Computerized tomographic demonstration of a retroperitoneal hematoma causing femoral neuropathy. Report of two cases. To the previously reported 28 cases of femoral neuropathy caused by a retroperitoneal hematoma in patients on anticoagulant drugs are added two cases in which the diagnosis was made by direct visualization of hematoma of the iliacus muscle by computerized tomography of the abdomen.


Infantile chronic subdural hematoma of the posterior fossa diagnosed by computerized tomography. Case report. A 9-week-old infant manifested continuous vomiting for 1 week accompanied by a tense fontanel, "sun setting" of the eyes, frequent opisthotonos, and hypertonicity. The head circumference was at the 50th percentile. Computerized tomography (CT) revealed acute hydrocephalus and a posterior fossa subdural hematoma. The brain stem and cerebellum were of greater density (54 Hounsfield units) than normal cerebral white matter (42 Hounsfield units) whereas the subdural hematoma was the same density as normal cerebral white matter ("isodense"). The cerebellum and brain stem became enhanced by contrast (68 Hounsfield units), but no enhancement occurred in the cerebral white matter or subdural hematoma. A shunt followed by occipital craniectomy resolved both the hydrocephalus and subdural hematoma. Repeat CT scan 15 days postoperatively disclosed continuing higher density of the cerebellum and brain stem (60 Hounsfield units) relative to cerebral white matter. Increased density of the infantile cerebellum has been noted previously but not to the same extent as in this patient.


Long-term control of recurrent cyst of the conus medullaris. Case report. The authors report a case in which decompression of an intramedullary epidermoid cyst was maintained by intermittent drainage via an implanted subcutaneous Ommaya reservoir.


Choroidal epithelial cyst. Case report.

Choroidal epithelial cyst. Case report. A supratentorial cyst in the leptomeninges of an 8-month-old infant was studied with the electron microscope. The lining of the cyst consisted of a single layer of peg-shaped epithelial cells rich in organelles and glycogen. Their free border had numerous microvilli but no cilia, and their basal portions rested on a basement membrane. Tight junctions and interdigitations were frequent between contiguous cells. The blood vessels were fenestrated. Since these features characterize developing choroidal epithelial cells, we felt the diagnosis of choroidal epithelial cyst was justified. Cysts lined by choroidal epithelium may continue to secrete cerebrospinal fluid after surgical extirpation when this is incomplete. Accumulation of the fluid in the partially excised cyst bed may therefore account for recurrence of symptoms.


Mixed bacterial meningitis: a complication of ventriculo- and lumboperitoneal shunts. Infectious complications of ventriculo- and lumboperitoneal shunts in two patients are presented. Cerebrospinal fluid infection due to aerobic and anaerobic enteric flora was characteristic of each case. Both infections occurred several months after shunt surgery and were associated with colonic perforation by the distal limb of the peritoneal catheter. These cases emphasize this unusual hazard of peritoneal shunts and demonstrate methods for diagnosis and effective therapy.


Spontaneous subarachnoid hemorrhage first from an intracranial and then from a spinal arteriovenous malformation. Case report. A patient presented with spontaneous subarachnoid hemorrhage (SAH) from a cerebral arteriovenous malformation (AVM) which was later totally removed at surgery. The patient presented again with a new SAH from a spinal AVM that was also totally removed at surgery. Coexistence of spinal and cerebral arteriovenous malformations are exceedingly rare and hemorrhage from each is not previously reported. This case emphasizes the importance of investigating the spinal canal in otherwise unexplained spontaneous SAH.


Effect of dietary fat level on growth and lipogenesis in the colostrum deprived neonatal pig. Thirty male neonatal pigs were obtained by cesarean section and randomly allotted from littermate groups to three diets containing 2%, 17%, and 32% fat on a dry matter basis. Butterfat was used to replace glucose in the isoenergetic liquid, semipurified diets. Each pig was placed in a sterile isolator and fed ad libitum five times daily. After 14 days, pigs were weighed, killed, and samples of liver and backfat were obtained. The carcass of each pig was ground and samples obtained for determination of total body fat and protein. An increase in the level of dietary fat resulted in a significant increase in 14 day weight gain and a tendency for improved feed efficiency. These results demonstrate not only that the neonatal pig can utilize semipurified liquid diets high in butterfat content, but also that energy from butterfat appears to be used as efficiently as energy from glucose from growth purposes. Increasing dietary fat level decreased the activity of fatty acid synthetase and citrate cleavage enzyme in adipose tissue and liver, and decreased the activity of malic enzyme in adipose tissue. The specific activities of these three enzymes were higher in adipose tissue than in liver.


Independence of glycogen accumulation and glucose-6-phosphate dehydrogenase induction in rat liver. The responses of liver glycogen and glucose-6-phosphate dehydrogenase (G6PD) (EC 1.1.1.49) to a high glucose, adequate protein diet were compared between rats previously starved 2 days, then refed a high protein, carbohydrate-free diet for 2 days, and rats previously fed the high protein diet for 4 days. Glycogen levels increased dramatically during the first day the high carbohydrate diet was fed, then decreased gradually on the second day. The response was the same regardless of whether the rats had been starved more before the high protein diet was fed. Liver G6PD activity also increased when the high carbohydrate diet was fed, and continued to increase on the second day. The increase in G6PD, however, was significantly greater in the rats which had been starved before the high protein diet was fed. It is suggested that some process occurs during starvation that predisposes the induction of G6PD upon refeeding a high carbohydrate diet, over and above any effect of glycogen accumulation and breakdown. Glucose or glucose-6-phosphate derived from glycogen does not appear to be the primary inducer of G6PD in rat liver.


Tannic acid and oxidized tannic acid on the functional state of rat intestinal epithelium. Diets containing tannic acid at the level of 3% of dry matter were fed to rats in order to ascertain the origin of fecal nitrogen and the effect of tannic acid on the intestinal mucosa. At the same time in order to explain the effect of oxidation of tannins, we administered diets containing oxidized tannic acid or tannic acid associated with an antioxidizer (sodium sulfite) at the level of 1% of dry matter. The increased excretion of sialic acid and glucosamine during ingestion of tannic acid indicated that the excess of fecal nitrogen mainly corresponds to the mucus hypersecretion observed by histology. Fecal analysis revealed perturbations in movements of water and ions. The study of the metabolic activity of isolated enterocytes and the activity of some enzymes in a homogenate of these cells showed an inhibition of oxygen consumption and succinic dehydrogenase activity. Addition of reducing agent (sodium sulfite) to the diet had little effect on the action of tannic acid; but previous oxidation of the tannin reduced the effects observed, particularly in the case of fecal nitrogen loss.


Cystine content of legume seed proteins: estimation by determination of cysteine with 2-vinylquinoline, and relation to protein content and activity of cysteine synthase. The cystine content of the protein of a number of different lines of legume seeds has been determined by the method of Krull et al. which selectively reacts cysteine residues of intact, reduced proteins with 2-vinylquinoline, giving an adduct with an absorption maximum at 318 nm. Some seed lines were found to have 3.5 times as much cysteine as the seed line with the lowest cysteine content, perhaps offering opportunities for improvement in the nutritional quality of bean seed proteins through breeding and selections. While no correlation between cysteine levels and protein content was observed, a positive correlation was found between the specific activity of the terminal enzyme of cysteine synthesis, cysteine synthase, and the cysteine content of seeds.


Characterization of food binding of vitamin B-6 in orange juice. There is substantial evidence that natural vitamin B-6 exists largely in a bound form. It has been shown that the principal modes of binding represents an interaction of pyridoxal and/or pyridoxal phosphate with protein moieties. The nature and extent of binding of different forms of the vitamin in orange juice was investigated. Studies employing ultracentrifugation, ultrafiltration and, membrane dialysis of this food product suggested binding to a molecule of less than 3,500 daltons molecular weight. Binding was resistant to protease treatment although susceptible to heat-acid hydrolysis. Separation of pyridoxal, pyridoxine, and pyridoxamine species of the vitamin by ion exchange chromatography was followed by fluorometric analysis with and without preparative hydrolysis. Extensive and equal binding of both pyridoxal and pyridoxine was observed by this method. Thus, the binder(s) of vitamin B-6 in orange juice is a small dialyzable molecule which is heat stable, binds both pyridoxal and pyridoxine and is non-protein in nature.


Variations in the mast cell population of skin and bone marrow in magnesium-deprived rats. The influence of sex hormones. Comparative counts of Alcian Blue-Basic Fuchsin-stained mast cells of the facial skin and bone marrow have been made in young rats of different sexes and strains, fed a diet deficient in magnesium (0.8 to 1 mg/100 g dry weight) for 4 weeks. Normal rats fed a magnesium-supplemented diet (65 mg/100 g dry weight) had about three times as many mast cells in the tibial metaphysis as in the facial skin. In both males and females fed the Mg-deficient diet, the marrow mast cells increased five to six times, while their number was concomitantly decreased in the skin. The marrow mast cells became also polymorphic, an indication of a possible preferential renewal site. Gonadectomy in the males had no effect on the above pattern. The administration of large doses of testosterone to males and estradiol to females depressed the mast cell population increase in the bone marrow and at the same time, moderated the loss of skin mast cells.


Effects of magnesium deficiency on protein and nucleic acid synthesis in vivo. The effects of magnesium deficiency on the in vivo incorporation of labeled precursors into tissue macromolecules were studied. In severe Mg deficiency developing over 4 months, total protein synthesis in spleen and thymus was depressed by 40% to 50%, while DNA synthesis was increased by as much as 350%. RNA synthesis was not significantly altered. Protein synthesis in kidney was also reduced. In the intact liver, DNA synthesis was increased and RNA synthesis reduced, but protein synthesis was unchanged. The regeneration of the liver after partial hepatectomy was impaired, however, which suggested that the capacity of the liver protein synthetic system was reduced. The effects of magnesium deficiency were unaltered by the ingestion of ethanol that comprised approximately 25% of total energy. Each of the organs enlarged in Mg deficiency, and the spleen was strikingly hyperplastic. The increase in splenic DNA synthesis in the presence of depressed protein synthesis may be an early stage in a lymphoproliferative process leading ultimately to neoplasia.


