Juvenile astrocytomas with subarachnoid spread. The surgical and necropsy findings in five cases of extracerebellar astrocytoma showing subarachnoid spread and invasion of surrounding structures are presented. The patients varied in age from 6 to 23 yr, and all died of the effects of the tumour within 20 mth of the onset of the symptoms. In each case histological examination reveals areas of piloid astrocytes, but these show varying degrees of nuclear abnormalities. Oligodendrocytomatous foci are also seen in some cases. It is suggested that nuclear pleomorphism or oligodendrocytomatous areas indicate a poor prognosis in an otherwise typical juvenile astrocytoma, and may be associated with a partly anaplastic tumour.


Tumours arising in skeletal muscle in adults. A review has been made of 30 cases of tumours arising in skeletal muscle seen over a 21-yr period (1954-74) in the Department of Pathology, Western General Hospital, Edinburgh. There were 17 females and 13 males in the series. The age range was 15 to 88 yr. The commonest site was thigh muscles (18 cases). Seven of the 14 benign tumours were myxomas: the other benign tumours included two solitary myositis ossificans, two haemangiomas and three lipomas. The three tumours which might be considered as being of borderline malignancy were two haemangiopericytomas and one desmoid tumour. There were 13 malignant tumours in the series: five fibrosarcomas, five liposarcomas, two rhabdomyosarcomas and one undifferentiated (pleomorphic) sarcoma. The average length of survival of the nine patients with malignant tumours who have died was only 15 mth. The fibrosarcomas in particular behaved in a highly malignant fashion. These 13 intramuscular sarcomas accounted for approximately 11 per cent, of all mesenchymal (non-lymphoid) sarcomas seen during the period of study.


Cytotoxic carcinogeneic response to monocrotaline pyrrole. The cytotoxic and carcinogenic effects of MCP, the possible proximate metabolite of the alkaloid monocrotaline, were investigated in rats by the subcutaneous route. Sequential of MCP subcutaneously produced an acute inflammatory reaction with necrosis of the local tissue. A slight  delay in connective-tissue repair occurred and markedly enlarged fibroblasts were a distinctive feature of the lesion. Four injection site sarcomas were produced after repeated injection of 60 mug MCP in tricaprylin. Injection of 30 mug MCP in tricaprylin twice weekly gave rise to three local tumours. Controls injected repeatedly with tricaprylin developed two sarcomas at the injection site. The significance of these findings is discussed and it is concluded that MCP is undoubtedly cytotoxic but that its carcinogenic potency is equivocal.


The pathogenesis of experimental pulmonary aspergillosis in normal and cortisone-treated rats. Normal outbred adult Wistar rats were resistant to infection with intratracheally administered viable spores of Aspergillus fumigatus although although they developed a subacute interestitial pneumonia. While the lesions were more severe in animals immune suppressed with Azathioprine (immuran) there was no evidence of hyphal growth in the pulmonary tissue. Significant histological involvement was found only in those animals receiving repeared subcutaneous injections of cortisone and multiple intratracheal injections of spores. Granulomatous lesions were scattered throughout the parenchyma of the lung, and many eroded the walls of adjoining bronchioles permitting entry of the material in the necrotic centre of the granuloma into the lumen of the bronchiole.


Nephrotoxic action of rattlesnake and sea snake venoms: an electron-microscopic study. The fine structure of renal corpuscles and proximal convoluted tubules of the right kidneys of Suiss mice were studied 9 hr after the injection of the venom of Crotalus atrox (Western diamond-back rattlesnake) or the venom of Laticauda semifasciata (broad-banded blue sea snake). Rattlesnake envenomation resulted in several ultrastructural changes in the renal corpuscles and proximal convoluted tubules. Visceral epithelial changes included intracellular oedema, blebbing, vesiculations, the formation of microvillus projections and dilatation of the endoplasmic reticulum and mitochondria. Changes in the parietal epithelium were similar except that no microvillus projections were noted. Mesangiolysis was a consistent finding. Collagenous fibrils were very prominent in the lysed areas of the mesangial cells. Increased numbers of lysosome-related structures were noted in the proximal convoluted tubule cells. Most of the nuclear cisternae of the cells of the renal corpuscles and proximal convoluted tubules were greatly dilated. Sea snake envenomation resulted in focal organellar swelling and focal intracellular oedema of the visceral epithelium. This venom did not affect the cells of the proximal convoluted tubule. The presence of light and dark visceral epithelial cells has been a consistent finding for both the control and the environmated groups.


Prospective evaluation of treatment of Hemophilus influenzae meningitis. Fifty children with Hemophilus influenzae meningitis have been enrolled in a prospective study. Patients were randomly assigned chloramphenicol or ampicillin treatment; there were no significant differences between groups in other respects. Countercurrent immunoelectrophoresis proved to be a valuable tool for rapid diagnosis of the causative agent even in pretreated patients. Increasing quantities of capsular polyribosephosphate antigen detected in the initial cerebrospinal fluid correlated significantly (r=0.62419; p less than 0.01) with early and late sequelae of meningitis. None of the patients died. Severe and persistent neurologic or intellectual deficits were noted in four (8%) of the children, and an additional 14 (28%) had IQ scores between 70 and 90. The presence of bactericidal antibody in serum was not protective. Anti-PRP antibody generally was not present in acute serum specimens and irrespective of the quantity of antigenic stimulus provided by the disease was nondetectable in 21 of 24 children less than 17 months of age following recovery.


Detection of bacterial antigen in pleural fluid by counterimmunoelectrophoresis. Pleural fluid specimens from 87 patients were studied using counterimmunoelectrophoresis with pneumococcal, staphylococcal, and Hemophilus influenza b antisera. This method compared favorably with traditional bacteriologic methods and in addition provided a presumptive etiologic diagnosis in more than half of the specimens with negative bacterial cultures. One cross-reaction between H. influenza b antiserum and a pleural fluid specimen with an Escherichia coli isolate was observed.


Hepatitis B virus infection in the Wiskott-Aldrich syndrome. Testing of paired serum samples of 12 children with the Wiskott-Aldrich syndrome for the presence of hepatitis B surface antigen (HBsAg) antibody to HB, Ag, and antibody to the hepatitis B core antigen revealed evidence of hepatitis B virus infection in three. None of the three, however, developed overt clinical hepatitis or the chronic HBsAg carrier state. These data suggest that the immunologic defects seen in the Wiskott-Aldrich syndrome permit adequate immune responses to the hepatitis B virus and do not predispose to the chronic HBsAg carrier state.


Provocative tests for growth hormone release. Subnormal growth hormone responses to both insulin-induced hypoglycemia and arginine infusion (peak response less than or equal to 5 ng/ml) were found in five male subjects (aged 10 to 14 years) with short stature but with normal interval growth rates and normal bone ages (in 4 cases). They demonstrated one or more normal GH responses to subsequent provocation by glucagon stimulation, tolbutamide-induced hypoglycemia, and repeat insulin and arginine testing following pretreatment with sex steroids. Two subjects had received exogensou GH therapy for six months prior to the subsequent assessment; each one failed to demonstrate the growth response characteristic of GH deficiency. These studies indicate the need for multiple provocative human GH testing to exclude children whose growth would not be enhanced by GH therapy despite a subnormal response to provocative tests with insulin and arginine.


Constrictive pericarditis with dwarfism in two siblings (mulibrey nanism). Two siblings with marked dwarfism, now 11 and 19 years of age, have been followed from infancy. The girl had frequent episodes of pneumonitis and presented at age 4 years with hepatic enlargement and ascites which proved to be due to constrictive pericarditis. The boy presented with growth failure and pseudohydrocephalus. He had fibrous dysplasia of the tibia and a pathologic fracture; acute hepatic congestion followed physical activity at age 13 years and led to the diagnosis of constrictive pericarditis. Muscle function was normal, there was no evidence for a primary liver disorder, and mental development was normal so that the coined word "mulibray" seemed inappropriate. Pericardiectomy produced only partial improvement; both patients have hepatic enlargement and continue to need diuretics. A third patient with dwarfism, frequent respiratory infections, and pericardial calcification has certain features of the syndrome.


The acro-osteolysis syndrome: Morphologic and biochemical studies. The acro-osteolysis syndrome consists of dissolution of terminal phalanges of the hands and feet, dolichocephaly with multiple wormian bones, delayed closure of cranial sutures, absence of frontal sinuses, a prominent occipital ridge, skeletal demineralization, vertebral and extremity fractures, joint laxity, and coarse hair. Studies of bone morphology reveal diminished bone density and bone formation. Osteoblasts have widely dilated smooth endoplasmic reticulum. It is postulated that an abnormality of a structural protein is the pathogenic basis of this disease.


Leukocyte glutathione peroxidase deficiency in a male patient with chronic granulomatous disease. A male child with chronic granulomatous disease is described in whom glutathione peroxidase deficiency of leukocytes was identified. Stability and activity of G-6-PD and activity of NADPH oxidase were normal. The leukocytes of the parents showed intermediate activities of glutathione peroxidase, suggesting the possibility of autosomal recessive inheritance.


Joint contracture--common manifestation of childhood diabetes mellitus. Sixty-five of 229 seven to eighteen-year-old campers with diabetes were found to have contractures of finger joints; in two thirds of affected children only the fifth finger was involved. Stiff resistance to passive finger manipulation and thickened adherent skin over the dorsa of the hands were additional features. Short stature was associated with involvement of more than one finger; the shortest youngsters also had contractures of large joints. Joint changes were independent of age, sex, age of onset of diabetes, and control of diabetes, but correlated with duration of the diabetes.


Cerebellar hemorrhage in the premature infant. Lesions of the central nervous system were reviewed in 144 premature neonates without anomalies or infections coming to autopsy from the Intermountain Regional Neonatal Intensive Care Unit. Twelve neonates were found to have had cerebellar hemorrhages. Eleven of the 12 with cerebellar hemorrhage also had germinal plate hemorrhages at postmortem examination. Some hemorrhages destroyed one or both cerebellar hemispheres. Three of 19 (16%) infants between 20 to 24 weeks' gestation, six of 26 (25%) infants between 26 to 28 weeks' gestation, two of 24 (8%) infants between 28 to 30 weeks' gestation, and one of 19 (5%) infants between 20 to 32 weeks' gestation had cerebellar hemorrhage. No premature neonate after 32 weeks' gestation had cerebellar hemorrhage. It is probable that trauma does not play a role in the pathogenesis of the cerebellar hemorrhage.


