Transdermal delivery of erythromycin lactobionate--implications for the therapy of gastroparesis

BACKGROUND: The treatment of many diseases may be complicated by abnormalities in gastric emptying. Gastric motor dysfunction may lead to unpredictable food and medication delivery to the small intestine, their site of absorption. Prokinetic agents improve gastric motility, but orally administered drugs are unreliably absorbed, thereby limiting their effectiveness. A method of delivering prokinetic agents which bypasses the gastrointestinal tract could lead to more effective treatment. METHODS: Skin samples from rat, hairless mouse and man were placed in an in vitro diffusion chamber. The epidermal side of the skin was exposed to erythromycin lactobionate and passage of the drug across the skin sample monitored and quantitated by high-performance liquid chromatography with UV detection. RESULTS: Erythromycin passes across all skin types tested. Steady-state flux across hairless mouse skin was greater than for rat, full thickness human skin and human epidermis. In the first 3 h following introduction of erythromycin lactobionate, 1.85 mg/cm2 crossed human epidermis. Given that a dose of 50 mg may exert prokinetic effects in vivo in man, increasing the patch size to approximately equal to 28 cm2 should provide therapeutic levels of drug within 3 h. CONCLUSIONS: Erythromycin lactobionate, when administered transdermally, can be delivered at levels sufficient to treat gastroparesis. This technique warrants in vivo investigation.     

Innovative strategies for the oral delivery of drugs and peptides

Conventional forms of administration for nonabsorbable drugs and peptides often rely on parenteral injection, because the intestinal epithelium represents a major barrier to the oral absorption of these therapeutic agents. Recently, a number of innovative drug-delivery approaches have been developed, including entrapment within small vesicles and passage through the space between adjacent intestinal cells. This article reviews some of the most promising techniques currently available for oral delivery and their possible practical applications for the delivery of vaccines and drugs for the treatment of clinical conditions that require frequent, chronic parenteral administration.     

Nanoparticle technology for delivery of drugs across the blood-brain barrier

The Leu-enkephalin dalargin and the Met-enkephalin kyotorphin normally do not cross the blood-brain barrier (BBB) when given systemically. To transport these neuropeptides across the BBB they were adsorbed onto the surface of poly(butylcyanoacrylate) nanoparticles (NPs) and the NPs were coated with polysorbate 80. Central analgesia was measured by the hot plate test in mice. The antidepressant amitriptyline, which normally penetrates the BBB, was used to examine the versatility of the NP method. The concentration of amitriptyline in serum and brain of mice was determined by a gas chromatographic method. Furthermore, NPs were fabricated with different stabilizers. After the adsorption of the peptides on polysorbate 85-stabilized NPs, analgesia was noted after intravenous application when NPs were not coated. The amitriptyline level was significantly enhanced in brain when the substance was adsorbed onto the NP and coated or when the particles were stabilized with polysorbate 85.     

Development of drug delivery systems for macromolecular drugs

With a rapid progress in biotechnology, a variety of endogenous macromolecular substances have become a novel class of therapeutic agents. This review will focus on the development of delivery systems for macromolecular drugs. Current status and future perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First of all, we studied pharmacokinetic characteristics of macromolecules in relation to their physicochemical properties such as molecular weight and electric charge. Based on this information, we first developed macromolecular prodrugs as a delivery system for low molecular weight drugs. An antitumor antibiotic, mitomycin C (MMC) were covalently conjugated with dextran and various types of macromolecular prodrug of MMC were developed for tumor targeting. Secondly, delivery systems for protein drugs such as soybean trypsin inhibitor, uricase, and recombinant superoxide dismutase (SOD) were developed. In particular, successful targeting of SOD to the liver, kidney and blood circulation was achieved by chemical modification of the protein drug. Finally, we have been trying to develop delivery systems for nucleic acid drugs involving antisense oligonucleotides and plasmid DNA. Prior to the development of delivery systems, we found that the pharmacokinetics of the nucleic acid drugs are decided by their physicochemical properties as polyanions even if these materials contain genetic information. Several approaches were tested to control the in vivo behavior of the oligonucleotides and plasmid DNA based on the finding. Thus, we have established the strategy for rational design of delivery systems for various types of macromolecular drugs based on the pharmacokinetic considerations. This methodology can be a formidable tool for the development of clinically applicable macromolecular drugs.     

