Biomedical subjects
Publications and source records attributed to Michael Miller.
A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.
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The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.
Superimposed electrical stimulation techniques can be used to detect central activation failure (CAF), that is, incomplete central nervous system recruitment or suboptimal activation of motor units. The purpose of this study was to evaluate the effects of two stimulation parameters on perceived discomfort and torque increment size and variability. Discomfort was evaluated using a visual analog scale (0-100 mm) for pain. The rectus femoris muscle of the dominant leg of 24 young healthy men was stimulated during submaximal (80% maximal) voluntary contractions. The size and variability of torque increments and perceived discomfort were assessed following stimulation with: (1) pulse trains (100 HZ, 150 V, 0.2-ms pulse duration) of different lengths (50 ms and 100 ms); and (2) pulse trains (100 HZ, 100 ms, 150 V) with different pulse durations (0.2 ms and 0.1 ms). Pulse trains of 100 ms generated larger torque increments and produced less variability, but caused more discomfort than pulse trains of 50 ms. Average discomfort ratings for pulse trains of 100 ms were 43.1 mm, and of 50 ms were 53.2 mm. There was no difference in torque increment size or in variability between pulse trains with pulse durations of 0.1 ms and 0.2 ms, whereas discomfort was less for the shorter pulse durations; average discomfort ratings were 53.1 mm and 58.1 mm for pulse durations of 0.1 ms and 0.2 ms, respectively. Thus, the appropriate selection of stimulation parameters can reduce discomfort but maintain the ability to detect CAF.
BACKGROUND & AIMS: Hepatitis B virus (HBV) genotype may influence disease progression and antiviral response. We therefore analyzed the frequency and distribution of genotypes in patients from 2 multinational phase III studies of adefovir dipivoxil. Antiviral efficacy of adefovir dipivoxil 10-mg therapy was examined with respect to HBV genotype, hepatitis B e antigen (HBeAg) serostatus, and race. METHODS: HBV genotypes were assigned by phylogenetic analyses of DNA sequences amplified from baseline serum samples (n = 694). RESULTS: Patients from Asia/Oceania were infected predominantly with genotypes B and C, whereas patients from Western European countries were infected predominantly with genotypes A and D. In Mediterranean countries, genotype D was dominant. The most common genotype in North America was C, followed by A, B, and D. Regardless of location, Asian patients were infected predominantly with genotypes B or C, whereas Caucasian patients were infected predominantly with A or D. There were significant differences in the baseline serum HBV-DNA levels of patients infected with different HBV genotypes regardless of HBeAg serostatus. Forty-eight weeks of adefovir dipivoxil 10-mg therapy resulted in potent reductions in serum HBV DNA with no significant differences based on genotype, HBeAg status, or race; similarly, there was no statistical difference in HBeAg seroconversion rates between genotypes in these patients. CONCLUSIONS: HBV genotypes were distributed asymmetrically with respect to race, geography, and HBeAg status. Forty-eight weeks of adefovir dipivoxil therapy resulted in significant decreases in serum HBV-DNA levels in patients regardless of HBV genotype, HBeAg status, or race.
PURPOSE: To describe the pharmacokinetics occurring after the direct injection of triamcinolone acetonide into the vitreous humor of humans. DESIGN: Interventional case series. PARTICIPANTS: Five patients who received a single 4-mg intravitreal injection of triamcinolone acetonide. METHODS: An aqueous humor sample was obtained from 5 eyes via an anterior chamber paracentesis at days 1, 3, 10, 17, and 31 after injection. At each visit, visual acuity and intraocular pressure were measured and indirect ophthalmoscopy was performed. A fluorescein angiogram was carried out at day 10. Concentrations were determined using high performance liquid chromatography; pharmacokinetic analysis was carried out using PK Analyst, an iterative, nonlinear, weighted, least-squares regression program. MAIN OUTCOME MEASURES: Intraocular concentrations of triamcinolone were measured and population pharmacokinetic parameters were calculated. RESULTS: Pharmacokinetic data followed a two-compartment model. Peak aqueous humor concentrations ranged from 2151 to 7202 ng/ml, half-lives from 76 to 635 hours, and the integral of the area under the concentration-time curve (AUC(0-t)) from 231 to 1911 ng/h per milliliter. After a single intravitreal injection of triamcinolone, the mean elimination half-life was 18.6 days in nonvitrectomized patients. The half-life in a patient who had undergone a vitrectomy was shorter at 3.2 days. CONCLUSIONS: There was considerable intrasubject variation among peak concentration, AUC(0-t) values, and elimination half-lives. After intravitreal injection, measurable concentrations of triamcinolone would be expected to last for approximately 3 months (93 +/- 28 days) in the absence of a vitrectomy. Because triamcinolone pharmacokinetics were characterized only in elderly patients with macular edema, the results cannot be extrapolated to other patient populations.
