En Bloc Multivisceral and Kidney Transplantation in an HIV Patient: First Case Report.

The continual improvement in outcome with highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection and visceral transplantation for gut failure stimulated our interest in lifting HIV infection as a contraindication for intestinal and multivisceral transplantation. This report is the first to describe visceral transplantation in a patient with HIV infection. A HAART regimen was introduced in the setting of short-gut syndrome with successful suppression of HIV viral load. The indication for en bloc multivisceral and kidney transplantation was end-stage liver failure with portomesenteric venous thrombosis and chronic renal insufficiency. The underlying hepatic pathology was alcoholic and home parenteral nutrition-associated cirrhosis. Surgery was complicated due to technical difficulties with excessive blood loss and long operative time. The complex posttransplant course included multiple exploratory laparotomies due to serious intra-abdominal and systemic infections. Heavy immunosuppression was required to treat recurrent episodes of severe allograft rejection. Posttransplant oral HAART successfully sustained undetectable viral load. Unfortunately, the patient succumbed to sepsis 3 months posttransplant. With new insights into the biology of gut immunity, mechanisms of allograft tolerance, and HIV-associated immune dysregulation, successful outcome is anticipated, particularly in patients who are in need of isolated intestinal and less-organ-contained visceral allografts.

Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management.

Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non-liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti-HBc+) donors. Organs from anti-HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non-liver recipients but is not recommended in immune non-liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost-effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.

Progressive multifocal leukoencephalopathy in a heart transplant recipient following rituximab therapy for antibody-mediated rejection.

We report the case of a male heart transplant recipient who developed acute antibody-mediated rejection and was treated with 5 weeks of a rituximab-containing regimen. Two months later he presented with progressive motor and cognitive impairments and was diagnosed with progressive multifocal leukoencephalopathy (PML). He was treated with reduction of his immunosuppressive medications, mirtazapine, IVIG and plasmapheresis. He died within weeks. We reviewed the current literature on PML and its association with immunosuppression, highlighting its impact in the setting of solid organ transplantation and considering the potential effect of newer biologic drugs on the incidence of this devastating disease in the transplant population.

The HIV-1 reverse transcriptase mutants G190S and G190A, which confer resistance to non-nucleoside reverse transcriptase inhibitors, demonstrate reductions in RNase H activity and DNA synthesis from tRNA(Lys, 3) that correlate with reductions in replication efficiency.

We evaluated the replication efficiency of the HIV reverse transcriptase (RT) mutants K103N, G190A, and G190S, which confer resistance to the non-nucleoside RT inhibitor efavirenz, using growth competition assays in cell culture. In the absence of efavirenz, the fitness hierarchy was G190S < G190A < K103N < wild-type. The fitness reduction of G190S relative to K103N was less evident at high efavirenz concentrations, although K103N still replicated more efficiently. Efficiency of RNase H cleavage and RNA-dependent DNA synthesis from tRNA(Lys, 3) correlated with relative fitness, in biochemical studies of mutant RTs. Presteady state and steady state polymerization assays using DNA primers detected no abnormalities. This work is consistent with previous studies demonstrating that initiation of viral DNA synthesis is reduced in mutants with slowed RNase H cleavage, and suggests that both abnormalities contribute to the replication defect of these mutants. It also suggests that high concentrations of efavirenz are unlikely to favor the selection of G190S clinically.

Electrochemical determination of dissolution rates of lyophilized pharmaceutical formulations.

We present a method to measure dissolution times for rapidly dissolving lyophilized formulations. K4Fe(CN)6 was lyophilized in formulations containing sucrose, salts, and Tween 20. Dissolution of the lyophilized powders was measured by monitoring the time dependence of the oxidation of Fe(CN)6(4-) ion at the surface of a platinum rotating disk electrode. Reconstitution of lyophilized K4Fe(CN)6 formulations with aqueous solutions of 0.03% Tween 20 altered the time of dissolution for all cases. Salt and sucrose formulations without Tween 20 dissolved more slowly in a Tween 20 solution than in water alone. In contrast, formulations containing Tween 20 dissolved faster in the Tween 20 solution when compared to dissolution in water.

Solubilization of nicardipine hydrochloride via complexation and salt formation.

