of anorectal malformations were assessed on a clinical basis following Kelly score and by manometric study. Forty-six patients, aged 2--17, were personally interviewed and 25 of these 46 had manometric studies to evaluate postoperative continence. The manometric study was also performed on 35 normal children as a control group. Continent patients characteristically had marked high pressure zones as did the normal subjects. On the other hand, in the patients with fair or poor results, the anorectal pressure profile had no marked high pressure zone in the anal canal. The presence of normal anal pressure at rest as well as adequate ano-rectal pressure difference was found to correlate well with continence. In patients with perineoplasty, the ano-rectal reflex correlated well with continence but not in patients treated by abdominoperineal rectoplasty.


Can my child see? The evaluation of visual function in children.

Careful evaluation of all parameters of ocular function are required to delineate the cause of lack of visual responses in children. Any visual fixation, no matter how fleeting, is a sign of intact visual pathways. If no sign of ocular pathology can be found on the routine exam of the visually inattentive child, electrophysiologic testing may be necessary to confirm the presence of abnormality of the visual pathways. In the child with a generalized CNS disorder, the lack of visual response may be due to his inability to respond to visual information (perceptual blindness) rather than to organic pathology in the occipital cortex (cortical blindness).


Experience in the diagnosis of Hirschsprung's disease using the anomanometer.

Results of using electromanometry as the sole preoperative diagnostic test for Hirschsprung's disease are presented. Out of a total of 113 infants and children diagnosed to be suffering from the disease, manometry was the initial diagnostic test in 92 infants and children. In nine, manometry confirmed the diagnosis after a colostomy has been done. In 11, barium enema had diagnosed the condition at a peripheral hospital and manometry confirmed the diagnosis. In one, manometry was interpreted as normal, but laparotomy revealed Hirschsprung's disease. Histologic corroboration has been obtained in 97 instances. In 14, no operative treatment was undertaken and, hence, no histologic examination was made; in 2, histologic examination is still pending.


Acute lacrimal abscess in infancy: a report of 22 cases.

Twenty-two cases of acute lacrimal abscess in infancy seen between 1959 and 1976 have been presented. Twelve of them had more han one attack at the time of reporting to this hospital. Initial treatment of the condition was medical, utilizing local and systemic antibiotics. If this did not produce a prompt response, incision and drainage of the abscess was done. The cases showed a preponderance of infections by mixed organisms. In three cases, blocked lacrimal passages opened up spontaneously while on medical treatment. In the remaining 19 cases, probing in an attempt to remove the obstruction in the nasolacrimal duct was performed as soon as the acute inflammation was controlled. Reprobing was needed in nine cases. Only two cases eventually required surgery to achieve a cure. The study indicates that early probing is successful in a high percentage of cases of acute lacrimal abscess including those coming with recurrent attacks.


The surgical separation of pygopagous twins.

A set of female pygopagous twins was successfully separated. Preparation for the main operative procedure and the surgical anatomy encountered are described in details.


Surgical correction of caudal duplication.

The authors report the rare case of a dipygus monster. The infant had an omphalocele, a secondary pelvis with two limbs, an accessory pelvic kidney, and two bladders. At operation, the secondary pelvis and extremities were removed, and the omphalocele was repaired. The postoperative course was complicated by wound infection, urinary infections, proteinuria, cardiomegaly, and hypertension of renovascular origin. The infant died after right nephrectomy, 5 mo after the first operation.


Ultrasonic diagnosis of prenatal intestinal obstruction.

The prenatal ultrasonographic demonstration of distal bowel obstruction is described. The diagnosis proved to be intestinal aganglionosis involving colon and distal ileum.


Splenic pseudocyst: preoperative diagnosis with ultrasonography.

Ultrasonography was used to establish the preoperative diagnosis of splenic pseudocyst in a 12-yr-old girl. This procedure was tried after the exact nature of the mass could not be determined from an intravenous pyelogram and a 99m Tc liver-spleen scan. The patient was successfully treated by splenectomy. The advantages of ultrasonography for detecting splenic cysts are emphasized.


Diaphragmatic hernia associated with double pulmonary sequestration.

The association of pulmonary sequestration with diaphragmatic hernia is an infrequent but well known situation. We report a rare case in which the diaphragmatic malformation was accompanied by two extralobar pulmonary sequestrations.


Bronchial carcinoid tumor.

Bronchial carcinoid tumor occurring in an 11-yr-old boy is described. Pertinent diagnostic and therapeutic considerations are discussed briefly.


Ganglioneuroma, heterochromia iridis, and Horner's syndrome.

A child with mediastinal and supraclavicular ganglioneuroma, heterochromia iridis, and Horner's syndrome is described. The authors postulate that the thoracic neoplasm originated as a congenital neuroblastoma with metastasis to the supraclavicular lymph nodes and subsequent benign transformation, and that the ocular abnormalities resulted from sympathetic ganglion injury by the tumor in infancy. This seems to be the first published report of such ocular abnormalities associated with mediastinal ganglioneuroma.


Predicting suicide using the Rorschach Inkblot Test.

Three hundred and seventy-five Rorschach protocols were scored blind and then divided into three groups: psychiatric controls, suicide attempts, and suicide effectors. Using the stepwise procedure of multiple discriminant analysis a trio of formulas, composed of six weighted variables each, and a constant, were constructed to apply to each of the three groups based on a test sample of 100 subjects in each group. Cross validation results on a new sample of 25 subjects in each group predicted classification with 52% overall accuracy at step six (chance .33). Internal reliability tests showed all values significant beyond .001. Discussion integrates the test data into the literature on suicide, and attends to the problem of overlap of predictability which occurs with most prediction scales.


A validation study of the Draw-A-Person as a measure of racial identity acceptance.

The present study is a replication of Schofield's findings (1978) in the use of the Draw-A-Person as a measure of racial identity acceptance. Unlike Schofield's study, the present investigation involved an adolescent sample of blacks and whites, and race of figure drawn was determined by judges' consensus rather than an objective scoring system. The findings generally supported those of Schofield and the racial identity and preference literature as a whole in revealing blacks to be less accepting of their racial identity than whites.


Cross-cultural validity, reliability, and stimulus characteristics of the Lüscher Color Test.

The Lüscher Color Test (LCT) was administered to 125 Canadian university students, 88 of whom were retested 21 days later. Sample and sex-specific color preferences were found as well as discrepancies between Lüscher's color-naming system and two widely used color-naming systems. Test-retest reliability estimates were low. It was concluded that the LCT suffers from major shortcomings and that research investigating the relationship between color preference and personality should follow alternate paths.


Validation of a subjective helplessness measure.

Investigated the potential utility and validity of a measure of subjective helplessness, the H25. Helplessness is defined as the degree to which the individual perceives him/herself to be unable to influence or control the initiation and outcome of a variety of potentially reinforcing activities. Alcoholic subjects were classified into three levels of self-reported helplessness. An initial multivariate analysis of variance indicated that the groups differed with respect to severity level across a number of dimensions of depressive symptomatology, with the High Helplessness group appearing significantly more depressed on each of the measures than Low Helplessness subjects. Subsequent analyses supported the construct validity of the H25. Those measures found to be most descriminating between groups and most predictive of the level of helplessness reflected a dimension of behavioral retardation consistent with the motivational dificits noted in the learned helplessness model. Recommendations for the future validation of individual difference measures of helplessness are discussed.


Correspondence of the MMPI and MMPI-168 among incarcerated female felons.

This study was designed to assess the correspondence between the MMPI and MMPI-168 for a sample of adult incarcerated female felons. The results indicated a high degree of agreement, median correlation of .79, between corresponding validity and clinical scales of the MMPI-168 and the full MMPI. The MMPI-168 significantly overestimated scales L, F, and D, while it underestimated scales K, Hy, Pd, and Mf. Configural correspondence between the two instruments in terms of profile high points was somewhat less than has been reported for psychiatric populations. However, the MMPI-168 appeared to be a useful short screening instrument for incarcerated female felons with respect to accurate assessment of profile validity, configural correspondence to the full MMPI, and correlations between corresponding scales. Its utility in these respects far exceeds prior attempts to employ the Mini-Mult with a similar sample of incarcerated females.


Guilt and shyness: a profile of social discomfort.

The Mosher Guilt Scales, the Stanford Shyness Survey, and measures of anxiety, hostility, and self-esteem were administered to 54 college females in an effort to clarify the nature of the personality problems that beset shy and guilty persons in social situations. As was hypothesized, it was found that shy people also tended to be guilty. This complicates attempts to understand the nature of the problems with which shy and guilty persons must cope. In addition, it was found that both shy and guilty people tended to be high in trait anxiety, and low in hostility and self-esteem. Thus the profile of a shy, guilty person is that of an individual who is uncomfortable with her own feelings, actions, and beliefs across a variety of social situations.


A measure of intensity of parental punishment.

To test the possibilities that antecedents and consequents of certain levels of intensity of punishment may have far-reaching effects on behavior, a self-report measure of parental intensity of punishment was developed. Consisting of 33 different situations to which parents react, scores from the instrument were found to be reliable over time. Further construct validity was demonstrated with a variety of predicted relationships between punishment intensity and parent and child characteristics. Five samples of subjects were used with over 400 families, high intensity of punishment scores were found to be related to mothers' lack of warmth and to her intrusiveness when playing with her child; children's maladjusted behavior; aggression and impulsivity in boys; withdrawal and inhibition in girls, and uncooperativeness. Inconsistency of parental punishment also was associated with maladjustment. Results were discussed in terms of Rotter's social learning theory.


Defensiveness in exhibitionists.

Focuses on the excessive defensiveness and the psychodynamic factors that typify many exhibitionists. After reviewing some of the literature describing the marked guardedness of these offenders, a detailed discussion follows of the Rorschach protocol of an exhibitionist revealing his core emotional conflicts. These test results illustrate the value of the Rorschach in eiliciting material that in many cases would be difficult to obtain because of these patients' characteristically suspicious and defensive stance concerning their offense and their personal lives. The case demonstrates the significant role of psychological testing in the forensic process, particularly for defensive, less verbal, and unpsychologically-minded offenders.


Birth control practices and conservatism.

