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We report our observations about familial segregations of chromosomal aberrations: the simple forms and complex rearrangements. Congenital malformations and mental retardation, can be present both in unbalanced and in balanced translocations. Various hypotheses have been proposed to explain this phenomenon: in particular a possible "position effect" or genic mutation or genomic imprinting. In our study we have used both standard techniques and techniques with high resolution banding to investigate if the rearrangements were balanced or not. Molecular study and gene dosage have been used when possible, to define the correlation with the clinic phenotype.

The extent to which oral glutamic acid hydrochloride decreases mean gastric pH in fasting persons with and without simulated hypochlorhydria was studied. Healthy nonsmoking men were randomly assigned to one of two drug regimens followed by the other regimen after a one-week washout period. In regimen 1 the fasting subjects received two 680-mg doses of glutamic acid hydrochloride given 10 minutes apart. Regimen 2 was the same, except that an oral dose of ranitidine 300 mg (as the hydrochloride salt) was administered one to two hours before the first dose of glutamic acid hydrochloride to simulate hypochlorhydria. Gastric pH was monitored radiotelemetrically before and after glutamic acid hydrochloride administration by using the Heidelberg capsule technique. Six men 20 to 28 years of age participated in the study. For regimen 1, the gastric pH before glutamic acid hydrochloride was given was not significantly different from that after administration (grand medians, 1.4 and 1.3, respectively). In regimen 2, the median gastric pH increased to greater than 4.0 within two hours after ranitidine treatment. Median gastric pH after the second dose of glutamic acid hydrochloride was significantly lower than before the first dose (grand medians, 1.6 and 6.2, respectively). The time to minimum pH was 2 to 15 minutes, and pH remained less than 3.0 for a mean of 45 minutes. Glutamic acid hydrochloride alone did not decrease fasting gastric pH, but it significantly reduced pH in subjects with simulated hypochlorhydria produced by orally administered ranitidine.

Turner's syndrome was originally reported as sexual infantilism, short stature, webbed neck and cubitus valgus. Subsequent investigations, however, have disclosed many other abnormalities both in chromosomal and physical features occurring in this syndrome. An increased prevalence of Hashimoto's thyroiditis in patients with Turner's syndrome has been well documented and molecular defects of the TBG have been described. In our study we examined serum T3, T4, FT3, FT4, TSH and TBG levels in 18 girls with Turner's syndrome, in 18 healthy control girls and in the parents of both groups. We reported significant elevated levels of T3 and FT3 in the Turner's group (P 0.01). We did not find any quantitative abnormalities of immunoreactive TBG in the same patients.

In 20 cases of Turner's syndrome (10 with complete X monosomy, 10 with partial X monosomy or mosaicism) aged 3.47 to 15.5 years, the stature of the individual cases and their parents were evaluated. A significant frequency of short stature in mothers (25% below--2.0 S.D.S) has been observed, with a significant difference compared to the mean female stature of the general population. No significant difference has been observed on the stature of fathers. There was a closer correlation with mother's height (r = 0.65, p = 0.001) than with father's height (p = 0.07).

A program in which pharmacists were authorized to change parenteral histamine H2-receptor antagonist (H2RA) therapy to the oral route without first contacting the prescriber was evaluated on cost and appropriateness of use of the parenteral route. Parenteral therapy was received by 264 and 244 patients in the study and comparison groups, respectively. Length of parenteral H2RA therapy was less in the study group (4.8 vs. 7.5 d) as was length of total (parenteral + oral) therapy (8.4 vs. 12.1 d). Parenteral H2RA drug acquisition savings were $6225 in the six-week study period or $53 950 when annualized. Decreased oral therapy contributed additional savings. There was a significant decrease in the number of inappropriate parenteral doses of ranitidine per patient, the drug used in more than 80 percent of the patients. In addition to the direct effect of pharmacists' interventions, there appeared to be an indirect effect of the program, as physicians initiated route of administration changes on their own.

The pH in the upper gastrointestinal tract of young, healthy men and women was measured in the fasting state and after administration of a standard solid and liquid meal. Calibrated Heidelberg capsules were used to record the pH continuously over the study period of approximately 6 hr. In the fasted state, the median gastric pH was 1.7 and the median duodenal pH was 6.1. When the meal was administered the gastric pH climbed briefly to a median peak value of 6.7, then declined gradually back to the fasted state value over a period of less than 2 hr. In contrast to the pH behavior in the stomach, feeding a meal caused a reduction in the median duodenal pH to 5.4. In addition, there was considerable fluctuation in the postprandial duodenal pH on an intrasubject basis. The pH in the duodenum did not return to fasted state values within the 4-hr postprandial observation period. There was no tendency for the duodenal pH to be related to the gastric pH in either the fed or fasted phases of the study. Furthermore, pH in the upper GI tract of young, healthy subjects appears to be independent of gender. The differences in upper GI pH between the fasted and the fed state are discussed in terms of dosage form performance and absorption for orally administered drugs.

