Christopher J. Destache

Macrophage Delivery of Nanoformulated Antiretroviral Drug to the Brain in a Murine Model of NeuroAIDS

Antiretroviral therapy (ART) shows variable blood-brain barrier penetration. This may affect the development of neurological complications of HIV infection. In attempts to attenuate viral growth for the nervous system, cell-based nanoformulations were developed with the focus on improving drug pharmacokinetics. We reasoned that ART carriage could be facilitated within blood-borne macrophages traveling across the blood-brain barrier. To test this idea, an HIV-1 encephalitis (HIVE) rodent model was used where HIV-1-infected human monocyte-derived macrophages were stereotactically injected into the subcortex of severe combined immunodeficient mice. ART was prepared using indinavir (IDV) nanoparticles (NP, nanoART) loaded into murine bone marrow macrophages (BMM, IDV-NP-BMM) after ex vivo cultivation. IDV-NP-BMM was administered i.v. to mice resulting in continuous IDV release for 14 days. Rhodamine-labeled IDV-NP was readily observed in areas of HIVE and specifically in brain subregions with active astrogliosis, microgliosis, and neuronal loss. IDV-NP-BMM treatment led to robust IDV levels and reduced HIV-1 replication in HIVE brain regions. We conclude that nanoART targeting to diseased brain through macrophage carriage is possible and can be considered in developmental therapeutics for HIV-associated neurological disease.

Nanotechnology: A Focus on Nanoparticles as a Drug Delivery System

This review will provide an in-depth discussion on the previous development of nanoparticle-based drug delivery systems (DDS) and discuss original research data that includes the therapeutic enhancement of antiretroviral therapy. The use of nanoparticle DDS will allow practitioners to use drugs to target specific areas of the body. In the treatment of malignancies, the use of nanoparticles as a DDS is making measurable treatment impact. Medical imaging will also utilize DDS to illuminate tumors, the brain, or other cellular functions in the body. The utility of nanoparticle DDS to improve human health is potentially enormous.

Impact of a clinical pharmacokinetic service on patients treated with aminoglycosides : a cost-benefit analysis

In a prospective, randomized study, 75 adults receiving aminogly-cosides were followed by a clinical pharmacokinetic service and 70 followed as controls. The two groups were similar in age, gender, height, and APACHE II score. A cost-to-charge ratio was used to derive direct costs of hospitalization and calculate cost-benefit. Excluded from this comparison were patients with incomplete acceptance of pharmacokinetic service recommendations and patients followed by other clinical pharmacists. Pharmacokinetic service patients had shorter hospitalizations (322.67 ± 270.28 h; controls 442.89 ± 536.81, p = 0.087) and febrile periods (50.05 ± 79.38 h; controls 92.23 ± 122.50, p < 0.05). More pharmacokinetic service patients had adequate peak levels. Pharmacokinetic service direct costs were lower (7,102.56 ± 9,898.19; controls 13,758.64 ± 22,874.31, p < 0.05). Calculated direct cost of the service was 85.00/patient. Annual savings for 500 patients is 2,220,540.00.

Combination antiretroviral drugs in PLGA nanoparticle for HIV-1

BackgroundCombination antiretroviral (AR) therapy continues to be the mainstay for HIV treatment. However, antiretroviral drug nonadherence can lead to the development of resistance and treatment failure. We have designed nanoparticles (NP) that contain three AR drugs and characterized the size, shape, and surface charge. Additionally, we investigated the in vitro release of the AR drugs from the NP using peripheral blood mononuclear cells (PBMCs).MethodsPoly-(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing ritonavir (RTV), lopinavir (LPV), and efavirenz (EFV) were fabricated using multiple emulsion-solvent evaporation procedure. The nanoparticles were characterized by electron microscopy and zeta potential for size, shape, and charge. The intracellular concentration of AR drugs was determined over 28 days from NPs incubated with PBMCs. Macrophages were imaged by fluorescent microscopy and flow cytometry after incubation with fluorescent NPs. Finally, macrophage cytotoxicity was determined by MTT assay.ResultsNanoparticle size averaged 262 ± 83.9 nm and zeta potential -11.4 ± 2.4. AR loading averaged 4% (w/v). Antiretroviral drug levels were determined in PBMCs after 100 μg of NP in 75 μL PBS was added to media. Intracellular peak AR levels from NPs (day 4) were RTV 2.5 ± 1.1; LPV 4.1 ± 2.0; and EFV 10.6 ± 2.7 μg and continued until day 28 (all AR ≥ 0.9 μg). Free drugs (25 μg of each drug in 25 μL ethanol) added to PBMCs served as control were eliminated by 2 days. Fluorescence microscopy and flow cytometry demonstrated phagocytosis of NP into monocytes-derived macrophages (MDMs). Cellular MTT assay performed on MDMs demonstrated that NPs are not significantly cytotoxic.ConclusionThese results demonstrated AR NPs could be fabricated containing three antiretroviral drugs (RTV, LPV, EFV). Sustained release of AR from PLGA NP show high drug levels in PBMCs until day 28 without cytotoxicity.

Quantitative 1H magnetic resonance spectroscopic imaging determines therapeutic immunization efficacy in an animal model of Parkinson's disease.

