The safety and pharmacokinetics of recombinant soluble CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase 1 study

STUDY OBJECTIVE: To evaluate the safety and pharmacokinetics of recombinant, soluble human CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. The protein rCD4 binds to envelope protein, gp120, of the human immunodeficiency virus (HIV) and blocks HIV infection of CD4 lymphocytes in vitro. DESIGN: Phase 1 trial with dose escalation. SETTING: Two university-affiliated hospital clinics. SUBJECTS: Of 42 subjects enrolled, 29 had AIDS and 13 had AIDS-related complex. INTERVENTIONS: The rCD4 was administered by rapid intravenous infusion on day 1, followed by a 3-day washout, then once a day for 10 days, followed by a 7-day washout, and then three times a week for 8 weeks. Doses of 1, 10, 30, 100, and 300 micrograms/kg body weight per day of rCD4 were administered intravenously to 6 subjects at each dose level. Twelve additional patients received 300 micrograms/kg.d of rCD4: 6 by intramuscular and 6 by subcutaneous injection. All subjects were monitored for toxicity. Immunologic and virologic variables were also monitored. MEASUREMENTS and MAIN RESULTS: Administration of rCD4 was not associated with important toxicity as determined by clinical monitoring or by serum chemistry, hematologic, or immunologic variables. No subjects required dose reduction or discontinuation of therapy due to rCD4-related toxicity. No consistent or sustained changes in CD4 lymphocyte populations or HIV antigen levels were observed. The volume of distribution of rCD4 was small, and clearance remained constant over the dose range studied. The bioavailability of intramuscular injection and subcutaneous injection was 51% and 45%, respectively. CONCLUSIONS: At the dose levels used in this study, rCD4 appears safe and well tolerated. Serum concentrations of rCD4 were achieved that were comparable to concentrations shown to have antiviral activity in vitro. Further studies are indicated to determine whether rCD4 or related molecules will be useful in treating HIV infection.     

Postoperative troponin T elevation as a predictor of early acute kidney injury after orthotopic liver transplantation: a preliminary retrospective study

Background

Slight alterations in cardiac enzymes are frequently observed perioperatively among liver transplant patients. The significance of these changes in the absence of ongoing acute cardiac pathology is unknown. We sought to evaluate the link between early postoperative anomalies of serum cardiac troponin T (cTnT) in the absence of an evident cardiac cause and kidney injury during the first week of hospital stay.

Methods

We retrospectively enrolled 30 patients in the study, recording several perioperative variables, particularly cTnT on intensive care unit ICU arrival as well as 6 and 12 hours later. We grouped patients with cTnT levels >0.03 ng/mL as the high-TnT group; the others were control subjects. We recorded the highest serum creatinine, aspartate aminotransferase, alanine aminotransferase, and bilirubin levels during the first week of the hospital stay. Glomerular filtration rate (GFR) was calculated according to the Cockroft-Gault formula.

Results

Ten patients composed the high-TnT group. Their perioperative variables showed higher Model for End-Stage Liver Disease (MELD) scores and significantly greater incidences of acute kidney injury, failure, and dialysis need than control patients. GFR dropped from 118 to 66 mL/min among this group versus 112 to 105 mL/min in control subjects (P = .021). Binary logistic regression analysis revealed a higher association between the high-TnT group and acute kidney injury (P = .036) than with the MELD score (P = .719).

Conclusions

Serum cTnT levels could be influenced by both preoperative and intraoperative conditions that predispose to kidney injury.     

Rhabdomyoma of a rare type in a child: case report and literature review.

We describe a 9-year-old boy who presented with dyspnea and with a neck mass which was initially described as a thyroid nodule. At the end of the diagnostic-therapeutic research this mass was finally diagnosed as an adult rhabdomyoma originating from the mediastinum. This is an extremely rare tumor which is usually found in the adult population.     

Interspecies Scaling of Clearance and Volume of Distribution Data for Five Therapeutic Proteins

The clearance and volume of distribution of five human proteins (recombinant CD4, CD4 immuno-globulin G, growth hormone, tissue-plasminogen activator, and relaxin) in humans and laboratory animals were analyzed as a function of body weight using allometric scaling techniques. These proteins cover a 16-fold range of molecular weight (6 to 98 kD), are produced by recombinant or synthetic methods, and may be cleared by different mechanisms. The analyses revealed that the clearance and volume data for each protein were satisfactorily described by an allometric equation (Y = a Wb). The allometric exponent (b) for clearance (ml/min) ranged from 0.65 to 0.84, the allometric exponent for the initial volume of distribution (ml) ranged from 0.83 to 1.05, and the allometric exponent for the volume of distribution at steady state (ml) ranged from 0.84 to 1.02. Exponent values from 0.6 to 0.8 for clearance and 0.8 to 1.0 for volumes are frequently cited for small molecules and are expected based on empirical interspecies relationships. When the preclinical data were analyzed separately, the pre-clinical allometric relationships were usually predictive of the human results. These findings indicate that the clearance and volume of distribution of select biomacromolecules follow well-defined, size-related physiologic relationships, and preclinical pharmacokinetic studies provide reasonable estimates of human disposition. Employing this methodology during the early phases of drug development may provide a more rational basis for dose selection in the clinical environment.     