The solubility behavior of nicardipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic+ ++ acid methyl 2-[methyl(phenyl-methyl)amino]ethyl diester), a calcium channel blocker, used in the treatment of chronic stable angina and mild essential hypertension was investigated. Two techniques that are known to improve solubility, complexation and salt formation, were examined. Concentrations were determined with a specific reversed-phase HPLC assay. The solubility of nicardipine hydrochloride was enhanced exponentially via complexation with aliphatic carboxylic acid buffer systems in a pH dependent fashion. The solubility increased from 5 to 68.6 and 270 mg/mL as the acetate or propionate buffer concentrations, respectively, increased from 0.001 to 5 M, showing a positive deviation from linearity. The conversion of nicardipine hydrochloride to the phosphate salt resulted in a approximately 10-fold solubility improvement. The surface tension of the nicardipine phosphate in water as a function of concentration indicated a critical micelle concentration of 5-6 mg/mL. The critical micelle concentration was greater than the equilibrium solubility of the hydrochloride salt in water, suggesting that a self-association phenomena is responsible for the enhanced solubility of the phosphate salt. Both routes provided potential alternatives for the solubilization of nicardipine.

Crystallinity, hygroscopicity and dissolution of moricizine hydrochloride hemihydrate.

A typical anhydrous moricizine hydrochloride, an antiarrhythmic agent, is a non-hygroscopic crystalline material. Three lots of moricizine hydrochloride were found to deliquesce within a day at 85% relative humidity, exhibit different X-ray powder diffraction (XRPD) patterns and have more rapid dissolution rate than that of typical anhydrous material. No change in XRPD pattern was observed when the solvent (ethanol) was removed from these lots by heating to 80 degrees C. A two-step water release was observed by thermogravimetric analysis (TGA): a surface water release and a water of hydration release, for these heated samples. The stoichiometry of the water of hydration suggests that it is a hemihydrate. The dissolution rate of the hemihydrate was faster than that of typical anhydrous material. This hemihydrate could be converted to a typical anhydrous material by heating to 90 degrees C. The granules obtained by a simulated wet granulation process on typical lots and typical lots containing up to 20% of hemihydrate exhibited similar physical behaviour to that of typical anhydrous material.

Parenteral formulation of the kappa agonist analgesic, DuP 747, via micellar solubilization.

The nonopioid kappa agonist analgesic amine, DuP 747, as a hydrochloride salt exhibited an aqueous solubility of 3 mg/ml. This solubility was insufficient to provide the desired dose in a solution formulation for intramuscular administration. Aqueous solutions of the hydrochloride salt exerted surface activity behavior; however, the critical micellar concentration (CMC) was not reached at the saturation solubility. Enhanced aqueous solubility required to reach the CMC could lead to micellization of the compound and a possible i.m. solution formula. The methanesulfonate salt was more water soluble than the hydrochloride salt and yielded a micellar solution with a concentration of 60 mg/ml.

The effects of magnetic stabilization on the structure and performance of liquid fluidized beds.

Liquid fluidized beds containing porous magnetic ion-exchange particles with densities ca. 1.03-1.16 g mL-1 were examined. The effect of magnetic stabilization was studied, both in terms of bed physical characteristics and sorptive behavior. Maximum applied magnetic field strength was approximately 200 oersted. Breakthrough and pulse analyses were carried out with protein and acetone solutions, respectively, with liquid flow rates ranging from approximately 1 to 3 cm min-1. Acetone pulses in columns containing 7 mL of particles had plate numbers ranging from 2.5 to 18 for magnetically stabilized beds and from 7.8 to 20 for non-stabilized fluidized beds. Under any particular set of conditions, magnetic stabilization always resulted in poorer efficiency, both in pulse analyses and in protein breakthrough experiments.

Recovery of rat nasal mucosa from the effects of aminopeptidase inhibitors.

Aminopeptidase inhibitors may be useful for improving the systemic bioavailability of peptide drugs administered nasally or by other routes. Preferably, their effects would be rapidly reversible. The recovery of peptide hydrolytic activity after exposure of the rat nasal cavity to various aminopeptidase inhibitors was evaluated. Leucine enkephalin (0.1 mM) was used as a model peptide which is predominantly metabolized by aminopeptidases nasally. All experiments involved in situ perfusion of the rat nasal cavity with leucine enkephalin and the inhibitor for 90 min, followed by a washout with saline, and finally a second experimental phase of perfusion with leucine enkephalin but no inhibitor. Boroleucine (0.1 microM) was a potent inhibitor of leucine enkephalin metabolism, and, after its removal, the leucine enkephalin metabolism rate returned to control levels. Much higher concentrations of bestatin (0.1 mM) and puromycin (1 mM) did not inhibit leucine enkephalin metabolism as much as did boroleucine. Furthermore, when these inhibitors were washed out, the rates of leucine enkephalin disappearance rebounded to higher than control levels. With bestatin this could have been partially due to membrane disruption, as evidenced by significantly increased protein concentrations in the perfusates. However, protein release was much lower than that caused by sodium glycocholate, a nasal membrane permeation enhancer. In considering the use of peptidase inhibitors as pharmaceutical adjuvants for peptide drugs, the aminoboronic acid derivatives, including boroleucine, have the advantages of efficacy at very low concentrations and reversibility of effects.