Effect of low zinc intake and oral contraceptive agents on nitrogen utilization and clinical findings in young women. In a previous paper we reported that serum, urine and fecal zinc levels fell markedly in women taking a combination oral contraceptive agent (+OCA) and in women with normal menstrual cycles (-OCA) when they consumed a low-zinc diet (less than 0.2 mg/day) for 35 days. We evaluated other biochemical and clinical data in order to determine if depletion of accessible body zinc and/or physiologic adjustment to conserve body zinc stores had occurred. Neither low zinc intake nor oral contraceptive use appeared to influence nitrogen balance or body weight. Use of contraceptive drugs appeared to influence the response of blood parameters to zinc depletion. Serum transferrin and cholesterol declined significantly in the -OCA group, whereas alkaline phosphatase and gamma-globulin changed significantly in both groups. Clinical problems developed in all the subjects with serum zinc levels below 50 microgram/dl during the study; three of the six with serum zinc levels above 50 microgram/dl also complained of clinical symptoms. The results suggest that zinc deficiency through depletion of accessible body zinc stores developed during the 35-day study.


Biological activity of vitamin E compounds and natural materials by the resorption-gestation test, and chemical determination of the vitamin E activity in foods and feeds. The biological activity of the tocopherols and tocotrienols has been re-examined by the rat resorption-gestation test. The following values have been obtained (with d,l-alpha-tocopheryl acetate = 100%): d-alpha-tocopherol 80%; d,l-alpha-tocopherol 59%; d-alpha-tocopheryl acetate 136%; d-alpha-tocotrienol 13%; d-beta-tocopherol 45%; d-beta-tocotrienol 4%; d-gamma-tocopherol 13%; d-delta-tocopherol less than 0.4%. The possibility of alpha- and gamma-tocopherol being synergists has been tested, but no significant effect was found. The antioxidants BHT and ethoxyquin were without effect on the utilization of alpha-tocopherol by the rat. After chemical determination of the tocopherols and tocotrienols in foods and mixed feeds, these biological activities were used to calculate the vitamin E activity. For two samples of margarine and two samples of mixed feed, the calculated value of the vitamin E activity after chemical determination of the tocopherols and tocotrienols was compared with the value found by direct bioassay, and reasonably good agreement was found. The authors suggest that determination of vitamin E in foods and feeds as a rule should be carried out as a chemical determination of the individual tocopherols and tocotrienols followed by a calculation of the vitamin E activity from the biological activity of the tocopherols and tocotrienols.


Psychophysical applications of human electroretinography. Rapid developments in human electroretinography during recent decades have greatly increased its value for investigating psychophysical problems. This review of the current status of electroretinography considers the response waveform, recording techniques, and data analysis. Several examples of electroretinal data that have psychophysical significance are presented.


Spatiotemporal mapping of scalp potentials. Computerized analysis and display techniques are applied to the problem of identifying the origins of visually evoked scalped potentials (VESP's). A new stimulus for VESP work, white noise, is being incorporated in the solution of this problem. VESP's for white-noise stimulation exhibit time domain behavior similar to the classical response for flash stimuli but with certain significant differences. Contour mapping algorithms are used to display the time behavior of equipotential surfaces on the scalp during the VESP. The electrical and geometrical parameters of the head are modeled. Electrical fields closely matching those obtained experimentally are generated on the surface of the model head by optimally selecting the location and strength parameters of one or two dipole current sources contained within the model. Computer graphics are used to display as a movie the actual and model scalp potential field and the parameters of the dipole generators whithin the model head during the time course of the VESP. These techniques are currently used to study retinotopic mapping, fusion, and texture perception in the human.


Scotopic luminosity function and color-mixture data. The hypothesis that rods contribute to color information has not been generally accepted primarily because of the apparent lack of a connection between the scotopic luminosity function and color-mixture data. We present analyses showing that the scotopic luminosity function is intimately related to color data over the entire spectrum, indicating that rods play a central role in normal color vision. These results, not readily explainable in terms of the trichromatic theory, suggest an alternate idea of sensing in terms of the psychophysical quantities called brightness, hue, and saturation.


Chromatic two-pulse resolution with and without luminance transients. Two-pulse discrimination thresholds determined for homochromatic pulses presented as luminance increments or decrements are invariant with wavelength. Wavelength does affect two-pulse temporal resolution if chromatic pulses are presented in hue substitution, matched in luminance (with flicker photometry) to an achromatic background field. For relatively long pulses, the wavelength effect resembles trichromatic saturation discrimination, with poorest temporal resolution at 570 nm. For shorter pulses, temporal resolution for hue substitution stimuli appears related to saturation discrimination under conditions of artificial tritanopia. Under conditions of hue substitution, short-wavelength pulses yield good temporal resolution.


Heterogeneity of nonlethal severe short-limbed dwarfism. The Grebe syndrome is a nonlethal form of severe short-limbed dwarfism which was previously called "achondrogenesis-Brazilian or Grebe type". We have studied three patients with severe short-limbed dwarfism originally considered to have this syndrome. On re-evaluation of their clinical and radiographic features, only one of them had the typical features of the Grebe chondrodysplasia, whereas the other two appear to have clearly distinct, previously unreported skeletal dysplasias. These patients illustrate the heterogeneity that exists among the nonlethal forms of severe short-limbed dwarfism.


Serum iron concentration and transferrin saturation in the diagnosis of iron deficiency in children: normal developmental changes. A group of 359 healthy children and 49 adults were studied for the purpose of estimating the normal limits for serum iron concentration and transferrin saturation. The 144 children and seven adults who has any other laboratory evidence of iron deficiency (abnormal values of serum ferritin, free erythrocyte protoporphyrin, hemoglobin concentration, or mean corpuscular volume) were excluded. In evaluating the 215 children and 42 adults who met the criteria to be considered normal we found that serum iron concentration and transferrin saturation were significantly lower in children between the ages of 0.5 and 12 years than in adults. We conclude that in children between the ages of 0.5 and 12 years, a transferrin saturation of less than 16% constitutes good evidence of iron deficiency only in conjuction with anemia and low mean corpuscular volume.


At what age does iron supplementation become necessary in low-birth-weight infants? Prevention of iron deficiency in low-birth-weight infants requires iron supplementation before neonatal iron stores are exhausted. In order to accurately determine when this depletion occurs, we measured the hemoglobin, mean corpuscular volume, serum iron/iron-binding capacity, and serum ferritin in 117 low-birth-weight infants (1,000 to 2,000 gm) from 0.5 until 6 months of age. All infants received banked breast milk in the hospital and breast milk or cow milk formula later; those with odd birth dates received 2 mg iron as ferrous sulfate/kg/day starting at 0.5 months; those with even birth dates received no additional iron unless they developed anemia. The results indicate that low-birth-weight infants who receive no supplemental iron may develop iron deficiency by three months of age and that a dose of iron of 2 mg/kg/day started at two weeks of age prevents iron deficiency without providing excess.


Blood pressure in a high school population. I. Standards for blood pressure and the relation of age, sex, weight, height, and race to blood pressure in children 14 to 18 years of age. This is a report on the initial from an ongoing study of blood pressure in ninth to twelfth grade students in the St. Louis metropolitan area. The purpose was to establish standards, to determine the incidence of hypertension, and to examine the relationship of blood pressure to age, weight, height, sex, and race. Subjects with persistent hypertension were to be investigated and checked annually as long as they were in high school. Students in the ninth grade at the beginning of the project were to be screened each year for four years.


Electrophysiologic studies in sick sinus syndrome following surgery for d-transposition of the great arteries. His bundle electrograms and atrial pacing are reported in a 10 1/2-year-old boy and a 12-year-old girl, both of whom underwent Mustard repair for complete d-transposition of the great arteries. Each patient had progressive evidence of sick sinus syndrome culminating in syncope. Improvement occurred after insertion of a demand pacemaker.


Multiple hypothalamic-pituitary abnormalities in an adolescent girl with galactorrhea. A patient with multiple hypothalamic abnormalities is presented who had galactorrhea at seven years of age followed ten years later by secretory deficiencies of growth hormone, TSH, and gonadotropins. There was no clinical evidence of a mid-brain tumor. Patients presenting with galactorrhea and amenorrhea associated with hyperprolactinemia may develop additional hypothalamic malfunctions over a period of several years and should be observed carefully for appearance of them as well as for evidence of brain tumors.


Measurement of 24,25 dihydroxyvitamin D in sera of neonates and children. Serum concentration of 25OHD and 24,25(OH)2D were measured in lipid extracts of serum by competitive radioassay following separation of the metabolits by Sephadex LH-20 column chromatography. The concentration of 24,25(OH)2D in children and adolescents (3.3 +/- 1.3 SD ng/ml) was significantly greater (P less than 0.01) than the levels recorded in neonates (1.8 +/- 0.6 ng/ml), and was approximately one-tenth the concentration of 25OHD in the two populations (children 35.2 +/- 9.2 ng/ml; neonates 14.4 +/- 3.4 ng/ml, P less than 0.01). Although 24,25(OH)2D is present in significant quantities in the sera of children and adolescents, its metabolic function remains unknown at present.


Intracranial calcifications in childhood leukemia. An association with systemic chemotherapy. Children with acute lymphocytic leukemia were examined for evidence of intracranial calcifications with roentgenograms of the skull and computerized tomography. Of 39 children in their initial complete remission, ten were found to have subcortical cerebral calcifications. Significant associations were found between the presence of cerebral calcifications and systemic treatment with large cumulative doses of methotrexate.


Immunologic responses to therapy in allergic bronchopulmonary aspergillosis: serum IgE value as an indicator and predictor of disease activity. Two patients, a child and an adult, with allergic bronchopulmonary aspergillosis were studied over an 18-month period. Initially elevated total serum IgE levels fell during prednisone therapy and rose prior to and during an exacerbation. Total serum IgG fell with therapy, whereas the values of IgA and IgM remained constant. Specific IgG and IgE values against Aspergillus fumigatus as measured by radioimmunoassay were elevated in both patients. Specific IgE values increased in each patient prior to exacerbation, whereas specific IgG values increased in only one patient at the time of exacerbation. Immunologic evaluation may provide an assessment of disease activity of prospective value.


Solitary maxillary central incisor and short stature. Seven patients, three males and four females, each with a single (unpaired) deciduous and permanent maxillary central incisor, were studied. All the males and two the female children were growth hormone deficient. One adult woman and a female infant with a single maxillary central incisor were short in stature but had normal growth hormone responses. No other dental anomalies or pituitary-hypothalamic dysfunctions were found. The dental anomaly was not familial. No eye abnormalitis were present in the patients or their families.


