Colonic delivery of dexamethasone: a pharmacoscintigraphic evaluation.

BACKGROUND: Colonic delivery of corticosteroids may reduce the side-effects commonly associated with their use. Therefore, we tested the ability of the naturally occurring polysaccharide guar gum to deliver a corticosteroid, dexamethasone, to the colon using pharmacoscintigraphy. Guar gum is metabolized in the colon by resident bacterial enzymes to trigger drug release. MATERIALS: Each subject (eight per group, parallel study design) was administered one of four dexamethasone (9 mg) tablet formulations, radiolabelled with 153Sm using neutron activation, under fasted conditions. One formulation was designed to release drug rapidly following ingestion while the other three formulations were designed to delay release of dexamethasone to varying degrees. Progression of the formulations down the gastrointestinal tract was followed by gamma scintigraphy. Serum concentrations were measured over time to relate disintegration profiles of the tablets with pharmacokinetic observations. RESULTS: The immediate release formulation disintegrated in the stomach, on average, within 20 min of dosing. One of the three delayed release preparations (CD1) began to disintegrate in the small intestine 1.7 +/- 1.0 h after dosing. The second and third delayed release preparations (CD2 and CD3) did not begin to disintegrate until 5.8 +/- 2.3 and 3.6 +/- 1.6 h after dosing, respectively. All three colonic delivery preparations completely disintegrated in the colon ranging from 7.8 +/- 2.7 h (CD1) to 12.4 +/- 3.2 h (CD2) following oral administration. Pharmacoscintigraphic data indicated that 72-82% of the dexamethasone was delivered into the colon although not all the dexamethasone delivered into the colon was absorbed. CONCLUSIONS: Simple guar gum formulations are capable of delivering the corticosteroid dexamethasone to the colon of normal subjects. Locally delivered corticosteroids may be useful in the treatment of ulcerative colitis and Crohn's disease. Pharmacoscintigraphic evaluation is a useful method to discriminate between the in vivo behaviour of colonic delivery systems.

Insulin-like growth factor I receptors in the arteries of the rabbit: autoradiographic mapping and receptor characterization.

Insulin-like growth factor I (IGF-I) is a polypeptide hormone structurally related to insulin with insulin-like metabolic effects. It is a potent mitogen, eliciting cell multiplication in tissue culture by increasing deoxyribonucleic acid and protein synthesis. IGF-I was found to promote the growth of cultured arterial smooth muscle cells. We studied the in situ distribution of IGF-I receptors in different arteries of the rabbit by autoradiography and examined their binding characteristics in the wall of the thoracic aorta. The thoracic and abdominal aortas and carotid, superior mesenteric, renal, and iliac arteries of three adult New Zealand rabbits were harvested and stored at -70 degrees C. Autoradiographic analysis of 125I-labeled IGF-I binding to frozen arterial sections showed that silver-grain density was consistently located in the arterial wall. Binding studies in the thoracic aorta demonstrated high-affinity IGF-I receptors with a dissociation constant of 2 nmol/L and maximum IGF-I binding capacity of 4.17 pmol/mg protein. Inhibition studies with insulin, IGF-I, and IGF-II showed that these binding sites were more specific for IGF-I than for IGF-II or insulin, with a concentration of peptide that inhibits 50% of maximum binding of 1.75 nmol/L, 5 nmol/L, and greater than 100 mumol/L, respectively. The presence of high-affinity, specific IGF-I receptor binding in rabbit arteries suggests that IGF-I plays an important role in regulating the multiplication of arterial smooth muscle cells; a role that may prove important in different pathologic processes.

Indomethacin (i.c.v.) reverses the inhibitory action of peptides on gastric secretion.

Central administration of diverse peptides, such as dermorphin (100 ng), salmon calcitonin (250 ng), human-corticotropin-releasing-factor (10 micrograms) and human-calcitonin-gene-related-peptide (10 micrograms) inhibited gastric acid secretion in pylorus-ligated rats. With the exception of salmon calcitonin this suppressive effect was significantly reversed by the central administration of 400 micrograms indomethacin. These data suggest that the gastric inhibitory effect of dermorphin, human-corticotropin-releasing-factor and human-calcitonin-gene-related-peptide might be mediated by the central synthesis of a cyclooxygenase product(s).

Subcutaneously administered Repronex in female patients undergoing in vitro fertilization is as effective and well tolerated as intramuscular menotropin treatment. Repronex SC, IVF Study Group.

