Recent CO2 levels promote increased production of the toxin parthenin in an invasive Parthenium hysterophorus biotype.

Recent carbon dioxide (CO2) concentrations promoted higher parthenin concentrations in an invasive Parthenium hysterophorus biotype. Mean concentrations of parthenin, an allelopathic and defensive sesquiterpene lactone, were 49% higher at recent (~400 ppm) than at mid-twentieth-century (~300 ppm) CO2 concentrations, but did not vary in a non-invasive biotype, suggesting that recent increases in atmospheric CO2 may have already altered the chemistry of this destructive weed, potentially contributing to its invasive success.

Transdermal delivery of drugs for the treatment of bone diseases.

The current status of transdermal drug delivery for the treatment of bone diseases is described in this review. The structure, physiology and function of skin and their importance in determining delivery into and across skin are discussed. Special emphasis has been devoted to a description of the major pathways of transport across the skin and the quite continuing controversy over the importance of the transfollicular route. An overview of anatomic site-dependent drug absorption is also provided and is particularly relevant to determination of transdermal patch location. Brief descriptions of the criteria for selection of transdermal drug candidate, transdermal patch designs and currently marketed transdermal products are also included. Transdermal estradiol delivery systems are examined in more detail for their clinical and biological effects. Finally, the feasibility of delivering drugs such as bisphosphonates across skin is discussed.

The mandate project: institutionalizing a system of patient care quality assurance.

In 1970, prior to present-day requirements for quality assurance programs, a project was undertaken to institute such a program voluntarily in ten hospitals. Five hospitals succeeded in fully implementing the program which was based on the "Bi-Cycle Process" and each documented improvements in desired patient care behaviors. Two hospitals partially implemented the process and demonstrated no significant changes in desired patient care behaviors. Two hospitals failed to provide the data upon which assessments could be made and one hospital never got beyond preliminary efforts at instituting the process. The project demonstrates that a voluntary quality assurance program is feasible and has important implications for PSROs and continuing medical education. It also provides evidence that attention to psychosocial factors is essential in the institutionalization of programs designed to produce desired changes in patient care behaviors.

Drug, meal and formulation interactions influencing drug absorption after oral administration. Clinical implications.

Drug-drug, drug-formulation and drug-meal interactions are of clinical concern for orally administered drugs that possess a narrow therapeutic index. This review presents the current status of information regarding interactions which may influence the gastrointestinal (GI) absorption of orally administered drugs. Absorption interactions have been classified on the basis of rate-limiting processes. These processes are put in the context of drug and formulation physicochemical properties and oral input influences on variable GI physiology. Interaction categorisation makes use of a biopharmaceutical classification system based on drug aqueous solubility and membrane permeability and their contributions towards absorption variability. Overlaying this classification it is important to be aware of the effect that the magnitudes of drug dosage and volume of fluid administration can have on interactions involving a solubility rate limits. GI regional differences in membrane permeability are fundamental to the rational development of extended release dosage forms as well as to predicting interaction effects on absorption from immediate release dosage forms. The effect of meals on the regional-dependent intestinal elimination of drugs and their involvement in drug absorption interactions is also discussed. Although the clinical significance of such interactions is certainly dependent on the narrowness of the drug therapeutic index, clinical aspects of absorption delays and therapeutic failures resulting from various interactions are also important.

Oral delivery of HIV-protease inhibitors.

Strategies for optimizing the oral delivery of HIV-protease inhibitors draw from drug discovery efforts in molecular design, drug development tools in dosage formulation, and dosage regimen considerations in clinical medicine. This review outlines the evolution of these strategies for drugs that have been approved for human use, drug candidates still in development, and molecules that are no longer in development but from which valuable delivery information was obtained. Molecular design for obtaining desirable pharmacokinetics following oral administration primarily involved maximizing aqueous solubility and minimizing first-pass metabolism. Optimization of molecular design for oral drug delivery purposes is tempered by additional considerations for drug potency, toxicity, potential for interactions, and development of viral resistance. Strategies for improving oral bioavailability through dosage formulation use information from the effects of coadministered meals on drug plasma levels. Patient adherence to dosage regimens remains a major issue in assuring effective oral drug treatment and in preventing the development of resistance. Progress has been made in clinical studies where improved oral bioavailability and reductions in drug plasma level variability have been achieved with appropriate dosage regimen adjustment.

