Binocular color fusion limit.

When two lights of different wavelengths are dichoptically presented to the eyes to form a single visual field, the fusion of colors cannot be assured unless the difference is relatively small. The limit of the wavelength difference delta lambda beyond which no homogeneous color is obtained was determined for the wavelengths covering a range of about 500 to 660 nm. It varied from about 10 to 50 nm depending upon the wavelength region investigated, which is much larger than the delta lambda values normally obtained in wavelength discrimination experiments. The limit was also obtained for a pair made up of a white light and a colored light that varied in purity. The value was again quite large. These results suggested that the tolerance for color difference is fairly lenient as far as binocular color fusion is concerned.


Opponent chromatic mechanisms: relation to photopigments and hue naming.

Opponent chromatic response functions were determined from monochromatic, equal-luminance stimuli from 400 to 700 nm for three observers using a hue cancellation procedure. The same observers scaled the hue of the stimuli using the terms red, green, yellow, and blue. The results showed that the hue scaling was accurately predicted from the cancellation functions using the model of Hurvich and Jameson. Theoretical curves were generated to fit the chromatic response functions with a linear combination of three cone photopigments. The theoretical photopigments were based on an idopsin nomogram with lambdamax at a = 435, beta = 530, and lambda = 562 nm. An estimate of the density of each observer's preretinal optic media was obtained in order to relate the photopigment absorption spectra to the psychophysical data. Good linear fits were obtained for each observer's red-green curve, but not for the yellow-blue curves. A nonlinear model with an expansive exponent was used to fit the yellow-blue response functions with the three theoretical photopigments.


Luminace, not brightness, determines temporal brightness enhancement with chromatic stimuli.

Brightness-duration relations for chromatic stimuli were studied using three pulse-to-background luminace relations: chromatic equal-luminance pulses (3.2 cd/m2) were presented as increments of 0.3 or 1.0 log units above a lower luminance achromatic background, or were presented in hue substitution, equated in luminance to the achromatic background, so that no spatio-temporal luminance transients occurred during stimulus presentation. Incremental pulses produced temporal brightness enhancement (the Broca-Sulzer phenomenon), but hue substitution pulses did not. Temporal brightness enhancement thus depends upon the occurrence of luminance transients and cannot be produced by pulsed-to-background brightness differences associated solely with chromaticity differences.


A study of the Stiles-Crawford (S-C) function at 35 degrees in the temporal field and the stability of the foveal S-C function peak over time.

Directional sensitivity of the retina (the Stiles-Crawford function of the first kind) was measured at a point 35 degrees from fixation and at the point of fixation. Three normal observers were used. The peripheral test point intercepted the retina between the optic nerve head and the ora serrata. At both test points, photopic and scotopic (one subject) Stiles-Crawford function peaks were contained within the pupillary bound and approximated the center of the pupil. Directionality at the two points was rather similar. These findings add strength to the argument that retinal receptors align approximately with the center of the exit pupil of the eye. Evidence for stability in Stiles-Crawford peak location in time is also presented.


Detection threshold for lights of varying purity.

Duration thresholds for hue substitution stimuli of various wavelenghts and colorimetric purity were determined. Results indicated an inverse relationship between duration thresholds and colorimetric purity. It was also found that short-wavelength sensitive (SWS) cones can contribute to the detection of low purity, short duration (less than 5 ms) stimuli.


Retinoblastoma: some aspects concerning diagnosis, heredity, and treatment.

The authors set forth their views on the early diagnosis, heredity, and therapeutic problems of retinoblastoma. They regard as imperative the frequent ophthalmological check-up of familial tumors and of tumors of sporadic occurence, notably when they are bilateral. The further problems posed by the surviving patients are discussed in detail in the light of follow-up examinations extended up to 15 years.


Dysthyroid ophthalmopathy in children.

The observation in this study of 33 pediatric patients with thyroid disfunction supports the view that ocular changes are uncommon in this age group. If ophthalmopathy does occur, it is mild. No patient was found to have clinical myopathy, corneal involvement, or visual loss. B Scan Ultrasonography demonstrated extraocular muscle involvement despite the absence of clinical signs and symptoms of myopathy. There was no HLA antigen prevalence in those patients with ophthalmopathy as compared with those free of ocular change. It is suggested that the conservative medical management of the pediatric group with thyroid disease may account for the low incidence of severe ocular changes.


Bilateral Duane's syndrome associated with crocodile tears.

The rare association of two syndromes of paradoxical innervation, bilateral Duane's retraction syndrome and congenital crocodile tears is presented. This association assumes a central localization to explain both anomalies.


Restrictions in the diagnoses and management of strabismus problems.

Restrictions have been found to be a common cause of incomitant strabismus and limitation of ocular rotations. Different types of restrictions have been described and the technique of forced duction testing reviewed. Causes of restriction include endocrine eye disease, orbital floor and medical wall fracture, Brown's syndrome, tight lateral rectus syndrome, congenital tight muscles, scarring, muscle contracture, and orbital celluitis or tumors. The importance of recognizing restrictions in the management of these problems has been emphasized.


Colobomatous microphthalmia, heart disease, hearing loss, and mental retardation--a syndrome.

A syndrome consisting of colobomatous microphthalmia, heart disease, abnormalities of the external ear with associated hearing loss, and mental retardation is described. Nine children and one adult were evaluated. There is not race or sex predilection. The syndrome can be heritable, as shown by a mother and daughter who were among the patients. In addition to the four major components enumerated, multiple other anomalies may be associated. In some cases, the syndrome may occur incompletely. Whenever two or more of the four components are recognized, the other systems usually affected should be investigated.


Distichiasis of the lids and lymphedema of the lower extremities: a report of ten cases.

Ten members belonging to two different families were affected by distichiasis of the lids (double row of eyelashes) and lymphedema of the lower extremities. Other less frequent congenital anomalies, such as pterygium colli and ptosis were found in some affected members. The previously reported cases were reviewed. A single pleiotropic gene with a high penetrance and a variable expressivity is responsbile for the different anomalies of this dominantly inherited syndrome.


The early management of baby with Hallermann-Steriff-Francois Syndrome.

The importance of early management of sight in a baby with Hallermann-Streiff-Francois syndrome is described. Surgery for bilateral cataract was performed. Special postcataract contact lenses were fitted.


Giant papillary conjunctivitis and ptosis in a contact lens wearer.

A case of ptosis due to giant papillary conjunctivitis in a 24-year-old female is described. The contact lens was removed and the ptosis disappeared. A possible etiology is discussed.


Gyrate atrophy of choroid associated with hyperornithinaemia: report of the first case in Italy.

The first case in Italy and the youngest case in the world of gyrate atrophy of the choroid associated with hyperornithinaemia is reported. A therapeutical attempt has been made and the possibility of following the evolution of the ocular lesion is very interesting.


Paradoxical movements of the eyelid and eyeball.

Two cases of ptosis with paradoxical eye and lid movements have been reported. One of them was congenital, where there was narrowing of palpebral aperture on abduction and pseudo-Graefe phenomenon on looking down. The other case was acquired following head injury. Here there was narrowing of palpebral aperture on abduction and widening of palpebral aperture on adduction. Besides there was absence of elevation of the globe in looking up. The pseudo-Graefe phenomenon of lid retraction was present only on looking down and in and not on looking down and out. Probable causes of such associated movements have been mentioned.


The surgical treatment of overcorrected esotropia.

The medical records of 33 consecutive patients who developed secondary exotropia following surgery for esotropia were reviewed. Only six patients (18%) had normal medial rectus function. Lateral rectus recession proved to be an excellent procudure for correcting the deviation in these patients, provided the surgery was limited to the eye with the narrower palpebral fissure. Twenty-seven patients (82%) exhibited limitation of adduction secondary to medial rectus underaction. Of these patients, 75% were successfully corrected following a 12 mm advancement and resection of the underacting medial rectus muscle. The details of the surgical technique performed are discussed.


Primary congenital eversion of the upper lids.

A case of bilateral primary congenital eversion of lids in a newborn black male is described. It is a self-limiting disease and does not leave any sequelae. A higher incidence in black infants has been noted in the literature.


Visual functions following bilateral surgery of congenital cataracts in children.

The visual functions, before and after surgery, of 19 children with bilateral congenital cataract are evaluated. Some of the children, in spite of the poor vision before surgery and the late age at surgery, developed good vision with binocular functions. These children probably had an incomplete lens opacity in their early childhood which became completely opaque at an age at which irreversible stimulus deprivation amblyopia is unlikely to develop. Therefore, children over the age of 6 years with poor vision due to congenital cataract, on whom no information is available concerning the density of their lens opacities in early childhood, should not be regarded as having a poor visual prognosis.


Ureteral reimplantation in children with neurogenic bladder.

The treatment of urologic complications from myelomeningocele and especially of vesico-renal reflux is a controversial problem. A series of 26 reimplanted ureters in 17 children, with good results in more than 85%, is reported. Ureteroneocystostomy, carried out with a few technical innovation, may represent a useful method for the treatment of vesico-renal reflux and obstruction of the uretero-vesical junction in neurogenic bladder associated with myelomeningocele. This surgical approach leads to the disappearance of the reflux, decrease of dilatation of the upper urinary tract and preservation of renal function in most cases; moreover, infection can be more easily controlled. Ureteral reimplantation should be preceded by periodic urethral dilatation, external transurethral sphincterotomy, and pharmacologic regulation in order to attempt to decrease urethral resistance. After successful surgery, it is possible to try to reeducate the bladder. Reimplantation should be preferred to permanent urinary diversion even if there is gross reflux.


Traumatic simulated Brown's syndrome: a case report.

A case report of a simulated Brown's tendon sheath syndrome is presented which masks as an orbital floor fracture with entrapment. Despite a positive forced traction test, additional diagnostic information such as a normal tomographic exam of the orbital floor, vertical saccadic up gaze velocity measurements consistent with edema and hemorrhage, greater limitation to elevation in adduction than abduction, and tenderness and soft tissue injury in the region of the trochlea, persuaded us to conservatively manage this case. It behooves the ophthalmologist to consider a temporary superior restrictive phenomenon produced by edema prior to any surgical approach to improve elevation of the globe.


Sertoli cell tumor (gonadal stromal tumor) in an infant.

An 8-mo-old boy had an orchiectomy for a Sertoli cell tumor. Malignancy was suspected histologically. He underwent a retroperitoneal lymphadenectomy and no nodes contained metastases. The histologic criteria for malignancy in Sertoli cell tumors are controversial. Individual case reports of patients with these tumors are encouraged to help establish their natural history and optimum management.