4081 Background: Most 1st-line combination chemotherapy regimens in pts with advanced GC include 5-FU. Taxanes are also active agents in GC, either alone or in combination. However, there is no recognized 2nd-line regimen for use in pts with advanced GC. DJ-927 is a semi-synthetic novel taxane with in vitro activity against GC cells lines. It is administered orally, with hematologic dose-limiting toxicity (DLT) in Phase I studies. The primary objective of this study was to determine the objective response rate of DJ-927 as 2nd-line therapy in pts with advanced GC. Methods: Eligible pts had confirmed advanced GC with no more than 1 prior systemic 5-FU-containing regimen for advanced disease, with adequate hematologic, renal and liver function, and with measurable disease. The starting dose in the 1st cohort of 6 pts was 27 mg/m2 orally, every 3 weeks. If < 2 DLTs occurred at this dose, the next cohort of 6 pts would start at a dose of 35 mg/m2, every 3 weeks, and all subsequent pts would be treated at the optimal dose level. Measurable disease was assessed after every 2 courses. Pharmacokinetic sampling was performed during course 1 only. Sample size based on a 3-outcome 1-stage design was calculated to be 27 pts evaluable for response, with ≥ 4 responses of 27 pts indicating that DJ-927 has activity in advanced GC. Results: 36 pts (male=25; female = 11), KPS ≥ 60%, with GC (n = 23) or OG junction cancer (n = 13), received 104 courses (median = 2; range 1–9) of DJ-927. 2 DLTs (febrile neutropenia; Grade 4 neutropenia > 5 days) occurred at 35 mg/m2, and the optimal starting dose was confirmed as 27 mg/m2. 6 of 36 pts were not evaluable for response (< 1 complete treatment course) due to early disease progression (3), toxicity (2), and drug not given (1). Response data is available for 26 of 30 evaluable pts with confirmed PR (n = 5), SD (15), and PD (6). Toxicity, ≥ grade 3, in evaluable pts (n = 33) included neutropenia (17), anemia (5), thrombocytopenia (4), diarrhoea (7), fatigue (5), lethargy (4), neutropenic sepsis (5). Conclusions: DJ-927 has modest activity in pts with GC who have failed a 5-FU non-taxane based regimen. Toxicities include neutropenia ± sepsis, diarrhoea and lethargy. Further studies of DJ-927 in combination with other active agents are warranted in pts with GC. [Table: see text]

A new traveling sand pluviator to reconstitute small specimens for laboratory tests was developed in joint research between the Research Center of the Italian National Electricity Board (ENEL CRIS) of Milano and the Department of Structural Engineering of the Politecnico di Torino. The pluviator proved satisfactory in reconstituting small-size specimens because it provided a very high degree of spatial uniformity of density and grain-size distribution. Furthermore, it was shown that a traveling pluviator is preferable to a stationary one even in reconstituting large-size specimens to achieve a higher degree of spatial uniformity. The above advantages were mainly evident when dealing with well-graded silty sands. A noteworthy feature of the new traveling pluviator that sets it apart from existing ones is its ability to accommodate pluviation under evacuated conditions.

Monochloroacetic acid (MCA) causes front paw rigidity in 10% of mice surviving a single oral toxic dose (320–380 mg/kg). Mice exhibiting front paw rigidity were killed at various times after MCA treatment and their brains were prepared for histological examination. As early as 48 hr post-treatment, RBCs were found outside capillaries in several brain regions, especially the cerebellum. At time points up to 8 weeks after MCA, extracapillary RBCs were seen to be undergoing lysis, and there was loss of cerebellar Purkinje cells. Three hours after oral administration of an LD80 of MCA (380 mg/kg), entry of iv-injected [ 14 C ]inulin or [ 3 H ]dopamine (1.0 μCi) into all brain regions was significantly increased compared to controls. Increased entry of [ 14 C ]inulin into the brains of mice occurred as early as 2 hr after MCA, coinciding with the onset of signs of toxicity, and remained elevated for up to 8 hr following treatment. Further studies revealed that only those mice which were moribund but not those which were unaffected by MCA (380 mg/kg) 4–6 hr after treatment had significantly increased brain levels of [ 14 C ]inulin or [ 3 H ]dopamine. However, mice which survived an LD80 of MCA and exhibited front paw rigidity 24 hr later also had brain radiotracer concentrations significantly greater than controls. Both the lethal effects of MCA and the physical deficits observed in survivors may be associated with impairment of blood-brain barrier function.