Saethre-Chotzen syndrome: a broad and variable pattern of skeletal malformations. A family is described in which 15 persons in five generations are affected with a complex of skeletal malformations which variably includes peculiar asymmetric facies, delayed closure of large fontanels, brachycephaly, acrocephaly, brachydactyly, cutaneous syndactyly, broad great toes, and mild shortness of stature. Although craniosynostosis is either lacking or relatively mild in the members of this family, their features are otherwise strikingly similar to those of patients with the Saethre-Chotzen syndrome. We believe the findings in this family indicate that the Saethre-Chotzen syndrome comprises a broad pattern of carniofacial and other skeletal malformations in which craniosynostosis may sometimes occur.


The chromosome 2 distal short arm trisomy syndrome. A trisomy for the distal short arm of chromosome 2 (2p23 leads to 2pter) resulted in similar phenotypic and developmental abnormalities in three related males. The cytogenetic defect was traced to a familial balanced 2;3 translocation [t(2;3) (p23;27)]. Comparison of these patients with the seven previously published cases of 2p partial trisomy reveals a pattern of common features including severe mental and growth retardation, a characteristics facial dysmorphism particularly affecting the eyes, abnormalities of the sternum, spine, and digits, a heart defect, and, in males, cryptorchidism and a striking genital anomaly consisting of a very small penis buried in dorsally fused scrotal skin.


The effect of cuff width on systolic blood pressure measurements in neonates. The width of the blood pressure cuff was found to have an effect on the accuracy of systolic blood pressure measured in the arm and thigh in neonates. Data were collected in 26 infants of a variety of birth weights and gestational ages. They show that the effect of cuff size can be minimized by selecting a cuff width equal to approximately 50% of the extremity circumference.


Chronic viral funisitis.

Chronic viral funisitis. Four cases chronic funisitis, a rare variant of umbilical cord inflammation, are presented and compared with the acute and subacute forms. The distinctive findings are a predominantly lymphoplasmocytic infiltration, coagulative necorsis of the vascular media with secondary calcification, and the unusual association of chronic funisitis with chronic chorioamnionitis and chronic villitis. One fetus was stillborn, another was aborted, and two were live-born. Two fetuses were growth retarded and three had evidence of infection. Viral inclusions were identified in three placentas. The data strongly suggest that lymphoplasmocytic funisitis in these cases is the result of chronic intrauterine viral infection.


Outbreak of influenza in a neonatal intensive care unit. An outbreak of influenza A/Victoria/3/75 (H3N2) involving five infants in a neonatal intensive care unit is described. The clinical signs and symptoms were indistinguishable from those seen in bacterial sepsis. There was no evidence of meningoencephalitis. All infants recovered without any sequelae.


Cranial transillumination norms of the premature infant. Ninety-five infants from 26 to 42 weeks of gestational age were studied with a simple standardized cerebral transillumination technique utilizing a Chun gun fitted with a clear flexible disc to establish normal measurements and to test the hypothesis that transillumination is useful in differentiating "catch-up" growth from hydrocephalus. One group of infants were measured at birth; the other group were infants grown to similar gestational age and serially measured. Data from these groups were found to be similar. Transillumination was not found to be a useful technique for separating "catch-up" growth infants from the normal population, but was found to be potentially useful in separating the normal and "catch-up" population from children with hydrocephalus or serious anatomic abnormalities of the central nervous system.


Intraventricular chemotherapy in neonatal meningitis. All of 16 infants with neonatal meningitis treated during a 30-month period were found to have accompanying ventriculitis at the time of the initial ventricular puncture. Fifteen of these infants were caused by gramm-negative organisms. All infants received antibiotics systemically and intraventricularly via an implanted ventriculostomy reservoir or by direct ventricular injection. Antibiotic concentrations within the ventricular fluid were monitored during chemotherapy; the complications encountered during treatment are discussed. Fifteen infants survived the infection; of these, seven infants were normal at follow-up examinations. In our experience intraventricular chemotherapy as an adjunct to systemic administration of antibiotics has greatly reduced the mortality rate in neonatal meningitis.


Childhood myasthenia gravis.

Childhood myasthenia gravis. A boy aged five and a girl aged one year suffering from myasthenia gravis are described. Both cases had respiratory complications and were treated erroneously until their ptosis was noticed and the diagnosis of myasthenia gravis confirmed. The etiology, types, symptomatology, and treatment of the diseases are described. Attention of the pediatric ophthalmologists is called to the fact that they should consider myasthenia gravis in the differential diagnosis of ptosis and external ophthalmoplegia.


Neonatal opsoclonus.

Neonatal opsoclonus. Three cases of opsoclonus in normal neonates are reported. There was no evidence of neuroblastoma, encephalitis, or infantile polymyoclonia. It appears that opsoclonus may occur as a transient phenomenon in healthy infants.


Consecutive cyclic esotropia.

Consecutive cyclic esotropia. A 12-year-old girl who developed a cyclic esotropia following strabismus surgery for intermittent exotropia at the age of eight years is presented. Unusual findings and surgical results are described. We suggest the term of "consecutive cyclic esotropia" for this clinical entity.


Abnormal eye movements in rubella syndrome. A patient with a characteristic picture of rubella eye disease is presented. Its interest lies in the associated finding of asymmetric nystagmus and ocular flutter. The presence of flutter would indicate cerebellar or cerebellar pathway disease, a previously unassociated finding.


Juvenile retinal detachment.

Juvenile retinal detachment. Among the total of 537 patients treated for retinal detachment 27 (5.02%) were under the age of 20. In 44.44 percent of the cases, there was a history of trauma. In 58.33% of the fellow eyes in this group of patients, retinal pathology was found. This pathology is considered to be a predisposing factor and trauma itself is only a trigger in causing retinal detachment.


Pre- and post-operative treatment of constant and intermittent exotropia. Intermittent exotropia is classified according to the AC/A ratio. Convergence amplitude measured on a light includes accommodative convergence. Amplitude measured while maintaining clear, single, binocular vision on 20/30 print utilizes only true fusional convergence.


Recording ERGs and VERs from unsedated children. A technique for recording the electroretinogram and visual evoked response from very young or mentally retarded children without general anesthesia is presented. Illustrative results from both normal and abnormal subjects are shown. The advantages to the patient of avoiding general anesthesia in reduced risk, time, and especially expense are discussed.


Cyclopian monster with anophthalmos.

Cyclopian monster with anophthalmos. A cyclopian monster with anophthalmos is a rare occurrence. Such a case is presented along with a case of a cyclops with synophthalmos. The many abnormalities result from an anomalous development of structures derived from the prosencephalon.


Mechanism of surface lubrication: influence of duration of lubricant-excipient mixing on processing characteristics of powders and properties of compressed tablets. A mathematical expression for tablet hardness was related to lubricant mixing by considering increases in the surface coverage with prolonged mixing time. The duration of lubricant mixing significantly changed the apparent bulk volume of the mix, ejection force during tableting, hardness, and disintegration and dissolution properties of tablets. These findings may provide some rationale for the changes in processing characteristics and properties of finished drug products often encountered in the scale-up of solid dosage formulations. Several lubrication mechanisms are discussed in connection with the duration of mixing effects and scanning microscopy studies.


GLC determination of lidocaine in human plasma. A specific, sensitive, rapid, and reproducible analytical GLC method for lidocaine in human plasma, including pharmacokinetic parameters, is described. Aminopyrine is the internal standard. The method was used to study pharmacokinetics in four healthy volunteers following the administration of a lidocaine bolus at a dose of 1 mg/kg iv and in one patient with cardiac arrhythmias who had been given a 50-mg bolus followed by a prolonged intravenous infusion for 30 hr.


Kinetics and mechanism of blue tetrazolium reaction with corticosteroids. The kinetics of the reaction of blue tetrazolium with corticosteroids were investigated under pseudo-first-order conditions. The reaction rates for various corticosteroids were determined at various temperatures, and the enthalpy and entropy of activation for these compounds were determined. A mechanism is proposed in which an electron pair and a proton are transferred to blue tetrazolium from the anion formed by the action of tetramethylammonium hydroxide on the alpha-carbonyl moiety of the corticosteroid. The proposed mechanism is consistent with previous experimental results.


Dosage form index: an objective criterion for evaluation of controlled-release drug delivery systems. A dimensionless parameter, the dosage form index (DLtau) is proposed for evaluating the performance of drug delivery systems. The index is defined as the ratio of the maximum to minimum concentrations of the drug in plasma within each interdose interval (in hours), tau, during repetitive administration of the dosage form in the quasisteady state. Dosage form indexes can be averaged among subjects or within subjects at successive time periods to arrive at a mean value. As an example, two GI therapeutic systems--the 15- and 20-mg/hr acetazolamide systems that deliver drug at constant rates for 6 and 12 hr and contain 125 and 250 mg, respectively--were compared in normal subjects with a commercial sustained-release product containing 500 mg of acetazolamide. The dosage form index, DI24, was 4.9 for the sustained-release dosage form and 3.2 for the 20-mg/hr system; DI12 was 1.6 for the 15-mg/hr system.


Effect of aspirin on a subtoxic dose of 14C-acetaminophen in mice. The interaction of 14C-acetaminophen, 150 mg/kg (20 muCi/kg), and aspirin, 200 mg/kg po, was studied in male mice. The radiolabel was rapidly absorbed from the GI tract, achieving maximum blood levels 0.25 hr after oral dosing. Radioactivity in the blood equilibrated rapidly with the tissues and was concentrated in the liver and kidney. At 14 hr, most of the dose was eliminated in urine as the glucuronide, cysteine, sulfate, free drug, and mercapturate. Pretreatment with aspirin tended to reduce the rate and extent of acetaminophen absorption and altered the percentage of the dose excreted in the urine as sulfate, mercapturate, glucuronide, and cysteine. Interpretation of these data toxicologically as an indication of the potentiation of either toxicity or protection was not possible.


Colorimetric determination of aliphatic acids. A colorimetric method for the determination of carboxylic acids based on the dicyclohexylcarbodiimide-coupled reaction of 2-nitrophenylhydrazine and carboxylic acids is described. The product of the reaction is extracted into aqueous sodium hydroxide to produce a blue color. This method is suitable for the analysis of aliphatic acids, but aromatic acids do not react under these conditions.