Massive sequestration crisis in sickle cell disease following ocular evisceration.

A case of an 11-year-old Negro female with SC disease who sustained right eye injury with development of a massive and fatal sequestration crisis following ocular evisceration was presented. The inherent danger of SC disease in relation to surgical procedures and general anesthesia was stressed and recommendations as to preoperative management of SC disease was briefly discussed.


The importance of hepatic lymph drainage in experimental biliary atresia. Effect of omentopexy on prevention of cholangitis.

It is believed that partial destruction of the hepatic lymph drainage during the operation of hepato-portoenterostomy is probably the cause of postoperative attacks of cholangitis. Experimental evidence is described that appears to show that omentopexy to the porta hepatis will aid hepatic lymph drainage and may thus prevent postoperative cholangitis.


Treatment failure in anterior uveitis in children.

Anterior uveitis in children can present difficult management problems. While the course of the inflammation may defy the usual treatment modalities, attention to five specific areas of clinical management may enable the ophthalmologist to better preserve visual function. Careful examination, proper adjustment of corticosteroid dosage, repeated intraocular pressure measurement, patient compliance, and adequate follow-up are the areas discussed.


Waardenburg's syndrome: case reports in two Nigerians.

We saw two cases of Waardenburg's syndrome in Nigerian children. A 9-year-old girl had congenital deaf-mutism, high-arched palate, complete heterochromia iridis with pigment mottling in the posterior pole of the eye with the hypochromic iris, dyspigmented frontal scalp hair, a history of vitiligo, but with no dystopia canthorum. An 11-year-old boy had a harelip with cleft palate, heterochromia iridis, blonde fundus on the eye with blue iris, and dystopia canthorum.


A family with X-chromosomal recessive congenital cataract, microphthalmia, a peculiar form of the ear and dental anomalies.

An investigation has been made in a family with X-chromosomal recessive congenital cataract, microphthalmia, a peculiar form of the ear, and dental anomalies. The carrier females show only slight symptoms. They all have lens opacities, and most of them show more symptoms. For genetic counseling it is of utmost importance to examine all family members and to re-examine the females from time to time for early lens opacificaiton, which is the most constant finding. In literature families have been described with similar clinical symptoms only a few times. We have been trying to demonstrate a linkage with the Xga locus, which might enable us to locate the mutant gene on the X-chromosome and to exclude with more certainty the carrier status. The results of this blood group specification were not informative. In future we hope to be able to demonstrate a linkage with other markers located on the X-chromosome.


The unusual presentation of pancreatitis in infancy.

Two infants with acute pancreatitis are described. It appears that acute pancreatitis in infancy presents in one of two ways: part of a severe generalized illness, or as ascites. The outlook for the former depends on the prognosis of the generalized illness. If pancreatitis can be recognized as the cause of the ascites, then adequate treatment will result in survival. Although the cause in some infants is said to be idiopathic, exploration should be performed, the lesser sac investigated and if the child is in reasonable condition, appropriate study of the biliary tree and pancreatic ductile system should be considered. If a pseudocyst is present, adequate drainage is mandatory. Early diagnosis and appropriate treatment will be possible only if this rare disorder is suspected. The eventual prognosis is excellent and the chance of recurrent attacks is minimal.


Accidental ingestion of a Veirs rod.

We present a case of a young child whose canalicular laceration was repaired with a Veirs rod. The repair was likely successful. However, some time between four and six weeks postoperative, the rod slid down the nasolacrimal duct and was ingested. Its presence in the digestive tract was verified by radiographic studies. No untoward problems ensued.


Persistent hyponatremia and inappropriate antidiuretic hormone secretion in children with extensive burns.

Three children aged 2 1/2 to 5 1/2 yr, with burns covering 30%--45% of body surface area, developed hyponatremia and serum hypotonicity on the 5th--6th day following the burn injury. The hyponatremia persisted for 10--15 days. During this period, all three passed inappropriately concentrated urines. One child also demonstrated marked and inappropriate thirst. All three children demonstrated persistent respiratory alkalosis, which appeared and disappeared concomitantly with the hyponatremia. There were no signs of dehydration, and plasma volumes, measured in two children, were normal to high. These children are believed to show evidence of inappropriate antidiuretic hormone (ADH) secretion. In the absence of those conditions known to produce this syndrome, it is postulated that in these children it may have resulted from prolonged pain, anxiety, and/or pyrexia.


Treatment and sequelae of angiographic complications in children.

Fourteen cases of thromboembolic complications appeared in 267 consecutive angiographies during a 7-yr period. The arterial circulation has been evaluated both clinically and with oscillometry. The complication rate was substantially higher after cut down then after percutaneous approach (56% vs. 2.7%). Seven patients with signs of total vascular obstruction were subjected to acute thromboectomy whereas three patients with milder clinical symptoms were treated nonoperatively with anticoagulants. Four patients have died during the examination period, the remaining ten patients have been subjected to long term follow-up (mean follow-up period 3 yr). Seven demonstrated normal findings clinically, as well as oscillographically, whereas three patients subjected ot thromboectomy after cut down were clinically normal but decreased oscillographic pulsations could be demonstrated.


Hirschsprung's disease discordant in monozygotic twins: a study of possible environmental factors in the production of colonic aganglionosis.

The occurrence of Hirschsprung's disease, with histologically verified colonic aganglionosis, in only 1 of 2 prematurely born and presumed identical (monozygotic) twins is reported. The occurrence of monozygotic twinning was supported by the observed sharing of a single and common placenta and by ABO and HLA identity of peripheral blood erythrocytes and leukocytes. The affected twin was of a slightly lower birth weight and experienced early respiratory distress, necrotizing enterocolotis, and more prolonged umbilical artery catheterization (no encountered in the unaffected twin). This, to the authors' knowledge, is the first reported occurrence of Hirschsprung's disease discordant in monozygotic twins. The literature relating to genetic and environmental factors in clinical and experimental colonic aganglionosis is reviewed and speculation is presented regarding the occurrence of colonic aganglionosis discordant in monozygotic twins as reported here.


Bilateral cataract in acrodermatitis enteropathica.

Bilateral cataract was found in a case of acrodermatitis enteropathica. A possible role of zinc deficiency in causing cataract might be assumed.


The ileocecal segment: an anti-reflux conduit for hepatic portoenterostomy.

This paper describes an approach to prevent reflux and ascending cholangitis after hepatic portoenterostomy for biliary atresia. The method utilizes the terminal ileum and right colon as the conduit and a Nisson-type plication to the area of the ileocecal valve. It was used in one patient.


Bacterial peritonitis in patients with ventriculoperitoneal shunt.

Bacterial peritonitis is an unusual complication of ventriculoperitoneal (VP) shunt for hydrocephalus. This complication, usually associated with peritoneal cysts of perforated viscus, may occur as the first manifestation of shunt infection. Early recognition of this form of bacterial peritonitis and appropriate antibiotic therapy may avert major abdominal surgery in selected cases.


Congenital bilateral posterolateral and anterior diaphragmatic defects.

The occurrence of bilateral posterolateral and anterior diaphragmatic congenital defects has not been previously reported. We present a case with associated abnormalities including pulmonary hypoplasia and interventricular septal defect.


An ectopic gastric duplication arising from the pancreas and presenting with a pneumoperitoneum.

This case report describes a large gastric duplication, which had no attachment to the stomach, and it was found in the pancreas. The second unusual feature of this duplication was that it had eroded into the splenic flexure of the colon, resulting in a large pneumoperitoneum.


Traumatic incarceration of the jejunum between two lumbar vertebrae.

An unusual case of traumatic herniation of the upper jejunum into the lumbar spine is presented. A suggested mechanism of injury is discussed.


Choledochal cyst with cholelithiasis: 15-yr follow-up.

A 15-yr-old boy, who had had surgery for a choledochal cyst in infancy, was worked up for recurrent right upper quandrant pair. Intravenous cholangiogram and ultrasound demonstrated a choledochal cyst with stones. Angiogram showed only a distorted branch of the gastro-duodenal artery. These findings were confirmed at surgery.


Neonatal pseudoascites: an unusual presentation of long tubular duplication of small bowel.

This is a case report of a tubular duplication with a clinical presentation as pseudoascites. It was treated surgically by stripping its mucosal lining.


Stressful life events, personality, and health: an inquiry into hardiness.

Personality was studied as a conditioner of the effects of stressful life events on illness onset. Two groups of middle and upper level executives had comparably high degrees of stressful life events in the previous 3 years, as measured by the Holmes and Rahe Schedule of Recent Life Events. One group (n = 86) suffered high stress without falling ill, whereas the other (n = 75) reported becoming sick after their encounter with stressful life events. Illness was measured by the Wyler, Masuda, and Holmes Seriousness of Illness Survey. Discriminant function analysis, run on half of the subjects in each group and cross-validated on the remaining cases, supported the prediction that high stress/low illness executives show, by comparison with high stress/high illness executives, more hardiness, that is, have a stronger commitment to self, an attitude of vigorousness toward the environment, a sense of meaningfulness, and an internal locus of control.


Effects of amount of helplessness training and internal-external locus of control on mood and performance.

Based on Wortman and Brehm's integration of reactance theory with Seligman's model of learned helplessness, an investigation was conducted to examine the effects of amount of helplessness training and internal--external locus of control on subsequent task performance and on self-ratings of mood. Subjects were divided into "internal" and "external" groups and were then given either high, low, or no helplessness training on a series of concept-formation problems. After completing a mood checklist, all subjects worked on an anagram task presented as a second experiment by a second experimenter. The results revealed that internals exhibited greater performance decrements and reported greater depression under high helplessness than did externals. In the low helplessness conditions, internals tended to perform better than control subjects, while externals tended to perform worse than control subjects; low helplessness subjects also reported the highest levels of hostility. The results are discussed within the context of Wortman and Brehm's integration of reactance and learned helplessness theories.


Multidimensional reaction to therapeutic touch in a hospital setting.

A field experiment focused on some implication of interpersonal touch not explored in earlier research. Conceptually, the research included measuring the effects of touch over a relatively long time frame, for a broad range of response dimensions, and in a nonreactive setting characterized by dependency. On an applied level, the research studied the value of touch as a concomitant of nurse-patient interactions. Specifically, a 2 (touch vs. no touch) X 2 (male vs. female) between-subjects design assessed the effects of nurses touching patients, during preoperative teaching, on patient affective, evaluative, behavioral, and physiological responses. Results indicated that female subjects in the touch condition experienced more favorable affective, behavioral, and physiological reactions than a no-touch control group. In contrast, males in the touch condition reacted more negatively than control subjects on these dimensions.