Human Serum Albumin (HSA) accounts for 60% of the total protein in blood serum and it is the most widely used intravenous protein in a number of human therapies. HSA, however, is currently extracted only from blood because of a lack of commercially feasible recombinant expression systems. HSA is highly susceptible to proteolytic degradation in recombinant systems and is expensive to purify. Expression of HSA in transgenic chloroplasts using Shine-Dalgarno sequence (SD), which usually facilitates hyper-expression of transgenes, resulted only in 0.02% HSA in total protein (tp). Modification of HSA regulatory sequences using chloroplast untranslated regions (UTRs) resulted in hyper-expression of HSA (up to 11.1% tp), compensating for excessive proteolytic degradation. This is the highest expression of a pharmaceutical protein in transgenic plants and 500-fold greater than previous reports on HSA expression in transgenic leaves. Electron micrographs of immunogold labelled transgenic chloroplasts revealed HSA inclusion bodies, which provided a simple method for purification from other cellular proteins. HSA inclusion bodies could be readily solubilized to obtain a monomeric form using appropriate reagents. The regulatory elements used in this study should serve as a model system for enhancing expression of foreign proteins that are highly susceptible to proteolytic degradation and provide advantages in purification, when inclusion bodies are formed.
PURPOSE OF REVIEW: To review gene regulation of HDL-cholesterol and discuss molecular abnormalities in HDL candidate genes that may lead to human pathologic states. RECENT FINDINGS: The inverse association between HDL-cholesterol and vascular disease, especially coronary heart disease, has long been recognized, but understanding gene regulation of HDL in humans gained considerable momentum following the identification of ABCA1 as playing a pivotal role in reverse cholesterol transport. Recent data suggest that potentially important targets for upregulating HDL in humans include upregulators of ABCA1 and APOA1 (e.g. peroxisome proliferator activated receptor and liver X receptor agonists) and downregulators of CETP (e.g. JTT-705). A host of other nuclear receptors under investigation in animal models may advance to human testing in the near future. SUMMARY: Disorders affecting HDL metabolism are complex because monogenic disorders causing low HDL do not necessarily correlate with premature vascular disease. To date, pathologic phenotypes have only been deduced among several HDL candidate genes. Understanding the genetic underpinnings associated with variant HDL and reverse cholesterol transport provides an exceptional opportunity to identify novel agents that may optimize this process and reduce vascular event rates beyond currently available LDL lowering therapies.
The objective of this study was to investigate pharmacokinetic and pharmacodynamic interactions between midazolam and fluoxetine, fluvoxamine, nefazodone, and ketoconazole. Forty healthy subjects were randomized to receive one of the four study drugs for 12 days in a parallel study design: fluoxetine 60 mg per day for 5 days, followed by 20 mg per day for 7 days; fluvoxamine titrated to a daily dose of 200 mg; nefazodone titrated to a daily dose of 400 mg; or ketoconazole 200 mg per day. All 40 subjects received oral midazolam solution before and after the 12-day study drug regimen. Blood samples for determination of midazolam concentrations were drawn for 24 hours after each midazolam dose and used for the calculation of pharmacokinetic parameters. The effects of the study drugs on midazolam pharmacodynamics were assessed using the symbol digit modalities test (SDMT). The mean area under the curve (AUC) for midazolam was increased 771.9% by ketoconazole and 444.0% by nefazodone administration. However, there was no significant change in midazolam AUC as a result of fluoxetine (13.4% decrease) and a statistical trend for fluvoxamine (66.1% increase) administration. Pharmacodynamic data are consistent with pharmacokinetic data indicating that nefazodone and ketoconazole resulted in significant increases in midazolam-related cognition impairment. The significant impairment in subjects' cognitive function reflects the changes in midazolam clearance after treatment with ketoconazole and nefazodone. These results suggest that caution with the use of midazolam is warranted with potent CYP3A4 inhibitors.