Variance in albumin loading in exchange transfusions. To assess the rationale of albumin priming prior to exchange transfusions, 42 hyperbilirubinemic infants who required exchange transfusions were randomly assigned to one of two groups. Group I consisted of 15 infants who were given intravenously 1 gm/kg of salt-poor human serum albumin one hour before the exchanges.  Group II, which consisted of 27 infants, received simple exchanges. No statistical differences were found in variations in reserve albumin-binding capacity, bilirubin, albumin, or red cell bilirubin at pre and one-hour post albumin infusion in the primed infants. The amount of bilirubin removed per kilogram is directly correlated to plasma bilirubin concentration (r=0.87). No significant difference in efficiency on bilirubin removal was seen between the two groups. Beneficial effects of albumin therapy was apparent only in those infants with low RABC as determined by the sephadex gel filtration technique.


Persistent fetal circulation: Newly recognized structural features. Three infants died with pulmonary hypertension of unknown cause during the first three months of life. Their lungs were examined using quantitative morphologic techniques. In all three cases the intra-acinar pulmonary arteries were more muscular than normal, as shown both by an increase in thickness of the muscle coat in arteries which are normally muscular, and by extension of muscle into smaller and more peripheral intra-acinar arteries not normally muscular at this age. It is suggested that "persistent pulmonary hypertension" of the newborn infant is, in some infants, due to a structural abnormality of the pulmonary circulation which is present at birth.


Neonatal hyperuricemia.

Neonatal hyperuricemia. Serum concentrations and urinary excretion of uric acid were measured in ten normal newborn infants and in 13 patients with the idiopathic respiratory distress syndrome. In the normal infants, serum urate increased from a mean value of 6.0 mg/dl in cord blood to 7.0 mg/dl at 24 hours, followed by a decrease to 3.5 mg/dl over the next three days. The infants with IRDS had higher serum urate concentrations during the first three days of life, and the urinary excretion of uric acid over the period of 12 to 36 hours of age was also higher than in the normal infants. In both groups of neonates the correlation of maximal serum urate values with the urinary excretion was positive, which indicates that neonatal hyperuricemia is not due to renal retention but to increased production of uric acid. It is postulated that this overproduction results from increased nucleotide breakdown associated with perinatal hypoxia. Because of high serum and urinary uric acid concentrations, maintenance of adequate hydration and urinary flow as well as alkalinization of urine is recommended.


The relationship of serum alkaline phosphatase concentrations to sex maturity ratings in adolescents. The relationship of serum alkaline phosphatase concentrations to sex maturity ratings, age sex, and race was studied in healthy prepubertal and adolescent patients. Previous data concerning SAP concentrations in adolescents have been age related and do not give primary consideration to biologic growth during adolescence. The highest mean concentrations for girls occurred at SMR 2 and for boys at SMR 3, coinciding in each instance with peak height velocity and thus correlating with presumed maximum osteoblastic activity during growth. With increasing SMR or age, the SAP levels in both sexes decreased markedly. Black boys had higher SAP concnetrations than white boys at SMRs 2, 3 and 4, whereas black girls had higher values than white girls only at SMR 4. This study demonstrates the value of correlating the enzyme activity with sex maturity ratings rather than with chronologic age.


Neonatal narcotic abstinence: Effects of pharmacotherapeutic agents and maternal drug usage on nutritive sucking behavior. An uncoordinated and ineffectual sucking reflex is a major manifestation of neonatal narcotic abstinence and may have important consequences for the infant's subsequent well being. Measures of nutritive sucking were used to monitor the severity of neonatal narcotic abstinence in a series of infants born to narcotic-dependent mothers who were either attending the methadone clinic or else were "street addicts." In all these infants, sucking measures were significantly reduced relative to normal control subjects. Furthermore, the sucking behavior of infants born to mothers attending the methadone clinic was significantly more depressed than that of infants born to street addicts. In regard to the salutary effects of pharmacotherapy for neonatal narcotic abstinence, infants treated with paregoric approached normal control levels and showed significantly better sucking than those treated with phenobarbital or diazepam. The latter drug practically eliminated all spontaneous nutritive sucking behavior.


A study of factors that influence the severity of neonatal narcotic withdrawal. A prospective study of 196 drug-addicted mothers and their infants was conducted to determine the maternal, fetal, or environmental factors that may affect the severity of narcotic withdrawal in the infants. The severity of neonatal withdrawal did not correlate with the infant's gestational age, sex, race, or Apgar score, not to maternal age, parity, duration of heroin intake, or the level of morphine measured in the infant's urine or blood. Reduction in the amount of illumination and noise in a study nursery also did not lower the incidence of severe withdrawal in the infants. There was, however, significant correlation between the severity of withdrawal in the infant and the maternal methadone dose (p less than 0.025). It is therefore recommended that mothers on methadone treatment be put on a low dose of the drug (less than 20 mg/day) as soon as is safely possible to prevent serious withdrawal in her infant.


Treatment of skin irritation around enterostomies with cholestyramine ointment. Eight patients with inflammation of the skin about the cutaneous stoma responded to local application of a 20% cholestyramine ointment in a short period of time. Two children treated with the hydrophilic base (Aquaphor) alone did not respond to treatment. The ileal bile acid patterns of two children with ileostomies were found to be different from that of the control group. Ileostomy patients had a higher concentration for total bile acids and a higher percentage of free bile acids.


A six-year controlled trial of prevention of children's behavior disorders. Preschool interviews between a clinician and mothers were studied to determine their influence upon the behavioral patterns and learning abilities of the mother's children. After six years, 124 children of this experimental group were compared with 122 control children; the results indicated that a significant number of experimental children had fewer fears, sleep disorders, eating problems, loud modes of speech, and aggression toward others and fewer of the girls distorted events to their advantage or demanded their parents to share in joint play. A larger proportion of the experimental children had positive feelings, and to a lesser degree negative feelings, toward their mothers, but a greater number were late for school, with more of the boys being excitable and hard to control. The greater benefits, which were more apparent in the girls than in the boys, were consistent with an effectiveness of more firmly expressed views about the girls, whereas the confidence of the boys' mothers may well have been affected by too cautious an approach to discipline problems. The interviews probably had no influence on the children's learning capacities.


An attempt to identify frequency of use of technical skills and procedures by the primary care physician. Some technical skills required and learned during residency training are not often used in primary care. Pediatricians who practice primary care in rural settings for smaller communities) tend to perform a greater variety of procedures than those who practice in urban settings. Family practitioners report that they perform more of these procedures than either rural or urban practicing pediatricians. Training programs should define the skills and procedures which residents must learn to perform and should differentiate between those needed during the training period and those which will be used in primary care practice.


Fasciola gigantica Cobbold 1856 in the snail. Intramolluscan stages of Fasciola gigantica were followed experimentally in laboratory-reared Lymnaea natalensis, from the time of miracidial entry until the 85th day. Contrary to previous accounts, the miracidium was found to metamorphose directly into a first-generation redia during the first 4 days. About the 16th day, the redia migrated to the snail liver. Second-generation rediae gave rise to 3rd-generation rediae and/or cercariae by the 45th to 50th day. The release of cercariae from 3rd-generation rediae began around the 75th day, and from 4th-generation rediae after 85 days. All studies were conducted at ambient temperatures in the laboratory at Makerere University, Kampala, Uganda, in 1968-71.


Pilum pilum gen. et sp. n. (Acanthocephala: Echinorhynchidae) from freshwater fishes of the southeastern United States. Pilum pilum gen. et sp. n. is described from the warmouth, Lepomis gulosus (Cuvier); brown bullhead, Ictalurus nebulosus (Lesueur); yellow bullhead, I. natalis (Lesueur); redbreast sunfish, L. auritus (Linnaeus); bluegill, L. macrochirus Rafinesque; spotted sunfish, L. punctatus (Valenciennes); and redfin pickerel, Esox americanus (Gmelin), from the Alabama River Drainage, brown bullhead from the Mobile Bay Drainage in Alabama, and pirate perch, Aphredoderus sayanus Gilliams, from an Atlantic Coast drainage in Georgia. The new genus most closely resembles the genus Acanthocephalus; it differs from this genus in having a distinctive pear-shaped proboscis, a long neck, and hooks which abruptly differ in size.


Community ecology of helminth parasitism in an insular passerine avifauna. Three hundred and thirty specimens of 7 species of passerine birds from South Bass Island, Ottawa County, Ohio, were examined for helminth parasites. The total number of helminth specimens collected was 4,333. Forty-one helminth taxa were identified. Ten species of helminths were identified as having foci of infection on the island. An index of association for these 10 species is presented. The low association revealed between helminth species utilizing common species of intermediate hosts indicated that a single intermediate host specimen is likely to harbor infective stages of only one species of parasitic helminth. An index of similarity is presented to express the species importance relationships of the helminth faunas of the 7 species of birds: red-winged blackbirds (Agelaius phoeniceus), blue jays (Cyanocitta cristata), brown-headed cowbirds (Molothrus ater), common grackles (Quiscalus quiscula), house sparrows (Passer domesticus), starlings (Sturnus vulgaris), and robins (Turdus migratorius). The results reveal that competition between these avian species for invertebrate food resources helps to maximize the transmission of those helminth populations which utilize these same invertebrates as intermediate hosts. The aggregation of birds into mixed feeding flocks insures a heavy loading of the feeding grounds with agents infective for the invertebrate populations.


Tinaminyssus juxtamelloi sp. n. (Acari: Dermanyssidae; Rhinonyssinae) from the nasal passages of the band-tailed pigeon, Columba fasciata, in New Mexico. Tinaminyssus juxtamelloi sp. n. is described from the nasal passages of Columba fasciata in New Mexico. The new species is most similar to Tinaminyssus melloi (Castro) 1948 and T. turturi (Fain) 1962, but differs in (1) possessing only 5 pairs of ventral opisthosomal setae, (2) presence of 3 pairs of enlarged setae on the dorsal opisthosoma at the posterolateral margin of the podosomal plate (1 pair) and at the lateral margins of the opisthosomal plate (2 pairs), (3) elongate shape and larger size of the poststigmatic plates, and (4) chaetotaxy and solenidiotaxy of the legs, especially tarsus I with a cluster of 4 solenida and 1 club-shaped solenidion on the apex of the dorsum. The relationships of this with allied species of the genus Tinaminyssus from columbiform birds are briefly discussed.


Dermacarus jonesi sp. n. (acari: Labidophorinae: Glycyphagidae) from Peromyscus maniculatus from western North America. A new species of labidophorine hypopus, Dermacarus jonesi, is described from Peromyscus maniculatus from Washington, USA, and British Columbia, Canada. A single individual was also found on Sorex sp. from California.


Immunity to monomorphic Trypanosoma brucei: humoral response. Trypanosome-agglutinating antibodies, predominantly of the IgM class, are formed in T. brucei-infected rats cured with Berenil (diminazene). The duration of Berenil prophylaxis following administration of a minimum curative dose is approximately 28 days. Rechallenge of drug-cured animals with homologous organisms results in the production of IgG, indicating an apparent absence of interference under these conditions with B-cell, T-cell cooperativity.