Intestinal clearance of H2-antagonists.

Jejunal perfusion of cimetidine resulted in the appearance of lumenal cimetidine sulfoxide in both rats and humans. In the rat, ileal perfusion yielded negligible sulfoxide metabolite as compared with that of the jejunum. Jejunal co-perfusion of an anionic-exchange inhibitor, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, blocked the appearance of drug sulfoxide, and methionine co-perfusion yielded concentration-dependent inhibition of lumenal cimetidine sulfoxide. Intravenous injection of high concentrations of cimetidine sulfoxide did not produce detectable lumenal metabolite levels during jejunal perfusion of drug-free buffer, providing in situ evidence that lumenal metabolite is generated by the small intestine. The extent of the appearance of lumenal sulfoxide was significantly greater for cimetidine than for the other three marketed H2-antagonists in rat jejunum. Variable intestinal clearance of this extensively prescribed class of therapeutic agents may contribute to their absorption variability.

Management of the appendix in young patients with Crohn's disease.

Sixty-six young patients (average age, 17.2 years) underwent intestinal operations for Crohn's disease during a 14-year period at the UCLA Hospital. Nine had undergone previous appendectomy for suspected appendicitis, and in seven subsequent enteric fistulae and/or obstruction involving the cecum developed. None of the appendices were acutely inflamed. During the same period, a total of 125 children with Crohn's disease underwent medical or surgical care, and in none did acute appendicitis develop. Of the 66 patients under 22 years old who required intestinal resection, 60 had removal of the cecum. In a child with ileal Crohn's disease, rarely should a normal appendix be removed because of the high likelihood of complications and the low incidence of subsequent appendicitis.

CCK antagonist pre-treatment inhibits meal-enhanced drug absorption in dogs.

Duodenal administration of casein and oleate increased plasma levels from oral administration of a poorly water-soluble antiepileptic drug as compared to duodenal glucose and saline in a canine model. Pre-treatment with intravenous MK-329, benzodiazepine CCK A-receptor antagonist, blocked the duodenal oleate effect on drug plasma levels in a single dog preliminary study. In a follow-up study, oral drug co-administration with Intralipid increased drug plasma levels as compared to drug co-administration with a noncaloric equivalent-volume load in seven dogs. Pre-treatment with MK-329 reduced drug plasma levels from co-administration with Intralipid toward fasted-state values. While increased drug solubility in the lipid vehicle might have been projected to account for the fed-state effect in the oral studies, the gut peptide inhibitor studies suggest that biliary secretion plays a major role in promoting the dissolution and subsequent absorption of this lipophilic drug. The data also support the hypothesis that meal-enhanced pancreatic secretion provides a greater fluid volume for drug dissolution in the small intestine. An increase in the extent of drug dissolution in the stomach, as a result of meal prolongation of gastric residence time, does not appear to contribute substantially to fed-state increases in drug plasma levels from oral drug co-administration with a lipid meal.

The intestinal uptake of "enzymatically-stable" peptide drugs in rats as influenced by D-glucose in situ.

In previous in situ and in vivo rat perfusion studies, the intestinal absorption of several low molecular weight drugs was increased by the presence of luminal D-glucose. The intent of this study was to determine the potential of this fed-state effect to improve the intestinal uptake of poorly permeable, small peptide and peptide-like drugs. Jejunal wall permeabilities (Pw*) of di-(D-kyotorphin), tri-(cephradine), hexa-(growth hormone releasing peptide, GHRP-6) and octa-(octreotide, a somatostatin analogue) peptides and corresponding net water fluxes were determined in rats using an in situ single-pass perfusion technique. Glucose was shown to enhance the uptake of the smaller (di- and tri-) peptides but not the larger peptides despite the fact that glucose elicited a significant net water absorption with each of the four peptide drugs. It is concluded that glucose enhances jejunal permeabilities of smaller peptides by solvent drag and the enhancement is limited in situ by peptide molecular size. The studies with nonmetabolizable 3-O-methylglucose suggest that the augmentation of the proton gradient across the transmucosal membrane by glucose contributes to the carrier-mediated transport observed with the smaller peptides.