Drug migration during drying of tablet granulations I: effect of particle size of major diluent. Migration of a water-soluble drug, propoxyphene hydrochloride, during drying of tablet granulations was studied. Wet granulations of the drug were prepared using lactose as the major diluent and corn starch as a disintegrant. Particle-size fractions of lactose ranging from 53 to 177 micron in diameter were employed in different granulations to examine the effect of particle size of the major diluent on drug migration. Determination of drug concentration at various depths in a dried granulation bed was accomplished by using a drying cell consisting of four layers. A numerical coefficient of migration was developed to compare the extent of drug migration in the various lactose granulations. Migration increased with decreasing particle size of the major diluent, lactose. Two factors that may contribute to increased migration with smaller particles are increased entry suction due to decreased intragranular capillary size and increased intergranular contact area.


Drug migration during drying of tablet granulations II: effect of binder solution viscosity and drying temperature. The effect of binder solution viscosity and drying temperature on the integranular migration of propoxyphene hydrochloride was studied. Wet granulations containing the drug were prepared using binder solutions with viscosities ranging from 1 to 1000 cps. Temperature studies were conducted using granulations prepared with a 3-cps binder solution and dried at 40, 50, 60, 70, and 80 degrees. Drug migration decreased with increased binder solution viscosity, and insignificant migration occurred in granulations prepared with binder solutions having apparent viscosities above 90 cps. No significant effect on intergranular drug migration was observed within the drying temperature range studied. Tablets compressed from a granulation in which drug migration was high showed a greater tablet-to-tablet drug content variation than a granulation with lower migration, even though each dried granulation was thoroughly mixed before tableting.


Direct spectrophotometric determination of sulfathiazole in presence of sulfadiazine and sulfamerazine. A direct spectrophotometric method for the quantitative determination of sulfathiazole and the total pyrimidyl sulfonamide content in a mixture containing sulfadiazine and sulfamerazine is reported. This three-component system was readily reduced to the problem of a simple two-component system analysis. Based on dual isoabsorptive wavelength spectroscopy, simultaneous equations were developed that required absorbance measurements at only two selected wavelengths both isoabsorptive. The location of the isoabsorptive wavelengths was dependent on the pH of the solvent medium, and 0.1 M HCl gave the best results. The validity of the derived equations was demonstrated in a recovery study involving synthetic mixtures containing varying quantities of the three sulfonamides. The recovery was linear over a wide concentration range, and the precision of the method was about 1%.


Rapid and sensitive direct TLC fluorometric method for evaluation of impurities in oxytetracycline. A rapid partition TLC method for the determination of oxytetracycline and its degradation products is described. Quantitative determinination of the substances is performed by direct TLC fluorometry in 2 hr using plates prepared previously.


General class of multiparticulate dissolution models. The dissolution of multiparticulate systems under sink and nonsink conditions can be described rigorously according to a generally applicable formula on the basis of the single-particle dissolution model and the initial particle distribution. The kinetic model for log-normal systems dissolving under sink conditions is extended to nonsink conditions as a specific example. The equation presented describes a general class of multiparticulate models for various values of the dispersion parameter and the dissolution capacity coefficient.


Bioavailability of sulfadiazine in rabbits using tablets prepared by direct compression and fluidized-bed granulation. Experimental sulfadiazine tablets prepared by direct compression, using a commercially available direct compression tablet mass, were compared with experimental sulfadiazine tablets prepared by fluidized-bed granulation and commercially available sulfadiazine tablets USP. The values for friability and the time required to release 10 and 50% of the direct compression tablets were between those of the fluidized-bed tablets and the commercial product. With the commercial tablet as a standard, the extent of bioavailability was determined in rabbits; it was slightly higher for both the direct compression and fluidized-bed tablets. A statistically significant difference was found between the direct compression tablets and the standard with respect to the extent of bioavailability and the time of the peak.


Mass spectrometry of cannabinoids.

Mass spectrometry of cannabinoids. The mechanism of fragmentation of cannabinoids to fragments m/e 314, 299, 271, 258, 246, 243, and 231 is given. Cannabidiol cannabinoidiol, cannabinol, delta6- and delta1-tetrahydrocannabinol, cannabichromene, cannabicyclol, derivatives with pentyl, propyl, and methyl side chains, their methyl ethers, and cis-trans and ortho-para isomers were analyzed by GLC-mass spectrometry using different energies for fragmentation during GLC elution. The following mechanism was distinguished: loss of a methyl radical, ring closure and rotation, McLafferty rearrangement, retro Diels-Alder, internal protonation, isomerization and internal bond formation, and one-step fragmentation to m/e 231.


Pharmacokinetics of mercaptopurine.

Pharmacokinetics of mercaptopurine. The anatomical distribution of mercaptopurine was investigated in rats at dose levels of 2.5 and 25 mg/kg iv. The plasma and tissues were analyzed by radioisotopic dilution and spectrofluorometric techniques. The tissue-plasma ratios were: liver-plasma, approximately 4.0; kidney-plasma, approximately 2.4; spleen-plasma, approximately 1.7; muscle-plasma, approximately 1.4; gut lumen-plasma, approximately 3; and bone marrow-plasma, approximately 0.35. Physiologically based pharmacokinetic models were developed to simulate concentrations of mercaptopurine in plasma, kidneys, liver, muscle, spleen, bone marrow, and gut lumen. The agreement between experimental and predicted plasma and tissue profiles was good. Human plasma levels of mercapto-purine were predicted and, when compared with clinical data, demonstrated reasonable agreement.


Method of obtaining drug-macromolecule binding parameters directly from dynamic dialysis data. A new method of treating dynamic dialysis data to obtain binding parameters for drug-macromolecule interactions is presented. This method allows the determination of binding parameters directly from dialysis data according to a theoretical model. It is not necessary to determine the dialysis rate constant accurately in a separate experiment, and bias is not introduced due to differentiation. The proposed method should be applicable where the drug is substantially bound to the dialysis membrane.


Influence of granulation liquid flow rate on particle-size distribution in spray-granulate products. Granulations were made at various air speeds and various rates of addition of granulating liquid in a spray-granulatin assembly. The ensuring particle sizes were log-normal, and the data substantiate that the process is of the nature previously described. The mean diameter obtained was approximately proportional to the liquid flow rate squared but was independent of air rate. The standard deviation was independent of both parameters.


Effect of lipids on enzymatic activity of pig heart mitochondrial malate dehydrogenase monomolecular films. The effect of various lipids on the enzymatic activity of pig heart mitochondrial malate dehydrogenase monomolecular films was studied using the subphase exchange technique described previously. Surface pressure-surface area (pi-A) curves of mixed films of enzyme with dipalmitoyllecithin, egg lecithin, cholesterol, and phospholipids extracted from pig hearts showed that the enzyme interacted with all of the lipids and that the enzyme remained in the film at pressures well above the collapse pressure of malate dehydrogenase in the absence of lipid. The surface enzyme activity was dependent on surface pressure for each lipid; in all cases, the lipids greatly broadened the range of surface pressures where surface enzyme activity was observed. The pi-A and enzyme activity data showed good correlation. Although the simple model system employed does not simulate the complexity of the biological membrane, it gives some evidence for the role of lipids in the stability of membrane-bound enzymes.


Effect of sorbitol on interaction of phenolic preservatives with polysorbate 80. The effect of sorbital on the binding of several commonly used phenolic preservatives (i.e., p-hydroxybenzoic acid, methylparaben, ethylparaben, and propylparaben) with the nonionic surfactant polysorbate 80 was investigated using an equilibrium dialysis technique. The binding data were expressed in the form of Scatchard plots utilizing a modified form of the Scatchard equation. The data analysis indicated that all four phenolic preservatives were bound to two distinct loci within the polysorbate micelle; one exhibited a high affinity and a low capacity for the preservative molecules, while the other appeared to have a near-zero affinity but an almost infinite binding capacity. The high affinity site was assumed to be located near the junction of the hydrocarbon core with the polyoxyethylene region of the micelle. The interaction of the preservatives with the second class of sites apparently involved a non-specific and nonsaturable partitioning of the preservative molecules into the polyoxyethylene region of the micelle. Sorbitol was ineffective in displacing significant amounts of bound preservative from either binding site, presumably because it was too polar to partition into the micelle sufficiently to displace bound preservative.


Binding of N-substituted anthracenecarboxamides to double-stranded DNA: an electronic spectral study. The electronic absorption and fluorescence spectra of two isomeric anthracenecarboxamides substituted with quaternary alkyl ammonium groups were studied as a function of solvent polarity, solvent rigidity, and state of protonation. These relatively simple environmental perturbations of the electronic spectra were employed to interpret spectral shifts caused by complexation with the bases or base pairs of DNA. The exocyclic side chains of the compounds studied have some freedom of movement when the spectroscopic probes are bound to double-stranded DNA.


Contact angles of pharmaceutical powders. Contact angles of pharmaceutical powders were determined by measuring the maximum height of a drop of a saturated solution on a presaturated compact of the material. The results for a series of drugs are presented.


Small animal model for myocardial infarction. Myocardial infarctions were produced in rats by electro-cauterization of the left anterior descending artery, and the extent of myocardial damage was measured by serial serum levels of creatine phosphokinase activity utilizing spectrophotometric analysis. All animals were also evaluated for myocardial damage by electrocardiographic wave alterations. A correlation between myocardial infarct size and serum creatine phosphokinase was demonstrated. Significant arrhythmias and death occurred only in experimental groups where myocardial infarction had been produced. This small animal model offers a quick, inexpensive, and simple method for screening therapeutic agents that alter infarct size.


Cactus alkaloids XXXIII: beta-phenethylamines from the Guatemalan cactus Pilosocereus maxonii. TLC analysis of extracts of Pilosocereus maxonii (Rose) Byles and Rowley detected six identifiable alkaloids. Preparative TLC aided in the crystallization of the hydrochlorides of N-methyl-3,4-dimethoxyphenethylamine, N-methyl-3-methoxytyramine, and N,N-dimethyl-3-methoxytyramine. Traces of 3,4-dimethoxyphenethylamine (TLC and mass spectrometry), tyramine (TLC), and N-methyltyramine (TLC) were identified. While all of these compounds were isolated and/or detected previously in other cactus species, this study is the first reported crystallization of N-methyl- and N,N-dimethyl-3-methoxytyramine from a natural source.