Ambient temperature and the occurrence of collective violence: a new analysis.

Prevalent folklore suggests that riots tend to occur during periods of very hot weather. Baron and Ransberger examined 102 major riots in the United States between 1967 and 1971 and concluded that the frequency of collective violence and ambient temperature are curvilinearly related. The present article points out that the Baron and Ransberger analysis did not take account of the different number of days in different temperature ranges. The artifact is eliminated, and the probability of a riot, conditional upon temperature, is estimated. When this is done, the evidence strongly suggests that the conditional probability of a riot increases monotonically with temperature. Some general implications of such data analyses are discussed.


A linear recirculation model for drug disposition.

A new approach to the modeling of drug disposition is described. Disposition is regarded as the result of repetitive passes of the drug around the circulation. Mathematical analysis of experimental blood concentration data yields an expression describing the kinetics of a single pass through the tissues. In physicochemical terms the single-pass behavior depends to a large extent on the interaction of the drug with individual tissues, which greatly simplifies interpretation. The method may reveal features of disposition not apparent from experimental blood concentration data.


Pharmacokinetics/pharmacodynamics of furosemide in man: a review.

The pharmacokinetics of furosemide and the attempt to correlate biological fluid measurements with diuretic response have been the subject of a large number of studies since the original reports of Hajdú, Rupp, and coworkers in the mid-1960s. This article attempts to critically review these studies under seven different sections: furosemide pharmacokinetics in normal volunteers, furosemide pharmacokinetics in patients with decreased renal function, furosemide pharmacokinetics in patients with congestive heart failure, furosemide metabolism and assay methods, furosemide bioavailability, dose-response relationships, and the role of inhibitors and mediators on furosemide effects. The literature is reviewed through August 1978.


Estimation of tissue-to-plasma partition coefficients used in physiological pharmacokinetic models.

An important parameter in the development of pharmacokinetic models is the ratio of tissue drug concentration to the concentration of the drug in the arterial plasma or the effluent plasma. The relationship between these two tissue/plasma ratios is derived analytically for different routes of drug administration. The two are equal only in compartments with no elimination when the drug is infused at constant rate. For other routes of administration, the two ratios are identical in all compartments only when there is no elimination process. The tissue/plasma concentration ratios for infusion equilibrium are not equal to the corresponding values for the postdistribution phase after an intravenous bolus injection. When the plasma concentration for infusion and injection are the same, more drug will appear in the lung during infusion steady state than during the postdistribution equilibrium. The reverse is true for the other organs. The importance of properly defining the tissue/plasma ratio and its implication for pharmacokinetic modeling are discussed. The results may have important therapeutic implications for the availability of drugs using different routes of administration.


Pharmacokinetics of digoxin: relationship between response intensity and predicted compartmental drug levels in man.

A study designed to investigate the relationship between the pharmacokinetics of digoxin and a measure of its pharmacological effect has been conducted. Serum digoxin concentrations and systolic time intervals were measured concurrently in 12 normal male volunteers following a 1.0 mg i.v. bolus injection. The averaged serum digoxin concentration--time and response--time data were analyzed pharmacokinetically using a three-compartment open model and nonlinear least-squares fitting. When only the serum level--time data were analyzed, a close relationship was found between calculated digoxin levels in the slowly distributing (deep) peripheral compartment and response of the heart to digoxin, as measured by changes in the QS2 index (delta QS2I). Although it was not possible to distinguish clearly a linear from a nonlinear relationship between digoxin levels in the deep compartment and delta QS2I, the nonlinear relationship gave the best overall fit when both serum digoxin and delta QS2I data were fitted simultaneously. The simultaneous fit yielded a total body clearance of digoxin of 3.6 ml/min/kg and a terminal t1/2 of 42 hr.


Time course of carbamazepine self-induction.

Carbamazepine concentrations in plasma during repetitive oral dosing were analyzed by means of a nonlinear, variable parameter, regression program (VARPARM) assuming dose-to-dose changes in the apparent elimination rate constant of the drug. There was evidence of significant self-induction of carbamazepine metabolism as early as 1 or 2 days after initiation of the multiple-dose study. Additional self-induction appears to occur after about 2 weeks of treatment. The time course of carbamazepine self-induction appears to be complex, discontinuous, and prolonged.


Clinical pharmacokinetics of procainamide infusions in relation to acetylator phenotype.

The pharmacokinetics of procainamide was determined in 21 lidocaine-resistant patients who received the drug according to a pharmacokinetically designed double-infusion technique. Thirteen patients were phenotyped as slow acetylators, seven as fast, and one as intermediate. The total body clearances (ClT) of PA in slow and fast acetylators were 22.6 and 34.8 liters/hr, respectively. The fraction of PA cleared by the formation of NAPA in the corresponding acetylator group was 0.2 and 0.4. Renal impairment affected the pharmacokinetics of PA more profoundly as the ClT's of PA in patients with and without renal impairment were 17.9 and 31.2 liters/hr, respectively. None of the calculated volumes of distribution was affected by acetylator phenotype or renal impairment. These data identify the contribution of at least two of the major factors accounting for variability in PA disposition in patients undergoing therapy.


Fitting concentration--time data to biexponential equations.

A digital computer study using simulated data containing random error indicates no difference in the precision and accuracy of parameter estimation when the data are fitted to several different equations.


Mechanistic and quantitative evaluation of precorneal pilocarpine disposition in albino rabbits.

The low ocular bioavailability of topically applied pilocarpine is attributed to extensive precorneal drug loss in conjection with the resistance to corneal penetration. Several elements of precorneal loss were reported earlier, but a complete mechanistic understanding has not been available. The present study was designed to gain a better understanding of the mechanisms governing pilocarpine disposition in the precorneal areas as well as the relative influence of these parameters on ocular drug bioavailability. Radioactive pilocarpine and glycerin solutions were instilled into the precorneal area of the albino rabbit eye under various experimental conditions, and the drug concentration in the lacrimal lake was monitored as a function of time. The results demonstrated that nonconjunctival loss of pilocarpine, vasodilation due to the drug, and lacrimation due to vehicle formulation are additional aspects of precorneal drug disposition. The individual influence of all precorneal loss parameters on drug bioavailability was then assessed using a mathematical model formulated from experimental findings on both precorneal and intraocular drug disposition. Drainage and vasodilation, as well as nonconjunctival pilocarpine loss, exerted major influences on drug loss at the absorption site.


Controlled drug release from polymeric delivery devices V: Hydroxy group effects on drug release kinetics and thermodynamics.

The effects of progesterone hydroxylation on silicone matrix drug release kinetics and thermodynamics were investigated. Hydroxylation at positions 11, 17, and/or 21 substantially reduced progesterone release. The magnitude of this reduction depended on the number and position of the hydroxy groups and could be attributed to decreased polymer matrix diffusivity (Dm) and polymer solubility (Cp). Thermodynamically, hydroxy group addition to positions 11 and/or 21 reduced the activation energy for matrix diffusion (Ed,m) but increased the solvation energy for dissolution in silicone polymer (delta HT,m)). Adding an hydroxy group to position 17 increased the Ed,m but decreased the delta HT,m. The overall (Ed,m) + delta H(T,m)) values were relatively constant and independent of hydroxylation.


Antifertility and antiproteolytic activity of activated N-carbobenzoxy amino acid esters.

N-Carbobenzoxy L-phenylalanine, glycine, L-leucine, and L-proline derivatives, their vinyl esters, and their 1,2-dibromoethyl esters were tested for antifertility activity in mice. Intraperitoneal administration reduced the pregnancy percentage and the number of fetuses per litter. Intravaginal administration reduced the pregnancy percentage significantly, with N-carbobenzoxyglycine vinly ester, N-carbobenzoxyglycine-1,2-dibromoethyl ester, N-carbobenzoxyl-L-leucine-1,2-dibromoethyl ester, and N-carbobenzoxy-L-proline-1,2-dibromoethyl ester producing 100% inhibition at 10 mg/kg/day. Sperm enzyme hydrolysis of the nonspecific substrate azocasein was inhibited significantly by certain N-carbobenzoxy amino acid esters in vitro. Specific substrate N-benzoyl-L-arginine ethyl ester hydrolysis was also inhibited. Compounds that inhibited N-benzoyl-L-arginine ethyl ester hydrolysis also demonstrated in vivo intravaginal antifertility activity.


Bioavailability and dissolution behavior of trisulfapyrimidine suspensions.

The bioavailability of seven commercial trisulfapyrimidine suspensions was studied in 14 adult male volunteers. Fifteen blood samples were collected over a 48-hr period following administration of a 1-g dose of each suspension. Serum was assayed for each component (sulfadiazine, sulfamerazine, and sulfamethazine) by high-pressure liquid chromatography. Analysis of variance indicated several significant differences among the seven commercial preparations with respect to Cmax Tmax, and AUC for sulfadiazine, sulfamerazine, and sulfamethazine, The in vitro behavior of each suspension was then studied by the paddle method of the Food and Drug Administration. A 0.5-ml sample was introduced into 900 ml of hydrochloric acid (2.2 x 10(-4) M) at 37 degree and dissolved using a paddle speed of 25 rpm. Samples withdrawn at 15 and 30 min were analyzed by high-pressure liquid chromatography, and the percent of sulfadiazine, sulfamerazine, and sulfamethazine was calculated. Significant correlation was obtained between an in vivo parameter (Cmax for sulfadiazine) and an in vitro parameter (percent sulfadiazine dissolved in 30 min). Results indicate that this method is suitable for the in vitro screening of trisulapyrimidine suspensions.


High-performance liquid chromatographic assay for imipramine, desipramine, and their 2-hydroxylated metabolites.

High-performance liquid chromatographic method is presented for the simultaneous determination of imipramine, desipramine, and their 2-hydroxylated metabolites in plasma. The method involves a simple plasma extraction at basic pH with organic solvent, chromatography on a silica gel column, and fluorescence detection. Correlation with a GLC-mass spectrometric method for imipramine and desipramine is illustrated. The method can detect 1 ng of each component/ml of plasma, sufficient sensitivity for pharmocokinetic studies.


Chemistry of 8-chloroberberine.