The urinary protein binding, kinetics, and dynamics of furosemide were studied in five nephrotic patients after intravenous dosing. Serial plasma and urine samples containing furosemide were analyzed by HPLC, and drug binding to plasma and urinary proteins was determined using equilibrium dialysis techniques. In comparison to data reported previously in healthy subjects, the steady-state volumes of distribution and nonrenal plasma clearances were significantly increased in nephrotic patients, reflecting the reduced binding of furosemide to plasma proteins. Although there was no significant difference in renal clearance between these two groups, the unbound renal clearance of furosemide was significantly reduced in nephrotic patients even when compensated for by the number of functioning nephrons. Furosemide was extensively bound to urinary protein (19.6-78.4%), and the binding was dependent on the degree of proteinuria. Nevertheless, dose-response analyses, in which the response was represented by sodium excretion rate and the dose by urinary excretion rate of unbound drug, demonstrated that nephrotic patients were less responsive to equivalent amounts of unbound diuretic as compared to healthy subjects.

The effect of elevating gastric pH on the release characteristics of a single unit sustained release (SR) ibuprofen tablet (MOTRIN-SR®, Upjohn) was evaluated in 12 young, healthy men. Using a randomized crossover-type design, each subject received three treatments – ibuprofen SR 800 mg, ranitidine 300 mg followed by ibuprofen SR 800 mg, and conventional ibuprofen tablets (2 × 400 mg). Gastric pH, which was monitored radiotelemetrically, was maintained above pH 6 for at least 4 h after pretreatment with ranitidine. In absence of ranitidine, the pH remained mostly below pH 3. Serum levels of ibuprofen were measured for 24 h and urine was collected for 48 h after each treatment. Similarity of the serum levels after the two treatments with ibuprofen SR 800 mg indicated that the release of ibuprofen was unaffected by elevation in gastric pH. Comparison of profiles with the immediate release dosage form indicated that dose dumping did not occur in any subject.

The interference of cephalosporins and cefoxitin with serum creatinine (Crs) determinations was studied. Various concentrations of cephapirin, cefazolin, cefamandole, cephalothin, and cefoxitin were added to serum samples. Apparent creatinine concentrations were measured with the Beckman ASTRA, Technicon SMAC, and DuPont ACA analyzers. Pharmacokinetic models were used to predict serum drug concentrations as a function of time and renal function and to estimate the magnitude of interference in varying situations. The magnitude of the interference was proportional to the concentration of the drug in the sample and additive with baseline concentrations of creatinine in the serum. Negligible interferences occurred with cephapirin, cefazolin, and cefamandole. False elevations (i.e., Crs greater than or equal to 0.2 mg/dl over baseline) were detected with clinically achievable serum concentrations of cephalothin and cefoxitin. For patients with normal renal function (creatinine clearance greater than 50 ml/min), this drug interaction would be negligible from 20 minutes to two hours after drug administration, depending on the assay used. For patients with renal failure, measurable interferences could persist for up to 16 hours after dose administration. The critical concentrations were different for the three procedures and both antibiotics. The degree of interference varies with the assay procedure used, the serum concentration of the drug, and the patient's renal function. To minimize drug interference, blood samples for serum creatinine determinations should be drawn at the time of minimum drug concentration.

Influences of cimetidine dose and age on the cimetidine-theophylline interaction were evaluated. Group Y consisted of nine young adults, aged 22-35 years, and Group O of nine elderly adults, aged 60-74 years. Each subject completed three study phases in this randomized crossover study. During Phase A, oral dosing of 5 mg/kg theophylline was followed by 14 serial blood samples drawn over 36 h. Phases B and C involved the same procedures, but with oral cimetidine treatment of either 200 or 300 mg every 6 h, respectively. Theophylline pharmacokinetic parameters for Group Y, Group O, and Groups Y + O were calculated. Analyses of variance (ANOVA) for crossover design were performed for each variable. Intragroup interphase ANOVA results were interpreted using multiple range tests (Tukey's Q). Comparisons between groups were performed using two-sided Student's t tests (alpha = 0.05). Within each phase, the area under the concentration-time curve (AUC), elimination half-life (t1/2 el), clearance (Clp), and volume of distribution (Vd) of theophylline for the elderly subjects were not significantly different from those of the younger adults. Mean changes in AUC, t1/2 el, and Clp between Phases A and B for both Groups Y and O were highly significant (29.2 vs. 40.4, 36.7 vs. 44.8, and 25.9 vs. 29.8%, respectively). Further significant changes in those parameters were associated with 1.2 g/day of cimetidine (Phase C). Alterations of theophylline pharmacokinetics by cimetidine appear to be dose-related and are of similar magnitude in elderly and young healthy adults.

The gastroduodenal mucosal damage caused by aspirin and nonsteroidal antiinflammatory drugs is a common clinical problem. We compared two medications designed to diminish mucosal damage: enteric-coated aspirin and salicylsalicylic acid (salsalate). Ten healthy volunteers were randomized to receive either 1.5 g salsalate twice a day or 650 mg enteric-coated aspirin four times a day for six days and were then crossed over to the other drug after a one-week medication-free period. Endoscopic inspection of gastroduodenal mucosa was performed at entry and again after six days of drug therapy for each medicine. Mean serum salicylate concentrations taken before the morning drug dose were 11.2 mg/dl for enteric-coated aspirin and 18.1 mg/dl for salsalate. Only one of 10 subjects receiving salsalate developed mild (grade 1) mucosal damage while six of 10 receiving enteric-coated aspirin developed moderate to severe damage (grade 2-3) (P = 0.01). Symptoms were mild in both groups. We conclude that salsalate causes less gastroduodenal mucosal damage than enteric-coated aspirin.