OBJECTIVE: To determine the efficacy and safety of Repronex SC as compared with Repronex IM and Pergonal IM in patients undergoing IVF. DESIGN: Open-label, randomized, parallel-group, multicenter study. SETTING: Fifteen academic and private fertility clinics with IVF experience. PATIENT(S): Premenopausal women with regular ovulatory menstrual cycles undergoing IVF for infertility attributable to tubal factors, endometriosis (stage I or II), or unknown factors. INTERVENTION(S): Down-regulation with leuprolide acetate followed by up to 12 days of treatments with gonadotropins, hCG administration, oocyte retrieval, and embryo transplant. MAIN OUTCOME MEASURE(S): Mean number of oocytes retrieved, chemical, clinical, and continuing pregnancies, incidence of oocyte retrieval and embryo transfer, and peak serum E2 concentrations. RESULT(S): There were no significant differences among the treatment groups except for a higher percentage of continuing pregnancies in the Repronex SC group. Gonadotropin therapy was well tolerated in all three treatment groups. The Repronex SC group had a significantly higher incidence of transient mild/moderate injection site reactions during the first few days of therapy. CONCLUSION(S): Repronex SC is comparable in therapeutic effectiveness and safety to Repronex IM and Pergonal IM in patients undergoing IVF and provides an alternative route of injection for self-administration of gonadotropin.

Subcutaneously administered Repronex in oligoovulatory female patients undergoing ovulation induction is as effective and well tolerated as intramuscular human menopausal gonadotropin treatment.

OBJECTIVE: To determine the efficacy and safety of Repronex SC as compared with Repronex IM and Pergonal IM in patients undergoing ovulation induction. DESIGN: Randomized, open-label, multicenter, parallel group study. SETTING: Ten academic and private fertility clinics with expertise in ovualtion induction. PATIENT(S): Premenopausal anovulatory and oligoovulatory females (n = 115) undergoing ovulation induction. INTERVENTION(S): Down-regulation with leuprolide acetate followed by up to 12 days of treatment with gonadotropins and hCG administration and luteal phase progesterone support. MAIN OUTCOME MEASURE(S): Percentage of patients ovulating; percentage of cycles with follicular development meeting criteria for hCG administration; number of follicles recruited per cycle meeting hCG criteria; peak serum E(2) levels; rates of chemical, clinical and ongoing pregnancies; adverse events; injection-site pain scores. RESULT(S): There was no statistically significant difference in the percentage of women who ovulated among the treatment groups. However, Repronex SC was significantly more effective than Pergonal IM in producing follicular development in patients who met hCG criteria. There were no significant differences in clinical, ongoing, or continuing pregnancy rates or in multiple pregnancies among the treatment groups. No differences were found in the safety assessments, proportions or seriousness of adverse events or treatment discontinuations. Also, there were no differences between the three treatment groups in patient-recorded scores of injection-site pain or injection-site reactions. CONCLUSION(S): Repronex SC is as efficacious and well tolerated as Repronex IM or Pergonal IM in ovulation induction. Self-administration of Repronex SC provides a convenient treatment alternative to daily IM injections.

Benefit-risk assessment of investigational drugs: current methodology, limitations, and alternative approaches.

Development of investigational drugs is a process integrated traditionally into four overlapping phases. The goal is to introduce new therapies to clinical medicine by assessing benefits and risks associated with administering the new drug. Benefit assessment is performed with respect to the disease for which the drug may comprise an effective treatment. In contrast, safety assessment is relatively standardized across many pharmacologic classes of agents. For purposes of benefit-risk assessment, investigational drugs are developed to provide benefit in three major disease categories: acute, episodic, and chronic. Benefit assessment is the major focus of conventional methodologies. Inherent limitations of risk assessment produced by conventional approaches are illustrated by the historical inability to detect toxicities of various drugs until large patient populations have been treated, typically after the drug is marketed. Alternative approaches to overcome these limitations include assessment of safety in studies specifically designed to optimize such evaluation and more extensive safety testing of investigational drugs in patient subgroups at higher risk. Such approaches serve the interest of patients, physicians, and developers by facilitating the development of new therapies by providing a more complete benefit-risk assessment prior to initial marketing of the drug.

The use of a thymidine incorporation assay in the evaluation of the healing process following ethanol or indomethacin-induced gastric damage in rats.