This study examined the relationship of conservatism to reports of contraceptive usage, reasons for nonusage of a particular birth control method, and knowledge of birth control information. The never married high conservative subjects who were sexually experienced revealed that they had (a) a lower frequency of usage as well as a lower variety of contraceptive methods; (b) endorsed the beliefs that it was morally wrong and that it was unnatural to use a given birth control method significantly more often as reasons for not using contraceptive techniques; and (c) less knowledge of birth control methods than did low conservative subjects who were sexually experienced. Results were interpreted to support the notion that the fear of loss of control of one's impulses and hence the basis for conservative attitudes are determinants of contraceptive usage.


Negative and positive components of psychological masculinity and femininity and their relationships to self-reports of neurotic and acting out behaviors.

Negatively valued masculinity (M-) and femininity (F-) personality scales were developed to supplement the positively valued Masculinity (M+) and Femininity (F+) scales of the Personal Attributes Questionnaire (PAQ; Spence & Helmreich). M- consisted of traits that had been judged to be (a) more typical of males than females, (b) undesirable in both sexes, and (c ) agentic or instrumental in content. Two F- scales were developed, both containing stereotypically feminine, undesirable traits, one set of traits referring to communionlike characteristics (Fc-) and the other to verbal passive-aggressive qualities (FVA-). Significant sex differences in the predicted direction were found on all scales. In both sexes, low and typically nonsignificant correlations were found between parallel positive and negative scales, but highly significant negative correlations were found between positive and negative cross-sex scales. These findings provide additional evidence for the multidimentionslity of masculinity and femininity. Scores on a self-esteem measure were positively correlated with M+ and F+, uncorrelated with M-, and negatively correlated with the F- scales. Different patterns of scores were associated with two types of problem behaviors. In both sexes, neuroticism was most highly correlated (in a negative direction) with M+, and acting out behavoir was most strongly correlated (in a positive direction) with M-. The next highest correlation in both instances was with FVA-.


Telling lies.

Men and women (20 each) were videotaped while describing someone they liked, someone they disliked, someone they were ambivalent about, someone they were indifferent about, someone they liked as though they disliked him or her, and someone they disliked as thought they like him or her. Accuracy at detecting that some deception had occurred was far greater than accuracy at detecting the true underlying affect, and people who were good at detecting that deception was occurring were not particularly skilled at reading the speakers' underlying affects. However, people whose deception attempts were more easily detected by others also had their underlying affects read more easily. Speakers whose lies were seen more readily by men also had their lies seen more readily by women, and observers better able to see the underlying affects of women were better able to see the underlying affects of men. Skill at lying successfully was unrelated to skill at catching others in their lies. A histrionic strategy (hamming) was very effective in deceiving others, and this strategy was employed more by more Machiavellian people, who also tended to get caught less often in their lies. Methodological considerations and systematic programs for future research are discussed.


Acknowledgment of handicap as a tactic in social interaction.

Nonhandicapped people often report discomfort and uncertainty when interacting with handicapped individuals. The three studies reported here investigated a possible tactic that handicapped people could use to reduce a fellow interactant's discomfort and uncertainty. Nonhandicapped subjects watched two videotapes of handicapped individuals being interviewed. Each subject then chose the handicapped person with whom he would prefer to work on a cooperative task. Results of all three studies supported the hypothesis that a handicapped person acknowledging his handicap will be preferred to a handicapped person who does not acknowledge his handicap. In Study 1, subjects significantly preferred a handicapped person who acknowledged his handicap to a handicapped person who did not disclose anything personal. In Study 2, subjects significantly preferred an acknowledging person over one who made a personal disclosure other than about his handicap. In Study 3, subjects preferred the individual acknowledging a handicap over one who disclosed something else personal even when the acknowledging individual was clearly nervous about doing so. These results suggest that acknowledging the handicap may be a promising tactic.


Characterological versus behavioral self-blame: inquiries into depression and rape.

Two types of self-blame--behavioral and characterological--are distinguished. Behavioral self-blame is control related, involves attributions to a modifiable source (one's behavior), and is associated with a belief in the future avoidability of a negative outcome. Characterological self-blame is esteem related, involves attributions to a relatively nonmodifiable source (one's character), and is associated with a belief in personal deservingness for past negative outcomes. Two studies are reported that bear on this self-blame distinction. In the first study, it was found that depressed female college students engaged in more characterologial self-blame than nondepressed female college students, whereas behavioral self-blame did not differ between the two groups; the depressed population was also characterized by greater attributions to chance and decreased beliefs in personal control. Characterological self-blame is proposed as a possible solution to the "paradox in depression." In a second study, rape crisis centers were surveyed. Behavioral self-blame, and not characterological self-blame, emerged as the most common response of rape victims to their victimization, suggesting the victim's desire to maintain a belief in control, particularly the belief in the future avoidability of rape. Implications of this self-blame distinction and potential directions for future research are discussed.


Emergencies: what are they and do they influence bystanders to intervene?

Social psychological research on helping has, in part, been concerned with the intervention of bystanders into emergencies. Pertinent empirical literature does not seem to be available on what factors bystanders use to define an emergency nor the effect of such a decision on the rate of helping. A series of four studies was conducted to answer these questions. We found that (a) Emergencies are a subclass of problem situation that usually result from accidents; (b) there is a high degree of agreement concerning what problem situations are definitely an emergency; (c) emergency situations are differentiated from other problem situations by threat of harm or actual harm worsening with time, unavailability of an easy solution to the problem, and necessity of obtaining outside help to solve the problem; (d) disagreement on whether a problem situation is an emergency or not results from differing perceptions of the degree to which threat of harm or actual harm worsens with time; (e) bystanders are more likely to help in emergency than in nonemergency problem situations. The results were interpreted as indicating that the need of the victim is a salient feature used by bystanders in determining whether or not to help.


Self-awareness and transgression in children: two field studies.

Two field studies explored the relationship between self-awareness and transgressive behavior. In the first study, 363 Halloween trick-or-treaters were instructed to only take one candy. Self-awareness induced by the presence of a mirror placed behind the candy bowl decreased transgression rates for children who had been individuated by asking them their name and address, but did not affect the behavior of children left anonymous. Self-awareness influenced older but not younger children. Naturally occurring standards instituted by the behavior of the first child to approach the candy bowl in each group were shown to interact with the experimenter's verbally stated standard. The behavior of 349 subjects in the second study replicated the findings in the first study. Additionally, when no standard was stated by the experimenter, children took more candy when not self-aware than when self-aware.


Quinidine pharmacokinetics in man: choice of a disposition model and absolute bioavailability studies.

Parameters describing disposition and absolute oral bioavailability of quinidine were determined in ten normal male volunteers using a specific assay. Various models were compared for their ability to describe the experimental data. An intravenous quinidine gluconate and an oral quinidine sulfate solution were administered (3.74 mg/kg quinidine base). In three subjects the intravenous and oral studies were repeated. One-, two-, and three-compartment models with zero and first-order input were fitted to the plasma concentrations. The selection of the best model was made by the Akaike information criterion and by eye. After intravenous administration, plasma concentration-time curves could be adequately described by a two-compartment model. Mean disposition constants (+/- SD) were obtained from individualized fits (V1: 0.398 +/- 0.336 LITER/KG, Vdarea: 2.53 +/- 0.72 liter/kg, alpha: 0.316 +/- 0.294 min -1, beta: 0.00204 +/- 0.00262 min -1, k2: 0.0305 +/- 0.0101 min -1). A clearance of 4.9 +/- 1.5 ml/min/kg was observed. After oral administration, three-compartment models were needed to describe the observed data in some cases. Absorption was in most cases best described by a zero-order rather than by a first-order process. The time to peak concentration varied from 23 to 121 min, the lag time was always less than 3 min, and the mean elimination rate constant was 0.00171 min -1. The mean oral bioavailability of quinidine was 0.70 +/- 0.17.


Pharmacokinetic modeling of heparin and its clinical implications.

Experimental work on heparin has indicated that its half-life increases with dose. Two models to describe heparin's pharmacokinetic behavior are proposed, and the parameters in the models are fitted to experimental data. Both models exhibit an apparent first-order decay with a "half-life" that increases with dose. It is shown that, even though both models exhibit a bolus half-life of from 1 to 2 hr, over 2 days can be required for true steady-state conditions to be achieved in these models when a constant intravenous infusion of drug is given. The clinical implications of these models are discussed. Suggestions are made for further research on heparin kinetics.


Single-dose fasting bioequivalence assessment of erythromycin stearate tablets in man.

The bioequivalence of film-coated erythromycin stearate tablets produced by five different manufacturers was evaluated in a balanced incomplete block design involving the five formulations given to 30 fasted subjects over a 3-week study period. Serum levels of erythromycin activity were determined microbiologically. Statistical analysis of variance was performed on the observed bioavailability parameters: maximum serum concentration (Cmax), time to maximum serum concentration (Tmax), and area under the serum concentration-time curve (AUC). There was no statistical difference between formulations for the Tmax parameter. Formulation differences were found, however, based on the analysis of variance of the Cmax and AUC parameters. Two products, although not significantly different from one another, showed significantly greater Cmax and AUC values than the other three products.


Pharmacokinetics of piroxicam, a new nonsteroidal anti-inflammatory agent, under fasting and postprandial states in man.

The kinetic disposition of piroxicam, under evaluation in man as a new anti-inflammatory drug, was studied in human volunteers given a single oral dose after both overnight fasting and food. Total absorption was uninfluenced by food intake, although the data indicate that food causes some delay in attainment of peak serum levels. The half-life of drug in plasma in the fasting subjects (37.5 +/- 2.4 hr) was similar in both the fasting state and after food, suggesting that once-daily dosing may be appropriate for maintaining therapeutic plasma levels. Mean pharmacokinetic parameters for both studies in the fasting state and after meals are volume of distribution divided by availability, 0.140 or 0.136 liter/kg; total plasma clearance divided by availability, 2.68 or 3.12 ml/hr/kg. Approximately 10% of a single dose of piroxicam was eliminated in the urine within 8 days after oral drug administration. Renal clearance of the drug (0.28 +/- 0.10 ml/hr/kg) was 10.4% or less of plasma clearance, suggesting that piroxicam is extensively metabolized. In this study one subject showed a reduction in white blood count on the sixteenth day after a 60-mg dose; however, hematology values evaluated in both intra- and intersubject comparisons did not show any other differences in the present study.