The effect of pH and time on the stability of heparin sodium in dextrose 5% in water (D5W) injection and in dextrose 5% in 0.45% sodium chloride injection was studied. Admixtures of heparin sodium 5,000 units/250 ml were tested after 0, 10, 20 and 30 minutes and 1, 2, 6, 12 and 24 hours of storage at room temperature. The pH of the carrier solutions was adjusted to 2, 4 or 9 prior to adding the heparin sodium. Heparin activity was measured using a thrombin clotting time assay. Samples were tested for pH changes at the same times. No substantial changes in heparin activity over the 24-hour period occurred with any of the pH-adjusted solutions. The pH of the heparin-D5W admixtures remained constant over time. The two carrier solutions, over a pH range of 2 to 9, appear to be suitable vehicles for heparin sodium.

The objectives were to assess the parenteral route for cimetidine and ranitidine and to determine excess medication costs associated with inappropriate use. Criteria were based on clinical situations that do not permit oral therapy, result in questionable drug absorption, or require a more rapid onset of action. The parenteral route was assessed as appropriate, inappropriate, or questionable. During two months, parenteral therapy was prescribed for 199 adult inpatients. Initially, 63 percent received the parenteral form appropriately; only 16 percent continued to receive the parenteral form appropriately throughout therapy. Less than half of the parenteral doses were determined to be appropriate. A major reason appears to be that orders are not changed as patients' conditions improve. Excess medication costs attributed to inappropriate parenteral therapy for the study period amounted to $6796 or $8002, depending on whether questionable doses were considered appropriate or inappropriate, respectively. An annual projected savings of $40776 or $48012 could be achieved if oral doses had been administered in place of inappropriate parenteral therapy. Extracto El aumento en la utilización de formas de dosificación inyectables y el alto costo relacionado con la administración por la ruta parenteral motivó a los autores a realizar un estudio con los antagonistas de receptores H2. Los autores presentan una evaluación de la utilización de cimetidina y ranitidina por la ruta parenteral enfatizando los costos excesivos asociados con la administración de los medicamentos. Los criterios utilizados para evaluar el uso de la ruta parenteral incluyeron: Situaciones clínicas que no permitían la administración por la vía oral, situaciones en que se altera la absorción gastrointestinal, o situaciones en donde se requiere un inicio de acción rápido. La ruta de administración fue evaluada como adecuada, inadecuada, o cuestionable. Durante dos meses, la terapia parenteral fue prescrita en 199 pacientes adultos hospitalizados. En el 63 por ciento de los pacientes fue apropiada la ruta parenteral inicialmente, pero sólo el 16 por ciento continuó recibiendo esta terapia adecuadamente. El costo total en exceso atribuído al uso inadecuado de la terapia parenteral en estos 199 pacientes fue $6796 ó $8002 dependiendo si las dosis de la categoría cuestionable fueron consideradas adecuadas o inadecuadas respectivamente. El uso de dosis orales de cimetidina y ranitidina en lugar de la utilización inadecuada de la forma parenteral puede significar una econom***ía anual estimada de $41000 a $48000 en los costos de administración para esta institución. Resume La cimétidine et la ranitidine sont des antagonistes des récepteurs H2 et sont toutes deux disponibles sous forme orale et injectable aux États-Unis. Il semble que chez les patients hospitalisés, la voie d'administration parentérale soit utilisée fréquemment même si le patient est capable d'ingérer une médication orale. Les objectifs de l'étude sont d'évaluer l'utilization de la voie d'administration parentérale pour la cimétidine et la ranitidine et de déterminer les coûts supplémentaires associés à son utilisation inappropriée. Les critères utilisés pour évaluer la justesse du choix de la voie parentérale sont basés sur la présence de situations cliniques ne permettent pas une thérapie orale, résultant en une absorption erratique ou nécessitant un début d'action rapide. En fonction de ces critères, l'utilisation de la voie parentérale est jugée appropriée, inappropriée ou discutable. Les auteurs évaluent la justesse du choix de la voie parentérale chez 199 patients adultes. En début de traitement, l'usage de la voie parentérale est approprié chez 63 pour cent des patients; toutefois la poursuite du médicament par voie parentérale s'avère adéquate chez seulement 16 pour cent d'entre eux. Au total, moins de la moitié des doses parentérales administrées sont jugées appropriées. L'une des raisons pouvant expliquer ce phénomène est l'absence d'une modification de l'ordonnance lorsque la condition du patient s'améliore. Les coûts supplémentaires (en médicament seulement) attribués à l'utilisation inappropriée de la voie parentérale pour la durée de l'étude se chiffrent à $6796 ou $8002 selon que l'on considère les doses discutables comme appropriées ou inappropriées. Annuellement, des épargnes de $40776 ou $48000 pourraient être réalisées si la voie orale était utilisée à la place d'une thérapie parentérale inappropriée.