Topical delivery of growth hormone releasing peptide using liposomal systems: an in vitro study using hairless mouse skin.

The results of this study clearly demonstrates the utility of novel non-ionic liposomal systems in facilitating transfer of GHRP-6 into and across deeper strata of skin following topical application. These findings indicate that it may be possible to deliver therapeutic doses of a wide variety of peptides to local skin tissue via topical application. The results also suggest the possibility of controlled enhancement of skin penetration or metered polypeptide deposition through appropriate choice of liposomal lipid components. The pronounced enhancement of GHRP-6 and mannitol transport from emulsions containing the nonionic lipids suggests a promising delivery system for hydrophilic drugs in general.

Mixing-tank model for predicting dissolution rate control or oral absorption.

A mixing-tank model is used to simulate GI absorption of nonionized drugs. The model is useful for predicting circumstances under which dissolution rate dominates membrane transport and transit rate, thus limiting the extent of absorption. The model is developed from mass balance considerations in which the nonsink dissolution term is a function of the remaining surface area and the concentration gradient across the boundary layer. Other dissolution parameters include initial particle radius, dose, diffusivity, density, and boundary-layer thickness. Readily calculable estimators for the general solution of the model are derived and their ranges of usefulness are discussed. Drug examples chosen for simulation are griseofulvin and digoxin. The model correctly predicts bioavailability as a function of particle size for both of these poorly soluble drugs.

Influence of D-glucose-induced water absorption on rat jejunal uptake of two passively absorbed drugs.

The intestinal absorption of D-glucose is coupled to transepithelial sodium transport and this process generates intestinal water absorption. In situ jejunal perfusions were performed in rats to determine the extent of water transport as a function of perfusion flow rate, perfusate osmolality, and D-glucose concentration. Jejunal perfusions of iso-osmolar D-glucose, at flow rates and concentrations representative of the fed state, increased the dimensionless membrane permeabilities of the analgesic acetaminophen from 0.6 to 1.4, and that of the corticosteroid prednisolone from 1.6 to 2.2. This increase is less important for the more hydrophobic prednisolone since its baseline permeability (1.6) is indicative of complete uptake from solution, while the lower baseline permeability (0.6) of the more hydrophilic acetaminophen represents incomplete membrane uptake. The results suggest that nutrient-induced water transport can enhance jejunal uptake of small hydrophilic solutes. This phenomenon may contribute to variability in the absorption of drugs in this physicochemical class during the fed state.

Physicochemical model for dose-dependent drug absorption.

A two-tank perfect-mixing tank model was used to stimulate GI absorption. The effect of drug parameters (pK alpha, solubility, and intrinsic wall permeability) and system parameters (pH profile, volume of intestinal contents, and intestinal flow rate) on drug absorption were studied by numerical data stimulation. When the dose did not exceed the solubility of the drug in the intestinal lumen, the fraction absorbed depended on the transit rate relative to the absorption rate and the pK alpha relative to the pH profile, but was independent of drug dose. Saturation of one or both tanks led to dose-dependent absorption. The model was used to simulate absorption of chlorothiazide. Good agreement between simulated and experimental data led to the conclusion that the physical characteristics of chlorothiazide, rather than a saturable transport mechanism at the intestinal wall, may be responsible for the dose-dependent absorption observed for this drug. The model was also used to simulate hydrochlorothiazide absorption. By applying the same system parameters used for chlorothiazide, the model simulation correctly predicted the dose proportionality of hydrochlorothiazide absorption. The lack of dose dependency in this case may be attributed to the higher solubility and pK alpha of hydrochlorothiazide compared with chlorothiazide.

Application of a radiotelemetric system to evaluate the performance of enteric coated and plain aspirin tablets.