Chlorpheniramine. II. Effect of the first-pass metabolism on the oral bioavailability in dogs.

The pharmacokinetics of chlorpheniramine has been studied in six dogs by following the time course of plasma concentration of the drug after intravenous and oral administration of its maleate salt in solution form. After intravenous dosing the decline in chlorpheniramine plasma concentration was typically biexponential. The drug distributed rapidly and extensively to the extravascular tissues. The mean distribution phase half-life was 12.5 min, and the mean apparent volume of distribution, Vdb, was 525% of the body weight in four dogs with normal hematocrits. The mean half-life of elimination was 1.7 hr. The percent absolute availability following oral administration of the drug in the aqueous solution form was found to be dose dependent. At 100-mg dose, in six dogs, an average of 36% of the orally administered dose was found to be systemically available. At 50-mg dose, in one of the four dogs studied, no measurable plasma levels of chlorpheniramine were obtained, and the average bioavailability was only 9.4%. The average availability in four dogs at 200-mg dose was 39.4%. Even at 200-mg oral dose, the dogs did not show any signs of sedation and remained alert all through the experiment. Saturable first-pass gut and/or hepatic elimination has been postulated. The possible implications of these findings on the therapeutic effectiveness of the usual dosing regimen of chlorpheniramine in dogs are discussed.


Accumulation kinetics of drugs with nonlinear plasma protein and tissue binding characteristics.

The purpose of this investigation was to study, by digital computer stimulation, the accumulation kinetics of drugs which exhibit concentration-dependent binding to tissues and either linear (constant free fraction) or concentration-dependent (increasing free action with increasing drug concentration) binding to plasma proteins. It was assumed that elimination rate is proportional to free drug concentration in plasma and that there occurs instantaneous equilibration of drug between vascular and nonvascular spaces. Nonlinear binding can yield, under certain conditions, apparently biexponential plasma concentration-time curves which may be misinterpreted as being representative of a linear and biexponential system. Such misinterpretation would cause the following errors in the prediction of drug accumulation and elimination kinetics during and after constant-rate infusion: (a) the time required to reach steady state may be overestimated, and (b) the prominence of the apparent distribution phase after cessation of infusion may be underestimated. Drugs with linear and nonlinear plasma protein binding characteristics differ with respect to the relaionship between infusion rate and steady-state concentration. This relationship is linear when plasma protein binding is linear. Steady-state concentration increases less than proportionally with increasing infusion rate if plasma protein binding is drug concentration dependent.


A pharmacokinetic model to differentiate preabsorptive, gut epithelial, and hepatic first-pass metabolism.

A combined perfusion/compartmental pharmacokinetic model has been developed to describe the time course of drugs that are subject to preabsorptive, intestinal epithelial, and hepatic first-pass metabolism. Equations are derived to estimate the fraction of the administered dose which is metabolized at each of the three sites and to establish the limits of the true absorption rate constant. The model is tested using literature data for phenacetin.


Syntheses and bioactivities of 1-(hydroxyphenyl)-1-nonen-3-ones and related ethers and esters.

A number of nuclear hydroxy styryl ketones and related compounds were prepared and evaluated for antineoplastic and antimicrobial activities as well as for analgesic, anti-inflammatory, and antianaphylactic properties. The second-order rate constants for the reaction of several esters with hydroxide ion in aqueous dioxane (50% v/v) at 36.9 degrees were determined. The screening results showed that activity against P-388 lymphocytic leukemia was found solely with the ethers and that antimicrobial properties were obtained virtually exclusively with the phenolic derivatives. All compounds showed analgesic properties, except for four that were algesic. While little anti-inflammatory activity was found, several compounds showed some antianaphylaxis.


Differential thermal, solubility, and aging studies on various sources of digoxin and digitoxin powder: biopharmaceutical implications.

Unlike most organic compounds, both digoxin and digitoxin melted over a wide temperature range, with the widest range being 88 and 33 degrees for both compounds, respectively. Furthermore, the melting ranges varied markedly among several untriturated powders obtained from commercial sources and after recrystallization. Trituration produced dramatically sharper and generally lower melting temperatures. Apparent equilibrium solubility also varied considerably among different untriturated compounds. Correlation between solubility and final melting temperature was found. Results from dynamic solubility studies were used to explain the failure of trituration to enhance the apparent equilibrium solubility in certain samples. Storage at room temperature increased the melting points and decreased aqueous solubilities. Several reasons such as the presence of polymorphic and amorphous forms, crystal defects, impurities, and solvate formation were postulated to explain the findings. In a preliminary study, the in vitro dissolution rates of two commercial tablet products stored at elevated temperatures for 4-8 weeks progressively decreased. Biopharmaceutical implications and areas for further studies are discussed.


Microbial transformations and 13C-NMR analysis of colchicine.

Several microorganisms were screened for their ability to biotransform colchicine, and two were selected for preparative scale fermentations. Streptomyces spectabilis and Streptomyces griseus both produced O2-demethylcolchicine and O3-demethylcolchicine but in different amounts. The 13C-NMR assignments of colchicine, O10-demethylcolchicine, and trimethylcolchicinic acid are reported and were used to help identify the structures of the metabolites.


Surface properties of membrane systems: interaction of ketamine with monomolecular films of ganliosides and mitochondrial lipids.

Ketamine solutions did not form a film (pi=0) but had an appreciable surface potential (delta V=500 mv), indicating a significant array of +/- oriented charge dipoles at the air-water interface, as opposed to calcium chloride solutions whose delta V was zero. The delta V values of ganglioside films spread on the aqueous phase varied in the order water less than sodium chloride less than calcium chloride less than ketamine hydrochloride. At equivalent concentrations, calcium chloride was 500 times as effective as sodium chloride, and ketamine at the clinical concentrations of 10-20 microgram/ml (36-72 micrometer) was 6000 times  as effective as calcium chloride in raising the surface potential of gangliosides; the delta V effect with mitochondrial lipid was in the reverse order; water less than sodium chloride = ketamine hydrochloride less than calcium chloride. This calcium-ketamine inversion indicates a unique specificity of ketamine for gangliosides. Since ketamine acts on the brain and did not affect mitochondrial respiration, the surface potential data suggest that part of the mechanism of action of ketamine could be its interaction with synaptic surfaces and, specifically, with the sialic acid of gangliosides and/or glycoproteins present on the synaptic membrane surface.


Long-range substituent effects in morphine-type agonists and antagonists: a possible explanation for some opiate anomalies.

Anomalous variations in the pKa values of variously substituted morphine-type agonists and antagonists are interpreted as a reflection of long-range substituent effects operating in these molecules. Based on the operation of long-range effects, a mechanism is proposed by which substitution into the N-normorphine portion of morphine-type agonists and antagonists changes the activity of the parent molecule. Thus, a remote substituent would distort the whole molecule via a conformational transmission effect and thereby (a) change the fit between the opiate and its receptor; (b) change the electron density distribution throughout the molecule and, therefore, at the nitrogen; (c) modify the directionality of the lone electron pair on the nitrogen; and (d) affect the pKa of the drug. The operation of long-range effects as proposed here could account for some of the anomalous changes in opiate activity effected by substitution into the parent molecule.


Modification of metoclopramide GLC assay: application to human biological specimens.

A modified electron-capture GLC assay for metoclopramide in human biological specimens is reported. This assay involves the incorporation of a back-extraction method to remove endogenous contaminants. Its applicability was demonstrated by studying the time course of metoclopramide in plasma and urine from a human subject. The lowest quantifiable metoclopramide concentration in plasma was 7 ng/ml, provided 0.5 ml of plasma was used.


Kinetic studies of hydralazine reaction with acetaldehyde.

In vitro kinetic studies of the reaction of hydralazine with acetaldehyde at physiological concentrations and pH were conducted. This reaction, which leads to the formation of 3-methyl-S-triazolo[3,4-a]phthalazine, may occur in the plasma and may represent an alternative pathway for hydralazine metabolism. The reaction of hydralazine with acetaldehyde followed second-order kinetics with an activation energy of 16.9 kcal/mole. At 37 degrees, the half-life of the reaction for a colution containing 2.3 microgram of acetaldehyde/ml and 1 microgram of hydralazine/ml was 4.5 hr. The rate increased with increasing acetaldehyde concentrations.


High-performance liquid chromatography of two peripheral vasodilators, nylidrin hydrochloride and isoxsuprine hydrochloride, in pharmaceutical dosage forms.

A reliable and selective high-pressure liquid chromatographic (HPLC) procedure for the quantitative determination of nylidrin hydrochloride or isoxsuprine hydrochloride in pharmaceutical dosage forms is described. The specificity of the stability-indicating HPLC procedure is presented for nylidrin hydrochloride.


Solubility determination of barely aqueous-soluble organic solids.

Solubility determination of organic molecules having very low solubilities is hampered by such problems as slow equilibration during measurement, influence of impurities, and inherent heterogeneity in the energetic content of the crystalline solid. Three approaches to meeting these problems are presented. The first approach involves enhancing the dissolution rate by the addition of a water-immiscible solvent in which the organic solute is more soluble, thereby increasing the surface area available for dissolution. The second method is  a combination of experimental data with a group contribution approach that allows the estimation of extremely insoluble solids. This approach involves measurement of the solubility in an organic solvent and calculation of the aqueous solubility from the estimated partition coefficient and the organic solvent data. The third approach is based on using a large excess of the solid and a highly specific analytical determination of the main component. The first two approaches were explored in detail and tested using norethindrone, norethindrone acetate, methyltestosterone, and methyltestosterone acetate.


Determination of phenylmercuric nitrate by potentiometric titration.

A procedure was developed for measuring small amounts of phenylmercuric nitrate in aqueous solutions. The method depends on the formation of insoluble phenylmercuric iodide upon titration of phenylmercuric nitrate with potassium iodide. The end-point can be detected using an iodide-sensitive electrode. The method is able to measure down to 0.000125% aqueous solution of phenylmercuric nitrate with a 1% accuracy. Procedural details and dexcriptions of excipient effects on the assay are presented. Naphazoline hydrochloride, phenylephrine hydrochloride, fluroescein sodium, and antipyrine interfered with the method, while the common buffer systems, polyvinyl alcohol, sodium thiosulfate, edetate sodium, and chloramphenicol had no effect.