Development of the large American liver fluke, Fascioloides magna, in white-tailed deer, cattle, and sheep. The comparative development of Fascioloides magna in white-tailed deer, cattle and sheep has been studied. Flukes were recovered from 72% of 32 deer administered 40 to 500 metacercariae, from 82% of 11 cattle administered 10 to 500 metacercariae, and from 53% of 15 sheep administered 8 to 200 metacercariae. The percentage recovery of the flukes administered as metacercariae was 4.1% of 6,130 in deer, 5.7% of 2,510 in cattle, and 4.7% of 1,213 in sheep. Flukes were recovered only from livers of infected deer, while in cattle, 1 fluke was also found in the lungs of each of 2 animals. In sheep, all but 10 flukes were recovered from the livers; 6 were found in the lungs and 4 in the abdominal cavities. The black iron porphyrin pigment associated with F. magna infection was found to be most widespread in cattle and sheep, but was also a pathognomonic feature in deer. Growth of the fluke was similar in all 3 host species tested, but eggs were passed only from deer, the normal definitive host. In cattle, the eggs were retained in the liver, and F. magna was lethal to sheep before its own maturity was attained. In cattle and deer, flukes matured approximately 7 months after exposure, but immature migrating flukes were found 12 months after infection and apparently can remain in this retarded state for an undetermined period of time.


Ultrastructure of Pharyngostomoides procyonis Harkema 1942 (Diplostomatidae). I. Observations on the male reproductive system. Spermatogonia, nutritive cells, and developmental stages of spermatids were observed with the electron microscope. Spermatogonia are near the surface of the testis and contain large nuclei and comparatively little cytoplasm. Nutritive or supporting cells are associated with the spermatogonia. Early spermatids are characterized by a circle of mitochondria around the nucleus. Late spermatids have 2 parallel free flagella separated by a cytoplasmic process, and a nucleus containing electron-dense strands of chromatin arranged in coils or concentric layers. Mature sperm have 2 flagella enclosed by cytoplasm. Their nuclei contain dense, fibrillar chromatin. A microtubule-organizing center (MTOC) found between basal bodies of spermatids is described. Descriptions are presented of the seminal reservoir, seminal vesicle, and the sperm found in those organs.


Studies on resistance in snails. 3. Tissue reactions to Echinostoma lindoense sporocysts in sensitized and resensitized Biomphalaria glabrata. The resistance of Biomphalaria glabrata snails that have been sensitized by various levels of irradiated or nonirradiated Echinostoma lindoense miracidia increased after a second challenge infection with nonirradiated miracidia of the same species. This was demonstrated by increased suppression of migrating capacity of invading sporocysts, an accelerated host tissue reaction, and a greater tendency of snail amebocytes to flatten while attacking the parasite. Three methods of elimination of invading sporocysts were observed: (1) encapsulation by amebocytes followed by destruction of the sporocysts; (2) expulsion of the sporocyst through the host epithelium after its encapsulation in the subepithelial tissues; (3) blockade of the parasite's entry into subepithelial tissues by a localized amebocyte aggregation. The basic mechanism of host snail response to a single or a repeated challenge infection appears to be similar, though an anamnestic reaction is evident in the accelerated response following a second challenge exposure.


Corrigia Obscura Sp. N. (Trematoda: Dicrocoeliidae) from the North American black duck. Corrigia obscura sp. n. was found in the pancreatic ducts of a black duck, Anas rubripes. This is the first record of the genus Corrigia from an anseriform bird and from North America. Corrigia obscura differs from other Corrigia spp. by having a greater relative forebody length and greater relative body width. Noticeable hyperplasia and sloughing of the wall of the pancreatic ducts were associated with this infection.


Scanning electron microscopy of the integumental surfaces of Schistosoma haematobium. The integumental surfaces of critical point dried S. haematobium were studied by scanning electron microscopy at 34 to 8,000 magnifications. There are marked differences between the surface structures of male and female as well as from one part of the same parasite to another. The surface of the male schistosome is moderately rough while that of the female is relatively smooth. SEM reveals certain basic features such as spines in the oral sucker and the acetabulum of both sexes which may facilitate rasping and/or attachment of the parasite for residence in the bloodstream of the definitive host. The lining of the gynecophoral canal is roughened by minute spines. The presence of a gynecophoral fold may enhance anchorage of the female in the grasp of the male. The significance of visualization of surface features by SEM as a means for differentiating species is not yet known.


Some trypanorhynch cestodes from Hawaiian fishes, with descriptions of four new species. Examination of teleost and elasmobranch fishes for cestodes from the Pacific Ocean off the Hawaiian Islands resulted in the recovery of 7 species of trypanorhynchs, 4 of which are new. The new species are Pseudogrillotia basipunctata, Pterobothrium hawaiiensis, Prochristianella micracantha, and Nybelinia basimegacantha. Tentacularia coryphaena Bosc 1797, Dasyrhynchus giganteus (Diesing 1859), and Parachristianella monomegacantha Kruse 1959 represent new host and distribution records. The family Pseudogrillotidae Dollfus 1969 is emended.


Adsorption of bile salts by the cestodes, Hymenolepis diminuta and H. microstoma. The accumulation of purified sodium taurocholate (NaTC) and sodium glycocholate (NaGC) by Hymenolepis diminuta and Hymenolepis microstoma (Cestoda: Cyclophyllidea) was determined using radioactive bile salts. H. diminuta reached equilibrium levels of approximately 120 nmoles NaTC/g dry wt and 300 nmoles NaGC/g dry wt. Presentation of the bile salts in mixed micelles with 0.35 mM oleic acid did not alter these values. With H. microstoma, the maxima were 195 nmoles NaTC/g dry wt and 614 nmoles NaCG/g dry wt. These values were similarly unaffected by the addition of 0.35 mM oleic acid to the micelles. Equilibrium values of this magnitude, in media containing as much as 25 or 30 mM bile salt, and the maintenance of this level during incubations of 15 to 60 min eliminated the possibility that the accumulation was by diffusion or by any form of mediated transport into the worm. The accumulation on NaTC by H. diminuta was [Na+] independent, and insensitive to ouabain, DNP, and high [K+]. These observations, the maintenance of different levels of NaTC and NaGC, and the failure of the 2 bile salts to compete indicated that there was no active excretion mechanism operating in a fashion similar to the active transport of bile salts in the vertebrate small intestine. It was concluded that the accumulation of NaTC by H. diminuta was actually adsorption to the tegument. Comparable, although more limited, experiments extended this conclusion to the accumulation of NaGC by H. diminuta and of NaTC and NaGC by H. microstoma. It is suggested that bile salt monomers, rather than intact micelles, adsorb to specific loci on the tegument.


Effect of bile salts on the absorption of glucose and oleic acid by the cestodes, Hymenolepis diminuta and H. microstoma. The uptake of 2 mM 14C-glucose by H. diminuta during 1-min incubations was inhibited by addition of 10 mM sodium taurocholate (NaTC) to the incubation media. Preincubation in 10 mM NaTC for 30 min did not increase the inhibition, suggesting that the inhibition was competitive. This was confirmed with a standard Lineweaver-Burk experiment. Addition of 0.35 mM oleic acid to the NaTC micelles did not alter the level of inhibition. Sodium glycocholate (NaGC) did not inhibit the uptake of glucose by H. diminuta. The uptake of glucose by H. microstoma was also inhibited by NaTC, and was not affected by NaGC. H. diminuta absorbed 3.62 mumoles of oleic acid/g dry wt during 15-min incubations in mixed micelles of 10 mM NaTC and 0.35 mM oleic acid. The total uptake was determined as the sum of the ethanol extractable and nonextractable 3H-oleic acid. In 15 mM NaTC, the uptake of oleic acid was reduced by 50%; at 30 mM NaTC the uptake of oleic acid decreased by half again. Substituting NaGC for NaTC, the greatest uptake of oleic acid, 2.63 mumoles/g dry wt, was from mixed micelles of 15 mM NaGC and 0.35 mM oleic acid. Lesser amounts of oleic acid were absorbed from mixed micelles at 5 or 30 mM NaGC. H. microstoma exhibited a similar pattern of oleic acid uptake from mixed micelles with NaTC and NaGC. At all bile salt concentrations tested, H. microstoma absorbed more oleic acid than H. diminuta and incorporated more oleic acid into the nonextractable pool. The possible roles of bile salts in the absorption of oleic acid as indicated by the results herein are discussed.


Comparison of the uptake of vitamin B12 by Spirometra mansonoides and Hymenolepis diminuta and the functional groups of B12 analogs affecting uptake. Uptake of 57Co-vitamin B12 (CN-Cbl) by spargana (larvae) of the pseudophyllidean tapeworm, Spirometra mansonoides, was affected by temperature, was saturable with respect to concentration of CN-Cbl in the medium, and was inhibited in the presence of several structural analogs of CN-Cbl. In uptake studies with various analogs it was found that chemical modifications which altered the benzimidazole moiety greatly reduced the ability of the worm to take up these analogs. Modifications in which the amide groups of the propionamide side chains were removed, resulting in carboxylic acid derivatives, showed greatly reduced transport properties. The C-13 epimer in which the e-proprionamide side chain is no longer on the benzimidazole side (lower) of the molecule but is inverted to a position on the upper side was freely taken up. The pharmacological implications of this last observation are discussed. Adult Hymenolepis diminuta did not take up CN-Cbl in vitro, which correlated with the finding that no CN-Cbl was detected in the worm by Ochromonas malhamensis assay.


Effects of scoring norms on adolescent psychiatric patients' MMPI profiles. Effects of employing standard adult and age-appropriate norms on the profile elevation, patterning and classification of adolescent patients' MMPI profiles were examined. More elevated and more often psychotic profiles were obtained with adult norms. Some sex differences were observed, but patient race was not an important source of profile variation.


Some properties of the ego-resiliency subtle scale of the MMPI. The Ego Resiliency-Subtle (ER-S) scale was developed by Block (1965) as a social desirability free measure of the first factor of the MMPI. The purpose of the present experiments was to determine whether or not the 40-items comprising the ER-S scale remain neutral regarding social desirability and if the subject's score on the scale remains constant when taken out of the context of the other MMPI items; if so, the ER-S scale could be used as a screening device. Experiment I demonstrated that the items were not neutral regarding social desirability when taken out of context, but Experiment II indicated that this did not influence the responses subjects gave to the items. Because a memory factor may have been operating in Experiment II, a third experiment was conducted to minimize this factor resulting in a male-female vs. embedded-alone interaction and an order of presentation vs. embedded-alone interaction.