8-Chloroberberine (V), obtained by treatment of oxyberberine (I) with phosphorus oxychloride, is a reactive intermediate. Treatment with ammonia, methylamine, n-propylamine, aniline, and p-toluidine furnished the 8-berberinylidene derivatives IV and VII-X. Reaction of V with malononitrile, ethyl acetoacetate, and ethyl malonate anions yielded the 8-berberinylidene derivatives XII-XIV. Acid hydrolysis of XIV gave 8-berberinylacetic acid (XV) whose reduction provided 8-canadinylacetic acid (XVI). Grignard reagents react readily with V. Methylmagnesium iodide, ethylmagnesium iodide, and benzylmagnesium iodide led to 8,8-dimethyldihydroberberine (XVII), 8,8-diethyldihydroberberine (XIX), and the benzyl derivative XX, respectively. Sodium borohydride reduction of XX gave rise to 8-benzylcanadine (XXI).


Comparative studies on eight dissolution method using 21 commercial chloramphenicol tablets and a nondisintegrating benzoic acid tablet.

Eight dissolution methods (beaker, rotating basket, oscillating basket, solubility simulator, rotating flask, and column) were evaluated using 21 commercial film-coated chloramphenicol (I) tablets and a nondisintegrating benzoic acid (II) tablet. The relative agitating intensities obtained from different dissolution methods were compared through the relative zero-order nondisintegrating tablet dissolution rate constants. Correlation coefficients between I dissolution rate parameters (lag time, T20, T50, and T80) were determined. Significant correlation was observed for the lag time among seven methods, and all pairwise regression lines passed through zero except one. The regression line slopes reflected the relative destructive force intensities produced by each dissolution method on the coated I tablet films. The seven dissolution methods could be classified into two main groups according to correlations of four dissolution rate parameters. The classification criterion agreed well with that based on the agitation method. However, dissolution methods may not be interchangeable even though they belong to the same dissolution method group.


Antitumor agents: structure--activity relationships in tenulin series.

Systematic structural modifications were performed on the natural sesquiterpene lactone tenulin to define those groupings essential to, or significant in, its in vivo antitumor activity. Accordingly, the following tenulin analogs were prepared: dihydrotenulin, 2,3-epoxytenulin, isotenulin, dihydroisotenulin, 2,3-epoxyisotenulin, and tetrahydrodeacetylisotenulin. Both the cyclopentenone and the hemiketal units in tenulin were necessary for high in vivo activity.


GLC determination of whole blood antimalarial concentrations.

An assay was developed for determining mefloquine (quinolinemethanol) and pyridinemethanol derivative concentrations in whole blood. The method involved ion-pair extraction or usual solvent extraction for drug recovery from whole blood followed by trimethylsilylation. The silylated compounds were then submitted to GLC with electron-capture or flame-ionization detection. Mass spectrometry combined with GLC of the trimethylsilyl derivatives indicated that substitution of one trimethylsilyl group had occurred on the hydroxyl group. A phenyl methyl silicone column with temperature programming separated the drugs from normal blood extracts. The determination limit was 10 ng/ml of whole blood when an electron-capture detector was used with ion-pair extraction. Quantitation was achieved by using one antimalarial as an internal standard for the assay of the other. The utility of the present method was demonstrated by following the whole blood level time course after a single oral 250-mg tablet in beagle dogs.


Powder homogenization using a hammer mill.

Hammer mill applicability in the comixing milling operation is discussed with reference to a 1:1000 microfine salicylic acid-sucrose binary system. The hammer mill would not serve as a mixing machine under most circumstances because of the low holdup capacity. Grinding of pure materials was preferable to mixture grinding since active ingredients could be lost during the milling operation. Remixing was always necessary following comminution of the mixture in the hammer mill. Grinding followed by remixing considerably enhanced mixture homogeneity. A large size range was produced by comminution, which resulted in the segregation of ordered units such that the final mixture could be described as a randomized ordered mixture.


Vehicle effects on ocular drug bioavailability III: Shear-facilitated pilocarpine release from ointments.

Pilocarpine release from water-in-oil emulsion ointments was studied in vitro and in vivo, using albino rabbits. Pilocarpine release from the vehicle to the ocular fluids was dependent on shear, i.e.,blinking, and the dosing system emulsifying efficiency. A mechanical shearing component was vital for correlating corneal drug penetration and the in vitro pilocarpine release pattern. Simple diffusion studies with the vehicles did not predict drug in vivo release, but the ointment systems were all superior to an aqueous pilocarpine solution. Incorporation of a mechanical shearing component to mimic blinking gave good correlation of in vitro and in vivo results. Also, increasing the vehicle emulsifying efficiency by surfactant addition decreased shear-facilitated drug release and in vivo performance. Finally, increasing the internal aqueous phase volume fraction decreased in vivo performance and was linked to the influence of effective drug concentration in the vehicle.


Enhanced chartreusin solubility by hydroxybenzoate hydrotropy.

The apparent aqueous solubility of the water-insoluble cytotoxic agent, chartreusin, was increased at neutral pH in the presence of hydroxybenzoates. Water molecules play an important role in the chartreusin conformation. Studies included solubility and spectral examinations. The weakest and strongest interactants with chartreusin were sodium benzoate and sodium trihydroxybenzoate, respectively, while the effect of mono- and dihydroxybenzoates was intermediate. A plane-to-plane orientation of chartreusin and the ligand molecules brought together by electrostatic and hydrophobic interactions is postulated. The dramatic chartreusin aqueous solubility increase relative to its aglycone, chartarin, under similar conditions was best rationalized by micellization.


Stability-indicating analysis of injectable estrogen-androgen combinations in formulations containing corn oil.

A method was developed for the analysis of testosterone 17-enanthate 3-benzilic acid hydrazone, 17-beta-estradiol 3,17-dienanthate, and estradiol benzoate combinations dissolved in an oily vehicle. Testosterone 17-enanthate 3-benzilic acid hydrazone was separated from the other drugs and vehicle components by chromatography on an acetonitrile-infusorial earth column followed by quantitation using UV spectroscopy. The estradiol esters were separated from the oil by an additional chromatographic step using a heptane-silanized infusorial earth column prior to quantitation by GLC. Subjecting formulations to elevated temperatures resulted in detectable losses for testosterone 17-enanthate 3-benzilic acid hydrazone and 17-beta-estradiol 3,17-dienanthate. For both drugs, degradation was due to hydroxysis; the degradation products, testosterone 17-enanthate and 17-beta-estradiol 17-enanthate, did not interfere with the intact drug determination. Methods also were developed to estimate degradation product levels in the formulation.


syn-anti Isomerization in testosterone 17-enanthate 3-benzilic acid hydrazone.

UV spectrophotometry, high-pressure liquid chromatography, and NMR were used to investigate syn-anti isomerization in testosterone 17-enanthate 3-benzilic acid hydrazone. In the crystalline state, the isomeric ratio is dependent on the crystallization solvent. In solutions, including injectable pharmaceutical formulations, an equilibrium isomer mixture (2:1) is formed.


Spectrophotometric determination of tolbutamide, thiamine hydrochloride, and pyridoxine hydrochloride in combination products.

The first derivative curve is used for tolbutamide determination in unit-dose tablets and in combination products. The absorbance contribution from tablet excipient and coexisting components, thiamine and pyridoxine, is thereby nullified. The interference from tolbutamide during thiamine and pyridoxine determination is eliminated by solvent extraction and pH-induced differential spectrophotometry. Thiamine is measured at the isosbestic point of pyridoxine. The latter is determined by the differential absorbance measurement at two wavelengths with the consequent computation of the delta absorbance value.


Effect of serum protein binding on sulfisoxazole distribution, metabolism, and excretion in rats.

This investigation determined the effect of serum protein binding on the kinetics of sulfisoxazole distribution, metabolism, and excretion. Adult rats, whose serum free fraction of sulfisoxazole (at a total concentration of 81 +/- 6 micrograms/ml) was 0.05-0.24, received a rapid intravenous injection of 20 mg/kg. Sulfisoxazole concentrations in plasma declined biexponentially with time. There were pronounced and reproducible interindividual differences in the total, metabolic, and renal sulfisoxazole clearances, each positively correlated with the serum free fraction of sulfisoxazole. The renal sulfisoxazole clearance had a component unaffected by serum protein binding. The apparent central compartment volume increased with an increasing serum free sulfisoxazole fraction, but the latter had not apparent effect on the first exponential term of the biexponential equation describing sulfisoxazole elimination kinetics in rats. Serum protein binding was a major determinant of intersubject differences in sulfisoxazole excretion and biotransformation kinetics.


Analysis of hydrophobic amine antimalarials in biological fluids with the plastic ion-selective electrode.

Plastic ion-selective electrode analysis of the hydrophobic amine antimalarial mefloquine in blood samples was investigated. The direct electrode response in plasma samples provided poor drug sensitivity due to high mefloquine protein binding. The drug was analyzed in whole blood by initial extraction into ether as its trichloroacetate ion-pair. Mefloquine was monitored in whole blood extracts with the electrode to moderately low levels (to 0.4 microgram/ml). Rapid blood mefloquine level monitoring by this electrode was demonstrated in a bioavailability study. Mefloquine alkylation with various alkyl halides produced derivatives detectable by the electrode at much lower levels (up to two orders of magnitude) than the parent. A kinetic study of this alkylation reaction revealed that an alkyl amine base was necessary to scavenge the acid produced during reaction and to allow the reaction to go to completion. At room temperature, with benzyl bromide as the reagent, reaction was 99% complete in 30 min and mefloquine could be detected to approximately to 10(-8) M, a 100-fold improvement in sensitivity over electrode monitoring of underivatized mefloquine.


Colorimetric acetaminophen determination in pharmaceutical formulations.

Different approaches for the colorimetric determination of acetaminophen, based on its coupling with diazotized o-nitroaniline, are described. Copper(II) chelation with the coupled compound makes the method highly selective. Sensitivity is increased when the acetaminophen assay is carried out indirectly through the determination of the chelate's copper content. Optimum conditions for performing the different approaches are described. The stoichiometric balance for the reactants in the coupled compound and chelate is determined. The degree of dissociation and the instability constant are computed. The rectilinear relationship between the absorbance of the different products and the concentration of acetaminophen allows for its determination in different pharmaceutical formulations. Compared with the official method, the proposed methods give more accurate results.


Pharmacokinetics of morphine and its surrogates. III: Morphine and morphine 3-monoglucuronide pharmacokinetics in the dog as a function of dose.

