The drug lag: an update of new drug introductions in the United States and in the United Kingdom, 1977 through 1987.

This report updates previous studies that documented the existence of a significant lag between new drug introductions in the United Kingdom and in the United States. During the 11-year period from 1977 through 1987, the United Kingdom led the United States in the number of first introductions of new drugs (114 versus 41), in average lead time for mutually available drugs (60.7 versus 28.9 months), and in the number of exclusively available drugs (70 versus 54). Analysis by therapeutic category indicated large United Kingdom leads in the introduction of respiratory (5.1 years), cardiovascular (3.2 years), central nervous system (3.2 years), and anti-cancer (2.9 years) agents, and shorter leads for anesthetic and analgesic (2.0 years), gastrointestinal (2.0 years), endocrine (1.4 years), and anti-infective (0.8 years) agents. A comparison of the 5-year period from 1983 through 1987 with the previous 5-year period (1978 through 1982) showed no change in the length of the lag time (1.9 years for each period). These results indicate that the United States continues to lag behind the United Kingdom in the availability of new drugs.

Effect of contrast media on beta-endorphin secretion. An in vitro study.

The central nervous system may be highly susceptible to the toxic effects of contrast media (CM). Previous experiments demonstrated that vasopressin is released after the intravenous administration of CM. The present study examined the response of the opiocortin system to CM. Neurons of the rat basal hypothalamus, dispersed and attached to Cytodex-3 beads, were perfused with sodium diatrizoate, metrizamide or iohexol (3 mg iodine/ml). The effluent was collected, and the beta-endorphin (B-E) content was measured by a radioimmunoassay technique. Results, normalized to the internal positive control, were compared with release from normal saline (negative control) by analysis of variance. Diatrizoate and metrizamide caused significant release of B-E (p less than 0.03). Iohexol did not stimulate release of B-E. These results suggest that diatrizoate and metrizamide, but not iohexol, can stimulate the release of hormones from hypothalamic neurons. The phenomenon may play a role in some reactions to intravascular CM administration since these neurons are not protected by a blood-brain barrier.

Diatrizoate levels in cerebrospinal fluid following intravenous administration. Role of fluid production rate.

The central nervous system (CNS) may be highly susceptible to the toxic effects of conventional contrast media (CM). The current study quantifies levels of diatrizoate in canine cerebrospinal fluid (CSF) following intravenous administration and examines how these levels change as CSF production rate is reduced. Cerebrospinal fluid was collected continuously from the cisterna magna of anesthetized dogs before and after the administration of diatrizoate (1 mL/kg bolus followed by a 12.5 microliters/kg/minute maintenance infusion, IV). The influence of CSF production rate on CSF diatrizoate levels was examined by injecting acetazolamide (30 mg/kg, IV). Diatrizoate levels in CSF were quantified by a high performance liquid chromatography (HPLC) method. Baseline CSF production was 81.5 microliters/minute and dropped to 37.4 microliters/minute following diatrizoate and to 29.5 microliters/minute following acetazolamide. The concentration of diatrizoate in CSF averaged 166 micrograms/mL and increased significantly to 379 micrograms/mL following acetazolamide with no change in serum concentration (1.3 mg/mL). These experimental results suggest that appreciable quantities of intravenously administered diatrizoate may enter the CNS, and that these quantities may increase significantly with reduced CSF production. This may help to explain CSF enhancement and certain CNS toxicity after the intravenous administration of CM.

Iohexol inhibits adenylate cyclase.

Previous studies demonstrated that the intravenous administration of the ionic radiographic contrast agent, diatrizoate, and the nonionic agent, iohexol, causes a decrease in the rate of cerebrospinal fluid (CSF) production. Evidence suggests that adrenergic-mediated adenylate cyclase (AC) activity controls CSF production. Diatrizoate was found to inhibit AC activity. The authors now report that iohexol inhibits activity of this enzyme. Adenylate cyclase activity was measured in membrane fractions of bovine choroid plexus in the presence of various concentrations of iohexol. A concentration-dependent inhibition of basal and adrenergic-stimulated AC activity by the contrast agent was observed. The concentration of iohexol that produced a 50% inhibition was about 2.3 mM. This is similar to the concentration of diatrizoate that produced equivalent enzyme inhibition. These results support the contention that one mechanism for the action of contrast media in reducing CSF production involves inhibition of AC activity.

Opiate involvement in contrast media-induced blood pressure changes.