A statistical note on "differential misdiagnosis of blacks and whites by the MMPI". This report presents a critique of the conclusion by Strauss et al, that MMPI diagnostic decision-making rules derived from whites are inapplicable to blacks. It is shown that for the data from two of their three MMPI indices, a multiple discriminant function and the Goldberg Index, there was no clear evidence for greater misdiagnosis among blacks than whites when the hit rates among psychotics, behavior disorders or both are examined. For the third measure, semiactuarial profile analysis, the results show less diagnostic accuracy for blacks psychotics, but this one result does not warrant a broad generalization. A preferable method of analysis and a source of potential bias in one of the measures are pointed out.


Extraversion: sociability and impulsivity? The sociability and impulsivity components of extraversion were studied. Thirty experimental items were written to assess different aspects of sociability and impuslivity. These items, along with the 24 extraversion items of the MPI, were administered to 146 college students. Factor analyses of experimental items indicated that neither sociability nor impulsivity is unitary. Correlations among these sociability and impulsivity factors and the MPI extraversion items indicated that MPI extraversion is essentially a measure of one aspect of sociability: the quantity of social relationships. Extraversion touches on but does not adequately sample either the intensity (quality) of social relationships or aspects of impulsivity.


Primitive drive-dominated thinking: relationship to acute schizophrenia and sociopathy. To investigate primitive drive-dominated thinking in schizophrenic disorders and sociopathic behavior, responses on the Rorschach and other personality tests of 171 acute psychiatric patients were assessed using Holt's system. Results suggested that: (a) Acute schizophrenics were high on primitive drive content, but this was also characteristic of some nonschizophrenics, and other types of disturbed thinking were even more prominent in schizophrenics. (b) There were no significant differences between process and reactive schizophrenics in expression of primitive drive content. (c) Males showed more drive-dominated thinking than females (p less than .10), although sex was not a powerful variable. (d) Depressives showed less drived-dominated thinking than nondepressive (p less than .05). (e) Patients high on sociopathic or rule-breaking behavior tended to show more primitive drive-dominated thinking (p less than .01).


Factor specific differences in locus of control for emotionally disturbed and normal children. The Nowicki-Strickland Locus of Control Scale for Children was given to 20 normal and 20 emotionally disturbed children to investigate the differences between the two groups on self-reported locus of control. The locus of control score and scores for each separate factor were calculated. Separate analyses of variance indicated that emotionally disturbed children did not differ from normals on overall locus of control nor on four of the five factors. However, one factor, Helplessness, differentiated the two groups with emotionally disturbed children endorsing more Helplessness items. The results are discussed in terms of factor specific methodology and in regards to the clinical relevance of Helplessness as a key factor.


Self-image disparity, repression-sensitization, and extraversion-introversion: a unitary dimension? To determination (1) whether self-image disparity, repression-sensitization, and extraversion-introversion intercorrelated to a degree indicative of a unitary personality dimension and, (2) whether the interrelationships among these variables was accounted for by cognitive developmental variance, Byrne's Revised Repression-Sensitization Scale, Giedt and Downing's Extraversion-Introversion Scale, and two measures of self-image disparity were administered to 20 male college freshmen and 20 male seniors. All the correlations among the four measures were significant, but none correlated significantly with cognitive development, as measured by SATs. Factor analysis yielded a clearcut personality factor and a clearcut cognitive factor, indicating that the personality measures reflect a unitary dimension, even after cognitive developmental variance is extracted.


WAIS picture arrangement and premorbid social competence among process schizophrenics. A study with male process schizophrenics suggested that the Picture Arrangement (PA) subtest of the WAIS was related to a measure of social competence. There was evidence that the PA subtest may measure an entity such as social intelligence which is different from overall intelligence.


On the assessment of sexual orientation: a reply to Anderson. In response to Anderson's (1975) objections to Stone and Schneider's validation study of the Wheeler signs of homosexuality in the Rorschach, both the scientific and ethical-moral grounds for assessing sexual orientation were discussed. With respect to these two issues, it was argued that (a) an individual's sexual behaviors and attitudes, which includes sexual object preference, exert a significant influence on major portions of an individual's life and thus requires clinical assessment, and (b) only by gathering knowledge about human functioning in all domains can we effectively combat inappropriate stereotyping and prejudice, such as that which still exists towards homosexuals today.


Evaluation of ego strength based on certain Rorschach variables. Despite the importance of the assessment of ego strength for appropriate assignment of clients for psychotherapy and/or rehabilitation, existing techniques have not fulfilled expectations. A method for assessing ego strength through the Rorschach Test independent of clinical criterion is proposed. In addition to certain variables of Klopfer's RPRS (M+, FM+, FC+ plus CF+), sharply preceived space responses are included. They constitute a highly intercorrelated global measure of ego strength and are also highly correlated to a relatively independent Rorschach variable of global ego efficiency, i.e. integrated whole responses. In accordance with prediction, non-controlled color responses as well as accuracy of form perception did not correlate in a non-clinical sample with either measure of ego strength.


Chemical constituents of fruit of Cocculus carolinus D.C. (Menispermaceae). A phytochemical investigation of an ethanolic extract of the fruit of Cocculus carolinus resulted in the isolation and characterization of the alkaloids, cocculolidine and cocculine. The cyccculine, magnoflorine, and palmatine, previously reported in the stems and leaves of this species, were also isolated and identified.


Synthesis of 5-hydroxy-1-((5-(p-nitrophenyl)furfurylidene)-amino) hydantoin, a metabolite of dantrolene. The synthesis and structural elucidation of 5-hydroxyl-1-[[5-(p-nitrophenyl)furfurylidene]amino]hydantoin, a compound proposed as a metabolite of dantrolene sodium, are reported. In addition, a chromatographic comparison of the biological and synthesized materials is made.


Single-tablet enantiomeric purity assay of amphetamine by rotation enhancement. Enhancement of the optical rotation of dextroamphetamine by production of an optically active chromophore through reaction with 1-fluoro-2,4-dinitrobenzene to give alpha-methPYL-N-(2,4-dinitrophenyl)-beta-phenylethylamine is reported. This reaction forms the basis of an assay for both the content and optical purity of dextroamphetamine sulfate at single-dose levels (5 mg). Results of assays of standard solutions and of commercial tablets demonstrate the suitability of the method for the determination of enantiomeric purity and amphetamine content.


Pharmacological assessment of 3-tert-butylsydnone. The pharmacological effects of the mesoionic derivative, 3-tert-butylsydnone, were investigated. Administration to rats caused clonic convulsions. The CD50 of 3-tert-butylsydnone was 0.471 +/- 0.033 mmole/kg. Trimethadione, but not phenytoin sodium or proadifen hydrochloride, protected the rat from the effects of 3-tert-butylsydnone. After administration of this compound, pentobarbital sodium sleeping time was reduced in the rat, but blood pressure and ECG were unchanged in the dog. Pretreatment of the mouse with 3-tert-butylsydnone did not influence the LD50 of epinephrine hydrochloride. The action of methacholine chloride in the rat was not blocked, and the pupil of the rabbit eye was unaffected. Tests for analgesic and oxytocic activity were negative. Chronic administration of a small dose to the rat for 70 days had no effect on blood glucose, blood urea nitrogen, hemoglobin, or microhematocrit values.


Determination of nitroimidazoles in biological fluids by differential pulse polarography. A sensitive differential pulse polarographic assay was developed for the determination of metronidazole, ornidazole, and 2-nitro-1H-imidazole-1-(3-methoxy-2-propanol) in plasma. The compounds are selectively extracted into ethyl acetate from a protein-free filtrate of plasma, buffered to pH 7.0 +/- 0.2. The residue of the ethyl acetate extract is dissolved in 0.1 N NaOH and analyzed by differential pulse polarography for the reduction of the nitro group at approximately -0.600 v versus the saturated calomel electrode. The overall recovery from plasma was about 55 +/- 3.0% (SD) for the three compounds investigated. A TLC step after the ethyl acetate extraction may also be included to ensure specificity. This step reduced the overall recovery to approximately 45%. The sensitivity limit of detection from plasma using a 2-ml sample is 0.1 mug/ml. The assay may also be employed for the analysis of urine. The urine is adjusted to pH 7.0 +/- 0.2 and extracted with ethyl acetate, and the residue is analyzed as described for plasma. The assay was applied to the determination of ornidazole in blood and urine in the dog following 10 mg/kg po.


Effect of dioctyl sodium sulfosuccinate and poloxamer 188 on dissolution and intestinal absorption of sulfadiazine and sulfisoxazole in rats. The influence of two medicinal surfactants, poloxamer 188 and dioctyl sodium sulfosuccinate, on the dissolution of sulfisoxazole and sulfadiazine was investigated. A dramatic increase in the dissolution rate was observed at all surfactant concentrations. Drug absorption from the rat small intestine was also studied, and a significant but less dramatic increase was noted. Dissolution rate and absorption could be correlated only qualitatively. The two surfactants had no effect on the amount of sulfisoxazole excreted by the rat in 24 hr.


Polarographic determination of isosorbide dinitrate. Isosorbide dinitrate and two isomeric isosorbide mononitrates are shown to be polarographically reducible in aqueous sodium perchlorate or potassium chloride solution. The current, measured at -1.6 v, versus the saturated calomel electrode is proportional to the concentration of organic nitrate in the 10-100-mug/ml range. Inorganic nitrate produces no interference. However, the mononitrate isomers produce an additive response to isosorbide dinitrate and cannot be determined individually. The polarographic method is applicable to single-tablet assay for content uniformity determination, with precision and accuracy comparable to automated colorimetric analysis. Comparison is made between replicate analyses obtained polarographically and by IR and automated colorimetric analysis for six different commercially available formulations. The polarographic determination is sensitive, specific for nitrate esters, precise, requires little sample preparation, and utilizes relatively inexpensive apparatus.


Inhibition of synaptosomal accumulation of l-norepinephrine II: N-aryloxyalkylphentermines, quaternary d-amphetamines, and 3-aryloxypropylamines. The inhibitory potencies of a series of N-substituted phentermines on the synaptosomal uptake of l-norepinephrine were found to be similar to those of the corresponding amphetamines. Quaternization of N, N-dimenthyl-d-amphetamine diminished, but did not abolish, its inhibitory potency, indicating that a permanently charged cation is also effective. Since the addition of an aromatic moiety at the end of a four-atom chain originating at the nitrogen of amphetamine or phentermine significantly increased inhibitor strength, several 3-aryloxypropylamines and 4-phenylbutylamine were tested, but they were much weaker inhibitors than dl-amphetamine. Thus, the observed increase in inhibitor potency apparently was not simply the result of a specific interaction of the "nonmimic" portion of the N-substituted amphetamines or phentermines.