The bioavailability of enteric coated and plain aspirin tablets was studied in four beagle dogs. Blood sampling for enteric coated tablets was planned with the aid of a radiotelemetric system. The release of aspirin from its dosage form was detected by monitoring the change in intestinal pH. Aspirin and salicylic acid levels in plasma obtained from the enteric coated dosage form exhibited familiar concentration versus time absorption profiles. Variation in the plasma concentrations of these two compounds within each dog studied (four runs each) was relatively small when time zero was adjusted to the commencement of tablet dissolution. The plasma levels obtained from plain aspirin (three runs each), however, show atypical absorption. The estimated absolute bioavailability was 0.432 +/- 0.0213 and 0.527 +/- 0.0260 for enteric coated and plain aspirin, respectively. Other pharmacokinetic parameters for these two dosage forms such as the highest observed plasma concentration (Cmax) (10.9 +/- 0.535 microgram/mL versus 13.6 +/- 1.88 micrograms/mL) and the time to reach Cmax (tmax) (26.6 +/- 1.94 min versus 31.0 +/- 7.04 min) agree well. The mean values for gastric emptying time, in vivo coating dissolution time, and in vivo disintegration/dissolution time of the tablet core for enteric coated aspirin are 48.7 +/- 7.23 min, 44.3 +/- 3.80 min, and 34.7 +/- 2.04 min, respectively.

Oral absorption of 21-corticosteroid esters: a function of aqueous stability and intestinal enzyme activity and distribution.

The intestinal absorption of hydrocortisone and prednisolone are compared with three water-soluble derivatives (succinate, phosphate, and lysinate) in experiments at two levels of biological system complexity. Rates of absorption are compared by measuring permeabilities from rat intestinal perfusions of drugs and derivatives in solution. Extents of absorption are compared over a 10-fold dose range of parent steroid and with the steroid derivatives by measuring plasma levels from solid oral dosage in dogs. While the parent steroids are well absorbed over the entire length of the intestinal tract, variability in plasma levels is observed at higher doses. Limited solubility and resultant dissolution rate variability are likely to be playing a role in the early erratic blood level profiles found at higher doses. While the soluble prodrugs have a dissolution rate advantage which results in a greater concentration gradient, their absorption is limited by their aqueous luminal stability, their polarity and resultant passive membrane permeability, and the distribution and activity of enzyme reconversion sites in the intestinal tract. The unstable lysinate ester, targeted for aminopeptidase, has an absorption profile and permeability similar to that of the parent steroid. The absorption of the moderately stable succinate ester is limited by its polarity and the activity of intestinal esterases. The stable phosphate derivative is well absorbed in the upper intestine, where high levels of alkaline phosphatase exist, while the prodrug polarity and drop-off of enzyme activity limit its absorption from the lower gastrointestinal (GI) tract.

Contrasting nutrient effects on the plasma levels of an amino acid-like antiepileptic agent from jejunal administration in dogs.

The absorption of gabapentin was investigated by monitoring drug plasma levels as a function of time following midjejunal administration in mongrel dogs. From previous work, dose-dependent absorption had been postulated to be a consequence of carrier-mediated transport and a paracellular pathway had been postulated to contribute to the passive absorption component in mammalian small intestine. The potential for amino acid inhibition of the carrier-mediated absorption component was investigated by drug coinfusion with leucine and phenylalanine. The potential for monosaccharide-enhanced increases in drug absorption was studied by drug coinfusion with D-glucose and 3-O-methylglucose. While lower drug plasma levels were observed with amino acid coinfusion versus controls in each of the dogs studied, mean area under the plasma level time curves (AUC) were not statistically significantly different (p < or = 0.07). Monosaccharide coinfusion significantly increased gabapentin AUC over control studies (p < or = 0.014) and over coinfusion with L-system amino acids (p < or = 0.0025). Implications for the mechanisms of intestinal absorption of this amino acid-like antiepileptic drug in this canine model are discussed.

Intestinal absorption of amino acid derivatives: importance of the free alpha-amino group.

The intestinal absorption of L-lysine-p-nitroanilide, L-alanine-p-nitroanilide, and glycine-p-nitroanilide was studied in the presence of competitive inhibitors in a perfused rat intestine. It ws observed that L-lysine-p-nitroanilide absorption was inhibited by L-lysine methyl ester and L-arginine-beta-naphthylamide but not by N alpha-acetyl-L-lysine methyl esters. L-Alanine-p-nitroanilide absorption was inhibited by L-alinine methyl ester but not by beta-alanine methyl ester. It was further observed that N alpha-benzoyl-L-arginine-p-nitroanilide and N alpha-succinyl-L-phenylalanine-p-nitroanilide were poorly absorbed. It was concluded that the peptidase in the brush border region that serves as the hydrolysis site requires a free alpha-amino group (an aminopeptidase), and that passive absorption of these compounds occurs only to a small extent.