An aminoboronic acid derivative inhibits thymopentin metabolism by mucosal membrane aminopeptidases.

Thymopentin is a pentapeptide with immunomodulatory activity. Transmucosal delivery may offer advantages over other routes, but published data have shown relatively poor efficacy when dosed nasally. Metabolism of thymopentin by the rat nasal mucosa and the effects of an aminoboronic acid aminopeptidase inhibitor, boroleucine, were evaluated. Thymopentin concentrations in a solution perfused through the isolated nasal cavity decayed with a first-order half-life of 12 minutes. Thymopentin was metabolized primarily by aminopeptidases, based on the amount of tetrapeptide metabolite formed. In the presence of boroleucine, at an inhibitor/substrate molar concentration ratio of 0.015/1, the degradation half-life was prolonged to 37 minutes. Appearance of the tetrapeptide metabolite of aminopeptidases was delayed. Boroleucine and other aminoboronic acid peptidase inhibitors may be useful for improving thymopentin delivery.

Improved buccal delivery of opioid analgesics and antagonists with bitterless prodrugs.

Buccal delivery of opioid analgesics and antagonists is a useful way of improving bioavailability relative to the oral route. These compounds taste bitter, however. Various prodrugs of nalbuphine, naloxone, naltrexone, oxymorphone, butorphanol, and levallorphan, in which the 3-phenolic hydroxyl group was esterified, lacked a bitter taste. This taste difference was not due to differences in water solubility, suggesting that for these compounds the phenolic functional group is important for interaction with the taste receptor. In rats, nalbuphine, naloxone, and naltrexone administered buccally as prodrugs exhibited up to 90% bioavailability. In dogs, the bitter taste of buccally administered nalbuphine and naloxone caused salivation and swallowing, and bioavailability was low. Buccal dosing of the prodrugs of these compounds caused no adverse effects and the bioavailability ranged from 35 to 50%, a significant improvement relative to the oral bioavailability, which is 5% or less. The feasibility of buccal prodrug delivery using an adhesive patch formulation was demonstrated.

Improvement of the oral bioavailability of naltrexone in dogs: a prodrug approach.

In an effort to improve the oral bioavailability of naltrexone [17-(cyclopropylmethyl)-4,5 alpha-epoxy-3,14-dihydroxymorphinan-6-one;1], a number of prodrug esters on the 3-hydroxyl group were prepared: the anthranilate (2), acetylsalicylate (3), benzoate (4), and pivalate (5). The oral bioavailability of these prodrugs was determined in dogs. Compounds 2 and 3 exhibited the greatest enhancement of naltrexone bioavailability (45 and 28 times greater than 1, respectively). No correlation was found between the rates of plasma hydrolysis and bioavailability. Naltrexone-3-acetylsalicylate hydrolyzed in human and dog plasma with a fast deacetylation step to naltrexone salicylate followed by a slower hydrolysis step to naltrexone.

Accuracy of hearing prediction by the acoustic reflex.

Seven methods of hearing loss prediction from acoustic reflex data were compared in 225 adult subjects. The prediction methods were two versions of Sensitivity Prediction by the Acoustic Reflex (SPAR), four regression equations and a bivariate plot technique. Accuracy of hearing prediction varied significantly among methods. Hearing loss was identified most accurately with the bivariate plot technique. One SPAR version best categorized degree of hearing loss. With two of the regression equations, predicted hearing threshold level (HTL) was within +/- 15 dB of actual HTL in two-thirds of the subjects. When hearing level was categorized, all methods produced a sizeable proportion of predictive errors (29 to 48%). Serious errors, however, were uncommon.

Temporary threshold shifts for masked pure tones. II. Broad-band masker.

The amount of temporary threshold shift (TTS) measured in a particular individual is dependent on several factors. One such factor is the pre-exposure hearing level of the subject. In this study, the contribution of this factor to the measured TTS was examined in 8 normal-hearing subjects. TTS measurements were made in unmasked and masked conditions following a 4-hour exposure to noise. The masked condition was designed to simulate a flat mild hearing loss. Results indicated that TTS observed under conditions of broad-band masking was reduced as compared to TTS for the unmasked condition. The results, moreover, were consistent with the predictions of a model developed previously from earlier research with narrow-band maskers.