Synthesis and biological evaluation of tetrakis(acetylsalicylato)-mu-dicopper(II). The synthesis of a copper-aspirin chelate, previously reported to be a more active anti-inflammatory agent than aspirin itself, is given. Reaction of potassium acetylsalicylate with cupric sulfate gave a stable copper complex, which analysis and molecular weight determination showed to be a 4:2 chelate structure. Oil-water partition measurements showed the complex to be 10-fold more oil soluble than aspirin. Biological evaluation in rats showed the copper complex of aspirin to be approximately equal to aspirin in reducing carrageenan-induced inflammation, but it was 1.7 times more active than aspirin in reducing the primary lesion of adjuvant arthritis. Whereas aspirin produced a 50% or greater incidence of GI erosions at doses of 100-300 mg/kg in rats, the copper complex caused no erosions in doses up to 1200 mg/kg.


Transfer of alcohols and ureas across the oral mucosa measured using streaming potentials and radioisotopes. The permeability of the oral mucosa to an alcohol and a urea series was studied using radioisotope transfer and the measurement of streaming potentials. Both methods yielded similar quantitative estimates of permeability. The rate of transfer of the smallest member of both series (methanol and urea) was greater than the second member (ethanol and methylurea). In the alcohol series, permeability increased as the chain length increased from ethanol to butanol. In contrast, the permeability of the oral mucosa to ethylurea and propylurea was less than to methylurea. However, butylurea had a greater rate of transfer than either propylurea or ethylurea.


Mild and safe procedure for hydrolyzing oximes: improved synthesis of 1,2-indandione. Four ketoximes were hydrolyzed to the corresponding ketones in 66-91% yields using 75% sulfuric acid and 37% formaldehyde at room temperature. An earlier procedure involving hydrochloric acid and 37% formaldehyde is extremely hazardous because it leads to the formation of bis(chloromethyl) ether, a potent carcinogen.


Rapid TLC determination of methadyl acetate and some in vitro metabolites. Methadyl acetate was metabolized by microsomal preparations of rat liver to yield nor-methadyl acetate and 6-(dimethylamino)-4,4-diphenyl-3-heptanol. The identification and separation of these three compounds was established by TLC, using iodoplatinate spray as a visualizing agent.


Time-dependent change in renal clearance of bethanidine in humans. Blood levels and urinary excretion rates of bethanidine were determined in three normal human subjects following oral administration of a single dose of the drug. The postabsorptive decline of blood concentration with time was noticeably slower than the corresponding decline in the urinary excretion rate. The discrepancy can be attributed to a continual decrease in the renal clearance of bethanidine throughout the study. Therefore, pharmacokinetic modeling of urinary excretion data alone would lead to erroneous conclusions concerning the persistence of drug in the blood.


New compounds: synthesis of carboxymethyl carbodithioates. The synthesis and characterization of some new carboxymethyl carbodithioates are reported.


Glass for parenteral products: a surface view using the scanning electron microscope. The scanning electron microscope was utilized to explore the internal surface of glass ampuls and vials used in parenteral products. The surface topography of USP Type I borosilicate glass containers was viewed after exposure to "sulfur," ammonium bifluoride, and sulfuric acid treatments. The scanning electron micrographs showed startling differences in the appearance of the surface regions. "Sulfur treatment" of ampuls was associated with a pitting of the surface and the presence of sodium sulfate crystals. The sulfur treatment of vials altered the glass surface in a characteristically different manner. The dissimilarity between the surface appearances was attributed to the method of sulfur treatment. Ampuls exposed to sulfuric acid solutions at room temperature did not show the pitting associated with the sulfur treatment. Scanning electron micrographs of ammonium bifluoride-treated ampuls showed a relief effect, suggesting that the glass was affected by the bifluoride solution but that sufficient stripping of the surface layer did not occur to remove the pits associated with the sulfur treatment. Flakes emanating from the glass were identified with the aid of the electron microprobe. Scanning electron micrographs showed that these vitreous flakes resulted from a delamination of a thin layer of the glass surface. It is concluded that the scanning electron microscope, in conjunction with other analytical techniques, is a valuable tool in assessing the quality of glass used for parenteral products. The techniques studied should be of particular importance to the pharmaceutical industry where efforts are being made to reduce the levels of particulate matter in parenteral dosage forms.


Determination of coumarin and umbelliferone mixtures in whole blood by spectrophotofluorometry. A spectrophotofluorometric method is described for the quantitative analysis of coumarin, umbelliferone, and mixtures thereof in whole blood. The two drugs were selectively isolated from blood by solvent extraction. Analysis of the isolated coumarin was based on the measurement of the fluorophore at activation and emission wavelengths of 361 and 491 nm, respectively. The fluorophore was obtained by irradiating an alkaline methanolic solution of the drug with UV light. A linear relationship between fluorescence and concentration existed over the concentration range of 0.02-0.2 mug of coumarin/ml. A mean recovery value of 94.8% was obtained from whole blood. The isolated umbelliferone was determined according to established methods at activation and emission wavelengths of 370 and 450 nm, respectively, and the limit of detection was 10 times more sensitive than previously reported. A linearity response was obtained between 1 and 10 ng of umbelliferone/ml. Good recovery data for mixtures of coumarin and umbelliferone in whole blood were obtained.


Binding of salicylate and sulfathiazole by whole blood constituents. The binding of salicylic acid and sulfathiazole to bovine whole blood, plasma proteins, and purified albumin fraction was investigated using a dynamic dialysis system. The binding profiles for salicylic acid were quite similar in bovine plasma and 4% bovine serum albumin. In contrast, the binding of sulfathiazole was significantly greater in the plasma than in solutions of fraction V bovine serum albumin. Data from dynamic dialysis binding studies of the compounds, conducted in whole blood and suspended erythrocyte systems, did not lend themselves to analysis by classical methods. Hemolysis and alteration in the nature of the protein binding sites during the binding studies were shown to be factors that could explain the unusual binding observed in the whole blood system.


Comparison of antimicrobial activity of nuclear-substituted aromatic esters of 5-dimethylamino-1-phenyl-3-pentanol and 3-dimethylamino-1-phenyl-1-propanol with related cyclic analogs. A series of six aromatic esters of both 5-dimethyl-amino-1-phenyl-3-pentanol and 3-dimethylamino-1-(2-phenylcyclohexyl)-1-propanol was prepared. Antimicrobial evaluation showed that the cyclic analogs had approximately twice the activity of the open chain series; in particular, the o-chlorophenyl ester showed pronounced activity against three pathogenic fungi at approximately 10 ppm. Aromatic esters of 3-dimethylamino-1-phenyl-1-propanol were prepared and demonstrated lower activity than two esters of 2-dimethylamino-1-phenylcyclohexanol. The screening results showed that the best activity was found when a dimethylene chain was present between the phenyl ring and the carbon atom bearing the acyloxy function and that the cyclic derivatives were more active than their more flexible counterparts.


Spectrophotometric determination of sodium nitroprusside and its photodegradation products. A specific spectrophotometric method of analysis for sodium nitroprusside was developed utilizing the molar absorptivity values at the maxima appearing in the electronic spectrum at 394 and 498 nm that may be attributed to metal d leading to pi* NO transitions. These measurements appear to be indicative of the unaltered nitroferricyanide complex. A reaction sequence is postulated for aqueous solutions of nitroprusside exposed to normal artificial light. Evidence suggests that one species in the sequence is nitroferricyanide in a higher energy state but with the nitrosyl moiety still present in the coordination sphere, which exhibits an increased molar absorptivity at 394 nm. The molar absorptivity at the 498-nm maximum remains unchanged. Corroborating polarographic data are presented.


Effect of solvent flow Reynolds number on dissolution rate of a nondisintegrating solid (potassium chloride). An apparatus for measuring dissolution rates of solids in the form of disks was designed to possess the following features. The solvent flowed continuously and reproducibly past the disk at various rates associated with calculable Reynolds numbers, Re. The effluent solution was adequately mixed before analysis. The concentration of dissolved solute was much less than the solubility. The surface area of the disk in contact with the solvent was constant during measurements. The dissolution rate of the disk was reproducible, and the disk and its surface could be readily characterized. The apparatus was tested at 37 degrees with compressed potassium chloride and water. The intrinsic dissolution rate, G, was a linear function of Re from Re=360 to greater than 6000. This relationship enabled one unknown constant in each dissolution theory to be expressed in terms of Re. For the diffusion layer model, the thickness of this layer, calculated from the experimental value of G, agreed well with that calculated from the various physical properties, provided that natural convection did not predominate. The dissolution of potassium chloride in this system was, therefore, controlled by diffusion.


Fluorocarbon aerosol propellants VIII: solubility of trichloromonofluoromethane in dog blood and tissue homogenates. The solubility of trichloromonofluoromethane in dog blood and tissue homogenates was measured indirectly using the head-space method at 37 degrees. These values, except that in dog blood, were used to estimate the solubility in the whole tissues or organs. In most cases, the solubility so obtained was independent of equilibrium concentration. However, a considerable concentration dependence for the solubility was observed in dog heart and kidney. The highest solubility found was in dog fat versus air, i.e., 45.6, which is almost 220 times higher than the solubility in water or normal saline. Fat solubilization and specific binding interactions appeared to be the two major factors in determining the solubility. The pharmacokinetic implications of such findings are discussed.


Fluorocarbon aerosol propellants IX: adsorption on activated charcoal. The adsorption of three commonly used fluorocarbons, trichloromonofluoromethane, dichlorodifluoromethane, and dichlorotetrafluoroethane, on activated charcoal was studied at 25 degrees. The adsorption versus pressure plots are consistent with the Brunauer, Emmett, and Teller (BET) type II and type IV isotherms, which can be explained as the condensation of the gaseous molecules in a wide range of pores in the activated charcoal. The monolayer capacity derived from the BET equation is discussed and used to estimate the volume of micropores present in the activated charcoal. Below the relative pressure of 0.01, the adsorption deviated from the BET plot. The deviation revealed that the adsorption capacity and adsorption potential at these lower pressures are greater than the extrapolated values. It is concluded that activated charcoal can be used effectively to remove propellants from the air in pollution control.


Fluorocarbon aerosol propellants X: pharmacokinetics of dichlorotetrafluoroethane in dogs. An intravenous dosage form of dichlorotetrafluoroethane, a common fluorocarbon aerosol propellant, was formulated in polyethylene glycol 400 for single dosing to unanesthetized dogs. A  three-compartment open model was proposed for the disposition of this compound in dogs, with average half-lives of 1.3, 9.6, and 50.8 min for the three disposition phases. An analysis of tissue compartment distribution following a single dose showed that it took about 2 hr to achieve pseudo-distribution equilibration, following which more than 90% of the propellant remaining in the body was retained in the tissue compartments. Pulmonary clearance and volumes of distribution were calculated considering the first-pass effect through the lungs. The volume of distribution was approximately 10 times the body weight in terms of blood concentration, and about 84% of the propellant was cleared from the blood passing through the lungs in each cycle.