Effect of coadministered salicylamide on terbutaline metabolism in rats. Concomitant oral administration of salicylamide (200 mg/kg) and 3H-terbutaline (1 mg/kg) to rats with ligated bile ducts decreased absorption of terbutaline from the gut from 73 to 56% as measured by urinary excretion of radioactivity in 48 hr. No increase in the fraction of terbutaline excreted unchanged was observed, suggesting that salicylamide does not substantially inhibit the conjugation of terbutaline with glucuronic acid. An increase in the fraction of terbutaline excreted unchanged observed in normal animals may result from enhanced excretion of terbutaline glucuronide into bile rather than from inhibition of conjugation.


Dehydrodiisoeugenol: a naturally occurring lignan from Aristolochia taliscana (Aristolochiaceae). The ethanol-water extract of Aristolochia taliscana Hook and Arn (Aristolochiaceae) yielded a compound which was identified as dehydrodiisoeugenol by means of elemental analysis, IR, UV, NMR, and mass spectra, and direct comparison with a synthetic sample.


Rapid GLC determination of propranolol in human plasma samples. A rapid GLC method for measuring plasma propranolol levels is reported. 4-Methylpropranolol was utilized as an internal standard. Pentafluoropropionate derivatives of propranolol and the internal standard eluted rapidly and gave good sensitivity under the conditions employed. The advantage of this procedure over previously reported methods is the speed of analysis, which is facilitated by rapid elution of contaminant peaks.


Alterations induced in distribution and in vivo metabolism of imipramine by pregnenolone-16alpha-carbonitrile. Female rats were given pregnenolone-16alpha-carbonitrile (I) to investigate its in vivo effects on the loss of the righting reflex and the mortality rate induced by imipramine as well as the concentrations of this drug and its metabolite, desipramine, in plasma, brain, liver, lungs, and kidneys. The protective action of I was associated with diminished organ levels of imipramine (catatoxic mechanism), and the relationship between brain and plasma imipramine concentrations remained unaltered. Desipramine-imipramine molar ratios were increased, indicating an elevated rate of N-demethylation. The unbound imipramine in plasma was diminished, but the relationship between protein-bound and unbound imipramine levels was not modified.


Enteric-coated pellets: theoretical analysis of effect of dispersion in the stomach on blood level profiles. The advantages of encapsulated enteric-coated pellets as dosage forms are discussed theoretically and compared to enteric-coated tablets. An enteric-coated tablet may take from approximately 0.5 to more than 8 hr to pass from the stomach to the duodenum. On the other hand, enteric-coated pellets are subjected to dispersion in the stomach, but they pass through the pyloric sphincter after a mean residence time in the stomach that would not be different from that exhibited by a suspension dosage form. The dispersion effect causes a theoretical reduction in peak blood level over that of an enteric-coated tablet of equivalent potency while maintaining bioavailability. It is hypothesized that enteric-coated pellets will reduce intestinal side effects that may occur with enteric-coated tablet preparations.


Estimation of pharmacokinetic parameters from postinfusion blood level data obtained after simultaneous administration of intravenous priming and infusion doses. Occasionally, it is desirable to attain steady-state-state blood drug levels rapidly in pharmacokinetic studies as well as in the treatment of certain diseases. In these cases, it is useful to administer an intravenous priming dose in combination with continuous drug infusion. Mathematical relationships are presented for the determination of pharmacokinetic parameters in these situations using postinfusion blood drug level data. The parameters obtained by this method are identical to the parameters obtained after a rapid intravenous injection of a drug.


Hydrolysis mechanism of 7-acetylacroninium perchlorate, a novel prodrug of acronine. 7-Acetylacroninium perchlorate was hydrolyzed at 25 degrees by both water enriched with 18O-labeled water and by unenriched water. The acronine obtained was examined by mass spectrometry, which indicated the unusual fact that hydrolysis of this ester proceeded by aryl oxygen cleavage to the extent of about 30% under those mild conditions.


New rapid determination of pyridoxal phosphate using tyrosine phenol-lyase. A rapid, specific, and precise spectrophotometric assay for the determination of pyridoxal phosphate is described. The assay allows for the determination of the cofactor between 0.1 and 1.0 microgram/ml. Its applicability to pyridoxal phosphate in biological fluids was demonstrated by a determination of the plasma half-life in BDF1 mice. Pyridoxal phosphate is absorbed rapidly from the peritoneal cavity and cleared from the plasma with a half-life of about 15 min.


New compounds: organoboron derivatives of tetracyclines I: synthesis of carboxamido derivative of tetracycline with perhydro-2-phenyl-1,3,6,2-dioxazaborocine. An organoboron carboxamido derivative of tetracycline, designed for use in the 105B-thermal neutron-capture treatment of cancer, was synthesized under the conditions of the Mannich reaction using perhydro-2-phenyl-1,3,6,2-dioxazaborocine as the amine component. Spectral data (UV, IR, and NMR) for the compound and its hydrolytic stability are discussed.


Design and evaluation of an automated system for in vitro dissolution testing utilizing a high-pressure liquid chromatographic multiport switching valve. An automated system for the simultaneous dissolution testing of six samples was developed consisting of four basic units: dissolution vessels and stirring unit, a peristaltic pump, a rotary stream multiport switching valve and programmer, and a UV spectrophotometer with recorder. Among the major advantages of such a system are: (a) paddle or basket stirring with variable speed is used, (b) the tablet or capsule (wire coil required) locates reproducibly at the bottom of a round-bottom reaction flask when utilizing paddle-type stirring, (c) a USP basket for tablet or capsule dissolution testing can be used, (d) continuous or intermittent sampling is possible, (e) the flow system readily adapts to UV-visible detector or fluorescence spectroscopy, (f) the system readily adapts to automated determination of the intrinsic dissolution of a material, and (g) the cost is low because of the multiport switching valve and inexpensive UV monitor required. Studies were performed using this apparatus to demonstrate the response characteristics of the system, its reproducibility, potential problems, and precautions required. This dissolution system was used to determine the dissolution characteristics of a new steroid tablet formulation, including a formulation and lot demonstrated to be bioavailable.


Iodipamide kinetics: capacity-limited biliary excretion with simultaneous pseudo-first-order renal excretion. Iodipamide was infused into three dogs with bile fistulas to achieve various steady-state blood levels. When using ultracentrifugation techniques, iodipamide was found to be highly bound to plasma protein. The total blood clearance was low relative to hepatic blood flow. For either the whole blood concentration or the unbound concentration of iodipamide, the biliary excretion was shown to be capacity limited with a transport maximum, Tm, of approximately 1.0mumole/kg/min. The steady-state renal excretion rate, plotted against the whole blood concentration of iodipamide, resulted in a concave ascending curve, which could lead to the false conclusion that iodipamide was undergoing active renal tubular reabsorption. However, when corrected for plasma protein binding, a linear relationship was obtained, suggesting that the renal excretion of iodipamide is a pseudo-first-order process. The Michaelis-Menten parameters for the extrarenal elimination, when calculated using the whole blood concentration of iodipamide, led to a similar discrepancy compared to the parameter estimates obtained from biliary excretion rate data. This discrepancy can be eliminated when one uses the unbound concentration of iodipamide in the parameter estimates.


Physicochemical properties of beta-lactam antibiotics: oil-water distribution. Apparent partition coefficients Papp, of beta-lactam antibiotics were determined in octanol-water and 2-methylpropanol-water systems at various pH values. The pKa values also were determined by potentiometry under the conditions of partition experiments. The intrinsic partition coefficients for the unionized form, Pu, and the ionized form, Pi, of beta-lactam antibiotics were calculated from the equation Papp = Pu[aH+/(Ka + aH+)] + Pi[Ka/(Ka + aH+)]. The correlation between Pu and Pi values and lipophilic parameters of penicillins measured in other systems was examined.


Physiologically based pharmacokinetic model for digoxin disposition in dogs and its preliminary application to humans. A physiologically based pharmacokinetic model for digoxin disposition developed in the rat was modified to account for the interspecies differences in tissue-to-plasma digoxin concentration ratios and applied to the dog. The model provided a quantitative assessment of the time course of digoxin concentrations in dog plasma, various tissues, and urine. It also predicted the effect of renal failure on digoxin pharmacokinetics in the dog. An attempt to scale the dog model to humans by simply considering differences in organ volumes, organ flow rates, and digoxin clearances was partially successful. Good predictions of plasma digoxin concentration and urinary digoxin excretion after a single dose and of steady-state plasma, heart, and skeletal muscle digoxin concentrations were obtained. However, the model predicted considerably higher kidney digoxin concentrations than are actually found. Although the model adequately characterized the time course of digoxin concentrations in patients with moderate renal impairment, it provided a relatively poor fit to that observed in anuric patients.


Kinetic parameter estimation by numerical algorithms and multiple linear regression: theoretical. A new method is presented for the determination of kinetic parameters based on a functional relationship among experimental data derived from the postulated model. The data, even though containing errors, are manifestations of this relationship, which should be satisfied by parameters fitted to the system. The procedure involves the use of numerical integration and/or differentiation of the data, followed by multiple linear regression. It does not require initial estimates or repetitive iteration for linear systems and can be applied to nonlinear models. The accuracy of estimated parameter depends on the goodness of the particular numerical approximation method used.


Dissolution kinetics of soluble nondisintegrating disks. An equation describing the isotropical dissolution of soluble nondisintegrating disks was developed. It was equivalent to the cube root law only if the height and diameter of the disk were equal. The dissolution kinetics of sodium chloride disks were examined, using a beaker equipped with a centrifugal stirrer as the dissolution chamber. The fit of the experimental data to the cube root law had a coefficient of variation of about 4-5%. It was demonstrated statistically that a fit to a square root of mass versus time relation was significantly better. With increasing porosity, the dissolution process proceeded faster than predicted on the basis of the diffusion-convection model. An explanation is proposed by assuming an increased effective dissolution surface.