The sorption of diazepam in large-volume i.v. admixtures to administration-set components and in i.v. containers was analyzed quantitatively. Solubility of diazepam in phosphate buffer at various pH levels and in i.v. fluids was measured. Partition coefficients of diazepam into components of i.v. administration sets and i.v. containers were studied by shaking a solution of diazepam in 0.9% sodium chloride, with finely cut components and measuring the change in diazepam in the aqueous phase. Flow studies through an administration set of a 0.04-mg/ml diazepam solution in 5% dextrose injection were done, varying both the flow rate and the length of tubing. The maximum free-base solubility of diazepam in phosphate buffer was 0.048 mg/ml; its solubility was 0.058, 0.050, and 0.064 mg/ml in lactated Ringer's, 0.9% sodium chloride, and 5% dextrose injections, respectively. Equilibrium partition coefficients were highest for polyvinyl chloride tubing and flexible bags. Volume-control sets made of cellulose propionate had lower but sufficiently large partition coefficients to cause diazepam loss. Polyolefin semi-rigid and glass containers had low partition coefficients. In the flow studies, the amount of solution-contact time correlated with the extent of absorption. As flow rate decreased or tubing length increased, the amount of diazepam absorbed increased proportionately. A nomogram and a predictive dosing chart are presented for calculation of actual diazepam doses delivered at various flow rates and tubing lengths. Diazepam can be administered safely and effectively by i.v. infusion. The use of volume-control sets and flexible polyvinyl chloride bags should be avoided with diazepam solutions. Polyolefin semi-rigid containers are acceptable alternatives to glass. The concentration of diazepam infusions should not exceed 0.04 mg/ml.

Chlorine dioxide (ClO2) or monochloramine (NH2Cl) may be considered as an alternative to chlorine (HOCl) as a disinfectant in public water supplies, since chlorination produces trihalomethanes. This study was conducted to determine the effect of chlorine and monochloramine on rat fetuses. Female rats were administered 0, 1, 10 or 100 mg l−1 NH2Cl or HOCl daily in the drinking water for 2 1/2 months prior to and throughout gestation. Rats were sacrificed on Day 20 of gestation and fetuses were preserved for soft-tissue and skeletal examination. No significant increase in fetal resorptions was found in any treated group. A slight increase in skeletal variants (such as incompletely ossified or missing sternebrae, or rudimentary ribs) was seen in 10 and 100 mg l−1 HOCl groups. Soft-tissue defects, mainly improper orientation of the heart or adrenal agenesis, were observed in the 100 mg l−1 HOCl group. The percentage of total defects (skeletal and soft-tissue) was increased significantly over control in the 100 mg l−1 HOCl group; however, monochloramine did not produce any significant changes in rat fetuses at any dose level.

A two-way crossover bioavailability study of two commercial cimetidine formaulations was performed on 24 healthy male volunteers. Drug was administered after an overnight fast and plasma samples were withdrawn periodically for 12 h. Urine was collected throughout the study period. Results indicated that the two formulations were bio-equivalent since no statistically significant difference in means was detected for any of the parameters studied. Extensive interpatient variation in cimetidine blood concentration was observed during both treatments.

The primary objective of this study was to define the pH conditions under which supplemental pancreatic enzyme preparations must function in the upper gastrointestinal tract. The hypothesis was that normal or greater acid output in patients with cystic fibrosis (CF), combined with low pancreatic bicarbonate output, results in an acidic duodenal pH, compromising both dosage-form performance and enzyme activity. Gastrointestinal pH profiles were obtained in 10 CF and 10 healthy volunteers under fasting and postprandial conditions. A radiotelemetric monitoring method, the Heidelberg capsule, was used to continuously monitor pH. Postprandial duodenal pH was lower in CF than in healthy subjects, especially in the first postprandial hour (mean time greater than pH 6 was 5 min in CF, 11 min in healthy subjects, P less than 0.05). Based on the dissolution pH profiles of current enteric-coated pancreatic enzyme products, the duodenal postprandial pH in CF subjects may be too acidic to permit rapid dissolution of current enteric-coated dosage forms. However, the pH was above 4 more than 90% of the time on the average, suggesting that irreversible lipase inactivation in the duodenum is not likely to be a significant limitation to enzyme efficacy. Overall results suggest that slow dissolution of pH-sensitive coatings, rather than enzyme inactivation, may contribute to the failure of enteric-coated enzyme supplements to normalize fat absorption.