Mass spectral and pyrolytic behavior of the two main products of phenylbutazone degradation: simulation of unusual mass spectral fragmentation. The two major routes of degradation of phenylbutazone (I) are oxidation and hydrolysis. Hydrolysis gives rise to n-butylmalonic acid mono(N,N'-diphenyl)hydrazide (II). Oxidation at the C-4 position yields 1,2-diphenyl-4-n-butyl-4-hydroxpyrazolidine-3,5-dione (III), which is readily hydrolyzed to n-butyltartronic acid mono-(N,N'-diphenyl)hydrazide (IV). Whereas the mass spectra of I, III, and the methyl esters of carboxylic acids II and IV all demonstrate major peaks corresponding to their respective molecular ions, the mass spectrum of II is essentially identical with that of I, suggesting facile dehydration. In the mass spectrum of IV, the peak of highest mass is found at m/e 205; no peak could be perceived corresponding to the molecular ion or to loss of water, carbon dioxide, or both of these elements from the molecular ion. Under normal pyrolytic conditions, II is decarboxylated to N-caproylhydrazobenzene (V) and IV is readily dehydrated to yield III. The mass spectral fragmentation of IV was successfully simulated in the laboratory to give an excellent yield of aniline and alpha-keto-N-caproylaniline (VI) (mol. wt. 205). The probable course of this unusual transformation was elucidated from studies of the accelerated decomposition of IV and derivatives considered as possible intermediates in the degradation process.


Spectrophotometric determination of p-aminophenol alone or in the presence of acetaminophen. Small amounts of p-aminophenol were analyzed quantitatively by mixing with 4-nitro- or 2,4-dinitrobenzaldehyde in neutral alcoholic solution and then quantitatively forming the respective Schiff bases, 4'-nitro- and 2',4'-dinitrobenzylidene-4-hydroxyaniline, by evaporating the alcoholic solutions to dryness. The Schiff bases thus formed were examined spectrophotometrically. This procedure was also used for the determination of p-aminophenol in the presence of its degradation products. It was necessary, however, to separate the respective Schiff bases by TLC from the degradation products and the reaction mixture prior to spectrophotometric examination. Small amounts of p-aminophenol present in acetaminophen were quantitatively determined by applying the procedure to a water-ethanol (95:5 v/v) extract of the samples of acetaminophen. TLC was used to separate the respective Schiff bases from the reaction mixture and acetaminophen prior to spectrophotometric examination.


Fully automated analysis of phenylbutazone in plasma and urine. A rapid, automated method for the determination of phenylbutazone in plasma and urine was developed. The method offers distinct advantages over earlier procedures and is particularly suitable for large-scale bioavailability studies.


GLC determination of quinidines in human plasma. Human plasma was made alkaline and extracted with methylene chloride. To the extract was added the internal standard, cinchonine, followed by evaporation to dryness. The resultant residue was dissolved in a methanolic solution containing trimethylanilinium hydroxide. This solution was assayed by GLC for quinidines (quinidine and hydroquinidine). Evaluation of the method over a 0.5-10-mug/ml range in human plasma gave an overall precision and accuracy of +/- 4.5% (RSD and RE). Plasma of several patients was analyzed by the present method as well as by a fluorometric method for the level of quinidines. Results from the two methods were comparable.


Synthesis of histamine analogs.

Synthesis of histamine analogs. Nineteen histamine analogs were synthesized, and their biological actions were compared to those of histamine in blood pressure, gastric secretion, and nasal decongestant screens. The analogs include N-substituted 4-aminoethylimidazoles, N-substituted 2-pyridylethylamines, 2-pyridylcyclohexylamines, and 2-pyridylcyclopropylcarbamates. None of the compounds showed appreciable histamine agonist or antagonist properties.


NMR analysis of pharmaceuticals XIV: determination of amyl nitrite in its inhalant dosage form. An NMR procedure is described for the analysis of amyl nitrite as a drug entity and in inhalant dosage forms. The choices of solvent (carbon tetrachloride) and internal standards (biphenyl or benzyl benzoate) were made with respect to stability problems and the presence of stabilizers in the formulation. The method is precise, with a standard deviation of +/-0.5. The NMR results of synthetic solutions and commercial preparations were compared with those obtained by a published relative NMR procedure and a compendial titrimetric method. The results were generally satisfactory.


Solubility of straight-chain and branched alkyl barbiturates in straight-chain alcohols. The solubilities of a series of chemically related barbiturates, including some medically useful ones as well as phenobarbital, were determined at 25 degrees in the straight-chain alcohols methanol through butanol. The solubility values are given in both milligrams per milliliter and the mole fraction notation. The solubility in methanol was the highest and decreased nonlinearly for the solubility in 1-butanol. In several cases, mole fraction solubility gave shouldering or peaking as a function of the carbon number of the solvent. This series of barbiturates was broken down into two subsets of straight-chain and branched alkyl barbiturates, and solubility ratios in these subsets were considered.


Influence of hydrophobic materials on dissolution of a nondisintegrating hydrophilic solid (potassium chloride). A nondisintegrating hydrophilic solid was covered with coatings of hydrophobic materials as a model to study their influence on dissolution rates. Both solution and sublimation techniques were satisfactory for producing coatings of stearic acid. Only a sublimation method was applicable to magnesium stearate, but the resulting coating consisted mainly of a pyrolysis product, stearone. Reductions in dissolution rates in a continuous-flow system could best be interpreted by assuming that they reflected changes in the area of the hydrophilic solid exposed to the solvent. This concept is based on the assumptions that the intrinsic dissolution rate of uncoated potassium chloride did not change and that no dissolution occurred from coated areas. The most important factors controlling the dissolution rate were the strength of attachment of the hydrophobic coat to the surface of the hydrophilic substrate and the thickness of the coat.


GLC identification and determination of 3,4-methylenedioxyamphetamine (MDA) from plasma and urine. A GLC method for qualitative and quantitative determination of 3,4-methylenedioxyamphetamine in biological fluids is described. After extraction of the drug and the internal standard, 4-methoxyamphetamine, from plasma and urine, the solvent is evaporated and the residue is mixed with 20 mul of freshly distilled ether. Aliquots (1-2 mul) then are injected into the gas chromatograph. Both the drug and the internal standard give well-separated symmetrical peaks. Flame-ionization detection allows concentrations of 0.125 mug of 3,4-methylenedioxyamphetamine from plasma to be determined with a precision of 3.16%. The method is applicable to the estimation of 4-methoxyamphetamine, employing 3,4-methylenedioxyamphetamine as the internal standard. For identification purposes, various derivatives such as Schiff bases, isothiocyanates, trifluoroacetates, and heptafluorobutyrates of both compounds were formed following extraction from urine and their GLC behavior was investigated. Derivative formation was confirmed by GLC-mass spectrometry. Mass spectral data for these derivatives are presented.


Quantitative assessment of factors contributing to mottling of colored tablets I: manufacturing variables. By using a recently developed method for quantifying the degree of mottling of colored tablets, the effects of manufacturing variables such as the method and temperature of granule drying, granule size, and compaction pressure were investigated. Tablets of dibasic calcium phosphate colored with FD&C Blue No. 1 dye were used. Drying temperature had little effect, but the method of granule drying, granule size, and compaction pressure were major influences on mottling. Mechanisms to explain these results, based on the migration of dye during the drying process, are proposed.


Quantitative assessment of factors contributing to mottling of colored tablets II: formulation variables. The effects of several formulation variables were quantified with respect to factors affecting tablet mottling. Tablet mottling occurred with several commonly used binders and could not be prevented by using highly viscous binding solutions. However, mottling was reduced initially by increasing granule strength. Tablet diluents and dye-adsorbent materials had a profound effect on mottling, not by preventing dye migration but by affecting granule fragmentation on compression and the extent to which the dye-deficient material at the center of the granule was revealed. The lake form of FD&C Blue No. 1 was found to bleed in the presence of diluents that raised the pH of the granulating fluid above 6.4. Anionic impurities in the diluents also caused leaching of free dye and, consequently, increased tablet mottling. The conclusions from this study and previous papers were drawn together to give general principles for the production of uniformly colored tablets by aqueous granulation techniques.


Constant returns to scale for prescription dispensing in U.S. community pharmacy. By using data from a sample of 1767 community pharmacies, a total cost function was estimated by a polynomial regression of total cost on output. The Cobb-Douglas production function was estimated by a multiple linear regression of natural logarithmic transformations of output on natural logarithmic transformation of labor and capital. No economies of scale were found in prescription departments. Cost data led to a conclusion of constant marginal costs.


Drug permeation through membranes V: interaction of diazepam with common excipients. The effects of common tablet excipients on the permeation of diazepam through polydimethylsiloxane membranes and on the turnover time of goldfish were studied. The permeability coefficient decreased and the turnover time increased in the presence of talc, polysorbate 80, and, possibly, fumed silicon dioxide, but these parameters were unaffected by lactose, microcrystalline cellulose, and starch.


Effect of dimethyl sulfoxide on permeability of human skin in vitro. A diffusion flow cell is described for the continuous monitoring of skin permeability. The technique was used to study the permeability behavior of human skin subsequent to treatment with dimethyl sulfoxide. Such treatment produced an increased penetration rate of tritiated water, which was dependent upon the time of exposure and the concentration of dimethyl sulfoxide applied. Removal of the solvent resulted in partial recovery of barrier capacity. Skin, incubated in vitro in growth medium containing dimethyl sulfoxide, survived only at very low concentrations. Degeneration occurred after a few days in 4.5% dimethyl sulfoxide and much sooner at higher concentrations.


Evaluation of emulsion stability by diffuse reflectance spectroscopy. A new method is described for evaluating the stability of emulsion bases and active components contained within such emulsions. Diffuse reflectance spectroscopy (DRS) is a technique that has the capability of detecting changes in particle size, surface properties, or drug quality of emulsions as a function of time without disturbance of the system. Such physical or chemical changes are monitored by changes in the visible and UV wavelength spectral characteristics of the emulsified systems. Four basic emulsion systems were prepared and analyzed for physical stability for 6 months by three techniques: visible coalescence, particle counting measurement, and DRS. Two drugs, aspirin and ascorbic acid, were then incorporated within stable emulsion bases, and the chemical stability of these drugs was monitored by DRS for 6 months. Results were compared with concomitant quantitative drug assay procedures. Good agreement was observed when data from DRS and analytical measurements were compared. The DRS technique may be used as a supportive method, offering simplicity and expedience, with other methods of evaluating emulsion stability and drug stability within emulsified systems.