Determination of an anti-inflammatory methanesulfonanilide in plasma by high-speed liquid chromatography. A sensitive and chemically specific high-speed liquid chromatographic method was developed for the determination of 4-nitro 2-phenoxymethanesulfonanilide in plasma. The method includes selective extraction of the anti-inflammatory drug and an internal standard, 2-(4'-chlorophenoxy)-4-nitromethanesulfonanilide, into benzene from acidified plasma followed by reextraction into 0.2 N NaOH. The aqueous layer is acidified, and the drug is reextracted into benzene. The benzene is evaporated, and the residue is dissolved in a small volume of acetonitrile. A 10-microliter aliquot is analyzed on a reversed-phase column. The mean overall extraction recovery, after correction for aliquot factors, is 99%. The accuracy, expressed as the relative error, is 4, 0.3, and -3% at 0.60, 1.50, and 3.00 microgram/ml, respectively. Repeated analysis of reference standards indicates that the precision, expressed as the relative standard deviation, is 3% or less. The lower sensitivity limit is 0.2 microgram/ml with a 2-ml plasma sample. The method was applied successfully to the determination of plasma levels of 4-nitro-2-phenoxymethanesulfonanilide in humans and rats in metabolic experiments at pharmacological doses.


Equilibrium reaction of pyrazolodiazepinones in aqueous solution. This study of the behavior of some pyrazolodiazepinones in aqueous solution at near ambient temperature indicated that they form stable equilibrium mixtures consisting of ring and opened forms. Under isothermal conditions, mixtures are produced whose composition is dependent on pH and may vary from that corresponding to essentially complete ring opening to complete closure. Ring closure equilibrium constants were calculated, and the influence of methyl substitution was determined. Substitution of a methyl group for an amido hydrogen in the open form results in a fivefold increase in this constant. Methylation of the terminal amino group, however, did not cause a corresponding increase and may not significantly affect equilibrium.


Thebaine content of selections of Papaver bracteatum Lindl. at different ages. Approximately 200 accessions of Papaver species were evaluated for identification as P. bracteatum Lindl. and for thebaine content. Fifteen authentic P. bracteatum accessions were selected on the basis of chromosome count. Statistical analyses of variation in alkaloid content were made for these accessions. Four of the 15 warranted further study based on the vigor of the plant and the total thebaine present in the tissue. Significant variability in thebaine content was found in wild strains of P. bracteatum, thus requiring genetic selection studies. The data showed that total yield potential of thebain should be considered in selecting P. bracteatum strains for commercial growth rather than concentrating on strains that produce the highest thebaine concentrations. A method for the quantitative estimation of thebaine from P. bracteatum is presented.


Contaminants in commercial dapsone.

Contaminants in commercial dapsone. Three contaminants commonly found in commercial dapsone were identified as 2,4'-sulfonylbis(benzeneamine), 4-(phenylsulfonyl)benzeneamine, and 4-(4'-chlorophenylsulfonyl)benzeneamine. The identities were based on the spectral analysis and unambiguous synthesis of each compound. Solvent-free, pure dapsone was prepared by recrystallization from chloroform.


Evaluation of teratogenic potential codeine sulfate in CF-1 mice. The most prominent defect of codeine sulfate, 100 mg/kg sc, was delayed ossification of the supraoccipital bone, paws, xiphoid, and sternebrae as well as other sternebral defects such as checkerboard sternebrae and polysternebrae. Although these anomalies were similar to the minor defects seen in the fetuses of morphine sulfate-treated mice, the major anomalies such as exencephaly, cryptorchid testes, and rib and vertebral fusions produced by morphine were not present in the fetuses of mice challenged with codeine. Thus, codeine sulfate appears to be less teratogenic than morphine sulfate. A review of the incidences of the various defects in mice treated on a single day with codeine showed that there was a range of days on which the mouse fetus was susceptible to codeine's teratogenic effects, with the most critical days of gestation being Days 8-10. Furthermore, a comparison of the defects that occurred in those treated on both Days 8 and 9 with the defects that occurred in those treated on a single day of gestation reveals an additive or cumulative teratogenic response to codeine.


GLC determination of urinary chlorthalidone levels. A sensitive and specific GLC method for the determination of urinary chlorthalidone levels was developed using on-column methylation. Chlorthalidone is converted to a tetramethylated derivative with trimethylanilinium hydroxide in methanol. This method which permits the determination of as little as 0.1 microgram of chlorthalidone/ml of dog urine, should be adequate for use with human subjects receiving a clinical dose.


Progesterone retention by rat uterus I. Pharmacokinetics after uterine intraluminal instillation. Tritium-labeled progesterone was administered to mature female rats in the proestrous stage by three different routes, gastric intubation, subcutaneous injection, and uterine intraluminal instillation, to study the kinetics involved in the uptake and retention of radioactivity by the uterus and various other tissues. Progesterone was retained at a much higher level and for a more prolonged period in the rat uterus after uterine intraluminal instillation. Progesterone bioavailability to the uterus was 45 times higher by uterine intraluminal instillation than by either gastric intubation or subcutaneous injection. Progesterone absorption by the rat endometrium was extremely fast. The observed biphasic decrease of radioactivity from the uterine tissue was explained adequately by a pharmacokinetic model in which progesterone is assumed to be present in two compartments within the uterine tissue. The pharmacokinetic parameters showed that the progesterone biological half-life in the uterine tissue during the alpha-phase was about 6.5 min while that in the beta-phase was about 230 min.


High-performance liquid chromatographic analysis of methadone hydrochloride oral solution. A direct and rapid high-performance liquid chromatographic assay for methadone hydrochloride in a flavored oral solution dosage form is described. A syrup sample, one part diluted with three parts of water, is introduced onto a column packed with octadecylsilane bonded on 10 micrometer porous silica gel (reversed phase). A formic acid-ammonium formate-buffered mobile phase is linear programmed with acetonitrile. The absorbance is monitored continuously at 280 or 254 nm, using a flow-through, UV, double-beam photometer. An aqueous methadone hydrochloride solution is used for external standardization. The relative standard deviation was not more than 1.0%. Drug recovery from a syrup base was better than 99.8%.


Prednisolone bioavailability in the dog. With a fasted dog as an animal model, the bioavailability and pharmacokinetics of prednisolone were studied following rapid intravenous injection and oral dosing of a prednisolone sodium phosphate solution and also following oral doses of prednisolone as tablets and a slurry. Hydrolysis of the phosphate ester to prednisolone in the body is extremely rapid and complete, thus permitting accurate calculation of the distribution volume of prednisolone. Enteral absorption of prednisolone from a slurry is superior to that from prednisolone tablets and from a prednisolone sodium phosphate solution. Reduced absorption from tablets, compared to the slurry, is probably due to tablet disintegration characteristics; reduced absorption from the solution is probably due to poor membrane permeability of the ionized drug. Information obtained from a single animal may indicate the need for expanded studies in humans.


Teratogenicity of zinc chloride, 1,10-phenanthroline, and a zinc-1,10-phenanthroline complex in mice. Zinc chloride, in single doses of 12.5, 20.5 and 25 mg/kg ip on Day 8,9,10, or 11 of gestation in CF-1 albino mice, produced skeletal anomalies without accompanying soft tissue defects. Ripple ribs, the most unusual anomaly, first appeared when the zinc salt was given on Day 9  of gestation in a dose of 20.5 mg/kg, becoming more prevalent when 25 mg/kg of the drug was administered on Day 11.1,10-Phenanthroline, in single doses of 30 mg/kg ip on Day 8,9,10, or 11 of gestation elicited skeletal defects comparable to those caused by zinc chloride as well as soft tissue anomalies, but a significant incidence of the former occurred with this agent only following its injection on Day 8 of gestation. A zinc-1,10-phenanthroline complex in single doses of 50 mg/kg on Day 8,9,10, or 11 of gestation yielded significant incidences of skeletal and soft tissue anomalies only when the complex was administered on Day 8 or 9 of gestation. This dosage level was toxic to both the mother and fetus when given on Day 10 of gestation. However, when the complex was given on Day 8,9,10, or 11 in a dose of 25 mg/kg, neither toxic nor teratogenic effects were observed in the mother or fetus, respectively.


Determination of time course of tablet disintegration I: numerical method. A method is described for determining the time course of tabled disintegration. It involves a numerical analysis of the experimental dissolution profile of a tablet and the dissolution characteristics of the primary drug particles in the tablet. The disintegration profile is determined for an acetaminophen tablet to demonstrate the application of the method. Tablet dissolution is simulated with the disintegration-dissolution model, and the interrelationship between the two fundamental processes is studied theoretically by varying the parameters describing the two processes.


Bioavailability of three isoniazid formulations. The bioavailability of three isoniazid formulations was assessed using a procedure specific for the free drug. Nine human volunteers, all slow acetylators, were each given 4 X 100 mg of isoniazid of three different tablet formulations at weekly intervals; the plasma drug levels were measured at different times during the first 24 hr. No significant differences (p greater than 0.05) were detected among the three products as to relative bioavailability, peak plasma concentrations, Cmax, and the time of Cmax, tmax. Analysis of variance of the pharmacokinetic parameters obtained according to a one-compartment open model did not demonstrate any significant formulation or time effect but revealed a significant intersubject variation in all parameters involved.


Influence of human skin surface lipids on protection time of topical mosquito repellent. Skin surface lipids were extracted from volunteers who had been ranked according to the duration of protection from mosquitoes by diethyltoluamide. These lipids were analyzed by GLC-mass spectrometry for their fatty acid contents. Correlations were found between total skin lipid content and protection time of diethyltoluamide and between certain fatty acid concentrations in the skin lipids and the protection time of diethyltoluamide.


Gonadotropin-inhibitory contaminants in partially purified pharmaceutical preparations of human chorionic gonadotropin. Various commercial preparations of partially purified human chorionic gonadotropin, inactivated by heating, inhibited the uterine growth induced in immature mice with the same active gonadotropins as well as spontaneous uterine growth. The more purified preparations of chorionic gonadotropin failed to produce these effects after inactivation by boiling, suggesting that the inhibitory activity is not generated from gonadotropin by the procedure but may be related to some contaminant similar to the gonadotropin-inhibitory substance previously found in human urine.


Precautionary note for use of bisulfite in pharmaceutical formulations. The effect of sodium bisulfite on aspirin hydrolysis was studied at 40 degrees in the pH range of 6.5-7.5. Significant catalytic activity by the sulfite ion was observed. Second-order rate constants were calculated for this catalysis and compared to other buffer species. The sulfite ion was a much more efficient catalyst than acetate, phosphate, or carbonate.