Transdermal nicotine: The long and the short of it.

Cigarette smokers with a mean history of 35 smoking years (N?=?98) were randomly assigned to receive either 3 weeks or 12 weeks of transdermal nicotine treatment combined with a 5-session behavioral management program. Participants were followed for 20 weeks. At the conclusion of the study, 26% of the 3-week participants and 29% of the 12-week participants were abstinent. The number of abstinent participants and duration of abstinence were not significantly different between the 2 groups, although statistical power constraints do not rule out the possibility of small undetected differences in outcome. Most participants (68%) smoked at least once during their nicotine patch regimen. Smoking on the patch was associated with poor outcome. Those who smoked while using the patch reported more restlessness and cigarette cravings and lower confidence and intention to quit smoking than did participants who did not smoke during the drug regimen. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Immunoassay reagents for psychoactive drugs. Part 3. Removal of phenothiazine interferences in the quantification of tricyclic antidepressants

Phenothiazines and their metabolites are known to interfere in the quantification of tricyclic antidepressants (TCAs). A method for selective chemical modification of phenothiazines by chloramine-T in the presence of TCAs is described. This method allows for accurate quantification of the TCA analyte in a serum sample without interference from the modified phenothiazine.     

Assessing the potential of skin electroporation for the delivery of protein- and gene-based drugs

Although transdermal drug delivery has many potential advantages, the permeability of skin to macromolecules is extremely low. However, the application of short, high-voltage pulses to electroporate skin has recently been shown to make it reversibly permeable. A number of studies have demonstrated that electroporation-mediated transdermal delivery of peptides, polysaccharides, oligonucleotides and genes may be possible at clinically relevant rates, leading to the current commercial development of electroporation techniques.     

Transdermal delivery of ketorolac tromethamine: permeation enhancement, device design, and pharmacokinetics in healthy humans

Transdermal delivery of ketorolac tromethamine, a potent non-narcotic analgesic, through human skin in vitro and in vivo was investigated. In order to enhance and sustain the flux of ketorolac through human skin, various compositions of isopropyl alcohol (IPA), water, and isopropyl myristate (IPM) were evaluated. The solubility of ketorolac acid in an IPA/water binary vehicle mixture increased as the volume fraction of IPA increased from 0 to 90%. The solubility of ketorolac acid in an IPA/water/IPM (saturated) ternary vehicle mixture was practically the same as in the IPA/water binary vehicle mixture. The permeation of ketorolac acid through cadaver skin was evaluated using modified Franz diffusion cells. The skin flux increased as the IPA volume fraction was increased from 0 to 50% and then leveled off beyond 80% IPA loading. When IPM was added to the IPA/water binary vehicle mixture, a significant increase in the skin flux of ketorolac was observed. The skin flux decreased exponentially as the donor solution pH was raised from 3.5 to 7.0. The permeability of ketorolac through various membranes such as a microporous membrane and pressure-sensitive adhesive was evaluated. While a microporous membrane offered practically no diffusion resistance, the in vitro flux of ketorolac through cadaver skin decreased substantially upon lamination of pressure-sensitive adhesive onto a microporous membrane. Three liquid-reservoir type transdermal devices were fabricated using 6.5% ketorolac tromethamine gel, a microporous membrane, an adhesive membrane, and polyester backing film: TD-A (microporous membrane/acrylic adhesive), TD-B (microporous membrane/silicone adhesive), and TD-C (microporous membrane). The pharmacokinetics of ketorolac in 10 healthy humans following application of a transdermal device for 24 h was evaluated. The maximum plasma concentrations (Cmax) were 0.20, 0.18, and 0.82 microgram/mL for TD-A, TD-B, and TD-C, respectively. The total AUC values for the concentration-time curves were TD-C > TD-A > TD-B, and the terminal half-life ranged from 6.6 to 9.7 h.     