The pharmacokinetics of morphine and its derived metabolite, morphine 3-monoglucuronide, were studied in normal and bile-cannulated dogs. High doses (7.2-7.7 mg/kg iv) caused renal and biliary shutdowns and time lags in urinary drug and metabolite excretion and in biliary secretion of the hepatically formed conjugate. Intermediate doses (0.41-0.47 mg/kg iv) inhibited urine flow but not renal clearance. Low doses (0.019-0.07 mg/kg iv) had no apparent effect. Dose-related effects on the total, metabolic, and biliary clearances imply saturable enzymes and/or dose-inhibited hepatic flows, accounting for the major elimination half-lives of 83 +/- 8 and 37 +/- 13 min at the high and low doses, respectively. The slow terminal phase in plasma morphine and metabolite elimination and urinary accumulation is due apparently to the enterohepatic metabolite recirculation after biliary excretion, gastrointestinal hydrolysis, and hepatic first-pass reconjugation. Bile-cannulated dogs showed no fecal drug and no slow terminal plasma and urine elimination phases. Intravenous morphine 3-monoglucuronide was eliminated only renally and showed neither biliary excretion nor prolonged hepatically formed glucuronide elimination. Hepatic morphine clearances at normal therapeutic doses parallel hepatic blood flow and explain the lack of oral morphine bioavailability by anticipating complete first-pass liver metabolism. Renal morphine and morphine conjugate clearances were 85 (+/- 9 SEM) and 41 (+/- 4 SEM) ml/min, respectively, indicating glomerular filtration for the latter and glomerular filtration plus tubular secretion for the former. Urinary morphine and morphine conjugate excretion accounted for approximately to 83% of the dose. Biliary secretion accounted for 11-14% of the dose. Morphine showed dose-independent plasma protein binding of 36 (+/- 1 SEM) % and a red cell-plasma water partition coefficient of 1.11 +/- 0.04 SD. New equations were developed to model the discontinuous morphine and morphine metabolite pharmacokinetics.


Monoamine oxidase inhibition by beta-carbolines: a quantum chemical approach.

Monoamine oxidase inhibition by beta-carboline derivatives is related to the energy change, delta E, arising from complex formation between the inhibitor and the enzyme. The energy change was expressed in terms of electronic indexes, which were estimated for a set of aromatic beta-carbolines. The electronic indexes were correlated to the experimental activity indexes by a simplified quantum chemical perturbational treatment with a multiple regression procedure. A characteristic structure for the inhibitor-enzyme complex was derived from the correlation. The molecules are linked by two kinds of bond. One involves the lone pyridine nitrogen pair of beta-carbolines; the other is due to a pi-electronic interaction between the inhibitor indole fragment and a suitable area of the enzyme. Such a model explains the competitive inhibition by beta-carbolines compared to tryptamine and other aromatic amines that are monoamine oxidase substrates.


Modified USP assay for simultaneous determination of aspirin and nonaspirin salicylates in aspirin and buffered aspirin tablets.

Modified USP procedures are described for the simultaneous determination of nonaspirin salicylates and aspirin in aspirin and buffered aspirin tablets. The existing USP procedures are not stability indicating for intact aspirin when significant levels of nonaspirin salicylates are present, as is often the case in short-term, high temperature stability programs. The modified procedures yeld considerably shorter analysis times and stability-indicating assays for intact aspirin without the need for sophisticated equipment other than that presently required by USP XIX.


Evaluation of lanolin alcohol films and kinetics of triamcinolone acetonide release.

The film-forming potential of lanolin alcohol was evaluated. Inclusion of ethylcellulose in lanolin alcohol improved film integrity. The hardness and modulus of elasticity of these lanolin alcohol-ethylcellulose films were improved by incorporating propylene glycol or cetyl alcohol. Triamcinolone acetonide release from selected film compositions was investigated. The data were analyzed from the viewpoint of the first-order kinetic theory and the release from a planar system having a homogeneous or granular matrix. The results suggest that the drug release follows a diffusion-controlled matrix model and a square root of time release profile. The release rate constants were proportional to drug concentration. Drug release was maximal from a system containing the drug in a near-saturated solution.


Nortropacocaine hydrochloride conformation in aqueous and hydrophobic media.

The nortropacocaine hydrochloride PMR spectra in deuterium oxide and in deuterochloroform differed markedly. A detailed conformational analysis using vicinal 1H-1H coupling constants revealed the molecular conformation to be identical in both solvents. The preferred conformation was one in which the piperidine component existed as a deformed chair. The spectral differences were due to a decreased deshielding of the protonated nitrogen on the neighboring bicyclic ring protons, resulting in chemical shift changes.


Pharmacokinetics of drugs subject to enterohepatic circulation.

The influence of the changes in biliary excretion and reabsorption rates on the pharmacokinetics of drugs subject to enterohepatic circulation was examined analytically. A recently proposed two-compartment model with drug elimination occurring in each compartment was adapted to represent the body and the GI tract. Enhanced reabsorption was equivalent to biliary excretion rate reduction, except that the latter always decreased alpha and prolonged the alpha-phase half-life while the former always increased alpha and shortened the half-life. However, depending on the relative values of the two elimination rate constants, biliary excretion reduction (or reabsorption enhancement) could either increase or decrease the terminal drug half-life (beta-phase). Whether the terminal drug half-life was prolonged or shortened, a biliary excretion reduction always increased the area under the plasma decay curve for intravenous and oral doses and also raised the steady-state drug level in the body for constant-rate intravenous infusion. As a consequence, the lethality, toxicity, or effectiveness of the drug will be increased for patients with impaired bile flow or enhanced drug reabsorption; therefore, the clinical dosage may have to be reduced.


Progestin permeation through polymer membranes III: Polymerization solvent effect on progesterone permeation through hydrogel membranes.

Hydrogels prepared from poly(hydroxyethyl methacrylate) are biocompatible and highly permeable to low molecular weight solutes. Permeation rates can be varied by altering the cross-linker concentration or using copolymers; the latter are chosen to alter the hydrogel equilibrium hydration. These factors suggest that hydrogels are good candidates for controlled-release drug delivery devices. Hydrogels may be synthesized using various temperatures, initiators (nature and concentration), and solvents (nature and concentration). This study demonstrated that progesterone permeation through poly(hydroxyethyl methacrylate) films is independent of polymerization solvent (nature and concentration) for the solvents, water, ethanol, and tert-butyl alcohol. The importance of hydrogel equilibrium hydration in progesterone permeation is emphasized.


High-pressure liquid chromatographic analysis of veterinary anthelmintics I: Quantitative determination of tetramisole.

High-pressure liquid chromatography was used with a 10-micron C8-type bonded silica gel column to quantitate the tetramisole in veterinary anthelmintic preparations. The chromatographic elution time was less than 10 min, and other compounds present in the products analyzed did not interefere.


High-pressure liquid chromatographic feprazone determination in pharmaceutical formulations.

A high-pressure liquid chromatographic method was developed for the quantitative determination of feprazone, a nonsteroidal anti-inflammatory agent, in different pharmaceutical formulations. The results agree with those obtained with GLC and UV spectrophotometric assays.


GLC-mass spectrometry of Teucrium polium oil.

The essential oil of Teucrium polium, growing in Saudi Arabia, was thoroughly investigated for its constituents by GLC-mass spectrometry, TLC, and spectrophotometric methods. This investigation revealed the presence of 10 terpenoidal compounds including the hydrocarbons beta-pinene, limonene, alpha-phellandrene, and gamma- and delta-cadinenes and the alcohols linalool, terpine-4-ol, cedrol, cedrenol, and guaiol. The oil was rich in alcohols and devoid of esters. Preliminary pharmacological screening showed that the oil possesses powerful antispasmodic activity.


Pyridones as potential antitumor agents.

Based on the finding that 3-acetoxy-2-pyridone had reproducible activity against murine P-388 lymphocytic leukemia, derivatives in this series were synthesized and evaluated to determine structural parameters important for activity. Of the 32 compounds tested, 10 were active. At least two oxygen-containing functional groups are required for P-388 activity, and the 2,3-isomeric arrangement provides the greatest activity. Carbamate or acyloxy groups in the 3-position produced the most active 2-pyridones.


In vitro nitrosation of methapyrilene.

The reactions of sodium nitrite and methapyrilene were studied in aqueous solution at neutral pH and under simulated gastric fluid conditions. Reaction product formation was much more complex than nitrosation of the parent molecule dimethylamino moiety to form nitrosodimethylamine. Several new nitroso compounds were formed under the reaction conditions studied. The simultaneous incorporation of 2 moles of ascorbic acid/mole of nitrite ion prevented any destruction of methapyrilene under all conditions studied. The implications of these observations with respect to nitrosation theory, the general carcinogenicity of nitroso compounds, and methapyrilene dosage formulation are discussed.


Prostaglandin prodrugs. I: Stabilization of dinoprostone (prostaglandin E2) in solid state through formation of crystalline C1-phenyl esters.

Dinoprostone para-substituted phenyl esters were synthesized in attempt to improve the solid-state stability of the parent prostaglandin. A phenol series covering a wide melting-point range was employed, and a linear relationship was observed between the phenol melting points and the resulting prostaglandin C1-ester melting points. The crystalline esters showed improved solid-state stability over the parent compound, and many esters were biologically active.


Prostaglandin prodrugs. II: New method for synthesizing prostaglandin C1-aliphatic esters.

A new method for synthesizing C1-aliphatic esters of dinoprost and dinoprostone without using hydroxyl protective groups is described. Reaction of the prostaglandin with an alkyl halide in the presence of the sterically hindered amine N,N-diisopropylethylamine proceeds smoothly to give C1-esters in various solvents at ambient or slightly elevated temperatures. Polar solvents were strongly catalytic, and even the hindered tert-butyl esters were synthesized by employing solvents such as dimethylformamide or dimethyl sulfoxide. Biological evaluation in the hamster antifertility assay showed that some esters maintained high bioactivity.


Molecular topology and aqueous solubility of aliphatic alcohols.

A physically based method for arriving at topological indexes is described. The derived indexes correlate with molecular surface areas and with the molecular connectivity index. The newly derived index seems to account better for the expected distinctions among primary, secondary, and tertiary alcohol aqueous solubilities. This study suggests that the Del Re method for calculating molecular charges and dipole moments also may be used, without appreciable change, to provide estimates of molecular refraction.


Quinazolines and 1,4-benzodiazepines. LXXXIX: Haptens useful in benzodiazepine immunoassay development.

The syntheses of some 1,4-benzodiazepines potentially useful as haptens are reported. These compounds are related to chlordiazepoxide, diazepam, nitrazepam, clonazepam, and some of their metabolites. The chemistry reported here is intended to support specific immunoassay development for these drugs.