Viscosity and surface tension of dilute salicylic acid-cetrimide systems. The viscosity and surface tension of systems containing small amounts of salicylic acid in aqueous solutions of cetrimide were determined. An abrupt increase in viscosity was observed, and the molar ratio of salicylic acid to certrimide at which this viscosity increase occurred was 1:2. The surface tension of these systems also increased sharply after an initial lowering. The salicylic acid concentration at which this behavior was demonstrated was almost the same as that at maximum solubility in the surfactant solution.


Multiple sulfa compounds: high-pressure liquid chromatographic assay and mobile phase correlation. A mixture of sulfacetamide, sulfathiazole, and sulfabenzamide was used to develop a rapid high-pressure liquid chromatographic assay. In addition, this study provided a means to develop concepts relating solvent molar polarization parameters and retention times. A linear correlation between molar polarization and retention time was observed and will permit reasonably rapid predictions about the dependent variable.


Fluorescence characteristics of azaperone and of an azaperone mononitrogen oxide. The structure elucidation of the compound isolated after peroxide treatment of azaperone is described. A mononitrogen oxide was formed at the piperazine N1 atom after reaction with excess hydrogen peroxide. The fluorescence characteristics of derivative were examined and compared with the native fluorescence capacities of the azaperone base; both were identical, depending on the solvent nature. The phenomenon is explained by the fact that the fluorescent properties of the azaperone molecule are principally produced by its ortho-nitrogen substituted pyridine nucleus.


Stereoselective metabolism, pharmacokinetics and biliary elimination of phenylethylhydantoin (Nirvanol) in the dog. The influence of stereoisomerism on pharmacokinetics and rates of hepatic drug metabolism was investigated in four dogs using the enantiomers of phenylethylhydantoin (PEH) as model substances. After single i.v. administration of 98 micromoles of the pure enantiomers per kg b.wt., concentrations were measured by gas-liquid chromatography. The l-form exhibited a longer plasma half-life (23.3 +/- S.E. 1.0 hour) than the d-form (16.3 +/- 1.0 hour, P less than .005). Volumes of distribution and renal clearances were practically identical. The differences in plasma half-lives of PEH were explained by stereoselectivity of hepatic hydroxylation: an approximately 10-fold differences was found in urinary excretion of their major metabolities, d- and l-hydroxyphenylethylhydantoin (HPEH). Furthermore, in bile 7.3 +/- 1.6 mumol of of d-HPEH were eliminated within the first 6 hours, whereas l-HPEH could not be detected. The preference in biliary output of d- compared with l-PEH is consistent with the idea that both hepatic uptake and microsomal hydroxylation of PEH contribute to the high degree of stereoselectivity. In view of similar extrahepatic, but different metabolic behavior of these enantiomers, they represent an interesting research tool for in vivo studies of drug metabolism: in otherwise identical conditions, two different rates of PEH hydroxylation may be studied.


Plasma protein binding and metabolic clearance of phenytoin in the rat. The purpose [corrected] of this investigation was to determine the effects of certain changes in plasma protein binding on the disposition of phenytoin after i.v. administration in the rat. Treatment of rats with sulfisoxazole and oleic acid significantly reduced plasma protein binding of phenytoin. The displacement of phenytoin from plasma proteins by sulfisoxazole had no significant effect on the elimination of phenytoin whereas comparable displacement by oleic acid produced an increase in the apparent volume of distribution and a marked decrease in the metabolic clearance of the drug. A similar difference in metabolic clearance was noted when phenytoin elimination was determined as a function of the intrinsic ability of the rat to bind phenytoin in the plasma. Rats showing relatively high plasma protein binding of phenytoin cleared the drug much more rapidly than rats showing relatively low plasma protein binding of phenytoin. Assuming that an endogenous inhibitor is responsible for both the decreased plasma protein binding and decreased metabllic clearance of phenytoin in rats with an intrinsically reduced ability to bind phenytoin in plasma, this inhibitor is evidently similar to oleic acid in its effects.


Effect of the duration of infusion on the disposition of lidocaine in dogs. Lidocaine is a commonly used and efficacious antiarrhythmic agent whose pharmacokinetics after a rapid intravenous bolus injection have been extensively studied. Due to its short half-life, a continuous infusion of lidocaine is necessary whenever therapeutic blood levels need to be maintained for prolonged periods of time. Recent work in man has shown that the elimination of lidocaine is much slower after a prolonged infusion than after a bolus. We present the results of a pharmacokinetic study of the disposition of lidocaine after the discontinuation of short (90 minutes) and long (24 hours) intravenous infusions which demonstrate that in both cases the elimination of lidocaine is best explained by a two-compartment open model with elimination from the central compartment and that the longer half-life of lidocaine after a prolonged infusion is due to an impairment of its hepatic extraction. Lidocaine hepatic elimination data obtained at the end of short- and long-term infusions confirmed the inferences drawn from the pharmacokinetic analysis by demonstrating that a long-term infusion produces an important decrease in the arterial clearance and hepatic extraction rate of lidocaine.


Nitrous oxide analgesia: reversal by naloxone and development of tolerance. The objective of this study was to characterize further the nature of nitrous oxide analgesia and to establish if tolerance to nitrous oxide occurs. Methods for studying the analgesic action of a gas are described. In mice, nitrous oxide is analgesic in the phenylquinone and acetic acid abdominal constriction tests. Aspirin and very high doses of alcohol are also active in these tests; however, only nitrous oxide-induced analgesia is antagonized by narcotic antagonists. These data indicate the mechanism of action of nitrous oxide analgesia differs from that of the other two drugs. Nitrous oxide produced a dose-related analgesic response in rats (ED50, 67%) as measured by the tail-flick method. Naloxone, 5 to 30 mg/kg, also antagonized nitrous oxide analgesia in rats. Lower doses of the antagonist were not effective. Tolerance developed to the effects of nitrous oxide in both rats and mice after prolonged exposure. These data lend support to the hypothesis that nitrous oxide and opiates have a significant pharmacologic resemblance and may ultimately produce similar molecular events in the brain leading to the relief of pain.


Autoradiographic localization of [3H]reserpine binding sites in rat brain. [3H]Reserpine was administered (i.v.) to rats and they were killed 7 days later. At this time, the regional localization of radioactivity paralleled the distribution of specific binding sites observed in other laboratories. Autoradiographic studies of certain areas displayed a striking localization of radioactivity. There was a marked association of autoradiographic grains with areas containing catecholamine systems. In particular, the locus ceruleus, the caudate-putamen, the nucleus accumbens, the dorsolateral septum and the infundibulum had high grain densities. In the caudateputamen, there was a clear localization of grains to the neuropil. There was also a striking association of autoradiographic grains with certain hypothalamic nuclear, i.e., the dorsal premammillary nucleus, the prelateral mammillary nucleus and the lateral mammillary nucleus. In these areas, the grains were clearly localized in the cytoplasm of the cell bodies. All of the above localizations of autoradiographic grains were blocked by administration of unlabeled reserpine before injection of [3H]reserpine. The significance of these findings and their relationship to the clinical actions of reserpine are discussed.


Vesicular and juxtavesicular serotonin: effects of lysergic acid diethylamide and reserpine. An extensive analysis of subcellular serotonin (5-HT) compartmentation with and without reserpine was undertaken in order to localize further the effect of LSD on rat brain 5-HT. Modification of the subfractionation procedure resulted in an increase in purity of fractions and a decrease in variability of 5-HT content. With the modified procedure, the administration of LSD produced a significant increase in 5-HT in the nerve-ending fraction prepared from rat whole brain. LSD caused a 50% increase in 5-HT in the vesicular fraction which was recovered after osmotic disruption of nerve-endings. The increase of 5-HT in the vesicular fraction after LSD was not demonstrable in rats treated with reserpine for as long as 2 weeks postreserpine. Instead, with reserpine pretreatment the LSD-induced increase in 5-HT was localized to the intrasynaptosomally derived "end supernatant" as early as 48 hours postreserpine. Thus, an unanticipated "juxtavesicular" site capable of 5-HT retention or binding was detected. In crude subcellular fractions, by contrast, significant increase in 5-HT were not observed with LSD administration until 4 days after reserpine, at which time at least a 50% 5-HT repletion had occurred. This study of drug interactions suggests a juxtavesicular compartment that may be of functional importance in presynaptic binding or transport of 5-HT.


Adrenal origin of the increase in plasma dopamine beta-hydroxylase and catecholamines induced by hemorrhagic hypotension in dogs. Controlled hemorrhagic hypotension in anesthetized dogs causes progressive increases in dopamine beta-hydroxylase (DBH) and catecholamine (CA) plasma levels and in heart rate. The concentration (units per milliliter) and the calculated total plasma content of DBH activity [(units circulating + reservoir + samples] increased 2.6 and 2.3 times, respectively. A significant positive correlation (P less than .001) was found between the plasma levels of DBH and CA; however, the CA plasma levels increased earlier and were of greater magnitude (10-fold) than those of DBH. These results suggest that CAs are more sensitive indicators of acute changes in adrenergic activity than DBH. Surgical bilateral adrenalectomy completely abolished the increases in circulating CA and DBH levels and in heart rate induced by the hemorrhage, independently of the percentage of blood removed. These results indicate that the adrenal glands contribute almost exclusively to the rise in plasma DBH and CA caused by the bleeding stress and that high circulating CA concentrations seem to account for the tachycardia that accompanies the hemorrhagic hypotension. The infusion of the reservoir blood with a lower DBH and CA content than that present in the animal at that time produced a rapid fall in circulating CA levels (59.2 +/- 8.9 to 10.8 +/- 3.3 ng/ml) and no change in the DBH concentration (5.43 +/- 0.42 and 5.40 +/- 0.53 U/ml). A 38% increase in the calculated total plasma content of DBH occurred with the transfusion. Due to the large size of the DBH molecules, trapping in tissues during the hemorrhagic hypotension period might have occurred. The improvement in the hemodynamic conditions caused by the transfusion would facilitate the washout of the enzyme from the tissues into the circulation.