Stereospecific assay and stereospecific disposition of racemic carprofen in rats.

A procedure was developed for the separation and selective quantitative determination of the (S)(+)- and (R)(-)-enantiomers of the racemic anti-inflammatory drug carprofen as their diastereomeric l-(-)-alpha-methylbenzylamides. These derivatives are obtained in equivalent yields by reacint purified 14C-carprofen from biological specimens with l-(-)-alpha-methylbenzylamine via the 1,1'-carbonyldiimidazole intermediate, followed by extraction and differential radiometric quantitation of the TLC-separated diastereomers. In the rat, the (R)(-)-carprofen enantiomer was eliminated from blood and secreted in the bile as the ester glucuronide at a rate approximately twice that of the (S)-(+)-enantiomer, resulting in the accumulation of the pharmacologically more active (S)(+)-enantiomer in the rat blood. Evidence for an additional process favoring the elimination of the (R)(-)-enantiomer in the rat was derived from pharmacokinetic data evaluation.


ADS-12: an automated programmable 12-tablet dissolution testing system.

A novel computerized automated system is described which conforms to the basic requirements set forth in the compendia for testing the dissolution characteristics of solid dosage forms. This modular system can test 12 tablets simultaneously. It can maintain sink conditions at all times and can handle any chemistry amenable to an automatic analyzer. Dissolution, sampling, chemistry, and readout are all accomplished simultaneously, reducing the complete test time for 12 tablets to the dissolution time itself.


Use of rabbits for GI drug absorption studies: relationship between dissolution rate and bioavailability of griseofulvin tablets.

The correlation between the dissolution rate and bioavailability of griseofulvin tablets was studied in stomach-emptying-controlled rabbits and in humans. Three different test tablets, each consisting of two dose levels (62.5 or 125 mg) of griseofulvin, were used. The dissolution rates in 0.5 hr were approximately 75, 40, and 12%. With oral administration at 62.5 mg/rabbit, the ratio of peak plasma level, Cmax, was 1.00:0.66:0.40 and that of the area under the curve (AUC) was 1.00:0.73:0.46 for the three tablets. The corresponding C'max ratio was 1.00:0.74:0.34 and the AUC ratio was 1.00:0.72:0.33 in humans at the dose level of 500 mg. A good correlation was observed for the rank order of Cmax and AUC between rabbits and humans, but such a correlation was not seen between in vivo data and in vitro data at a larger dose of 125 mg/rabbit. This finding was attributable to the dose, which exceeded the GI drug dissolution or absorption capacities. These results suggest that the stomach-emptying-controlled rabbit is useful for evaluating oral dosage forms for human use and that dose level selection is important in the bioavailability study of a barely water-soluble drug.


Dissolution behavior of commercial enteric-coated aspirin tablets.

Dissolution behavior was studied for four commercial batches of enteric-coated aspirin tablets from two companies. The USP XIX dissolution procedure was modified by including pretreatment in simulated gastric juice. The effects of five pretreatment times were studied. Pretreated tablets yielded higher dissolution profiles and fewer undissolved fractions than nonpretreated tablets. Among pretreatments, 15 min was adequate and 60 min produced the highest dissolution profiles. None of the pretreatments differed significantly from each other. An F test and conducted on the data indicated that Product X was significantly better than Product Y at the p=0.05 level. Batch C was ranked as the best batch irrespective of pretreatment time, followed by Batch D. Batches A and B were equal, although Batch A appeared to be better than B for the 60-min pretreatment, as indicated by the lower t80% value.


Reversed-phase high-performance liquid chromatographic investigation of levodopa preparations I: Amino acid impurities.

A reversed-phage high-performance liquid chromatographic procedure with UV detection at 280 mm is presented for the determination of 6-hydroxydopa, tyrosine, 3-O-methyldopa, and other trace amino acid impurities in levodopa preparations. The method is fast and sufficiently sensitive to determine trace impurities at 0.1% of the levodopa concentration with a relative standard deviation of 4-6%. The trace impurities can be estimated at less than or equal to 0.01%.


Reversed-phase high-performance liquid chromatographic investigation of levodopa preparations II: Levodopa determination.

A reversed-phase high-performance liquid chromatographic procedure with UV detection at 280 nm is presented for levodopa determination in pharmaceutical preparations. The method is fast and specific for levodopa in the presence of its most likely impurities and degradation products.


Biosynthesis of prostaglandin D2, 15-ketoprostaglandin E2, and hydroxy fatty acids by ram seminal vesicle microsomes.

At high arachidonic acid concentrations (164 micrometer) and without exogenous cofactors, ram seminal vesicle microsomes produced prostaglandin E2 and two less polar products, identified as prostaglandin D2 and 15-ketoprostaglandin E2. The ratio of the biosynthetic products formed depended on the exogenous cofactor and on the arachidonic acid concentration. At high arachidonic acid concentrations (greater than 150 micrometer), tryptophan, phenol, and glutathione stimulated prostaglandin E2 formation, but each affected the formation of the other prostaglandins differently. Ascorbic acid markedly stimulated hydroxy fatty acid formation. GLC-mass spectral analysis of the hydroxy fatty acid fraction indicated the presence of 11-hydroxy-5,8,12,14-eicosatetraenoic acid, 15-hydroxy-5,8,11,13-eicosatetraenoic acid, and 12-hydroxy-5,8,10-heptadecatrienoic acid. At low arachidonic acid concentrations (30 micrometer), glutathione still stimulated prostaglandin E2 biosynthesis, but the other cofactors stimulated 6-ketoprostaglandin F1a and hydroxy fatty acid formation.


p-Aminophenol fluorescence and determination in the presence of acetaminophen.

The spectrophotometric and fluorometric properties of the aminophenols and of several compounds related to p-aminophenol were examined. A direct spectrofluorometric method for p-aminophenol determination at trace levels in methanol was developed and evaluated for the effect of inner filtering by acetaminophen. The method was applied to the determination of p-aminophenol as an impurity in acetaminophen and acetaminophen-containing tablets.


Double Latin square study to determine variability and relative bioavailability of methylprednisolone.

The variability and relative bioavailability of methylprednisolone tablets were evaluated utilizing  a double Latin square crossover design in which each of 20 subjects was given four of five treatments. Three different lots of methylprednisolone tablets exhibited virtually identical absorption, with similar ranges and coefficients of variation of some selected bioavailability parameters indicative of lot-to-lot uniformity in bioavailability. Within-lot and between-lot uniformities in bioavailability also were similar, suggesting that the observed variability in serum methylprednisolone levels was not due to manufacturing process variables. With respect to intra-versus intersubject variability, no differences were found for the absorption rate or terminal half-life. In contrast, between-subject variability associated with extent of absorption was greater than that within subjects. Relative to an aqueous suspension, methylprednisolone tablets were fully bioavailable.


Separation of penicillin G potassium and its degradation products using high-pressure liquid chromatography.

A high-pressure liquid chromatographic technique was developed for the separation of penicillin G potassium and several of its decomposition products. The method utilized a buffered acetonitrile-phosphate mobile phase on a reversed-phase C18 column. Separation of penicillin G potassium and six degradation products was attained within 25 min.


Sensitive high-pressure liquid chromatographic determination of disopyramide and mono-N-dealkyldisopyramide.

A high-pressure liquid chromatographic procedure for the accurate determination of disopyramide and its chief metabolite in plasma is presented. The method is suitable for monitoring patients receiving disopyramide therapy. A reversed-phase cyanopropylsilane column is utilized with a mobile phase of 50% acetonitrile and 50% 0.01 M sodium acetate buffer at pH 4.0. Absorption was monitored at 254 nm with a detection limit of 0.2 microgram/ml of plasma. The reproducibility and precision of the procedure were demonstrated on samples containing 0.50-12 microgram/ml of plasma.


Identification of an imidazolinium salt, the major product from reaction of benzathine with iodine.

The isolation and identification of an imidazolinium salt are described. Unambiguous determination of structure was accomplished by independent synthesis. The isolated product interferes in the iodometric assay of the benzathine salts of penicillin.


4-Acetoxy-1,2,3,4-tetrahydro-2,2-dimethyl-6,7-methylenedioxyisoquinolinium iodide, an acetylcholine analog.

4-Acetoxy-1,2,3,4-tetrahydro-2,2-dimethyl-6,7-methylenedioxyisoquinolinium iodide, an analog of acetylcholine, was synthesized and a pharmacological profile of its GI effects was compiled. The agent inhibited dog colonic contraction in response to pelvic nerve stimulation and to acetylcholine. In rats, the compound markedly reduced gastric acid output and the volume of gastric secretions. The lack of inhibition of chromodacryorrhea production in response to carbachol indicates a lack of anticholinergic action. The agent failed to affect the acute inflammatory response of the rat hindpaw in response to carrageenan. The precursor of the compound was ineffective in the pharmacological tests.


Urinary excretion of dyphylline in humans.

The pharmacokinetics and urinary excretion of a single dyphylline dose were studied in five normal volunteers. The mean dyphylline half-life was 1.8 +/- 0.2 hr; the mean total body clearance rate and mean renal clearance rate were 333 +/- 62 and 276 +/- 52 ml/min, respectively; and the mean volume of distribution was 0.8 +/- 0.2 liter/kg. In the urine, 83 +/- 5% of the dose was excreted as unchanged drug, and theophylline was not detected. Dyphylline doses of 19--27 mg/kg, resulting in peak serum dyphylline concentrations of 19.3--23.5 micrograms/ml, were tolerated well by four subjects. One subject had a severe headache following a 28-mg/kg dose, associated with a peak serum dyphylline concentration of 36.4 micrograms/ml. This study confirms speculation that dyphylline is not metabolized to theophylline in vivo.


Stability of amitriptyline hydrochloride in a commercial aqueous solution.