IR studies of development of order in aluminum hydroxide gels. The usefulness of deuteration in detecting the development of order in aluminum hydroxide gel by IR spectra is demonstrated. By treatment of gel samples with deuterium oxide vapor at room temperature, the relative ease with which deuteroxyl-hydroxyl exchange takes place is determined as a function of the age of the gel. The use of scale expansion in conjunction with deuteration allows detection of IR absorbance characteristic of gibbsitic material long before such detection is possible by conventional IR analysis or X-ray diffraction.


Utilization of an enantiomer as a solution to a pharmaceutical problem: application to solubilization of 1,2-di(4-piperazine-2,6-dione)propane. An enantiomer of the cytotoxic agent (+/-)-1,2-di(4-piperazine-2,6-dione)propane [(+/-)-I] (ICRF 159) was utilized to overcome a solubility problem in the preparation of a solution suitable for intravenous use. The enantiomers were about five times more soluble and melted at about 40 degrees lower than the racemic compound. This study appears to be the first reported instance in which the difference in the physical properties of a racemic compound and its enantiomers was utilized to improve a pharmaceutical formulation. The expected differences in the physical properties of racemic solids and their corresponding enantiomers are discussed briefly in relation to the three racemic modifications known to exist.


Limitations in interpretation of digoxin adsorption using averaged pharmacological response intensities. In this paper, the interpretation of averaged pharmacological effect data for the cardiac glycoside digoxin is reconsidered through a comparison with theoretically simulated data. Four parameters, with their standard deviations calculated from the best-fit biexponential equation for the experimentally derived transformed pharmacological response intensity, were the basis for the random development of a series of 17 individual sets of data with average parameters and standard deviations identical to the values found experimentally. Parameters from these 17 data sets were averaged and randomly altered as a function of the standard deviations for each average. Loo-Riegelman analyses, modified for application to the peripheral compartment, and fraction remaining to be absorbed plots were made. Results of this comparison of experimental pharmacological simulated data indicate that the presence or absence of enterohepatic recycling may not be unambiguously determined here.


Anaerobic photodecomposition of an acridan drug through energy transfer. Anaerobic irradiation of 2-chloro-9-(3-dimethylaminopropyl)acridan phosphate (1:1) (IIIa) with filtered visible light (300-400 nm) resulted in its quantitative conversion to its acridine derivative IV. Photoproduct IV exerted significant product catalysis on the reaction rate at concentrations of 5 x 10(-6) M. The anaerobic photodecomposition of IIIa to IV was catalyzed by the monosodium salt of riboflavin 5-phosphate (Ia). Loss of Ia was insignificant relative to that of IIIa, and reagents known to serve as quenchers of the triplet state of Ia retarded the reaction. Fluorescence spectra of Ia in the presence of IIIa and 1 x 10(-4) M KI indicated no quenching of the Ia singlet excited state. No deuterium isotope effect was noticed when IIIa and its deuterated derivative IIIb were subjected to anaerobic photodecomposition in the presence of Ia. It is suggested that the anaerobic photodecomposition of IIIa by visible light in the presence of Ia proceeds via a triplet-triplet energy transfer from Ia to IIIa.


Solution thermodynamics of alkyl p-aminobenzoates. Equilibrium solubilities of the first four homologous alkyl p-aminobenzoate esters were determined in methanol, ethanol, and 1-propanol at 25, 33, and 40 degrees; the esters and the alcohols comprise separate homologous series. The solution process of a solute may be considered to be the summation of two sequential steps, melting and mixing, and the magnitude of solubility depends upon temperature and the extent of interactions between solute and solvent molecules. Quantitative solute concentrations, obtained from spectrophotometric analysis, were converted to mole fractions. Statistical analysis of the logarithmic mole fraction solubilities of the aminobenzoates, which were linear with respect to both reciprocal absolute temperature and the logarithm of absolute temperature, generated enthalpies and entropies of solution, respectively. The heats of fusion and the melting points of these aminobenzoates were determined to calculate their ideal solubilities. Excess free energies and partial molal free energies of each solution were calculated from the activity coefficients of the solutes; the thermodynamic elements for these systems are discussed.


Simultaneous determination of pilocarpine and isopilocarpine in pharmaceutical preparations by liquid chromatography. A liquid chromatographic assay method is described for the simultaneous determination of pilocarpine and isopilocarpine in pharmaceutical preparations. The method involves separation of the isomers on a high-resolution ion-exchange column, followed by detection of pilocarpine and isopilocarpine by UV absorption in the 217-nm region. The specificity of the method is such that pilocarpine and isopilocarpine can be assayed separately in the presence of one another and in the presence of the excipients commonly found in commercial pilocarpine solutions. Its sensitivity for isopilocarpine is at least 25 ppm (independent of the concentration of pilocarpine). In contrast, USP methods lack both specificity and sensitivity. It is concluded that this method is applicable to the routine analysis of commercial pilocarpine preparations and is an improvement over the official methods.


Electron beam ionization mass fragmentographic analysis of tricyclic antidepressants in human plasma. A method for the measurement, in human plasma, of all tertiary and secondary tricyclic antidepressants prescribed in the United States is described. The method uses electron beam ionization GLC-mass spectrometry, employing a computer-controlled multiple-ion detector. This method, mass fragmentography, is used with internal standards for each drug. Plasma levels to as low as 10 ng/ml of the following drugs can be measured: amitriptyline, nortriptyline, doxepin, desmethyldoxepin, imipramine, desipramine, and protriptyline. Deuterium-labeled amitriptyline and imipramine are used as internal standards for those two drugs; for the other drugs, deuterated amitriptyline, nortriptyline, desmethyldoxepin, or desipramine is used. The method can measure up to 15 samples/hr, making it practical for large-scale studies of these drugs in patients. Spectra of each drug and examples of their analysis are given.


Isomeric inversion of ibuprofen (R)-enantiomer in humans. Enantiomeric compositions of the major urinary metabolites of ibuprofen [(RS)-2-(4-isobutylphenyl)propionic acid]were characterized after oral administration of the racemic mixture and oral administration of the individual enantiomers to normal human volunteers. Resolution of the diastereomeric amides, formed by reaction of the urinary metabolites with (S)-(-)-alpha-methylbenzylamine, was achieved by GLC. Only the (R)-(-)-enantiomer of the intact drug was inverted to its optical antipode, (S)-(+), in humans. However, both (S)-(+)- and (R)-(-)-enantiomers of the intact drug were transformed independently in vivo to the major metabolites, i.e., 2,4'-(2-hydroxy-2-methylpropyl)phenylpropionic acid and 2,4'-(2-carboxypropyl)phenylpropionic acid. In vivo metabolism of ibuprofen to its carboxy metabolite was not stereoselective.


Determination of methyl methacrylate in surgical acrylic cement. A methyl methacrylate cement used in hip surgery as well as in dentistry was identified and quantitatively analyzed for its monomer content in starting materials and in the finished cement by proton magnetic resonance spectroscopy. IR data indicated that the monomer continued to escape from the product after it had hardened. The presence of 21% methyl methacrylate monomer relative to the polymer was demonstrated at the time the cement normally would be inserted into the body.


Tumor inhibitors II: constituents and antitumor activity of Sarracenia flava. The chloroform extracts of the roots and leaves of Sarracenia flava showed antitumor activity against lymphocytic leukemia P-388. Lupeol was identified as one constituent responsible for this activity. Beta-Sitosterol and alpha-amyrin were isolated from the hexane extract of the roots.


Potential organ or tumor imaging agents XV: radioiodinated phenytoin derivatives. Three radioiodinated phenytoin analogs were synthesized, and tissue distribution studies were conducted in rats. Except for a greater retention of radioactivity following administration of the radioiodinated derivatives, the tissue distribution patterns were qualitatively similar to those found for 14C phenytoin. In nearly all cases, the adrenals, heart, kidneys, and liver displayed the greatest capacity to retain radioactivity. The high uptake of radioactivity observed for the thyroid was attributed to in vivo metabolic deiodination of the radioiodinated derivatives.


Permethylation of barbiturates: variation in product ratios with varying methylsulfinylmethide carbanion. Permethylation of a barbiturate with the methylsulfinylmethide carbanion and methyl iodide gave three products clearly separable by GLC. Alteration of the reaction conditions by varying the barbiturate to carbanion ratio or the barbiturate to carbanion exposure time resulted in a single product for only one examined barbiturate, secobarbital. This derivatization technique is useful for the GLC analysis of polar barbiturate metabolites, such as glucuronides, in biological fluids but is of limited value for the analysis of the parent compounds.


Synthesis of 2'-acetoxybiphenyl-2-carboxylic acid and its derivatives as potential anti-inflammatory and analgesic agents. 2'-Acetoxybiphenyl-2-carboxylic acid and a series of derivatives were synthesized. The title compound and its unsubstituted amide had both anti-inflammatory and analgesic properties. Its aminoethyl esters exhibited only analgesia. None of the compounds showed any significant antimicrobial activity.


Isolation and chemistry of alkaloids from plants of the family Papaveraceae LXVII: Corydalis cava (L.) Sch. et K. (C. tuberosa DC). From Corydalis cava (L.) Sch. et K. (C. tuberosa DC) (Papaveraceae: genus Corydalis Med.), a mixture of alkaloids (0.53%) was isolated. The main alkaloid was (+)-bulbocapnine, and the minor alkaloids were coptisine, (+)-domestine, adlumidiceine, (+)-predicentrine, protopine, (-)-capnoidine, (+)-stylopine, (+)-isoboldine, 8-oxocoptisine, 1,2-methylenedioxy-6a,7-dehydroaporphine-10,11-quinone, and corysamine. In addition, fumaric acid was obtained. Coptisine, adlumidiceine, predicentrine, 8-oxocoptisine, corysamine, 1,2-methylenedioxy-6a, 7-dehydroaporphine-10,11-quinone, and isoboldine were found in C. cava for the first time, but rhoeadine and papaverrubine alkaloids were not detected. Predicentrine and isoboldine were identified on the basis of the UV, IR, mass, and PMR spectra.