Benoxaprofen, a new anti-inflammatory agent: particle-size effect on dissolution rate and oral absorption in humans.

The particle-size effect of benoxaprofen, a new nonsteroidal anti-inflammatory agent, on the in vitro dissolution rate and oral absorption in humans was evaluated. Ten normal subjects participated in a randomized crossover-designed absorption study with two sieved particle-size formulations: one with crystals larger than 60 mesh (mean equivalent spherical diameter = 640 micron) and the other with crystals smaller than 100 mesh (mean equivalent spherical diameter = 67 micron). Plasma drug concentrations and urinary drug excretion were used to determine the relative absorption of the two formulations. The standard USP procedure was used for the dissolution study. Particle size had a dramatic effect on both the in vitro drug dissolution and its oral absorption in humans. In vitro, the smaller crystals dissolved more rapidly and more efficiently than the larger crystals. In vivo, the smaller crystals produced higher plasma concentrations, more rapid peak concentration attainment, and more drug excreted in the urine.


Controlled drug dissolution by radiation-induced polymerization in the presence of dimethylaminoethyl methacrylate-methyl methacrylate copolymer or methacrylic acid-methyl acrylate copolymer.

Polymer-containing tablet preparation was studied using radiation-induced polymerization of glass-forming monomers at low temperatures in the presence of dimethylaminoethyl methacrylate-methyl methacrylate copolymer or methyl acrylate-methacrylic acid copolymer. Drug dissolution from tablets was in the pH 3.0-8.0 range. A copolymer contained in the tablets dissolved in the dissolution medium at a specific pH. Drug dissolution from tablets took place rapidly at pH greater than 6.0 in the presence of methyl acrylate-methacrylic acid copolymer and at pH less than 5.0 in the presence of dimethylaminoethyl methacrylate-methyl methacrylate copolymer. The polymers had fibrous or capillary pore structures in contrast to the spherical pore structures formed in the presence of polyethylene glycol 600.


Cefoxitin sodium: solution and solid-state chemical stability studies.

Studies were undertaken to provide the basic physicochemical information necessary for preparing a suitable parenteral formulation of cefoxitin sodium. Emphasis was placed on the physico-chemical properties of the compound in solution and in the solid state. Cefoxitin sodium is very soluble in water and exhibits apparent first-order decomposition in this medium at pH 3-9. Maximum stability in water is at pH 5-7. Under these pH conditions, cefoxitin sodium loses about 10% of its activity in 2 days at 25 degrees. Thermal decomposition rates for amorphous and crystalline cefoxitin sodium samples were determined. Amorphous cefoxitin sodium was considerably less stable than its corresponding crystalline form. Solid-state decomposition plots are biphasic, displaying initial rapid losses followed by a slower decay period. The extent of loss in the crystalline solid at the end of the more rapid initial phase can be correlated with the water content of the solid.


Synthesis and evaluation of benzylfluorenyl and 1-arylethyl quaternary ammonium salts for antimicrobial and antineoplastic activities.

A number of substituted benzyldimethyl-9-fluorenylammonium bromides (II) and 9-benzylfluorenyl-9-trimethylammonium bromides (IV) were synthesized and examined for antimicrobial and anticancer activites. Series IV showed greater antimicrobial activity than Series II while some corresponding acyclic fluorene analogs were bereft of antimicrobial activities. Significant antineoplastic activity was not found in Series II and IIV. Representative fluorenes subjected to a preliminary screen for various pharmacological activities revealed marked anti-inflammatory and analgesic properties coupled with some antihistaminic activities. The acyclic quaternary ammonium compounds demonstrated substantial pressor activites.


Separation and determination of testosterone and testosterone esters in selected pharmaceutical formulations.

A rapid quantitative procedure is presented for the separation of testosterone esters from their hydrolysis products through the use of the acetonitrile-infusorial earth column. The method was applied to testosterone cypionate, testosterone enanthate, and testosterone propionate. Recovery and replication of reference standard testosterone and its three esters through the proposed method ranged from 99.1 to 100.3%, and the percent relative standard deviation ranged from 0.6 to 1.0%. Two samples can be separated into testosterone and testosterone ester fractions in about 1.5 hr. The analyses of 20 injectable and one buccal tablet formulations made by 12 different manufacturers are reported.


Application of thermochromism in spectrophotometric analysis: selective determination of berberine in pharmaceuticals by solvent extraction.

A solvent extraction and spectrophotometric method for selective determination of berberine in pharmaceuticals is proposed. Berberine forms an ion associate with tetrabromophenolphthalein ethyl ester, which is extracted into ethylene dichloride. Secondary and tertiary amines and alkaloids are coextracted with the berberine and complicate the berberine determination. The absorbance of the secondary and tertiary amines and alkaloids into ethylene dichloride, however, decreases nearly to zero when the temperature is elevated from 25 to 60 degrees. Thus, berberine can be determined successfully in the presence of the secondary and tertiary amines and alkaloids by using thermochromaism.


High-pressure liquid chromatographic determination of saccharin in artificial sweeteners and pharmaceuticals.

A high-pressure liquid chromatographic procedure is presented for determining saccharin in various formulations. The method is fast, precise, and accurate and is specific for saccharin in the presence of its most likely impurities and degradation products. Reversed-phase chromatography on a micro-C18 column is utilized with an internal standard, and detection is by UV absorption at 280 nm.


High-performance liquid chromatographic assay for the anthelmintic agent mebendazole in human plasma.

A rapid and specific high-performance liquid chromatographic (HPLC) assay for quantitative plasma mebendazole determination is described. After a simple extraction, the compound was analyzed by HPLC using a reversed-phase column and a UV detector (313 nm). Quantitation was accomplished using an internal standard; peak area ratios were determined with an integrating computer. The average mebendazole recovery over a concentration range of 0.01-0.20 microgram/ml was 75.9 +/- 3.8% SD, and the maximum assay sensitivity was approximately 10 ng/ml.


Antitumor agents. XXXIV: Mechanism of action of bruceoside A and brusatol on nucleic acid metabolism of P-388 lymphocytic leukemia cells.

The quassinoids bruceantin, brucein D, brucein E, bruceoside A, and brusatol significantly inhibited P-388 lymphocytic leukemic cell RNA and protein synthesis in tissue culture. However, DNA synthesis inhibition seemed to correlate more directly with the anti-neoplastic activity of these compounds in the in vivo P-338 survival system. In vitro, brusatol and bruceoside A marginally inhibited 10-day P-388 lymphocytic leukemia DNA polymerase, RNA polymerase, thymidylate synthetase, dihydrofolate reductase, phosphoribosyl pyrophosphate aminotransferase, and cathepsin protease activities. In vivo studies demonstrated similar inhibition and elevated cyclic AMP levels, correlating positively with the antineoplastic activity of individual compounds. Purine synthesis was inhibited drastically by brusatol in vivo, and one key inhibition site in purine synthesis was at phosphoribosyl pyrophosphate aminotransferase, the regulatory enzyme. Histone phosphorylation and ribonucleotide reductase activity also were inhibited marginally by brusatol.


Synthesis of phenyl-3- and phenyl-5-acetamidosalicylates as potential analgesics.

Phenylsalicylate was nitrated to obtain two nitro isomers, which were separated and reduced to the corresponding amines followed by acetylation to give phenyl-5- or phenyl-3-acetamidosalicylate. Phenyl-5-acetamidosalicylate displayed analgesic activity comparable to that of aspirin and phenacetin at doses of 25-50 mg/kg sc and was much less toxic than the latter compounds. Phenyl-3-acetamidosalicylate, however, was ineffective at a similar dose range and caused restlessness at larger doses.


Conductivity and hardness changes in aged compacts.

Batches of sodium, potassium, and ammonium chloride tablets containing no excipients and spray-dried lactose tablets containing 0.5% magnesium stearate were stored at 20 and 76% relative humidity. Electrical resistance and hardness measurements were made within 1 hr after compression and at intervals during a 45-day period. Hardness values of sodium, potassium, and ammonium chloride tablets stored at 20% relative humidity increased from 70 to 200% at 45 days, while conductances decreased 10-fold. Tablets stored at 76% relative humidity showed no increases or slight decreases in hardness with slight increases in conductance. Lactose tablets decreased slightly in hardness with corresponding increases in conductance.


Cytotoxic saponins from the Chinese herbal drug Yunnan Bai Yao.

Two cytotoxic saponins were isolated from the acetone extracts of the herbal preparation "Yunnan Bai Yao" by column chromatography. They were identified as a 3-([alpha-L-rhamnopyranosyl()Rha leads to 2Glu)]-[alpha-L-arabinofuranosyl(1Ara leads to 4Glu)]-beta-D-glucopyranosyl)-25(R)-spirost-5-en-3beta-ol (I) and 3-([alpha-L-rhamnopyranosyl(1Rha leads to 4Rha)-alpha-L-rhamnopyranosyl(1Rha leads to 4Glu)]-[alpha-L-rhamnopyranosyl(1Rha leads to 2Glu)]-beta-D-glucopyranosyl)-25(R)-spirost-5-en-3 beta-ol (VI). Both saponins exhibited significant cytotoxicity in the standard P-388, L-1210, and 9KB tissue culture screens.


Molecular connectivity analysis of hallucinogenic mescaline analogs.

The hallucinogenic (psychotomimetic) potency of 10 mescaline analogs was examined by molecular connectivity analysis. Potencies could be described by a two-term relating equation, which explained 94% of the variance in activity, on the basis of structural variation, 2,5-Dimethoxy substitution as well as the nature of the 4-position substituent played an important role in determining hallucinogenic potency. With the relating equation, reasonable potency predictions were made for six compounds not included in the initial investigation.


Fluorometric determination of chlorzoxazone in tablets and biological fluids.

A fluorometric determination for chlorzoxazone was developed based on the intrinsic drug fluorescence in chloroform using excitation and emission wavelengths of 286 and 310 nm, respectively. A calibration curve for chlorzoxazone in chloroform gave a linear working range of 0.027-2.3 microgram/ml (r = 0.9999) with the minimum detectability at 27 ng/ml. The procedure was applied to chlorzoxazone analysis in spiked plasma and urine samples. Minimum detectable drug levels in these samples were 60 and 130 ng/ml, respectively. Data revealed that chlorzoxazone could be determined in plasma and urine even in the presence of 20-fold molar excesses of its major metabolite, 6-hydroxychlorzoxaxone, and acetaminophen. The method also was applicable to chlorzoxazone analysis in a commercial dosage form containing acetaminophen.