A commercial amitriptyline hydrochloride solution was stored at 80 degrees for up to 3 months. High-performance liquid chromatography showed no evidence of amitriptyline hydrochloride degradation. The method also indicated that two reported degradates, 3-(propa-1,3-dienyl)-1,2;4,5-dibenzocyclohepta-1,4-diene and dibenzosuberone, were present at levels less than 0.1% (the detection limit of the method) under the storage conditions. The stability of the commercial solutions is attributed to their relatively low ratio of headspace oxygen to amitriptyline hydrochloride.


1,2-Dialkyl-4-pyrazolidinethiols as potential antiradiation agents.

The reaction between 3-chloropropylene sulfide and the 1,2-dialkylhydrazines was employed to prepare a series of 1,2-dialkyl-4-pyrazolidinethiols. Evidence is presented to support the structure proposed for the product. These mercaptoheterocycles are related to the beta-mercaptoethylamines and were prepared as potential radiation protective agents. No significant activity was observed.


Colorimetric determination of penicillins and related compounds in intravenous solutions by nickel (II)-catalyzed hydroxamic acid formation.

Solutions of ampicillin, carbenicillin, methicillin, oxacillin, penicillin G, and cephalothin in 5% dextrose were analyzed by nickel(II)-catalyzed hydroxylaminolysis. The reactions of these antibiotics were complete within 20 min at room temperature. Under the analytical conditions, molar absorptivities of the ferric-hydroxamate complexes ranged from 830 to 1005 liters/mole/cm. Coefficients of variation for the analysis of these antibiotics in 5% dextrose were typically less than 3% at concentrations of 1 mg/ml. Oxacillin was analyzed by the same method in normal saline and/or lactated Ringer solutions. The method also was applied to the analysis of chloramphenicol in aqueous solutions. Only ampicillin showed a significant decrease in concentration in 48 hr.


Physical model evaluation of topical prodrug delivery-simultaneous transport and bioconversion of vidarabine-5'-valerate I: Physical model development.

A physical model approach to the topical delivery of a vidarabine ester prodrug was investigated. It involved modeling, theoretical simulations, experimental method development for factoring and quantifying parameters, and, finally, employment of the deduced parameters to determine the steady-state species fluxes and concentration profiles in the target tissue. The present report describes the physical modeling and theoretical simulation aspects. The physical model for the simultaneous transport and bioconversion of a topically delivered prodrug was formulated assuming homogeneous enzyme distributions and constant diffusivities in the membrane. The mathematical problem was solved, and the solution yielded concentration profiles and fluxes of all species in the biomembrane. These results provided the prevailing levels of the prodrug, the drug, and the metabolite at the target site and the transport rates of all species into the bloodstream. Computations of concentration profiles and fluxes were carried out for a reasonable range of the parameters. The relative activities of the esterase and the deaminase enzymes, as well as the stratum corneum permeabilities, were important in influencing the concentration profiles and fluxes of all species.


Physical model evaluation of topical prodrug delivery-simultaneous transport and bioconversion of vidarabine-5'-valerate II: Parameter determinations.

Results of initial studies on methods for determining various model parameters are reported. By employing excised hairless mouse skin in a diffusion cell system, numerous model parameter values were deduced. The stratum corneum permeability was estimated from steadystate fluxes with preparations of heat-separated epidermal membranes. Determinations of dermis diffusivities and enzyme rate constants in situ involved considering the simultaneous transport and the enzyme processes and factoring the diffusivities and enzyme rate constants from the overall kinetics. Dermal diffusivities were on the order of 10-6 cm2/sec for vidarabine and its 5'-valerate ester. The enzyme rate constants were 1.70 x 10-3 sec-1 for the esterase and 8.68 x 10-3 sec-1 for the deaminase.


Synthesis of new mercaptotriazoles with potential antibilharzial activity.

Several 3-mercaptotriazoles with the 8-hydroxyquinoline moiety in the 5-position were prepared and tested for antiparasitic activity. Preliminary biological tests on experimentally infected mice with Schistosoma mansoni worms revealed that the new compounds possess potent schistosomicidal activity.


Evaluation of 1-(3,4-dichlorophenyl)-4-dimethylaminomethyl-1-nonen-3-one hydrochloride effect on nucleic acid and protein syntheses using murine leukemia L-1210 cells.

Several Mannich bases derived from conjugated styryl ketones were shown to have potent cytotoxicity toward murine leukemia L-1210 cells and Walker 256 carcinosarcoma cells in culture. The most cytotoxic derivative, (E)-1-(3,4-dichlorophenyl)-4-dimethylaminomethyl-1-nonen-3-one hydrochloride, profoundly inhibited the incorporation of tritiated leucine into protein(s) and tritiated deoxythymidine into DNA at concentrations of 0.79-1.32 muM in L-1210 cells. At higher concentrations, incorporation of triated uridine into RNA and tritiated deoxyuridine into DNA was inhibited to a lesser degree. This compound failed to inhibit the enzymes thymidylate synthetase or dihydrofolate reductase up to a concentration of 10-4 M and was ineffective in retarding the growth of the Walker 256 carcinosarcoma in rats.


Simultaneous automated determination of free and total sulfisoxazole and sulfamethoxazole in plasma and urine.

A fully automated method for the determination of sulfisoxazole, N4-acetylsulfisoxazole, sulfamethoxazole, and N4-acetylsulfamethoxazole in human plasma and urine was developed. Untreated plasma is analyzed by automation of dialysis, hydrolysis, color development, and quantitation. The method has a sensitivyt limit of 2 microgram/ml of plasma and has been used successfully to determine sulfonamide levels following administration of sulfoxazole and a combination drug product containing sulfamethoxazole and trimethoprim in humans. Samples are processed at the rate of 40 per hour, with a minimum of sample handling, data reduction, and materials.


Discontinuous absorption processes in pharmacokinetic models.

The limited contact time of absorbable drug with absorbing surfaces is, in some cases, a significant factor determining the fraction of the dose absorbed. A simple modification of customary linear compartmental models is presented to account for this situation, and a general input function in the Laplace domain for truncated first-order absorption is derived. An extension to series of truncated absorption processes is discussed.


NMR spectroscopic determination of preferred conformations of quinidine and hydroquinidine.

NMR spectra of quinidine (I), hydroquinidine (II), and their respective acetyl derivatives (III and IV) were compared. The chemical shifts of some protons in I differed from those of their counterparts in II. These values were concentration dependent in I and II; they were similar in III and IV but not concentration dependent. The implications of these findings and the correlation of the NMR data with the preferred conformations are discussed.


Cytotoxicity of modified indole alkaloids.

Indole alkaloids of the iboga series were structurally modified by incorporation of a 3,4-dimethoxybenzyl or -benzoyl unit so that they contained the N-O-O triangle required for antileukemic activity according to the triangulation hypothesis. The cytotoxicities of the modified alkaloids in the in vitro P-388 system were not significantly increased over the unmodified alkaloids, suggesting that the triangulation hypothesis does not apply in this series at least.


Sarin transport across excised human skin I: Permeability and adsorption characteristics.

The transport rates and permeability coefficients for the transport of sarin in solution across both hydrous and anhydrous excised human skin were determined quantitatively. An activation energy was determined from study of the temperature influence on the transport of sarin in solution across anhydrous callus membranes. The transport of pure sarin and of sarin as a water-soluble and water-insoluble gel was studied also. The adsorption characteristics of sarin on powdered keratin were studied to determine their role in permeation. Both equilibrium and nonequilibrium measurements were made, which allowed calculation of the heat of adsorption, the heat of activation for adsorption, and the heat of activation for desorption. The results show that interaction between the membrane and penetrant plays a significant role in sarin transport across human skin.


Sarin transport across excised human skin II: Effect of solvent pretreatment on permeability.

The effect of pretreating callus membranes with dimethyl sulfoxide, dimethylacetamide, dimethylformamide, formamide, dioxane, or methyl orthoformate on sarin permeability was studied at three temperatures to determine the activation energy for transport. In addition, the effect of membrane pretreatment on permeability through callus membranes from either a sarin-carboxypolymethylene gel or a sarin-polymethyl methacrylate gel was studied.


High-performance liquid chromatographic determination of azosemide in commercial animal feed.

A high-performance liquid chromatographic (HPLC) method was developed for the assay of 2-chloro-5-(1H-tetrazol-5-yl)-4-[(2-thienylmethyl)amino]benzenesulfonamide (I) in animal feed diet mixtures. The sample is extracted with acetone, an aliquot of the extract is evaporated to dryness, and the residue is dissolved in chloroform. This solution can be subjected to either of two cleanup procedures. The first traps I on a sodium hydroxide-diatomaceuous earth column. Compound I is then recovered using an acetic acid-ethyl acetate-chloroform eluent, which is removed by evaporation, followed by dissolution of the residue in aqueous sodium hydroxide. The second procedure involves the direct extraction of I from the chloroform solution. A linear relationship exists between the HPLC UV detector response at 254 nm and concentration up to 170 microgram/ml. The sodium hydroxide extraction procedure resulted in an overall recovery (+/- SD) of 92.9 +/- 1.6 and 97.4 +/- 1.8% (n = 5) at levels of 200 and 6000 ppm, respectively. Overall recoveries (+/- SD) obtained by the diatomaceous earth column procedure for the 20- and 6000-ppm levels were 90.0 +/- 2.0 and 95.9 +/- 1.6% (n = 5), respectively.


Potentiometric determination of iodine in pharmaceutical preparations.

Methods for the determination of organically bound iodine were compared. A preliminary destruction of the sample was preferable. The sample was mineralized using the Schöniger combustion. Since direct potentiometry of the iodide ion was used, further reduction of the sample was necessary. Several reductors were compared, and the best results were obtained with Devarda alloy. The proposed method was amployed for the determination of iodine in X-ray contrast products. Pure compounds and pharmaceutical preparations were investigated. The coefficient of variation of the method was 0.9%.


High-pressure liquid chromatographic assay for hydralazine in human plasma.