The intravenous administration of contrast media (CM) often alters blood pressure (BP). Osmolality plays a role, but the magnitude and even direction of change varies under similar (osmotic) conditions, indicating the involvement of other mechanisms. Male Wistar rats, anesthetized with pentobarbital, received sodium/meglumine diatrizoate, iohexol, or normal saline, 4 ml/kg, via a tail vein, while blood pressure was recorded continuously. Additional groups were pretreated with the opiate antagonist, naloxone (1 mg/kg, IV), or with an equal volume of normal saline 5 minutes prior to the diatrizoate injection. Comparisons of BP change were made with the Student's t-test. Diatrizoate caused a significant (P less than .0002) increase in BP relative to the saline control group, iohexol did not. Thus, the increase with diatrizoate was significantly greater than with iohexol (P less than .00006). Neither the saline nor naloxone pretreatment altered BP significantly. Saline pretreatment did not alter the significant increase in BP produced by the diatrizoate. However, the diatrizoate-induced increase in BP was prevented by the naloxone pretreatment and was significantly less than after the saline pretreatment (P less than .0001). Based on these and previous results, the authors hypothesize that release of endogenous opioids may play a role in BP changes caused by intravenous CM and that significant CM-induced changes may be prevented pharmacologically with the selective opiate blocker, naloxone.

Mechanisms of decreased cerebrospinal fluid production by radiographic contrast media: role of adenylate cyclase activation.

The i.v. administration of radiographic contrast media decreases cerebrospinal fluid (CSF) production as measured by negative pressure collection from the lateral ventricles of anesthetized dogs. Evidence suggests that adrenergic-mediated adenylate cyclase (AC) activity controls CSF production. AC activity was measured in membrane fractions of bovine and canine choroid plexus and rat heart and lung in the presence of various concentrations of the contrast agent sodium diatrizoate. A concentration-dependent inhibition of isoproterenol-stimulated AC activity by the contrast agent was observed in vitro. Specific binding of [3H]dihydroalprenolol to membrane fractions of bovine choroid plexus was also inhibited by sodium diatrizoate. An indication that the inhibition of choroidal AC activity by contrast media is significant in vivo was obtained by measuring CSF production in dogs. The inhibition of CSF production by sodium diatrizoate was reduced 50% when the contrast agent was administered during an i.v. infusion of isoproterenol (100 ng/kg/min). These results indicate that the mechanism of decreased CSF production by contrast media may involve inhibition of beta adrenergic-stimulated AC activity.

Dopamine-stimulated adenylate cyclase and tyrosine hydroxylase in diabetic rat retina.

The effects of streptozotocin-induced diabetes on the retinal dopaminergic system have been examined in Long-Evans (pigmented) rats. Tyrosine hydroxylase activity was significantly decreased while dopamine-stimulated adenylate cyclase was increased in 2-month-diabetic rats. The observed increase in dopamine-stimulated adenylate cyclase activity in diabetic retinae may be related to neurotransmitter receptor changes because postreceptor activation of adenylate cyclase by guanylyl imidodiphosphate was not altered.

Localization of prostaglandin synthetase in chicken epiphyseal cartilage.

Prostaglandin synthetase activity in high-speed particulate fractions of chick epiphyseal cartilage has been characterized with respect to cofactor requirements, pH optimum, buffer-ion effects, types of prostaglandins formed, and the distribution of prostaglandin synthetase activity in zones of the epiphyseal plate. Direct homogenization of cartilage was found to be more efficacious than releasing chondrocytes by enzymatic digestion for preparation of prostaglandin synthetase, a homogenization time of 4 min yielding maximal activity. The optimal incubation medium contained 50 mM Tris buffer (pH 7.5), 2.5 mM epinephrine, 1 micronM hemoglobin, 3.25 mM glutathione, 200 microgram/ml enzyme protein, and 5 micronM substrate. Glutathione was effective only if present during homogenization. Rates of PGE2 biosynthesis were linear up to 15 min and then rapidly declined, indicative of self-deactivation. The low levels of PGF2alpha formed, and their decrease after 20 min incubation, suggests the possible presence of degradative enzymes. Prostaglandin synthetase was inhibited by aspirin, indomethacin, and vitamin E, but not vitamin K1. Cation concentrations in the physiological range had only modest effects on prostaglandin biosynthesis, and then only if present during tissue homogenization. In the presence of phosphate buffer, Ca2+ was somewhat inhibitory. Since in the absence of phosphate Ca2+ had no deleterious effect, it is probably that the inhibitory effect was caused by precipitation of calcium phosphate. Hypertrophic and calcified cartilage exhibited significantly higher prostaglandin synthetase activity than the proliferating and maturing zones. The increased synthesis of prostaglandins in the low layers of the growth plate may indicate a role of these factors in chondrocyte differentiation and/or calcification.