Drug delivery during pregnancy: evaluation in vitro of new drugs

Indications for the treatment of the pregnant woman fall into three general categories: mother and infant require treatment, only the mother should be treated, or only the infant. Directing therapy towards the affected subject is an important aspect of good care, although it is not the only one. It is argued that a rational selection of the appropriate drug can be made without endangering mother or infant, with the aid of select laboratory investigations, including placental perfusion, and a knowledge of placental physiology. Examples are presented to support this contention. The intra-amniotic administration of drugs is briefly discussed. A plea is made to develop drugs that are designed specifically for use during pregnancy.     

Evaluation of intravenous tenoxicam for postoperative cesarean delivery pain relief. Preliminary report

BACKGROUND AND OBJECTIVES: To assess safety and efficacy of tenoxicam for postoperative pain relief after cesarean delivery. METHODS: Postoperative pain relief, supplemental analgesic requirements, and adverse side effects were evaluated in 80 patients undergoing cesarean delivery. Forty patients received a slow intravenous injection of tenoxicam at a fixed dose of 20 mg (2 mL), immediately before induction of spinal anesthesia with 15 mg (3 mL) of 0.5% hyperbaric bupivacaine. The other 40 patients received 2 mL of saline solution. Newborns were evaluated by means of Apgar score and umbilical cord blood gases. RESULTS: There was a significant prolongation of analgesia in the tenoxicam group (365 +/- 91.1 minutes versus 305 +/- 53.2 minutes in control group, P < .001). Supplementary analgesic requirements were significantly decreased by intravenous tenoxicam (1.55 +/- 0.70 versus 2.25 +/- 0.68). Adverse side effects did not differ between groups and few complaints of phlebitis were noted. Apgar scores and blood gas analyses were similar in neonates from both groups. CONCLUSIONS: Intravenous tenoxicam is safe and slightly increases the length of postoperative analgesia provided by the local anesthetic. It is effective in decreasing analgesic consumption in cesarean delivery patients.     

Combined dipyridamole and aspirin pellet formulation for improved oral drug delivery. Part 2: In-vivo evaluation and stability

The N-terminal signal sequence of glucitol permease of Escherichia Coli (Gut22) and its analogue (Gut22Ana) were synthesized. The analogue had a Pro residue substituting for the His at the 7th position of Gut22 and a Val residue substituting for the Glu at the 10th position. The intrinsic fluorescence emission spectra indicated that the binding of Gut22 with lipid bilayer was much stronger than that of Gut22Ana. The leakage experiments with calcein-loaded liposomes showed that Gut22 strongly perturbed lipid bilayers while Gut22Ana did not. The apparent partition constant of Gut22 for partitioning into phosphatidylserine/phosphatidylcholine bilayers was measured; the effect of membrane potential on the interaction of Gut22 with lipid bilayers was studied and the conformation changes of Gut22 and Gut22Ana upon interacting with liposomes were studied by the method of circular dichroism analysis.     

Distribution of drugs following controlled delivery to the brain interstitium

Intracranial controlled release polymers have been used for drug delivery to the brain, bypassing the blood brain barrier (BBB). By understanding the rates and patterns of transport in the local tissues, it is possible to design delivery systems that provide the optimal spatial and temporal pattern of chemotherapy within the intracranial space. This paper reviews the kinetics of drug release from polymeric controlled release implants, and describes the fate of drug molecules following release into the brain interstitium. Potential improvements in drug delivery based on the understanding of the mechanisms of drug release, transport and elimination are discussed.     