A specific high-performance liquid chromatographic assay for hydralazine in human plasma was developed. Plasma hydralazine is reacted with 10 microliter of p-anisaldehyde for 7 min at room temperature to form hydralazine p-anisaldehyde hydrazone. This derivative is extracted into ethyl acetate, and the solvent is removed by evaporation. The residue is reconstituted in 100 microliter of methanol, and 90 microliter is injected onto a reversed-phase column. The mobile phase is 32% acetonitrile in 0.75 M acetate buffer, pH 3.4, at a flow rate of 2 ml/min. The retention time of hydralazine p-anisaldehyde hydrazone is 6.5 min. The average coefficient of variation over 10-200 ng/ml is 5.5%, and the sensitivity limit is 5 ng/ml. Under the assay conditions, hydralazine pyruvic acid hydrazone, a known plasma metabolite of hydralazine, yields less than 0.1% hydralazine. Detectable plasma hydralazine levels of 5-20 ng/ml were found 10-30 min after a 0.5-mg/kg oral dose of hydralazine hydrochloride was given to a male volunteer.


Occurrence of short-duration hypotensive phospholipid from dog peritoneal dialysate.

From the total lipid fraction of dog peritoneal dialysate after freeze drying and extraction, a hypotensive phospholipid was isolated through silicic acid, cellulose, and Sephadex LH-20 column chromatography in a pure grade; it showed a single spot on TLC. The purified hypotensive factor, designated as Peritoneal Dialysate Depressor-I, elicited potent depressor responses in anesthetized rats, and its threshold dose was approximately 35 microgram/kg. The material resisted proteases and 15-hydroxyprostanoate oxidoreductase. In mobility on TLC, the hypotensive factor was distinuishable from water-soluble hypotensive substances and also from depressor lipids. Judging from its behavior on TLC and column chromatography during the purification procedure, the hypotensive factor seems to be a choline-containing phospholipid and shows the general characteristics of hysolecithin, except for its potent hypotensive activity, and 2',7'-dichlorofluorescein on TLC. The molar ratio of phosphorusurated ones such as stearic and palmitic acids.


Pseudomonas cepacia resistance to antibacterials.

Reproducible growth rates of Pseudomonas cepacia were obtained. P. cepacia had a markedly different resistance pattern to single and combined antibacterials from that characteristic of Pseudomonas aeruginosa. Benzalkonium and chlorhexidine were more active against log phase P. cepacia than against log phase P. aeruginosa, but polymyxin B sulfate was inactive against log phase P. cepacia at all concentrations tested (smaller than or equal to 16 units/ml). Antagonism of antibacterial activity between edetate disodium-benzalkonium and edetate disodium-chlorhexidine combinations was marked with 16-hr P. cepacia and with 16-hr Staphylococcus aureus. Phenylethanol-benzalkonium and phenylethanolchlorhexidine combinations had no more than additive activity against log phase P. cepacia. These results have relevance to hospital disinfection and preservation of pharmaceutical solutions.


Analysis of cyclazocine in plasma.

The analysis of plasma cyclazocine by two methods is described. The radioimmunoassay employed a 125I-labeled radioligand, rabbit antiserum, and sepration of bound from free cyclazocine with a second antibody. The radioimmunoassay was specific for cyclazocine and had a detection limit of approximately 20 pg/ml. The GLC method employed a mass spectrometer as the detector and had a detection limit of approximately 109 pg/ml. Both techniques had acceptable accuracy and precision when used to quantitate cyclazocine in dog and human plasma. The methods were used successfully to quantitate cyclazocine from beagle hounds receiving 0.5 mg of 3H-cylazocine/kg iv. The decline in plasma cyclazocine fitted a two-compartment body model with a mean plasma clearance rate of 39.2 liters/hr.


High-pressure liquid chromatographic analysis of ticrynafen and one of its metabolites in urine and serum.

A method is described for the extraction of ticrynafen, a new hypotensive agent, and its reduced metabolite from serum and urine. Drug-related material is extracted from biological fluids with ether under strongly acidic conditions and then back-extracted into an alkaline aqueous phase, which is subjected to high-pressure liquid chromatographic analysis. Separations are performed on a reversed-phase column with a mobile phase consisting of phosphate buffer-acetonitrile. This accurate and reproducible method measures serum concentrations of ticrynafen and its reduced metabolite as low as 1.0 and 0.4 microgram/ml, respectively.


Frozen conformers of clotrimazole: reaction of imadazole with 1-Chloro-9-hydroxy-9-phenylxanthene.

1-Chloro-9-hydroxy-9-phenylxanthene reacts with imidazole at 180 degrees to form a 5:1 mixture of the 9-(imidazo-1-yl)- and 9-(imidazo-2-yl)-1-chloro-9-phenylxanthenes. These products lack significant antifungal activity.


High-performance liquid chromatographic determination of (Z)- and (E)-doxepin hydrochloride isomers.

A high-performance liquid chromatographic method for the determination of (Z)- and (E)-doxepin hydrochloride isomers was developed. The analysis employs a column packed with spherical silica microparticles (5-6 mum), and a mobile phase of acetonitrile-chloroform-diethylamine (750:250:0.2) permits baseline resolution and simultaneous determination of the (Z)- and (E)-doxepin isomers. Process-related substances do not interfere. The method is accurate and precise (the relative standard deviation was 0.3% for both isomers). The simple procedure is highly suitable for routine doxepin hydrochloride analysis.


Sensitive assay for determination of hydroxyzine in plasma and its human pharmacokinetics.

An assay suitable for hydroxyzine determination in human plasma following therapeutic doses was developed. The method involves GLC and chemical-ionization mass spectrometry of the acetate derivatives of hydroxyzine and of a pentadeuterated analog internal standard. Following administration of 100-mg single oral doses to normal male volunteers, peak plasma concentrations of approximately 80 ng/ml were observed; the half-life of drug removal was approximately 3 hr.


High-performance liquid chromatographic determination of plasma propylthiouracil.

A reversed-phase high-performance liquid chromatographic analysis was developed for propylthiouracil in plasma (1 ml). After protein precipitation with acetonitrile, the solution was diluted with water and injected into a liquid chromatograph equipped with C-18 and C-8 columns in series. The peak area was linear over the 0.25-10-mg/liter range, and the recovery was 101 +/- 4.5%. This assay has the advantages of specificity, simplicity, and speed over previously published methods and requires smaller sample volumes. None of 19 drugs tested interfered with the assay.


High-pressure liquid chromatographic determination of propylthiouracil in human plasma.

A high-pressure liquid chromatographic procedure was developed for the determination of prophylthiouracil in plasma. The method utilizes a reversed-phase C18 chromatographic column and UV detection at 280 nm. The method is sufficiently sensitive for most bioavailability and pharmacokinetic studies. Coinentrations between 0.1 and 5.0 microgram/ml were measured with a coefficient of variation of 0.6-5.3% for a given day. Methylthiouracil was employed as an internal standard.


Ion-pair reversed-phase high-pressure liquid chromatography of cough-cold syrups I: pseudoephedrine hydrochloride, brompheniramine maleate, and dextromethorphan hydrobromide.

Pseudoephedrine hydrochloride (I), brompheniramine maleate (II), and dextromethorphan hydrobromide (III) in a cough-cold sytup were separated and determined by ion-pair reversed-phase high-pressure liquid chromatography. The separation was carried out using a muBondapak C18 column (30 cm x 3.9 mm i.d.) and a mobile phase of acetonitrile-water-acetic acid (40:60:1) with 0.01 N 1-octanesulfonic acid sodium salt and 0.05 N potassium nitrate. Detection was accomplished using a UV detector at 265 nm for I and II; III was monitored at 280 nm. Concentration versus peak height plots in the ranges of 0.37-1.9 mg/ml for I, 0.025-0.126 mg/ml for II, and 0.125-0.625 mg/ml for III were linear. Ten consecutive injections of a mixture gave a percent relative standard deviation of less than 1% for all three components. Average recoveries from laboratory-prepared samples were 100.5% for I, 100.9% for II, and 100.1% for III. No precolumn cleanup was necessary, and the chromatogram was complete in 16 min.


Stability-indicating assay of acetaminophen in an effervescent tablet by ion-pair high-performance liquid chromatography.

A stability-indicating analytical method is described for determining acetaminophen and its degradation product, p-aminophenol, in an affervescent tablet. Tablets assayed by ion-pair high-performance reversed-phase liquid partition chromatography required no sample cleanup. The method applied to tablets containing 325 mg of acetaminophen yielded an average recovery of 99.6% with a relative standard deviation of 0.70% (n = 10). As little as 0.005% p-aminophenol could be detected.


High-pressure liquid chromatographic determination of chloridazepoxide and its major metabolites in biological fluids.

A simple, isocratic, reversed-phase, high-pressure liquid chromatographic procedure was developed for the determination of chlordiazepoxide and its major metabolites in plasma and urine. The within-run coefficient of variation was 3.4-8.0%, and the day-to-day variation was 4.0-8.0%. Recoveries of 80-91% with sensitivity limits of 50 ng/ml were obtained for the parent drug and its metabolites. Plasma and urine samples collected after single intravenous and single oral doses were analyzed using this procedure.


Effect of diffusional lag time on multicompartmental pharmacokinetics for transepidermal infusion.

A simple proof is given to demonstrate that the lag time to reach steady state from transepidermal infusion is the sum of the diffusional and pharmacokinetic lag times.


Effect of diuretics on ADP incorporation in kidney mitochondria.

The effect of diuretics on incorporation of ADP in mitochondria isolated from rabbit renal cortex and medulla was examined. Inhibition of incorporation of [14 C]ADP into both types of mitochondria was observed following pretreatment with furosemide, ethacrynic acid and meralluride at high drug concentrations (7.5 x 10-4 M furosemide and ethacrynic acid, 6.4 x 10-3 M meralluride). At lower concentrations (7.5 x 10-5 M furosemide and ethacrynic acid, 6.4 x 10-4 M meralluride), only entry of ADP in medullary mitochondria was inhibited. Chlorothiazide, 1.7 x 10-3 M, did not inhibit incorporation of ADP into either mitochondrial preparation. Atractyloside, a classic inhibitor of ADP-ATP exchange, showed inhibition in both preparations. Furosemide, injected in vivo inhibited incorporation of ADP into medullary but not cortical mitochondria. These results are consistent with the possibility that loop diuretics may reduce tubular sodium reabsorption by inhibiting ADP-ATP exchange across the mitochondrial membrane, thereby depriving active transport processes of ATP. The differential action on cortical and medullary mitochondria by loop diuretics is consistent with their predominant site of action in the tubule and with the different morphologic characteristics of both types of mitochondria.