Peptic ulcer disease is a chronic, relapsing disease. Successful healing of duodenal and gastric ulcers with antacids, cimetidine, ranitidine, famotidine, or sucralfate is frequently followed by ulcer recurrence. The need for long-term, low-dose maintenance therapy is based on disease severity, ulcer history, complications, therapeutic intervention, response to treatment, and potential risk factors. Comparison of ulcer maintenance trials requires consideration of important factors such as frequency of endoscopy, duration of follow-up period, and the method used to calculate ulcer recurrence rates. Clinical trials indicate that chronic treatment with low-dose cimetidine, ranitidine, famotidine, and probably sucralfate decreases the frequency of duodenal ulcer recurrence and that ranitidine may be superior to cimetidine. Preliminary studies indicate that higher doses of these same medications may be required to prevent gastric ulcer recurrence. Long-term maintenance therapy with these agents must be continuous in order to prevent relapses, but treatment should be limited to one year because of unknown consequences beyond this period.

Monochloroacetic acid (MCA) causes front paw rigidity in 10% of mice surviving a single oral toxic dose (320-380 mg/kg). Mice exhibiting front paw rigidity were killed at various times after MCA treatment and their brains were prepared for histological examination. As early as 48 hr post-treatment, RBCs were found outside capillaries in several brain regions, especially the cerebellum. At time points up to 8 weeks after MCA, extracapillary RBCs were seen to be undergoing lysis, and there was loss of cerebellar Purkinje cells. Three hours after oral administration of an LD80 of MCA (380 mg/kg), entry of iv-injected [14C]inulin or [3H]dopamine (1.0 microCi) into all brain regions was significantly increased compared to controls. Increased entry of [14C]inulin into the brains of mice occurred as early as 2 hr after MCA, coinciding with the onset of signs of toxicity, and remained elevated for up to 8 hr following treatment. Further studies revealed that only those mice which were moribund but not those which were unaffected by MCA (380 mg/kg) 4-6 hr after treatment had significantly increased brain levels of [14C]inulin or [3H]dopamine. However, mice which survived an LD80 of MCA and exhibited front paw rigidity 24 hr later also had brain radiotracer concentrations significantly greater than controls. Both the lethal effects of MCA and the physical deficits observed in survivors may be associated with impairment of blood-brain barrier function.

The effect of cimetidine therapy on serum uric acid concentration was studied in four healthy men with normal renal function. Beginning four days before the 16-day study, subjects were permitted no beverages containing caffeine or alcohol and no medications and were placed on a weight-maintenance, isocaloric, purine-free 152-meq-sodium diet. On days 1-12 one cimetidine 300-mg tablet was taken four times daily; on days 13-16 no cimetidine was taken. On each study day, serum uric acid and creatinine and urine uric acid and creatinine concentrations were determined. Daily mean values for serum uric acid, total uric acid excreted, and uric acid clearance were not significantly different from baseline. No significant change occurred in creatinine excreted or creatinine clearance. Cimetidine administration to healthy men with normal renal function did not significantly affect serum uric acid concentration or renal clearance of urate.

A review of about 300 patients with unilateral renal disease shows that echography is valuable for a correct diagnosis in numerous cases. The authors emphasize the role of A-B mode ultrasonographic scanning in the exploration of IVP nonvisualized kidneys, renal trauma, and other disorders.

The Authors describe two cases of Noonan's Syndrome (Turner phenotype and normal Karyotype), underlining the necessity of a differential diagnosis with the "True" Syndrome of Turner, for the presence, in the latter, of a non development of the height, weight and phenotype, which moves away from the standard much. While on the contrary in the Noonan's syndrome both the sexual development and the evolution of the height and weight may be normal and in the latter syndrome, so, the attention of the Doctors has to be turned prevalently to the congenital cardiopathy (almost always stenosis of the pulmonary artery), which can also impair the life of the patient.

The authors consider the association of colonic neoplasia and hernia of abdominal wall. Such association, although not so frequent, was formerly remarked in literature 23 times; with the personal casuistic contribution of the authors, who recently observed a case thereof in an old patient woman, such remarks amount to 24. The authors describe the case they have the opportunity to observe, and report the experience of the other authors thereabout, through a careful reviewing of the literature starting from 1930 up to our time.