Isolation and identification of 3,3',5,5'-tetrabis(tert-butyl)stilbenequinone from polyethylene closures containing titanium dioxide and butylated hydroxytoluene.

A yellow compound was isolated from commercially available, discolored, polyethylene ophthalmic closures containing titanium dioxide and butylated hydroxytoluene (I). This compound was present at 7.46 ppm (w/w). It was identified by UV, IR, and mass spectra as 3,3',5,5'-tetrabis(tert-butyl)stilbenequinone (II), a dimer of I. Further structural confirmation was obtained by NMR. Formation of II is catalyzed by titanium dioxide.


Dihydroquinidine contamination of quinidine raw materials and dosage forms: rapid estimation by high-performance liquid chromatography.

Dihydroquinidine is a commonly encountered contaminant in quinidine raw materials. The USP allows 0-20% dihydroquinidine in quinidine products, but the assays used to quantitate dihydroquinidine have been lengthy or have required sophisticated equipment. The present method separates dihydroquinidine from quinidine and provides rapid, precise quantitation of both dihydroquinidine and quinidine. The clinical importance of dihydroquinidine contamination of quinidine dosage forms remains unanswered.


Stability-indicating sulfa drug analysis using high-performance liquid chromatography.

Sensitive and efficient methods for sulfonamide determination as single entities and in combination with other drug substances in pharmaceutical dosage formulations were developed using high-performance liquid chromatography. These stability-indicating procedures involved a nitrile bonded phase column and nonaqueous mobile phases having diverse polarities. Sample potency was determined using peak height measurements. The methods may be used to determine trace sulfonamide quantities because detection limits are in the nanogram range.


Antibacterial activity of Artemisia herba-alba.

The antibacterial activity of Artemisia herba-alba was investigated. Only its essential oil was active against some Gram-positive and Gram-negative bacteria. The essential oil was fractionated by column chromatography, and these fractions were tested for antibacterial activity. The principal component of the most active fraction was santolina alcohol.


Quantitative dexamethasone and dexamethasone sodium phosphate determinations in pharmaceutical dosage forms by high-pressure liquid chromatography.

A high-pressure liquid chromatographic procedure for quantitative dexamethasone and dexamethasone sodium phosphate determinations in all types of commercially available pharmaceutical dosage forms was developed. The method also separates dexamethasone from its phosphate salt and separates dexamethasone or its salt from a number of inactive ingredients such as benzoic acid, benzyl alcohol, some colors, creatinine, and parabens. Inactive ingredient concentrations may be estimated without additional cost. Part of the parabens present in the commercial injections may be adsorbed by the rubber closures.


Terpenoid biotransformation in mammals. II: Biotransformation of dl-camphene in rabbits.

The biotransformation of dl-camphene in rabbits was investigated. Four neutral metabolites, 6-exo-hydroxycamphene, 10-hydroxycamphene, and diastereoisomers of camphene-2,10-glycol, were identified and two alcohols, 7-hydroxycamphene and 3-hydroxytricyclene, were estimated by IR, UV, NMR, and mass spectra and chemical degradations. The formation of these compounds can be explained through a homoallylic oxidation or an epoxide formation.


Effect of phenytoin (DPH) treatment on methoxyflurane metabolism in rats.

The toxicity and metabolism of the fluorinated anesthetic methoxyflurane were compared in Fischer 344 rats pretreated with phenytoin or phenobarbital. Treatment with either drug potentiated the polyuric effects of methoxyflurane by more than 100%. Also, serum inorganic fluoride (F-) levels and urinary F- excretions after methoxyflurane exposure were comparable in phenytoin- and phenobarbital-treated rats, a 26 to 49% increase as compared to rats treated with methoxyflurane alone. In vitro, 10-fold increases in the rate of hepatic microsomal methoxyflurane defluorination were observed after treatment of rats with either phenytoin or phenobarbital. Kinetic studies with microsomes demonstrated inhibition of methoxyflurane defluorination in the presence of phenytoin. Defluorination of three additional fluorinated ether anesthetics, enflurane, isoflurane and sevoflurane, also was examined in vitro. Phenytoin and phenobarbital treatment resulted in similar enhancement of defluorination of the latter two anesthetics, but not enflurane. Phenytoin and phenobarbital treatment increase defluorination of fluorinated ether anesthetics to approximately the same extent in vitro and in vivo in Fischer 344 rats.


Electrophysiological effects of mexiletine (Kö1173) on ovine cardiac Purkinje fibers.

To clarify the electrophysiological mechanisms of the antiarrhythmic effects of mexiletine, we examined the actions of mexiletine (0.1--30 mg/l) on action potential characteristics (phase 0 amplitude, overshoot, maximum upstroke velocity, maximum diastolic and activation voltages, duration at 50% and 90% repolarization) of cardiac Purkinje fibers using standard microelectrode techniques. In fibers stimulated at constant rate, mexiletine decreased phase 0 amplitude and Vmax and shortened the action potential. Mexiletine shortened action potential duration at lower concentrations than those which altered phase 0 depolarization. The effect of mexiletine on normal automaticity in cardiac Purkinje fibers was studied in fibers made automatic either by hypokalemia or by isoproterenol. Mexiletine suppressed normal automaticity by shifting activation voltage, so that spontaneous phase 4 depolarization reached a stable resting voltage without triggering regenerative phase 0 depolarization. The effects of mexiletine on abnormal automaticity were studied in Purkinje fibers intoxicated by ouabain. Mexiletine decreased the amplitude of or abolished either early or delayed after depolarizations induced by ouabain.


Cellular pharmacology of 7(R)-O-methylnogarol: a new anticancer agent.

The cellular accumulation and disposition of 7(R)-O-methylnogarol (7-OMEN), a derivative of the anthracycline antibiotic, nogalamycin, were compared to those of daunorubicin. Although both drugs were avidly accumulated by cells, intracellular concentrations of 7-OMEN were 5 to 10 times those of daunorubicin. Lowered temperature (0 degrees C) reduced intracellular accumulation of both drugs, but 10 mM sodium azide reduced the accumulation of 7-OMEN only. Both drugs exited from cells placed in drug-free medium, a process that was reduced at 0 degrees C. Sodium azide, 10 mM, did not alter the efflux of daunorubicin from cells but hastened the efflux of 7-OMEN. Unlike whole cells, isolated nuclei accumulated more daunorubicin than 7-OMEN. This process was not reduced at 0 degrees C. Both drugs were lost from nuclei placed in drug free buffer with only slight reduction at 0 degrees C. Unlike daunorubicin which localized in cell nuclei, 7-OMEN localized in the cytoplasm with no detectable nuclear fluorescence. Both drugs produced nearly equivalent dose-dependent inhibition of [3H]thymidine incorporation by L1210 and P388 cells. P388/ADR cells proved resistant to both anthracyclines. [3H]uridine and [3H]valine incorporations were inhibited by daunorubicin but were not altered by 7-OMEN.


Pharmacokinetics of heparin. II. Studies of time dependence in rats.

The purpose of this investigation was to determine whether the time course of heparin activity (bioassayed heparin concentration) in plasma of rats during and after constant rate i.v. infusion of heparin can be predicted from the pharmacokinetic characteristics of a single i.v. bolus dose of heparin administered to the same animals. Five rats received a rapid i.v. injection of heparin, 320 to 517 U/kg, and on the following day, an i.v. infusion of heparin, 2.7 to 4.0 U/min/kg, for 10 to 11 hr. Heparin activity in plasma at the end of the infusion was about twice as high as predicted on the basis of the total clearance of the bolus dose. Even though the maximum heparin activity immediately after the bolus dose and at the end of the infusion were similar, the biologic half-life of heparin at the end of the infusion was about twice as long as that of the bolus dose. Apparently, the pharmacokinetics of heparin are time dependent. This may explain, at least in part, the clinical observation that heparin infusion rate must often be reduced after the initial days of therapy.


Evidence for luminal uptake of gentamicin in the perfused rat kidney.

Gentamicin nephrotoxicity is preceded by proximal tubular accumulation of the drug. To determine whether gentamicin enters cells from the peritubular surface or from the tubular lumen after filtration, we studied filtering and non-filtering isolated perfused rat kidneys. Filtering kidneys were perfused with 6 g/dl of albumin, non-filtering kidneys with 11 g/dl of albumin and a lower perfusion pressure after ureteral occlusion. Accumulation of [14C]gentamicin in filtering or non-filtering kidneys was compared to that of [14C]cephaloridine, which is taken up primarily at the antiluminal cell surface. Renal accumulation of gentamicin was approximately 4 times greater in filtering than in non-filtering kidneys after 1 hr of perfusion. In contrast, accumulation of [14C]cephaloridine was 38% greater in the non-filtering model. Gentamicin did not significantly change sodium reabsorption or glomerular filtration rate during the 60-min study. Fractional potassium excretion, however, was slightly but significantly increased by perfusion with gentamicin. Our results indicate that 1) renal tubular gentamicin uptake is primarily by filtration and subsequent reabsorption and 2) the non-filtering and filtering isolated perfused rat kidney may be used to investigate mechanisms of renal accumulation of other nephrotoxic agents.


The effects of phenytoin and lidocaine on a proprioceptor of the cockroach, Blaberus discoidalis: a simple method for discriminating between inhibitors of sensory transduction and axonal conduction.

Three linearly aligned tibial tactile spines of the cockroach Blaberus discoidalis were stimulated by a mechanically driven glass probe. A "window" was cut at the base of the central spine and various concentrations of phenytoin, lidocaine and colchicine were applied. Colchicine, phenytoin and a low concentration of lidocaine selectively inhibited stimulus-evoked discharges from the central spine, while lidocaine in higher concentrations inhibited discharges from the central and distal spines. We conclude that phenytoin and colchicine suppress afferent discharges by their ability to interfere with sensory transduction, while lidocaine suppresses afferent responses by interfering with axonal conduction as well as sensory transduction.


Isoproterenol excretion and metabolism in the isolated perfused rat kidney.

[3H]isoproterenol excretion and metabolism were studied in the isolated perfused rat kidney using a one-pass, non-recirculating perfusion system with constant infusion rates of [3H]isoproterenol. The [3H]isoproterenol (U/P) to inulin (U/P) ratio was approximately 15 indicating extensive tubular secretion. A major renal metabolite, 3-O-methylisoproterenol, appeared in the urine and renal vein perfusate and also accumulated in the renal tissue. The fractional excretion of isoproterenol decreased with time while fractional excretion of p-aminohippurate remained stable. The observed decreasing urinary clearance and percent extraction of isoproterenol with time may be due to the progressive intrarenal accumulation of 3-O-methylisoproterenol.