Synthesis of site-directed chelating agents II: 2-formyl-3-hydroxy-4,5-bis (hydroxymethyl)pyridine thiosemicarbazone. 2-Formyl-3-hydroxy-4,5-bis(hydroxymethyl)pyridine thiosemicarbazone was synthesized in an attempt to direct the chelating potential of this agent to the active site of the zinc-requiring enzyme pyridoxal phosphokinase. Evaluation of the antineoplastic activity of this agent in the sarcoma 180 and L-1210 leukemia systems in mice showed potent activity. The presence or absence of pyridoxine hydrochloride in the diet did not influence the degree of inhibition of the growth of sarcoma 180 ascites cells. In addition, 2-formyl-3-hydroxy-4,5-bis(hydroxymethyl)pyridine thiosemicarbazone was inactive against a subline of sarcoma 180 resistant to 1-formylisoquinoline thiosemicarbazone, suggesting that the former agent may have a biochemical mechanism of action similar to that of the latter. In keeping with this expectation, 2-formyl-3-hydroxy-4,5-bis(hydroxymethyl)pyridine thiosemicarbazone inhibited the synthesis of DNA but not of RNA or protein in sarcoma 180 ascites cells in vitro.


N-bromosuccinimide assay of penicillins and cephalosporins. All penicillins and cephalosporins known to possess biological activity respond to an N-bromosuccinimide assay. The developed method is not yet usable for determining stability, but it is useful as a bulk or batching assay.


Effect of polyethylene glycol 4000 on dissolution properties of sulfathiazole polymorphs. The dissolution rates of the two polymorphic forms of sulfathiazole containing polyethylene glycol 4000 were significantly different in water. The effect of agitation on the dissolution rates also was studied. At higher stirring speeds, the dissolution rates of the stable form were affected more than the metastable form. A high concentration of polyethylene glycol 4000 seemed to affect the dissolution properties of the metastable polymorph more than the stable polymorph.


Selenium heterocycles XVIII: Synthesis and antibacterial activity of 4-substituted (1,2,3-selenadiazol-5-yl) carbamic acid esters and their sulfur analogs. 4-Substituted (1,2,3-selenadiazol-5-yl)carbamic acid esters and their sulfur analogs were prepared from the Curtius rearrangement of the corresponding carboxazides. None of the compounds showed significant antibacterial activity.


Urinary excretion of heroin and its metabolites in man. The purpose of this study was to investigate the kinetics of urinary excretion of heroin and its metabolites in human subjects. Heroin and its metabolites were determined with gas-liquid chromatography. Two studies were conducted, each using 10 subjects. After i.v. administration of heroin HC1, 10 mg/70 kg, urine was collected every 8 hours and ad libitum for 1 week in the first study and every 2 hours in the first 8 hours and then at less frequent intervals for 24 hours in the second study. Heroin, 6-acetylmorphine, morphine, the sum of conjugates (morphine plus 6-acetylmorphine) and total normorphine were determined in the first 24-hour urine and accounted for 0.5, 1.5, 7.2, 52 and 4%, respectively, of the administered dose. Conjugated morphine could be detected in the urine 96 hours after drug administration. Eighty-eight percent of the free morphine and 84% of the total morphine found in the urine were excreted in the first 8 hours. The half-lives of urinary excretion of free morphine, 6-acetylmorphine, the sum of conjugates (morphine plus 6-acetylmorphine) and total normorphine were 1.28, 1.31, 2.76 and 2.72 hours, respectively. It was concluded that heroin in the body was rapidly metabolized and its metabolites were rapidly excreted in the urine.


Physiological disposition and biotransformation of [allyl-1', 3' - 14C naloxone in the rat and some comparative observations on nalorphine. A sensitive method is described for the estimation of [14C]naloxone in biological materials. After a 1 mg/kg s.c. dose of [14C]naloxone to male Wistar rats, mean peak levels of drug in brain (506 ng/g) and plasma (119 ng/ml) were attained within 15 minutes. No persistence of drug in brain was observed at this dose. After a 10 mg/kg s.c. dose, the peak levels of naloxone in brain and plasma were 4.31 mug/g and 1.27 mug/ml, respectively, and extensive localization of extractable free drug and its minor metabolite, naloxol, occurred in tissues with high levels in kidney, spleen, lung, heart, skeletal muscle and somewhat lower concentration in the liver. The T1/2 of naloxone and nalorphine in rat brain and plasma with 1 and 10 mg/kg s.c. doses was 0.4 hour. With a 10 mg/kg dose, significant amounts of radioactivity persisted in tissues but not in plasma 96 hours after injection. The brain/plasma ratios and degree of plasma-protein binding were significantly higher for naloxone as compared to nalorphine. The amounts of free naloxone excreted as a percentage of the dose in urine and feces 96 hours after injection of the 10 mg/kg s.c. dose were 4.1 and 3.9 (for nalorphine 4.7 and 8.3); conjugated drug 15.4 and 1.2 (for nalorphine 13 and 0.9); total radioactivity 43.3 and 20.9 (for nalorphine 34.8 and 19.2), respectively. Naloxone-3-glucuronide (major), 3-sulfate (minor), naloxol and conjugated naloxol (minor), 7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphine and their conjugates were shown to be the metabolites of naloxone. In addition, tentative evidence was obtained for two polar hydroxylated metabolites (with hydroxylation presumably in the 17-side chain or in position 2 of the aromatic nucleus). 7,8-Dihydro-14-hydroxynormorphinone and 2-polar metabolites were also observed in brain. Rapid metabolism of naloxone and rapid elimination are important factors in its short duration of action. Possible relevance of these observations on differential antagonistic properties of these two antagonists are discussed.


Studies on tolerance. I. The role of the interval between doses on the development of tolerance to morphine. The effect of varying the interval between doses on the rate of development of tolerance to a series of injections of morphine was studied in two strains of rats. Morphine sulfate injections (15 mg/kg s.c.) were given at intervals of 1, 2, 3, 7, 10, 14 or 21 days to adult male Wistar/Furth or Wistar-Lewis rats and drug effect was measured by means of the hot-plate assay technique. A diminution of morphine effect on the second or subsequent injections of drug was considered to be the result of the development of tolerance. Little or no tolerance was observed with the Wistar/Furth animals when a second injection or morphine was administered 7 days after the first, although there was marked tolerance when there were shorter or longer intervals between the first two injections. Subsequent injections of morphine sulfate, given to the animals at the predetermined intervals, resulted in wiping out out the differences between all interval groups, with the exception of the 1-day group, by the fifth injection. Although the differences between the 7-day and longer or shorter intervals were not as great with the Wistar-Lewis animals, they were significant and may reflect a slightly different rate of tolerance development in the latter strain. These observations are consistent with the hypothesis that there may be two types of tolerance, one appearing very rapidly, the other taking a longer period of time to develop.


Behavioral effects of L-5-hydroxytryptophan after destruction of ascending serotonergic pathways in the rat: the role of catecholaminergic neurons. Lesions in the medial forebrain bundle of the rat produced a 68 to 74% decrease in telencephalic serotonin (5-HT) and a 30 to 43% decrease in jump threshold. L-5-Hydroxytryptophan (L-5-HTP; 37.5 mg/kg) returned the 5-HT content and jump threshold of lesioned rats to normal levels. These effects of L-5-HTP were also observed after the inhibition of extracerebral decarboxylase activity with Ro 4-4602 (50 mg/kg). Pretreatment with 6-hydroxydopamine (6-OHDA), which selectively destroys catecholamine neurons, had no effect on the jump threshold of nonlesioned rats nor did it further change the 5-HT content or jump threshold of lesioned rats. Lesioned rats pretreated with 6-OHDA demonstrated an increase in 5-HT content after L-5-HTP; however, their jump threshold remained significantly lower than that of controls. This ability of 6-OHDA to block the behavioral effects of L-5-HTP in lesioned rats was also observed after Ro 4-4602. In rats given Ro 4-4602, the accumulation of 5-HT at 90 minutes after injection of L-5-HTP was significantly correlated (r = 0.98) with total monoamine content. Thus, 6-OHDA pretreatment significantly decreased the net accumulation of 5-HT from L-5-HTP in nonlesioned rats. These rats also demonstrated further decreases in norepinephrine and dopamine content after L-5-HTP. It was concluded that L-5-HTP can be decarboxylated to 5-HT in serotonergic and catecholaminergic neurons and that the behavioral effects of L-5-HTP in lesioned rats may be due to the formation of 5-HT in catecholaminergic neurons where it may act as a "false-transmitter."


Opiate receptor interactions of benzomorphans in rat brain homogenates. Minor structural variations of benzomorphans opiates are associated with striking, unpredictable shifts in the relative extent of agonist or antagonist properties in vivo. The relative abilities of a number of benzomorphans in inhibit 3H-naloxone binding in the absence and presence of sodium in vitro show some correlations with their pharmacologic properties in vivo, although distinct exceptions exist. The ability of opiate agonists to inhibit 3H-naloxone binding is greatly reduced by sodium, while pure antagonists are affected very little, if at all, and mixed agonist-antagonist benzomorphans display an intermediate response.


Reduction of tryptophan hydroxylase activity and 5-hydroxytryptamine concentration in certain rat brain nuclei after p-chloroamphetamine. High-pressure liquid chromatography and mass fragmentography have been used to determine tryptophan hydroxylase activity and 5-hydroxytryptamine (5-HT) concentration, respectively, in certain rat brain nuclei. (+/-)-p-Chloroamphetamine (100 mumol/kg i.p.) decreased enzyme activity in 5-HT terminals of the caudate, hippocampus and septum to a minimum level within 3 days. In hippocampus, but not in septum, the enzyme activity and 5-HT content remained maximally depleted (about 80%) for as long as 2 months after the p-chloroamphetamine injection. Of the 5-HT cell body areas investigated, only in the B9 nucleus was the tryptophan hydroxylase activity and 5-HT content still significantly reduced (about 25-50%) at 21 and 60 days after the drug injection. The enzyme activity and 5-HT content of the B7 and B8 nuclei were not significantly different from control values at these times. These results suggest that the primary site of action of p-chloroamphetamine is on nerve terminals followed by secondary effects on serotonergic cell bodies.


Effect of tetrahydrocannabinols on 3H-acetylcholine biosynthesis in various rat brain slices. The effects of delta8- and delta9-tetrahydrocannabinol on the biosynthesis of 3H-acetylcholine (ACh) from 3H-choline in cortical, hypothalamic and striatal rat brain slices were examined. The two cannabinols were found to inhibit the synthesis of 3H-ACh in the three brain regions. Treatment with cannabidiol did not alter ACh synthesis. Delta8-tetrahydrocannabinol was approximately twice as effective as the delta9-isomer. This effect was not associated with alterations in striatal and cortical choline acetyltransferase or with an impaired high-affinity uptake system for choline in the striatum. Treatment with delta8- and delta9-cannabinols, likewise, did not change striatal choline and ACh levels. Antagonism of the ACh biosynthesis inhibition occurred when slices from treated animals were incubated in depolarizing concentration of K+ ion. These results suggest that the inhibition of ACh synthesis observed in tetrahydrocannabinol-treated rats may be related to interference with the propagated action potential or with the depolarization process in cholinergic neurons.