A 23-year-old man was brought to the emergency department after eating four boxes of brodifacoum-containing rodenticide over a 4-day interval and pieces from approximately two bottles of glass over the previous 2 weeks. He was asymptomatic but his prothrombin time was markedly elevated with an international normalized ratio (INR) of 37.8. A plain abdominal film showed diffuse radiopaque foreign bodies, presumably glass, in the large and distal small intestines. Treatment for ingested glass consisted of stool softeners and bulk-forming laxatives. The patient developed mild gingival bleeding and received fresh frozen plasma (FFP) infusions and vitamin K1 orally. At a vitamin K1 dosage of 300 mg/day, the INR corrected to less than 2.0 and the patient was discharged taking that dosage. He returned 26 days later with hematuria and flank pain, and his INR was 189. He was administered FFP and packed red blood cells, and his vitamin K1 dosage was increased to 800 mg/day; his INR returned to baseline. Compliance with taking the vitamin K1, which required ingestion of 60-160 tablets/day, was a serious problem, requiring numerous follow-up calls and visits to the patient at home and work. At 5-month follow he was doing well. Compliance with large daily doses of vitamin K1 for treatment of "superwarfarin" ingestion may be poor because of the duration of treatment and large number of pills required. A more concentrated formulation may be advantageous for management of patients with brodifacoum poisoning.
An in vitro assay to evaluate the bacteriolytic activity of the complement pathway was applied to 2 strains of Borrelia bissettii, CO501 and DN127, and compared with that of B. burgdorferi sensu stricto B31. Sera from mule deer (Odocoileus hemionus) and the Western Fence lizard (Sceloporus occidentalis) were completely borreliacidal for B. burgdorferi and for both strains of B. bissettii. Serum from Bobwhite quail (Colinus virginianus) was nonlytic for B. burgdorferi and partially lytic for B. bissettii strains, CO-501 and DN127. Serum from a New Zealand White rabbit (Oryctolagus cuniculus) was partially lytic for all 3 strains of Borrelia, whereas serum from white-footed mice (Peromyscus leucopus) were nonlytic for all 3 Borrelia strains. The spectrum of complement sensitivity of B. bissettii appears to be similar to that of European B. afzelii in that tested rodent serum is not lytic to these 2 genospecies. Interestingly, both B. bissettii and B. afzelii have been found to be closely associated with rodents. Complement sensitivity demonstrated in these experiments may suggest and possibly predict specific reservoir-host associations.
BACKGROUND: The National Cholesterol Education Program (NCEP) recently revised the "desirable" fasting triglyceride (TG) to < 150 mg/dL, and levels exceeding 200 mg/dL are defined as "high." METHODS: To evaluate the postprandial response to dietary fat, 50 studies were conducted in nonobese, normocholesterolemic subjects. Following an overnight fast, subjects consumed an oral fat load (70 g/m2), and postprandial triglyceride (ppTG) measurements were assessed at 2, 4, 6, and 8 hours. Subjects were divided by fasting TG cutpoints of 100 and 150 mg/dL. RESULTS: The prevalence of ppTG samples exceeding 200 mg/dL was significantly lower with fasting TG < 100 mg/dL (n = 116) compared with TG 100 to 150 mg/dL (n = 56) (8% versus 25%; p = .004, chi-square analysis). In addition, fasting TG < 100 mg/dL (n = 29) was associated with a reduced mean 4-hour peak ppTG level compared with fasting TG > 100 mg/dL (n = 21) (125 mg/dL versus 249.8 mg/dL; p < .0001). Multiple linear regression analysis identified fasting TG as the most important determinant of the postprandial response after adjustment for other covariates (p = .0005). CONCLUSIONS: Because ppTG-rich lipoproteins contribute to coronary heart disease risk, fasting TG < 100 mg/dL may be a more desirable cutpoint than fasting TG < 150 mg/dL in coronary heart disease risk factor assessment.