The effect of monoamine oxidase and catechol O-methyltransferase inhibitors on the accumulation and metabolism of [l-3H] norepinephrine by the adventitia and media of rabbit aorta. The effects of catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) inhibitors on the accumulation and metabolism of [l-3H] norepinephrine ([l-3H]NE) were studied in the isolated adventitia and media of rabbit aorta. The COMT inhibitors produced a greater inhibition of O-methylation in the isolated media than in the isolated adventitia. In addition, exposure to these drugs was associated with an increased level of [l-3H]NE and increased formation of the catechol deaminated metabolites by the isolated media but not by the isolated adventitia. The effects of these drugs on the balance of the oxidized vs. reduced forms of the deaminated metabolites was interpreted to mean that 3-methoxy-4-hydroxyphenylethylglycol is formed from normetanephrine rather than from 3,4-dihydroxyphenylethylglycol whereas 3-methoxy-4-hydroxymandelic acid is formed from 3,4-dihydroxymandelic acid. 3,4-Dihydroxyphenylethylglycol does not seem to serve as a substrate for 3-methoxy-4-hydroxyphenylethylglycol becuase it rapidly passes out of the tissue after it is formed. Parglyline and iproniazid markedly decreased deamination of [l-3H]NE and increased the tissue level of [l-3H]NE. However, these drugs produced little if any compensatory increase in O-methylation of [l-3H]NE. The effects of these drugs are compatible with the hypothesis that adrenergic nerves contain MAO and vascular smooth muscle contains MAO and COMT. Harmaline seemed to block both MAO and COMT. Based on the effects of clorgyline and deprenyl and the other MAO inhibitors tested, the isolated adventitia seems to contain primarily type A MAO and the isolated media seems to contain primarily type B MAO.


Studies on the uptake and binding of propranolol by rat tissues. The tissue distribution of propranolol after i.v. administration (1.5 and 7.5 mg/kg) was studied in rats. Lung, brain and kidney showed extensive propranolol tissue binding. Propranolol uptake by lung seemed to be a saturable process. In contrast to the above tissues, liver propranolol concentrations remained low over the time period of study. An increase in the propranolol T1/2 was noted at the high dose and seemed to result from reduced systemic clearance and an increase in the apparent volume of distribution. Microsomal and mitochondrial fractions from several tissues contained substantial amounts of propranolol after i.v. administration and in vitro incubation with homogenates. Cytosol proteins did not bind significant amounts of propranolol. Equilibrium dialysis studies with rat liver mitochondrial and microsomal fractions revealed both high affinity, low capacity propranolol binding sites and low affinity, high capacity sites. At low concentrations, propranolol interaction with rat liver microsomes produced a type I difference spectrum with high affinity binding of similar magnitude to that observed with equilibrium dialysis. Higher concentrations of propranolol produced a saturable shift in the difference spectra with reduced binding affinity for propranolol. Results from these studies indicate that particulate fractions from several tissues contribute to the extensive tissue binding of propranolol.


Pharmacologic stimulation of erythrocyte 2,3-diphosphoglycerate production in vivo. The ability of phosphate alone and in combination with sodium bicarbonate, vitamin C and pyruvate to elevate 2,3-diphosphoglycerate (DPG) levels was examined in normal human subjects in vivo. Statistically significant increases in DPG levels were  noted (P less than .001) for all regimens pooled. Average rise in DPG levels reached 6% above pretreatment levels after 2 to 3 days of treatment. No changes in DPG levels were detectable in a group of control subjects over the same time period. Variation among pharmacologic trials and among subjects within trials in the actual magnitude of DPG build-up was marked. Significant differences could not be detected among the pharmacologic regimens in their ability to produce DPG increases. Previous reports suggested the use of these agents to stimulate red cell glycolysis but it seems that their effects and the mechanisms of glycolytic control in vivo are considerably more complex than has been previously suggested.


Effect of ring substitution on the metabolic fate and anti-inflammatory activity of some prodolic acid analogs. Prodolic acid, 1-n-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, exhibits potent anti-inflammatory activity in adjuvant arthritic rats. The potency of prodolic acid is enhanced by indole ring substitution. This increase correlated well with higher and sustained drug concentrations in the serum of normal animals. Pharmacokinetic studies demonstrated that ring substitution prolonged the serum half-life without affecting the absorption or volume of distribution. Because, in the rat, indole ring hydroxylation is a major pathway for the disposition of prodolic acid, we ascribe the increased pharmacological activity of ring substituted derivatives to the interference of substituents with the hydroxylation reaction.


Kinetics of glucose transport by the perfused mid-gut of the freshwater prawn Macrobrachium rosenberg ii. 1. Mucosal influx of [3H]glucose was examined in the mid-gut of a freshwater prawn, Macrobrachium rosenbergii, using an in vitro perfusion technique. 2. [3H]glucose transfer across the apical cell membrane of the epithelium exhibited Michaelis-Menten kinetics (Jmax.in = 0-15 mumole glucose  equiv/g. min, Kt = 0-17 mM). Under Na-free conditions, glucose influx was significantly reduced and a linear function of substrate concentration, indicative of either slow cellular diffusion (KD = 7-6 X 10(3) mumole glucose equiv/g. min. mM) or a facilitated process with a low carrier affinity for the sugar. 3. Phlorizin was a potent competitive inhibitor of glucose influx (K1 = 3-6 X10(-3) mM), galactose and 3-O-methylglucose (3-O-MG) were weak inhibitors, and fructose had no evident effect on glucose uptake. Azide, but not iodoacetate (IAA), significantly depressed influx. 4. Absorbed [3H]glucose was rapidly metabolized by the mid-gut. The majority of accumulated activity within the tissue was in the form of phosphorylated compounds and tritiated water (THO), while only 0-3% was recovered as a free-glucose. 5. Preliminary studies examining transmural [3-H]glucose transport, however, demonstrated a significant net mucosal to serosal free-glucose flux across the prawn mid-gut which was Na-dependent and IAA- and phlorizin-sensitive. Two alternative interpretations of the data are advanced as possible mechanisms for transepithelial glucose transport: (1) group translocation, or (2) the operation of an energized, high affinity, baso-lateral sugar transport carrier.


The response of Golgi tendon organs to single motor unit contractions. 1. Cross-correlation analysis has been used to quantify the responses of cat soleus tendon organs to repetitive twitch contractions of: (a) different motor units within the muscle, (b) single motor units at different muscle lengths, and (c) single motor units when the pulse-train pattern of stimulation delivered to the motor unit axon was altered. 2. Ib afferents were observed which responded to each of several hundred successive motor unit twitches with identical numbers of spikes and with relatively invariant latencies. 3. The present results show that tendon organs are sensitive to subtle alterations in motor unit twitch wave form and amplitude, and that this sensitivity is reflected in the precise timings of their afferent discharge. 4. Examination of these tendon organ responses indicates that the forces produced by single motor units couples to the receptor capsule are well above threshold. Calculations based on these results, and earlier soleus motor unit and muscle fibre data, suggest that the absolute force threshold for tendon  organs may be as little as 4 mg, which is less than the estimated minimum twitch force generated by individual soleus muscle fibres. 5. Considering the number of tendon organs in a muscle, and the likelihood that every motor unit is connected with at least one receptor, the sensitivity of tendon organs ensures that every twitch of every motor unit will be reflected in the population of afferent signals projecting to the spinal cord.


Sodium chloride transport across the chicken coprodeum. Basic characteristics and dependence on sodium chloride intake. 1. The transport characteristics of the chicken coprodeum have been examined in vitro using the isolated mucosa. The short-circuit current (I(sc)), the transepithelial electrical potential difference (p.d.), the unidirectional transmural fluxes (J(ms), J(sm)) of sodium and chloride measured in the short-circuited state, and the unidirectional influx of sodium and chloride across the brush border membrane measured under open-circuit conditions have been studied. The effect of the sodium chloride contents of the diet on these parameters have been investigated.2. The isolated mucosa depends functionally on the presence of glucose in the incubation media. This dependence reflects the need of glucose as a fuel. There is no indication of coupling between transport of sugars and sodium across the brush border membrane. For preparations from chickens on a low sodium diet a very high and stable I(sc) can quantitatively be accounted for by the net transport of sodium. Influx of sodium across the brush border membrane is not significantly different from the net flux of sodium. By feeding the chickens a high sodium diet the I(sc) is reduced by more than 95%, the net transport of sodium is abolished, and the transepithelial electrical conductance is reduced by more than 50%.3. Both unidirectional transepithelial fluxes of chloride, and the serosa to mucosa flux of sodium appear to proceed through a paracellular shunt.4. Under the conditions of the low sodium diet the paracellular pathway appears to be anion selective. Whereas, under the conditions of the high sodium regimen the paracellular route appears to be cation selective. After adaptation to a high sodium diet the influx of sodium across the brush border membrane is only moderately reduced. Consequently the decisive event in the adaptation must be localized elsewhere.


Properties of isolated adult rat muscle fibres maintained in tissue culture. 1. Adult rat skeletal muscles were dissociated by collagenase treatment and trituration, and the isolated muscle fibres were maintained in vitro for 2-3 weeks. At various stages, the fibres were examined physiologically and morphologically. 2. The isolated fibres underwent some changes characteristic of muscle denervated in vivo. For instance, input resistance increased and extrajunctional acetylcholine (ACh) receptors appeared. In addition, the beginning stages of apparent muscle fibre fragmentation were observed. 3. In other respects, the cultured isolated fibres behaved differently than in vivo denervated fibres. Fibrillation developed only occasionally in vitro. The onset of ACh supersensitivity was slower (6 days) than after denervation in vivo (2-3 days). Some fibres developed localized regions of destriation, which apparently was due to loss of in-register alignment of myofibrils.


A quantitative study of C-mechanoreceptors in hairy skin of the cat. 1. Single C-mechanorecptor afferent units were examined by recording from fibres dissected from the saphenous nerves of cats anaesthetized with chloralose. The receptive fields, averaging 4 X 3 mm when 10-50 X threshold stimuli were used, were in the hairy skin of the leg and foot. 2. The extent and excitability of receptor terminals was tested by two-and three-point field studies. The excitability of terminals in one part of the field of a unit could be depressed without affecting the excitability of terminals elsewhere in the field. 3. The afferent units could be excited by both inward and outward movement of the stimulus probe, in appropriate conditions; that is, there was non-directional sensitivity. 4. After-discharge was found to depend on restorative movements of the skin, not on a persistence of the response of the receptor to the original movement. 5. The response to mechanical stimulation was slowly adapting with two time constants and the stimulus-response relationship was exactly described by a power function, with exponents ranging from 0-6 to 1-3. 6. The C-mechanoreceptors could be depressed by rapidly repeated or prolonged mechanical stimulation and the effect was confined to the excited terminals.