Measurements of the extent of gastric damage and measurement of [3H]-thymidine uptake by gastric cells were performed over time in rats whose stomach had been damaged with 2 ml 100% EtOH or 80 mg/kg indomethacin. Both compounds decreased the uptake of [3H]-thymidine, with the lowest values observed 10 min or 6 h after administration of EtOH or indomethacin, respectively. A slow recovery, toward control values, was then observed. An almost complete normalization was observed 1 day or 3 days after indomethacin or EtOH. The variations of [3H]-thymidine uptake correlated with the extent of gastric damage, with low values observed during the expansion phase of a lesion. In conclusion, measurement of [3H]-thymidine uptake by gastric cells is a reliable index of gastric damage and can be used in the study of healing process.

Computer-based quantitative morphometric analysis of the dynamic characteristics of indomethacin and ethanol-induced gastric lesions in the rat.

A computerized morphometric analysis was used to measure the gastric lesions in rats induced by oral administration of 2 mL of 100% EtOH or indomethacin 80 mg/kg. In both cases, the lesions were followed over a period of several days to determine their time course characteristics. Indomethacin lesions were present 1 hr after the administration of the drug and reached a peak after 6 hr. Ethanol lesions appeared as early as 1 min after administration and were fully expressed after 1 hr. Recovery of the gastric mucosa was observed after 2 and 6 days, respectively. The use of this computerized systems allows precise measurements of gastric lesions and facilitates the evaluation of the effect of drugs in the gastrointestinal tract.

The resolution of membrane proteins based upon size, charge, and hydrophobicity.

Currently available systems for resolving membrane proteins are based only on size and charge differences. Recently, it has been shown that Triton-urea-acetic acid gels which separate proteins on the basis of charge, size and hydrophobicity are capable of resolving proteins differing only by the substitution of a single neutral amino acid. We have applied this new method to the resolution of bacterial envelope proteins. Conditions for optimal resolution of different bacterial envelope proteins were determined by electrophoresis through transverse urea and Triton X-100 gradient gels. We have also correlated the components resolved in this system with those resolved by classical sodium dodecyl sulfate-gel electrophoresis by using two-dimensional slab gels combining the two systems. Furthermore, envelope protein fractions from different species and strains of bacteria were compared to identify specific proteins. This system appears to be a promising method for investigating envelope proteins which are due to missense mutations.

Insulinlike growth factor I receptors in rabbit gastrointestinal tract. Characterization and autoradiographic localization.

Insulinlike growth factor I is a potent mitogen with insulinlike metabolic effects. Insulinlike growth factor I is synthesized in the liver, intestine, and other organs. Insulinlike growth factor I receptors are widely distributed and structurally similar to insulin receptors. Frozen sections of rabbit gastrointestinal tract were incubated in buffer containing 40 pmol/L [125I]insulinlike growth factor I. Binding was saturable, temperature- and time-dependent, and reversible. Saturation binding experiments showed a single class of high-affinity receptors (Kd = 0.9 nmol/L, Bmax = 0.36 pmol/mg protein). The IC50s for insulinlike growth factor I and insulinlike growth factor II were 3 nmol/L and 90 nmol/L, respectively; whereas insulin at 1-3 mumol/L displaced 50% of specific binding. Autoradiography of insulinlike growth factor I binding demonstrated significant differences in receptor density in gastrointestinal smooth muscle, epithelium of the esophagus, stomach, small intestine, and colon. These results indicate that a single class of specific, high-affinity insulinlike growth factor I receptors were distributed in muscular and mucosal layers of the entire rabbit gastrointestinal tract. Insulinlike growth factor I is likely to be an important local mediator of intestinal growth and metabolism.

Effect of platelet-derived growth factor-BB on indomethacin-induced gastric lesions in rats.

The effect of platelet-derived growth factor-BB (PDGF-BB) was evaluated in rats with indomethacin-induced gastric lesions. Animals were treated with either saline solution or several doses of PDGF-BB given orally. Rats treated with 0.1 nmol/kg PDGF-BB showed a statistically significant reduction of gastric damage. Higher doses did not produce any further reduction of gastric damage, and a return toward control values was observed. The effect on lesions was independent of inhibition of gastric acid secretion, since a dose of 0.1 nmol/kg of this growth factor failed to modify gastric acid secretion stimulated by pylorus ligation.