Dimethylaminoethanol (deanol) metabolism in rat brain and its effect on acetylcholine synthesis.

Specific methods utilizing combined gas chromatography mass spectrometry were used to measure the metabolism of [2H6] deanol and its effects on acetylcholine concentration in vitro and in vivo. In vitro [2H6]deanol was rapidly taken up by rat brain synaptosomes, but was neither methylated nor acetylated. [2H6]Deanol was a weak competitive inhibitor of the high affinity transport of [2H4]choline, thus reducing the synthesis of [2H4]acetylcholine. In vivo [2H6]deanol was present in the brain after i.p. or p.o. administration, but was not methylated or acetylated. Treatment of rats with [2H6]deanol significantly increased the concentration of choline in the plasma and brain but did not alter the concentration of acetylcholine in the brain. Treatment of rats with atropine (to stimulate acetylcholine turnover) or with hemicholinium-3 (to inhibit the high affinity transport of choline) did not reveal any effect of [2H6]deanol on acetylcholine synthesis in vivo. However, since [2H6]deanol did increase brain choline, it may prove therapeutically useful when the production of choline is reduced or when the utilization of choline for the synthesis of acetylcholine is impaired.


Pharmacokinetics and cardiovascular effects in rabbits of a major hydralazine metabolite, the hydralazine pyruvic-acid hydrazone.

The hydrazone of hydralazine and pyruvic acid (HPH) has been recognized as a quantitatively important metabolite of hydralazine in human plasma. We evaluated the disposition of [14C] HPH after its i.v. administration to normal, anephric and probenecid-pretreated rabbits. Renal clearance of HPH in normal rabbits exceeded the glomerular filtration rate by a factor of 3 to 4 and accounted for 80 to 90% of the total body clearance. Active tubular secretion was established by the effect of probenecid pretreatment to reduce the renal clearance of HPH by 80%. Total body clearance of HPH in anephric rabbits was 10% of that of normal animals, emphasizing the minor importance of metabolic conversion for the overall disposition of HPH. HPH in a maximum dose of 50 mumol/kg i.v. had no hypotensive effect in renal hypertensive rabbits and did not interfere with the subsequent hypotensive response to hydralazine. This HPH dose produced plasma levels at least 50 times in excess of those reported  in humans after administration of therapeutic doses of parent hydralazine. HPH is consequently of negligible clinical significance, despite the relatively high plasma concentration of this metabolite which occurs after administration of parent hydralazine.


Effect of desmethylimipramine on the kinetics of chlorphentermine accumulation in isolated perfused rat lung.

A number of basic amines are preferentially accumulated by the lung and there is the possibility that drug interactions in this organ may be important in vivo. In this study, the kinetics of the accumulation process for chlorphentermine were examined in a "single pass" isolated perfused rat lung. Chlorphentermine (2.5 x 10-7-2.5 x 10-5 M) was rapidly taken up over the 10-min perfusion period, and the rate of uptake was well described by a biexponential equation. One component of the uptake was small in capacity and nonsaturable while the other was large in capacity and saturable. The smaller component could not be explained solely by distribution into total lung water. When desmethylimipramine (10-6-10-3 M) was added to the perfusate, it had little effect on the nonsaturable component but markedly affected the other; the initial velocity of uptake was decreased and the (negative) rate of change of uptake was increased with increased desmethylimipramine concentration. The data suggested that there were at least two mechanisms involved in uptake of chlorphentermine: a saturable transport process and tissue binding. It is not clear without further work whether the transport saturability is a mainfestation of a carrier-mediated process or of drug-induced membrane changes affecting diffusion.


Toxicity of platinum complexes on hemopoietic precursor cells.

Four platinum compounds, cis-dichlorodiammineplatinum, dichloro- 1,2-benzenediamine-N,N'-platinum, cis-dichlorobis-(cyclohexylamine)platinum and cis-dichlorobis(cyclopentylamine)platinum, were studied for their toxicity toward myelocytic progenitor cells (CFC assay) and pre-antigen reactive cells (P-PFC assay) in murine bone marrow and toward antigen reactive cells in the mouse spleen (MD-PFC assay). It was demonstrated that each of the platinum compounds markedly suppressed the ability of splenic antigen reactive cells to generate antibody producing cells (MD-PFC) 3 days after i.v. injection. At the same time, certain doses of each of the platinum compounds induced selective recovery of the preantigen reactive cells (P-PFC) and myelocytic progenitor cells (CFC) in the bone marrow with a pattern that was unique for each compound. It was also demonstrated with cis-dichlorodiammineplatinum that the recovery for both bone marrow precursor cell populations was multiphasic with time. In general, the results indicated that the platinum compounds induced unique patterns of immunosuppression with relatively minor hemopoietic toxicity.


Termination of "ventricular" arrhythmias from digoxin by selective production of complete atrioventricular block with physostigmine in the dog.

In previous studies we have come to doubt that ventricular rhythms of an automatic nature will arise spontaneously from the peripheral Purkinje system. In 20 anesthetized dogs, digoxin was administered i.v. (0.1-1.0 mg/kg) and in 12 dogs by selectively perfusing the atrioventricular (AV) node artery (2 ml; 40 microgram/ml). We obtained the following results. First, selective pharmacological production of complete AV block (acetylcholine or physostigmine) interrupts the "ventricular" arrhythmias considered characteristic of digitalis intoxication.Second, digitalis arrhythmias are difficult to produce when this type of complete heart block had been previously established. Third, abolition of ventricular arrhythmias by selective pharmacological production of heart block can be reversed (i.e., the arrhythmia restored) with atropine. Fourth, rapid pacing of the ventricles during complete heart block in dogs poisoned with digitalis can eventually induce ventricular arrhythmias, but not quickly. We interpret that these digitalis arrhythmias originated within the acetylcholine-sensitive portion of the AV node-His bundle region.


Phenytoin stimulates renin secretion from rat kidney slices.

Phenytoin stimulated renin secretion from rat renal cortical slices. A sigmoid relationship was found between stimulatory effect and log concentration, from 1 to 8 mg/100 ml. The ED5C was 2.8 mg/100 ml. Basal secretion and the stimulation of secretion elicited by phenytoin were blocked by incubating slices in a K-free medium and by adding 1 mM ouabain to the medium (both of which inhibit Na,K-adenosine triphosphatase activity and increase intracellular Na concentration), and by reductions in the Na concentration of the incubation medium. NaCl in the incubation medium was replaced by choline chloride so that osmolality and Cl concentration were held constant. It is suggested that renin secretion rate is directly related to the transmembrane Na gradient, that phenytoin stimulates secretion by increasing the gradient, and that ouabain, K-free medium and reductions in Na concentration of the medium inhibit secretion by reducing the gradient.


Acrylic microspheres in vivo. I. Distribution and elimination of polyacrylamide microparticles after intravenous and intraperitoneal injection in mouse and rat.

Microspheres of 14C-labeled highly cross-linked polyacrylamide (mean diameter 0.25-0.30 micron) have been prepared by emulsion polymerization. The label was introduced in the polymer via the cross-linking monomer. N,N'-[14C]methylenebisacrylamide. The microparticles were used to follow qualitatively and quantitatively the distribution and the fate of polyacrylamide in mouse and rat after i.v. and i.p. injection. The polyacrylamide particles are rapidly cleared from the circulation (t 1/2 in rat approximately 40 min) by macrophages of the reticuloendothelial system. They are mainly (about 80%) found in the liver and spleen both after i.v. and i.p. injection (4.1 mg given totally to mice weighing 20-25 g). They can also be detected early (1 hr after i.v. injection) in the bone marrow, and particle aggregates are also initially found in the lungs, although no respiratory problems were noted. After about 16 weeks, the radioactivity rapidly decreases in the liver and spleen, with t 1/2 10 to 14 weeks and 15 to 24 weeks, respectively, depending on the route of administration. Radioactivity in the gut and gut walls detected 2 months after injection suggests that the polyacrylamide is slowly metabolized. No toxic effects-apart from transient hepatospleenomegaly-were detected in mice 45 weeks after they were given a total of 9.8 mg of polyacrylamide.


Acrylic microspheres in vivo. II. The effect in rat of L-asparaginase given in microparticles of polyacrylamide.

L-Asparaginase was immobilized in spherical microparticles of polyacrylamide. Particles of three different sizes, mean diameter 0.34, 18 and 36 micron, respectively, were used. The Michaelis constant Km, for L-asparaginase, immobilized in small particles (0.34 micron), is virtually the same as in solution. L-Asparaginase in microparticles was also more stable than free enzyme after storage for 140 days at +4 and +37 degrees C. After an i.v. injection of 200 I.U./kg into rat, the plasma L-asparagine fell to very low values (less than 10 nmol/ml), but was normalized again after 4 to 5 days with both the native and immobilized enzymes. After an i.p. injection of 1000 I.U./kg into rats, the microparticles containing L-asparaginase lowered the plasma L-asparagine level for a substantially longer period of time than L-asparaginase in free solution. Normal L-asparagine level was thus reached on day 14 after the injection with immobilized enzyme. However, L-asparaginase activity was still present in the abdominal lymph nodes after this period of time.


Ethanol-induced prenatal growth deficiency: changes in fetal body composition.

Ethanol (6 g/kg/day) produced intrauterine growth retardation (both body weight and length) in rat fetuses compared to pair-fed controls. Associated with this retardation was an increase in fetal body water and sodium content and a decrease in lipid-free solid content. Comparable electrolyte changes were not observed in maternal blood. These effects in fetal body content are not commonly observed in fetal malnutrition studies and are suggestive of a direct teratogenic effect of ethanol.


Nonhemodynamic effects of histamine on gracilis muscle capillary permeability.