Absorption of ACE inhibitors from small intestine and colon.

The intestinal absorption of two ACE inhibitors was studied to determine the potential for colonic delivery of small peptides. In addition, studies were also performed to assess intestinal tissue uptake and evaluate a canine intestinal-access-port model as techniques for screening absorption. To evaluate the impact of differences in the contributions of passive permeation and carrier-mediated peptide transport on in vitro uptake and in vivo absorption, an esterified prodrug, benazepril, and a free diacid non-prodrug, CGS 16617, were selected for study. Potential colonic absorption enhancement utilizing coadministration of Intralipid was also investigated. Studies in rat everted intestinal rings verified that jejunal benazepril uptake included a carrier-mediated component while that of the diacid did not. Uptake of both drugs was purely passive in colonic rings. Equilibrium uptake and uptake rate of the more lipophilic prodrug was 2-fold greater than the diacid. Benazepril and CGS 16617 jejunal uptake rate at 0.01 mM was 3.5 and 2.5 times higher, respectively, than from colonic rings. Following jejunal administration in dogs, maximum benazepril plasma levels (Cmax) and area under the plasma level versus time curve (AUC) were 5.5 and 3.0 times higher, respectively, than following colonic administration. Maximum benazepril plasma levels following colonic administration in dogs was 2-fold greater than for CGS 16617, consistent with in vitro results. Colonic coadministration of the poorly-absorbed CGS 16617 with 2 mL of Intralipid (within dietary range for fecal fat content) enhanced Cmax and AUC 2.5- and 3.5-fold, respectively, in the dog and AUC 1.5-fold in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of gastrointestinal pH in dogs and humans: implications on the use of the beagle dog as a model for oral absorption in humans.

Gastrointestinal pH as a function of time was recorded for 4 beagle dogs and 10 human subjects using radiotelemetric pH measuring equipment. Results indicated that in the quiescent phase, gastric pH in the dogs (mean = 1.8 +/- 0.07 SEM) was significantly (p less than 0.05) higher than in humans (1.1 +/- 0.15). No significant difference in the time for the pH monitoring device to empty from the stomach was noted for the two species (99.8 +/- 27.2 min for dogs, 59.7 +/- 14.8 min for humans, p greater than 0.05). The fasting intestinal pH in dogs was consistently higher than in humans, with an average canine intestinal pH of 7.3 +/- 0.09 versus 6.0 +/- 0.14 for humans. The implication of these observations for extrapolation of drug absorption data from dogs to humans are discussed.

Regional-dependent intestinal absorption and meal composition effects on systemic availability of LY303366, a lipopeptide antifungal agent, in dogs.

Low oral bioavailability and a negative meal effect on drug plasma levels motivated studies on formulation and meal composition effects on the absorption of LY303366, a poorly water-soluble, semisynthetic, cyclic peptide antifungal drug. Solid drug particle size and meal composition studies were evaluated in beagle dogs. Canine regional absorption studies were also carried out utilizing surgically implanted intestinal access ports, and Caco-2 studies were performed to evaluate drug candidate intestinal permeability. Particle size and Caco-2 data indicate that drug permeability limitations to absorption are more important than dissolution rate limits. Caco-2 cell-associated LY303366 approached 10% of incubation concentration that is in the range of the oral bioavailability of the drug. Canine regional absorption studies showed that the extent of LY303366 absorption following duodenal administration was similar to that following oral administration. Significantly lower drug plasma levels were obtained following administration through a colonic access port, a result consistent with poor membrane permeation. Administration of drug with meals of mixed composition, as well as simple fat and protein meals, resulted in significant reductions in AUC(0-48h) compared with results from fasted dogs. In contrast, carbohydrate meals did not reduce drug plasma levels compared to controls. Intravenous pretreatment with devazepide, a cholecystokinin (CCK) antagonist that blocks canine biliary secretion, did not reverse the negative effect of the fat meal on LY303366. Taken together, the results from the present study suggest that membrane-permeability-limited absorption is the cause of the observed regionally dependent absorption of LY303366 in the dog and that the observed negative meal effects depend on composition but are independent of biliary secretion.