Transdermal delivery of narcotic analgesics: comparative metabolism and permeability of human cadaver skin and hairless mouse skin

The permeation of hairless mouse skin and human cadaver skin by narcotic analgesics was investigated to determine the interspecies variation. Permeability coefficients of morphine, fentanyl, and sufentanil across full-thickness hairless mouse skin were 1 order of magnitude higher than those found for human epidermis. The permeability coefficient of morphine for stripped hairless mouse skin was 500-fold higher than that for intact skin, showing the stratum corneum to be the principal barrier to its penetration. The permeability coefficient of fentanyl for stripped hairless mouse skin was also raised, but stripping caused an inappreciable increase in the permeation rate of sufentanil. The thick dermis of excised mouse skin obviously offered a significant resistance to the permeation of these lipophilic compounds. In comparison, the permeability coefficients of fentanyl and sufentanil through stripped cadaver epidermis (n > or = 25) were 67 and 37 higher than for intact human epidermis, respectively. The skin metabolism of the narcotics was investigated. No significant metabolic degradation of morphine, fentnayl, and sufentanil was observed in either fresh human cadaver skin or hairless mouse skin homogenates in the presence of NADPH cofactor, suggesting a low monooxygenase enzyme presence in skin. Moreover, no measurable glucuronidation of morphine took place in human skin or hairless mouse skin. Both processes proceeded rapidly in liver homogenates (mouse) under identical circumstances. It thus appears that these drugs pass through in intact form.     

Evaluation of the retinal nerve fiber layer

In normal eyes, the retinal nerve fiber layer (RNFL) is usually best visible in the inferior temporal part of the fundus, followed by the superior temporal region, the nasal superior region and the nasal inferior region. This distribution correlates with the configuration of the neuroretinal rim, the diameter of the retinal arterioles, the location of the foveola, and the lamina cribrosa morphology. With increasing age, the RNFL visibility decreases diffusely without preferring special fundus regions and without the development of localized defects. With all optic nerve diseases, the visibility of the RNFL is decreased in addition to the age-related loss, in a diffuse and/or a localized manner. The localized defects are wedge-shaped and not spindle-like defects, running toward or touching the optic disk border. Typically occurring in about 20% of all glaucoma eyes, they can be found also in other ocular diseases, such as optic disk drusen, toxoplasmotic retinochoroidal scars, longstanding papilledema or optic neuritis due to multiple sclerosis. Since they are not present in normal eyes, they almost always signify an abnormality. RNFL evaluation is especially helpful for early glaucoma diagnosis and in glaucoma eyes with small optic disks. In advanced optic nerve atrophy, other examination techniques, such as perimetry, may be more helpful for following optic nerve damage. Considering its great importance in the assessment of optic nerve anomalies and diseases and taking into account the feasibility of its ophthalmoscopic evaluation using green light, the retinal nerve fiber layer should be examined during any routine ophthalmoscopy.     

CEO summit. Building the new health care delivery alliance, Part III. Roundtable discussion

In cooperation with McManis Associates, Hospitals & Health Networks recently convened a CEO summit on physician/hospital integration activities. In the third report of a three-part series on the summit, leading health care executives discuss investor capital needs, strategic information management needs, and the management competencies required for capitated managed care success.     

Pharmacoangiography in experimental tumours. Evaluation of vasoactive drugs

Pharmacoangiography with four vasoactive drugs was performed in experimental renal and hepatic tumours in rats in order to compare their ability to demonstrate tumour vascularity. Three vasoconstrictors, angiotensin, norepinephrine and vasopressin, and one vasodilator, tolazoline, were tested, vasoconstrictors giving most diagnostic information and the difference in effect among these sometimes being small and probably dose-related. This diagnostic effect is based upon the primitive character of tumour vessels, being unable to react upon a vasoactive stimulus. Angiotensin turned out to be the superior drug which corresponds to clinical experiences of this drug.     

Poly (ADP-ribose) polymerase, a potential target for drugs: Part II. Regulation of differentiation by the poly ADP-ribose system

It is shown that eukaryotic differentiation is specifically sensitive to pADPRT regulation in Trypanosomna, Leishmania and Mytilus models. There is powerful inhibition of early differentiation without cell toxicity by pADPRT ligands.