The pathogenesis, clinical signs, and conventional treatment of peptic ulcer disease (PUD) are briefly discussed, and the use of drugs with tricyclic structures in the treatment of PUD is reviewed. Peptic ulcers occur most commonly in the duodenal bulb and the stomach. Numerous factors contribute to the formation of peptic ulcers, but an imbalance between acid and pepsin secretion and mucosal resistance is considered important. Conventional drug therapy of PUD with antacids, H2-receptor antagonists, anticholinergic drugs, and sucralfate is designed to correct this imbalance by neutralizing acid, inhibiting acid secretion, preventing contact of the ulcer with acid and pepsin, and enhancing mucosal defense mechanisms. Tricyclic agents that appear to be useful in the treatment of PUD are the tricyclic antidepressants, trimipramine maleate and doxepin hydrochloride, and the selective antimuscarinic drug, pirenzepine hydrochloride. The therapeutic effects of tricyclic antidepressants may result from their anticholinergic, antidepressant, and H2-receptor blocking actions. Controlled clinical trials suggest that trimipramine 50 mg/day (as the maleate salt) and pirenzepine hydrochloride 100-150 mg/day are superior to placebo and may be as effective as cimetidine for the short-term treatment of duodenal ulcers. Limited data suggest that these drugs are also effective for treating gastric ulcers. Assessment of the apparent efficacy of doxepin in duodenal ulcer treatment requires further study. Anticholinergic side effects and sedation associated with the administration of tricyclic agents may limit their usefulness as first-line anti-ulcer agents. With further evidence of their efficacy, trimipramine, doxepin, and pirenzepine may play an important role in the treatment of patients unresponsive to conventional anti-ulcer therapy.

A screening program for congenital hypothyroidism has been starting in Siena since November, 1977 with the Guthrie's test for PKU. According to the recommendations of the Committee of the European Thyroid Association the program were performed on capillary blood samples collected between the fourth and sixth days after birth on an adsorbent paper. The screening began with the measurement of T4 RIA (up to May, 1980), and T4 and TSH RIA (from may, 1980, to december, 1981). At december, 1981, 23.693 newborns have been screened. The recall rate was 2,5% up to may, 1980, and 0,11% from may, 1980 to december, 1981. Ten newborns with congenital hypothyroidism have been detected; the incidence is one in 2.400 live births. There were no cases of transient hypothyroidism and no cases of TBG deficiency. All patients are treated before the age of one month. The diagnosis is confirmed in seven cases at one year of life after stopterapy for one month. Our program confirm the high incidence of congenital hypothyroidism. Clinical control, based on physical and psychomotor development testing in seven patients treated confirmed that all infants are normal.

Influences of cimetidine dose and age on the cimetidine-theophylline interaction were evaluated. Group Y consisted of nine young adults, aged 22-35 years, and Group O of nine elderly adults, aged 60-74 years. Each subject completed three study phases in this randomized crossover study. During Phase A, oral dosing of 5 mg/kg theophylline was followed by 14 serial blood samples drawn over 36 h. Phases B and C involved the same procedures, but with oral cimetidine treatment of either 200 or 300 mg every 6 h, respectively. Theophylline pharmacokinetic parameters for Group Y, Group O, and Groups Y + O were calculated. Analyses of variance (ANOVA) for crossover design were performed for each variable. Intragroup interphase ANOVA results were interpreted using multiple range tests (Tukey's Q). Comparisons between groups were performed using two-sided Student's t tests (alpha = 0.05). Within each phase, the area under the concentration-time curve (AUC), elimination half-life (t1/2 el), clearance (Clp), and volume of distribution (Vd) of theophylline for the elderly subjects were not significantly different from those of the younger adults. Mean changes in AUC, t1/2 el, and Clp between Phases A and B for both Groups Y and O were highly significant (29.2 vs. 40.4, 36.7 vs. 44.8, and 25.9 vs. 29.8%, respectively). Further significant changes in those parameters were associated with 1.2 g/day of cimetidine (Phase C). Alterations of theophylline pharmacokinetics by cimetidine appear to be dose-related and are of similar magnitude in elderly and young healthy adults.

The pharmacodynamic, therapeutic, and toxicologic properties of famotidine are evaluated and compared with those of cimetidine and ranitidine. Famotidine, an H2-receptor antagonist with a thiazole nucleus, is approximately 7.5 times more potent than ranitidine and 20 times more potent than cimetidine on an equimolar basis. Therapeutic trials indicate that famotidine 20 mg b.i.d. or 40 mg at bedtime is as effective as standard doses of cimetidine and ranitidine for healing duodenal ulcers. A dose of 40 mg at bedtime appears to heal benign gastric ulcers. A single nocturnal dose of 20 mg is effective in preventing duodenal ulcer relapse. Further studies are required that compare the efficacy of famotidine with cimetidine and ranitidine in the treatment of gastric ulcers and in the prevention of recurrent duodenal ulcers. The overall incidence of adverse effects observed with famotidine appears to be similar to that reported for cimetidine and ranitidine. Like ranitidine, famotidine does not have antiandrogenic effects or substantially inhibit the hepatic metabolism of drugs. Because of its increased antisecretory potency and lack of antiandrogenic effects at higher doses, famotidine may be the H2-receptor antagonist of choice in treating Zollinger-Ellison syndrome. Additional clinical experience, as well as cost and safety factors, will determine the place of famotidine in treating and preventing acid-peptic disorders.