Ionic currents in response to membrane depolarization in an Aplysia neurone.

1. Action potentials recorded in the soma of R15 neurones in the abdominal ganglia of Aplysia juliana were not suppressed by selective inhibition of either Na or Ca conductance alone. It was necessary to block both conductances to suppress action potentials. 2. Membrane currents generated by step depolarizations of the soma consisted of early transient and delayed steady-state currents. The early transient current could have one or two components depending on the activating depolarization. 3. The early more rapid component had a reversal potential at +54 mV and the reversal potential changed with extracellular Na concentration in accord with the Nernst equation. It was blocked by substitution of impermeant cations for Na, by TTX and by internal injections of Zn. It was concluded that this component was normally a Na current. 4. The later slower component of the transient current had a reversal potential at about +65 mV and the reversal potential changed with extracellular Ca concentration is accord with the Nernst equation. It was blocked by substitution of Mg for Ca or addition of Mn, Co, Ni or verapamil to the extracellular solution. It was concluded that this component was normally a Ca current. 5. Na and Ca currents were generated at different threshold potentials, Na currents first appearing at about -20 mV and Ca currents at -5 to 0 mV. 6. The time-to-peak of both Na and Ca currents was affected by the holding potential, by the amplitude of the activating depolarization, by temperature and by divalent ion concentration. 7. The peak Na and Ca conductances both increased sigmoidally with increasing depolarization, the maximum Na conductance of 10--15 microS being approximately twice the maximum Ca conductance. Peak conductances for Na and Ca reached half-maximum at -8 and +3 mV, respectively. 8. The amplitude of the delayed steady-state current could be varied by changing the extracellular K+ ion concentration or by adding tetraethylammonium to the extracellular solution. The reversal potential for 'tail currents' was -67 mV and shifted 18 mV when the extracellular K concentration was doubled. It was concluded that the delayed steady-state current was K current. 9. With prolonged depolarizations, K current decayed with a time constant of the order of 1 sec. Peak K conductance increased with increasing depolarization with the half-maximum occurring at a potential more positive than +20 mV. The maximum rate of fractional activation of K conductance was independent of the amplitude of the clamp step.


Characteristics of sodium and calcium conductance changes produced by membrane depolarization in an Aplysia neurone.

1. The time course and voltage dependence of Na and Ca conductance changes produced by depolarization of the soma of the neurone R15 in the abdominal ganglion of Aplysia juliana were examined at temperatures of 10--14 degrees C. 2. During a maintained depolarization, Na currents turned on then decayed (inactivated). Inactivation was exponential with time constant tauh. Activation (after correction for inactivation) was reasonably well described by the expression G'Na(t) = G'Na (infinity) (1 - exp [-t/taum])3 over a wide range of potentials. 3. taum and tauh were both voltage dependent. In the range -20 to +40 mV, taum varied from 5 to 0.5 msec and tauh from 25 to 8 msec (13.5 degrees C). Steady-state Na conductance (corrected for inactivation) was voltage dependent also, increasing sigmoidally with depolarization to a maximum of 25--30 muS at +10 to +20 mV. Half-maximal Na conductance occurred at a membrane potential of -8 mV and from -15 to -5 mV, a 5 mV change in membrane potential produced an e-fold change in steady-state Na conductance. 4. Steady-state inactivation of Na conductance (hNa(infinity)) was voltage dependent with half-inactivation occurring at a membrane potential of -32 mV. Recovery from Na inactivation followed an exponential time course with a voltage-dependent time constant. 5. During a maintained depolarization Ca currents activated then decayed (inactivated) more slowly than Na currents. The decay was exponential with time constant tauH. The decay of Ca current was not an artifact porduced by an outward current. The amplitude of calcium tail currents, produced by voltage steps back to epsilonK at different times during the decay of ICa, decayed also with a time constant close to tauH. 6. Ca conductance (after correction for inactivation) could be described approximately by the expression G'Ca(t) = G'Ca(infinity) (1 - exp [-t/tauM])p but it was necessary to vary p from 1 to 2 at different potentials. No value of p gave as good a fit to this model as that obtained for Na currents. 7. taum and tauH were voltage dependent. In the range of potentials from 0 to +60 mV, tauM varied from 9 to 5 msec and tauH from 300 to 50 msec (13.5 degrees C). Steady-state Ca conductance (corrected for inactivation) was voltage dependent also, increasing sigmoidally with depolarization to a maximum of 10--15 muS at +30 to +40 mV. Half-maximal Ca conductance occurred at a membrane potential of +12 mV, and from +10 to +20 mV a 6 mV change in membrane potential produced an e-fold change in Ca conductance. 8. Steady-state inactivation of Ca conductance (hCa(infinity)) varied with holding potential (VH). Half-inactivation occurred with depolarization to -20 mV. At potentials more negative than -40 mV, hCa(infinity) was less than at -40 mV, i.e. hyperpolarization produced Ca 'inactivation'. 9...


Open loop increase in trunk temperature produced by face cooling in working humans.

1. Five human subjects pedalled on a bicyle ergometer for at least two 74 min periods at 10 degrees C ambient temperature. During the first period the subjects cycled for 42 min with face fanning, followed by 32 min with the head thermally insulated. In the second period, this procedure was reversed. Oesophageal (tes), tympanic (Tty), forehead and hand skin temperatures were recorded. In addition, heart rate (H.R.) was counted throughout the experiments, and the technique of perceptual rating of cool and warm stimuli was used in order to appreciate whether the subjects were hypo-, normo-, or hyperthermic. 2. Face fanning resulted in decreased Tty, decreased H.R., mild skin vasoconstriction but increased Tes. 3. Head covering resulted in increased Tty and H.R., while Tes decreased slightly, due to peripheral vasodilatation. 4. When their faces were being fanned so that Tty was low and Tes was high, the subjects gave slightly hypothermic ratings. Ratings were clearly hyperthermic when their heads were covered and Tty was high and Tes was low. 5. The close correlation between vasomotor response and H.R. on the one hand and Tty on the other confirms that this variable is a better approximation of regulated core temperature than Tes. 6. Increase in Tes during face fanning and decrease in Tes during face insulation is new evidence for the possibility of the human brian being cooled during exercise by cool blood returning from the face. 7. We suggest that this selective brain cooling determines the apparent upper resetting of core temperature during exercise while brain temperature remains precisely regulated and constant.


Contraction time and voluntary discharge properties of individual short toe extensor motor units in man.

1. The contraction time and the voluntary discharge properties of forty-five short toe extensor motor units were studied in man. 2. The contraction time of the individual motor unit was studied by using selective electrical nerve stimulation or by averaging the increase in force related to its electromyographic potential in tonic voluntary contraction. 3. Both methods showed a range of contraction times from 40 to 90 ms. 4. The discharge properties of the individual motor unit were studied with e.m.g. techniques, permitting the identification of its potentials during maximum voluntary effort. 5. A motor unit which could be driven continously and had a minimum rate of about 10/s and a maximum rate of about 30/s had a contraction time between 60 and 90 ms. 6. A motor unit which could not be driven continously and had a minimum rate of about 20/s and a maximum rate above 40/s had a contraction time between 40 and 55 ms. 7. A motor unit with intermediate voluntary discharge properties had an intermediate contraction time. 8. It is concluded that each motor unit fires at its fusion frequency in voluntary contraction and that the voluntary discharge frequency range of a motor unit can be used as an indication of its contraction time.


Scaling factor relating conduction velocity and diameter for myelinated afferent nerve fibres in the cat hind limb.

1. Compound action potentials were recorded from certain muscle and cutaneous nerves in normal and chronically de-efferentated hind limbs of cats during stimulation of the appropriate dorsal spinal roots, 2. The peaks for groups I, II and III in the compound action potential were correlated with the corresponding peaks in the fibre-diameter histograms of the same de-efferentated nerve after processing it for light microscopy. 3. The scaling factor (ratio of conduction velocity in m/sec to total diameter in micrometer) was not constant for all sizes of fibre nor did it increase progressively with fibre size. Evidence is presented that a logarithmic relation between conduction velocity and fibre diameter is not appropriate. 4. In muscle nerves the scaling factor for fibres fixed by glutaraldehyde perfusion and embedded in Epon was 5.7 for group I afferent fibres and 4.6 for myelinated fibres in both group II and group III. 5. In cutaneous nerves the scaling factor was 5.6 for large fibres (group I or Abeta) and 4.6 for small fibres (group III or Adelta). 6. The scaling factor for group I fibres is the same as was found previously for alpha-efferent fibres, and that for groups II and III is the same as for gamma-efferent fibres (Boyd & Davey, 1968). 7. The possibility that there is a clear discontinuity in scaling factor between fibres in groups I and alpha, and those in other functional groups, is discussed. 8. It is concluded that there must be some structural feature of alpha and group I fibres which differs from that of smaller myelinated fibres. It is likely that a difference in the relative thickness of the myelin sheath is involved and possibly also in the conductances responsible for generating the action potential.


The mechanism of peripherally evoked responses in retinal ganglion cells.

1. Responses to stimulation of retinal regions remote from the classical receptive field were recorded from optic tract fibres in lightly anaesthetized cats. 2. X- and Y-cells gave reliably different responses to the sudden reversal of the phase of a high contrast grating that fell on the retina more than 15 deg from the centre of the receptive field. 3. The mechanism that generates these responses ('shift effect' or 'periphery effect') in Y-cells is insensitive to the spatial phase of the stimulating grating. It can resolve gratings of higher spatial frequency than can be resolved by the classical receptive field mechanisms of Y-cells but its temporal resolution is poorer. 4. Signals that contribute to peripherally evoked responses are accumulated over a region that extends to at least 35 deg from the centre of the receptive field. Although this region is not uniformly sensitive, regions in the periphery of the visual field are as effective as regions around the area centralis in eliciting the responses, and do not require coarser gratings. 5. In some Y-cells the response to peripheral stimulation was amplified by increasing (on-centre units) or decreasing (off-centre units) the steady illumination of the centre of the receptive field. This confirms Krüger & Fisher (1973), but the effect is only found in a proportion of cells. 6. The mechanism that generates peripherally evoked responses is tentatively identified with the 'rectifying subunits' postulated by Hochstein & Shapley (1976b) to account for the spatial non-linearity in the receptive fields of Y-cells. Transient (bistratified) amacrine cells are known to have many of the properties attributed to these mechanisms (Chan & Naka, 1976).