The effects of histamine were studied in the maximally vasodilated gracilis muscle. Dog gracilis muscles were isolated in a plethysmograph and perfused at constant inflow pressure (102 +/- 2 mm Hg). Maximal vasodilation was produced with constant infusion of papaverine (0.2 mg/ml). Constant infusion of blood labeled with albumin-131l or red blood cells (RBC)-51Cr was made throughout the duration of the experiment. Tissue radioactivity and tissue volume changes were continuously measured. Papaverine did not increase transcapillary movement of protein, Histamine (5 microgram/kg/min) was added to the blood and 10 to 15 min later the dose level was increased to 60 microgram/kg/min. Since the vasculature was maximally dilated, changes in tissue radioactivity and tissue volume would be due to transcapillary movement rather than to vascular volume effects. The low dose of histamine significantly steepened the slopes of tissue volume and tissue albumin-s131l increase. The highest dose of histamine significantly further increased these rates. The tissue red cells-51Cr slope was not significantly increased with either dose of histamine. The capillary filtration coefficient was significantly increased above the papaverine vasodilation value by the histamine. The data would support increased transcapillary movement of proteins by other than hemodynamic mechanisms.


Analgesic activity of diflunisal [MK-647; 5-(2,4-difluorophenyl)salicylic acid] in rats with hyperalgesia induced by Freund's adjuvant.

A method is described for testing analgesia for narcotic or nonnarcotic drugs in rats injected with Freund's adjuvant in the tail, by manipulation of the tail the day after injection, or of the feet after the development of adjuvant arthritis. The method is responsive to a behavioral depressant or an anti-inflammatory steroid. Diflunisal (MK-647; 5-(2,4-difluorophenyl)salicylic acid] exhibited activity in this assay after oral administration with potency about 25 times greater than that of aspirin, about 3 times that of glafenine and twice that of zomepirac. The onset of activity was within a 1/2 hour for narcotic analgesics but required about an hour for non-narcotic compounds. With the latter, the peak of activity was not attained until 2 to 4 hr, depending on the compound. The peak for diflunisal was delayed until the 3rd or 4th hour, but the onset of action was more prompt and the duration greater as the dose was increased. [14C]Diflunisal was concentrated to some extent in the inflamed tissue after adjuvant injection. Peak levels both in plasma and tissue appeared about 2 hr before peak analgesic effect. Repeated administration of large doses produced neither tolerance nor sensitization to the analgesic action of diflunisal. Naloxone and naltrexone did not antagonize the action of the compound, but when morphine and diflunisal were given together, the overall effect was enhanced.


Age-dependent alteration in the response of isolated rabbit basilar arteries to vasoactive agents.

Responses to vasoactive agents were compared in helical strips of basilar arteries isolated from rabbits, 15 to 360 days of age, which were stretched under optimal resting forces. Contractions induced by serotonin, histamine, norepinephrine, angiotensin II and K+ increased with increasing age. However, the maximum forces developed by these drugs relative to those by 50 mM K+ as well as ED50 values of these drugs were not significantly different in the arteries from mature and immature rabbits; only the response to serotinin at day 360 was significantly less. Basilar arteries contracted with histamine relaxed in response to isoproterenol; the relaxing effect was suppressed by treatment with 10-6 M propranolol and was inversely related to age. On the other hand, relaxations induced by adenosine and prostaglandin E1 did not significantly differ in the arteries from rabbits of different ages. Relaxations induced by small amounts of K+ (0.5-10 mM) increased with age; the relaxations were suppressed by ouabain. It may be concluded that the cerebroarterial relaxation related specifically to the beta adrenergic mechanism is reduced with increasing age. The electrogenic Na+ pump mechanism appears to mature in rabbit basilar arteries during an early postnatal period.


Segmental and descending control of the external urethral and anal sphincters in the cat.

1. The present work concerns the contribution of the somatic central nervous system to two viscero-somatic reflexes, micturition and defecation. Descending and segmental actions and properties of the motoneurones innervating the striated external urethral and external anal sphincters were studied with intracellular recording in male cats, under chloralose anaesthesia. 2. Motoneurones innervating the external urethral and external anal sphincters were intermingled and most strongly concentrated in the lateral part of the ventral horn in the S2 segment of the spinal cord. 3. Stimulation of the S1 to S3 ipsilateral dorsal roots or of the homonymous pudendal nerve branches showed that less than half of the sphincter motoneurons receive monosynaptic excitatory connexions from low threshold afferents. 4. The after-hyperpolarization recorded in the external urethral and external anal sphincter motoneurones was relatively short lasting, not long lasting as would have been expected for motoneurones innervating slow-twitch, tonic type muscles. 5. There was no evidence for recurrent inhibition in pudendal motoneurones innervating the external urethral and external anal sphincters. 6. Descending excitation and inhibition to the sphincter motoneurones originated in the nucleus reticularis gigantocellularis of the medullary reticular formation. The descending reticulospinal actions are comparable to those observed in hind limb motoneurones. 7. It is suggested that the segmental reflex connexions play a role in controlling bladder and rectal continence. The descending actions studied also modulate the segmental reflex actions and may provide voluntary control of the sphincter muscles.


The electrogenic potential in rat C nerve fibres: some effects of lithium and thallium.

1. Subsequent to bathing a desheathed vagus nerve in a K-free medium Li (5-50 mM) generates a hyperpolarizing response in the same manner as does K except that Li is 23 times less potent than K. Preincubation with small concentrations of either Li or K inhibits a subsequent K response.2. The Li response is less phasic than the K response. In the presence of a cardiac glycoside Li has no effect whereas K depolarizes the preparation. Thus Li is presumed to generate a relatively pure ouabain-sensitive electrogenic response.3. If a Li response is always terminated with 50 mM-Li, but various concentrations are used during the first half, the total response has a constant area despite the wide range of activation during the first half. This implies that the electrogenic pump ratio is constant over this range of activation.4. Thallium (1 mM) also generates a ouabain-sensitive response, but even short exposures (5 min) produces a strong and lasting inhibition of subsequent potassium responses. On a slower time scale Tl also inhibits the electrogenic post-tetanic hyperpolarization. After exposure to Tl a test action potential shows that the afterpotential is also decreased.5. If action potentials are produced during an electrogenic response the hyperpolarizing afterpotential reverses polarity. It is supposed that this is due to a short-circuiting of the electrogenic potential during this time.


Adaptive hyperplasia and compensatory growth in the salt glands of ducks and geese.

1. The incorporation of [3H]thymidine into salt-gland DNA has been studied in vivo and in vitro during adaptation of birds to salt water. 2. No increase in [3H]thymidine incorporation in vivo was apparent in birds on salt water for 0.25 and 1 day compared with those on fresh water. However, by 2 days there was a marked increase. At 7 and 14 days, incorporation was again low but by these later stages the DNA content of the glands was significantly increased. 3. Increased incorporation of [3H]thymidine was also evident in salt-gland slices incubated in vitro from birds on salt water for 2 or 4 days, but not for 14 days, compared with those on fresh water. 4. It is concluded that hyperplasia, as well as the hypertrophy demonstrated previously, occurs as part of the over-all adaptive response of the salt glands during the continual ingestion of salt water, but that the time course of the two processes is different. 5. In geese with one salt gland removed, no indication of compensatory growth of the remaining gland was evident in birds kept on fresh water for 24 days. In such birds on salt water for 14 days, some compensatory growth occurred but, as judged by measurements of DNA, RNA and protein, this could be ascribed to hypertrophy.


Potent stimulation of the avian exocrine pancreas by porcine and chicken vasoactive intestinal peptide.

1. The actions of chicken and porcine secretins and vasoactive intestinal peptides (VIPs) were compared on the rate of flow and rate of protein secretion from the exocrine pancreas in urethane anaesthetized turkeys and rats. 2. Chicken VIP was about twice as potent as porcine VIP and 100-150 times as potent as chicken and porcine secretins in stimulating the flow of pancreatic juice in the turkey. 3. Porcine secretin was a strong stimulant of the flow of pancreatic juice in the rat, but chicken secretin and the two VIPs were only active in doses 20-50 times higher than those of porcine secretin. 4. Neither the two VIPs nor the two secretins significantly stimulated the rate of pancreatic protein secretion in the turkey or rat. 5. In the turkey I.V. infusion of graded doses of chicken VIP produced graded increases in the flow of pancreatic juice; in the presence of an infusion of a low dose of CCK8 the flow of juice secreted in response to the highest dose of chicken VIP was significantly lower compared with the infusion of VIP alone, and responses to the other doses of VIP were lower but not significantly so. The infusion of chicken secretin reduced the flow of juice in response to infusions of chicken VIP, but the differences were not significant. There was no significant difference in either the rate of flow, or rate of protein secretion from the turkey pancreas in response to an infusion of chicken secretin and CCK8, compared with CCK8 alone. 6. The results cast doubt on the importance of secretin for regulation of the avian pancreas, and suggest instead that VIP might have a physiological role in regulating the flow of pancreatic juice in birds.


Initial-image and afterimage discrimination in the human rod and cone systems.

1. The rod-isolation technique of Aguilar & Stiles (1954) was used to obtain scotopic increment-threshold functions in the dark-adapted eye. Increment-threshold functions were obtained for background durations of 50 to 500 msec, but the onset of the background and increment fields was always simultaneous. In all conditions the duration of the increment field was 50 msec. 2. The pattern of results obtained is the same as that reported earlier for the cone system (Geisler, 1978). For background durations greater than that of the increment field, the increment-threshold functions have two distinct branches. It was shown, by measuring action spectra, that both branches reflect the sensitivity of the rod system. 3. When the increment thresholds are plotted as a function of background retinal illuminance, all the lower branches superimpose. This implies that those thresholds are dependent only on the number of background quanta absorbed during presentation of the increment field. On the other hand, when the increment thresholds are plotted as a function of background energy, all the upper branches superimpose, implying that those thresholds are determined by the total number of background quanta absorbed. 4. For the thresholds falling on the lower branches observes reported that the increment field was detected in the initital image of the background and increment fields when they were flashed. For the upper branches, the increment field was detected in a short-term afterimage that appeared after the background was extinguished. The higher the background intensity the longer was the latency until the increment appeared in the afterimage. 5. All of the above findings appear to be consistent with the known properties of the electrical responses of vertebrate photoreceptors. A model based on Penn & Hagins' (1972) model for the photocurrent in rat rods predicts, fairly accurately, the rod and cone increment-threshold results. The parameters estimated by fitting the model support the hypothesis that the short-term rod and cone afterimages are due to the relatively slow decay of internal transmitter, but they suggest that post-receptor mechanisms are responsible for the threshold saturation observed with flashed backgrounds.