The sorption of diazepam in large-volume i.v. admixtures to administration-set components and in i.v. containers was analyzed quantitatively. Solubility of diazepam in phosphate buffer at various pH levels and in i.v. fluids was measured. Partition coefficients of diazepam into components of i.v. administration sets and i.v. containers were studied by shaking a solution of diazepam in 0.9% sodium chloride, with finely cut components and measuring the change in diazepam in the aqueous phase. Flow studies through an administration set of a 0.04-mg/ml diazepam solution in 5% dextrose injection were done, varying both the flow rate and the length of tubing. The maximum free-base solubility of diazepam in phosphate buffer was 0.048 mg/ml; its solubility was 0.058, 0.050, and 0.064 mg/ml in lactated Ringer's, 0.9% sodium chloride, and 5% dextrose injections, respectively. Equilibrium partition coefficients were highest for polyvinyl chloride tubing and flexible bags. Volume-control sets made of cellulose propionate had lower but sufficiently large partition coefficients to cause diazepam loss. Polyolefin semi-rigid and glass containers had low partition coefficients. In the flow studies, the amount of solution-contact time correlated with the extent of absorption. As flow rate decreased or tubing length increased, the amount of diazepam absorbed increased proportionately. A nomogram and a predictive dosing chart are presented for calculation of actual diazepam doses delivered at various flow rates and tubing lengths. Diazepam can be administered safely and effectively by i.v. infusion. The use of volume-control sets and flexible polyvinyl chloride bags should be avoided with diazepam solutions. Polyolefin semi-rigid containers are acceptable alternatives to glass. The concentration of diazepam infusions should not exceed 0.04 mg/ml.

The effect of pH and time on the stability of heparin sodium in dextrose 5% in water (D5W) injection and in dextrose 5% in 0.45% sodium chloride injection was studied. Admixtures of heparin sodium 5,000 units/250 ml were tested after 0, 10, 20 and 30 minutes and 1, 2, 6, 12 and 24 hours of storage at room temperature. The pH of the carrier solutions was adjusted to 2, 4 or 9 prior to adding the heparin sodium. Heparin activity was measured using a thrombin clotting time assay. Samples were tested for pH changes at the same times. No substantial changes in heparin activity over the 24-hour period occurred with any of the pH-adjusted solutions. The pH of the heparin-D5W admixtures remained constant over time. The two carrier solutions, over a pH range of 2 to 9, appear to be suitable vehicles for heparin sodium.

A deficiency of growth hormone (GH) was detected in a male child with "empty sella syndrome" (ESS). Association between ESS and defeciences of pituitary hormones has been previously reported in adult subjects. It seems likely that GH deficiency is be related to ESS in the case described in this paper. An appropriate evaluation of the endocrine system seems suitable in this condition, since ESS in childhood is not to be regarded only from neuroradiologic point of view.

Six patients with chronic renal failure (CRF group) and four healthy subjects (HS group) were given 5 mg oral and intravenous doses of bumetanide in a random, crossover design. The CRF group had significantly lower plasma and renal clearances, resulting in a five- to sixfold reduction in the fractional urinary excretion of the drug. The percent free drug in plasma for the CRF group was more than double that for the HS group, and significant correlations were observed for volume of distribution at steady state vs. percent free (r = 0.661; P < 0.05), nonrenal clearance vs. percent free (r = 0.796; P < 0.01), and renal clearance vs. creatinine clearance (r = 0.995; P < 0.001). Although bioavailability was relatively consistent among the HS (0.664 ± 0.112) and CRF (0.689 ± 0.149) groups, the absorption-time profiles were more irregular for both groups. Cumulative sodium excretion and overall efficiency of response to bumetanide did not differ significantly between the two routes of administration in either group. Clinical Pharmacology and Therapeutics (1986) 39, 635–645; doi:10.1038/clpt.1986.112

The interference of cephalosporins and cefoxitin with serum creatinine (Crs) determinations was studied. Various concentrations of cephapirin, cefazolin, cefamandole, cephalothin, and cefoxitin were added to serum samples. Apparent creatinine concentrations were measured with the Beckman ASTRA, Technicon SMAC, and DuPont ACA analyzers. Pharmacokinetic models were used to predict serum drug concentrations as a function of time and renal function and to estimate the magnitude of interference in varying situations. The magnitude of the interference was proportional to the concentration of the drug in the sample and additive with baseline concentrations of creatinine in the serum. Negligible interferences occurred with cephapirin, cefazolin, and cefamandole. False elevations (i.e., Crs greater than or equal to 0.2 mg/dl over baseline) were detected with clinically achievable serum concentrations of cephalothin and cefoxitin. For patients with normal renal function (creatinine clearance greater than 50 ml/min), this drug interaction would be negligible from 20 minutes to two hours after drug administration, depending on the assay used. For patients with renal failure, measurable interferences could persist for up to 16 hours after dose administration. The critical concentrations were different for the three procedures and both antibiotics. The degree of interference varies with the assay procedure used, the serum concentration of the drug, and the patient's renal function. To minimize drug interference, blood samples for serum creatinine determinations should be drawn at the time of minimum drug concentration.