Nigrostriatal degeneration, the pathological hallmark of Parkinsons disease (PD), is mirrored by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. MPTP-treated animals show the common behavioral, motor, and pathological features of human disease. We demonstrated previously that adoptive transfer of Copaxone (Cop-1) immune cells protected the nigrostriatal dopaminergic pathway in MPTP-intoxicated mice. Herein, we evaluated this protection by quantitative proton magnetic resonance spectroscopic imaging (1H MRSI). 1H MRSI performed in MPTP-treated mice demonstrated that N-acetyl aspartate (NAA) was significantly diminished in the substantia nigra pars compacta (SNpc) and striatum, regions most affected in human disease. When the same regions were coregistered with immunohistochemical stains for tyrosine hydroxylase, numbers of neuronal bodies and termini were similarly diminished. MPTP-intoxicated animals that received Cop-1 immune cells showed NAA levels, in the SNpc and striatum, nearly equivalent to PBS-treated animals. Moreover, adoptive transfer of immune cells from ovalbumin-immunized to MPTP-treated mice failed to alter NAA levels or protect dopaminergic neurons and their projections. These results demonstrate that 1H MRSI can evaluate dopaminergic degeneration and its protection by Cop-1 immunization strategies. Most importantly, the results provide a monitoring system to assess therapeutic outcomes for PD.

Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs.

Study Objective. To examine the impact of individualized pharmacokinetic monitoring (IPM) on the development of aminoglycoside‐associated nephrotoxicity (AAN).

Patient satisfaction and costs associated with insulin administered by pen device or syringe during hospitalization.

PURPOSE Patient satisfaction, safety and efficacy outcomes, and cost savings with insulin pens versus conventional insulin delivery via vials and syringes in hospitalized patients with diabetes were compared. METHODS Patients were recruited from two general medical-surgical units from July 2005 to May 2006. Patients completed a survey regarding satisfaction with the method in which insulin was administered before discharge. Patients completed a telephone survey approximately four weeks after discharge to determine home insulin use. Cost savings were determined using the average wholesale price of insulin vials and syringes, pens, and pen needles. RESULTS A total of 94 patients were randomized to receive insulin administered via pen devices (n = 49) or using conventional vials and syringes (n = 45). Significantly more subjects in the pen group prepared or self-injected at least one dose of insulin during hospitalization, wanted to continue taking insulin at home using the method used during hospitalization, and would recommend their method of insulin administration used during hospitalization to other patients with diabetes compared with the vial and syringe group (p < 0.05). A cost saving of

Quantitative magnetic resonance and SPECT imaging for macrophage tissue migration and nanoformulated drug delivery

36 per patient was projected if only insulin pens were dispensed during the entire hospital stay compared to insulin vials and syringes (p < 0.05). CONCLUSION Increased patient satisfaction and continuation of the method of insulin administration used in the hospital at home were reported by patients who received insulin pens compared with patients who received conventional vials and syringes during hospitalization. A substantial cost saving was projected for patients in the insulin pen group if insulin pens had been dispensed during their entire hospital stay.

Omeprazole: A Comprehensive Review

We posit that the same mononuclear phagocytes (MP) [bone marrow (BM) and blood monocytes, tissue macrophages, microglia, and dendritic cells] which serve as targets, reservoirs, and vehicles for HIV dissemination, can be used as vehicles for antiretroviral therapy (ART). Toward this end, BM macrophages (BMM) were used as carriers for nanoparticle‐formulated indinavir (NP‐IDV), and the cell distribution was monitored by single photon emission computed tomography (SPECT), transverse relation time (T2)∗ weighted magnetic resonance imaging (MRI), histology, and γ‐scintillation spectrometry. BMM labeled with super paramagnetic iron oxide and/or 111 indium oxine were infused i.v. into naïve mice. During the first 7 h, greater than 86% of cell label was recorded within the lungs. On Days 1, 3, 5, and 7, less than 10% of BMM were in lungs, and 74–81% and 13–18% were in liver and spleen, respectively. On a tissue volume basis, as determined by SPECT and MRI, BMM densities in spleen and liver were significantly greater than other tissues. Migration into the lymph nodes on Days 1 and 7 accounted for 1.5–2% of the total BMM. Adoptive transfer of BMM loaded with NP‐IDV produced drug levels in lymphoid and nonlymphoid tissues that exceeded reported therapeutic concentrations by 200‐ to 350‐fold on Day 1 and remained in excess of 100‐ to 300‐fold on Day 14. These data show real‐time kinetics and destinations of macrophage trafficking and demonstrate the feasibility of monitoring macrophage‐based, nanoformulated ART.

Antiretroviral release from poly(dl-lactide-co-glycolide) nanoparticles in mice

Omeprazole is a member of a new class of substituted benzimidazoles. These agents inhibit the proton pump in the gastric parietal cell, blocking the final step in the gastric acid secretory pathway. Omeprazole has been investigated for the treatment of gastric ulcer, duodenal ulcer, gastroesophageal reflux, and various hypersecretory states. The prolonged inhibition of gastric acid secretion allows for once‐daily dosing in patients with peptic ulcer disease and gastroesophageal reflux, and once‐ or twice‐daily dosing in patients with Zollinger‐Ellison syndrome. Compared with currently available therapies, omeprazole is well tolerated and demonstrates a more rapid ulcer healing rate. It is superior to conventional therapies in the treatment of Zollinger‐Ellison syndrome. Side effects are infrequent when the drug is used for the short‐term management of ulcers.