Treating patients with isolated low high-density lipoprotein cholesterol (HDL-C) remains daunting. The decision to treat depends on the individual patient's overall risk for coronary heart disease (CHD). Strategies for raising HDL-C levels can include various lifestyle and drug therapies, which should be tailored to individual patients. While no current therapy is optimal, many can yield modest increases that translate into reduced risk for CHD events.
Dyslipidemia is one of the most important modifiable risk factors for coronary disease. Despite the availability of highly effective lipid-modifying agents, many patients still do not reach lipid targets established by national guidelines. Niacin has been known to be an effective treatment of dyslipidemia for almost half a century. Niacin substantially increases high-density lipoprotein cholesterol (HDL-C) levels while lowering levels of low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein(a). In addition, niacin converts small LDL particles into more buoyant, less atherogenic LDL particles. Combined with other agents, niacin offers an important treatment option for patients with dyslipidemia. In particular, niacin complements LDL-C-lowering drugs; it is the most effective agent available for increasing HDL-C levels while lowering levels of LDL-C and triglycerides and improving other lipid risk factors such as lipoprotein(a). Combining niacin with statins or bile acid sequestrant therapy is safe and effective for improving lipid levels and decreasing coronary risk. Differences in niacin formulations dictate tolerability profiles and should be considered when selecting niacin as part of lipid therapy. Furthermore, adverse effects on glucose and insulin sensitivity should be considered when selecting candidates for niacin therapy. Adding niacin to lipid-lowering regimens is a valuable option for physicians treating patients with dyslipidemia and should be considered in appropriate patients.
On June 18th, Maine governor John Baldacci signed into law a comprehensive health care initiative know as Dirigo Health. Dirigo is Latin for "I lead", the state motto. Dirigo is often referred to as Maine's new universal coverage law. The law seeks to achieve universal access to coverage by integrating access, cost, and quality initiatives. While Dirigo responds to and takes advantage of particular circumstances in Maine, it has naturally drawn a great deal of interest from other states seeking to deal with similar problems. This issue brief provides an overview of Dirigo Health and outlines areas that might inform the health policy debate in Massachusetts (and perhaps other states as well).
Incorporation of acidic functional groups into a lead CCR5 antagonist identified from a targeted combinatorial library resulted in compounds with enhanced anti-HIV-1 activity and attenuated L-type calcium channel affinity.
A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.
Cavity solitons are localized intensity peaks that can form in a homogeneous background of radiation. They are generated by shining laser pulses into optical cavities that contain a nonlinear medium driven by a coherent field (holding beam). The ability to switch cavity solitons on and off and to control their location and motion by applying laser pulses makes them interesting as potential 'pixels' for reconfigurable arrays or all-optical processing units. Theoretical work on cavity solitons has stimulated a variety of experiments in macroscopic cavities and in systems with optical feedback. But for practical devices, it is desirable to generate cavity solitons in semiconductor structures, which would allow fast response and miniaturization. The existence of cavity solitons in semiconductor microcavities has been predicted theoretically, and precursors of cavity solitons have been observed, but clear experimental realization has been hindered by boundary-dependence of the resulting optical patterns-cavity solitons should be self-confined. Here we demonstrate the generation of cavity solitons in vertical cavity semiconductor microresonators that are electrically pumped above transparency but slightly below lasing threshold. We show that the generated optical spots can be written, erased and manipulated as objects independent of each other and of the boundary. Numerical simulations allow for a clearer interpretation of experimental results.