Childhood nail psoriasis: a useful treatment with tazarotene 0.05%

Nail psoriasis occurs in 7% to 40% of children, with a similar pattern of clinical presentation to that of adults. In 0.6% to 2.3% of the patients nail changes appear as the only sign of the disease, preceding other skin and articular involvement. No pediatric clinical trials are available yet, but considering the successful use of tazarotene for nail dystrophy therapy in adults, we chose this drug to treat a child.     

The use of topical diphenylcyclopropenone for the treatment of extensive alopecia areata

BACKGROUND: Highly variable results of topical diphenylcyclopropenone (DPCP) in the treatment of alopecia areata have been reported so far. OBJECTIVE: The purposes of our study were to evaluate the efficacy and tolerability of DPCP in the treatment of chronic, extensive alopecia areata and to assess the long-term overall benefit of treatment. METHODS: Fifty-six patients with chronic, extensive alopecia areata were enrolled in an open-label clinical trial. After sensitization with 2% DPCP, progressively higher concentrations beginning at 0.001% were applied weekly for 6 to 12 months to one side of the scalp. RESULTS: Fifty-two of 56 patients completed therapy. Total regrowth of terminal hair was achieved in 25 of 52 patients (48%) at 6 months. The most frequent side effect was an eczematous reaction at the site of application. Notably, persistent response was observed in 60% of these patients after 6 to 18 months of follow-up (mean, 12 months). CONCLUSION: Topical DPCP treatment for alopecia areata is effective and well tolerated and provides prolonged therapeutic benefits.     

Effects of Formulation and Food on the Absorption of Hydrochlorothiazide and Triamterene or Amiloride from Combination Diuretic Products

The absorption of three combination formulations of hydrochlorothiazide and either triamterene or amiloride was studied over a 5-year period in seven separate investigations under varying conditions of food and fasting. The most widely prescribed combination, containing 25 mg of hydrochlorothiazide and 50 mg of triamterene, demonstrated impaired absorption in the fasting state that was partially corrected by the addition of a breakfast high in fat. The increase in the fat content of the food appeared to correlate directly with the amount of both drugs absorbed from this formulation. The second formulation studied, a new combination formulation of 50 mg of hydrochlorothiazide and 75 mg of triamterene, demonstrated acceptable absorption in the fasting state that was not altered by the concurrent administration of a high-fat breakfast. The absorption of the third formulation, a combination of 50 mg hydrochlorothiazide and 5 mg amiloride, was acceptable in the fasting state and demonstrated a slight reduction in the absorption of the amiloride component when administered concurrently with a high-fat meal. The clinical and biopharmaceutic implications of these observations are discussed.     

Intraocular pharmacokinetics and safety of a humanized monoclonal antibody in rabbits after intravitreal administration of a solution or a PLGA microsphere formulation.

Poly(lactic-co-glycolic) acid (PLGA) bioresorbable microspheres are used for controlled-release drug delivery and are particularly promising for ocular indications. The objective of the current study was to evaluate the pharmacokinetics and safety of a recombinant human monoclonal antibody (rhuMAb HER2) in rabbits after bolus intravitreal administration of a solution or a PLGA-microsphere formulation. On Day 0, forty-eight male New Zealand white rabbits (2.3-2.6 kg) were immobilized with intramuscular ketamine/xylazine, and the test materials were injected directly into the vitreous compartment. Group 1 animals received rhuMAb HER2 in 50:50 lactide: glycolide PLGA microspheres; Group 2 animals received rhuMAb HER2 in solution (n = 24/group). The dose for each eye was 25 microg (50 microl). After dosing, animals were sacrificed at 2 min, and on 1, 2, 4, 7, 14, 23, 29, 37, 44, 50, and 56 days (n = 2/timepoint/group). Safety assessment included direct ophthalmoscopy, clinical observations, body weight, and hematology and clinical chemistry panels. At necropsy, vitreous and plasma were collected for pharmacokinetics and analysis for antibodies to rhuMAb HER2, and the vitreal pellet (Group 1) was prepared for histologic evaluation. All animals completed the study per protocol-both treatments were well tolerated, and no suppurative or mixed inflammatory cell reaction was observed in the vitreal samples (Group 1) at any of the time points examined. Antibodies to rhuMAb HER2 were detected in plasma samples by Day 7 in both treatment groups, but infrequently in vitreous samples. There were no safety implications associated with this immune response. The in vitro characterization of the PLGA microspheres provided reasonable projections of the in vivo rhuMAb HER2 release kinetics (Group 1). The total amount of antibody that was released was similar in vitro (25.9%) and in vivo (32.4%). RhuMAb HER2 (Group 2) was cleared slowly from the vitreous compartment, with initial and terminal half-lives of 0.9 and 5.6 days, respectively. The volume of distribution approximated the vitreous volume in a rabbit eye.     

Trisomy 20 in a papillary urothelial carcinoma of the ureter

To contribute to the knowledge on tumorigenesis and the evolution of urothelial carcinoma of the ureter, we analyzed the clinical, histological, and cytogenetic aspects of a case. Primary cell cultures obtained from tumor specimens showed a trisomy of chromosome 20 where the c-src protooncogene, already described in literature as having an important role in the etiology and progression of some tumors, is located. In our case trisomy 20 is the only present marker and for this reason we think that it could play a role in the tumorigenesis of the urothelial carcinoma of the ureter.