Infrequent Administration Research Articles

A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges.

Pre-exposure prophylaxis (PrEP) using antiretroviral drugs (ARVs) has been shown to reduce HIV transmission in people at high risk of HIV infection. Adherence to PrEP strongly correlates with the level of HIV protection. Long-acting injectable ARVs provide sustained systemic drug exposures over many weeks and can improve adherence due to infrequent parenteral administration. Here, we evaluated a new long-acting formulation of raltegravir for prevention of vaginal HIV transmission. Long-acting raltegravir was administered subcutaneously to BALB/c, NSG (NOD-scid-gamma) and humanized BLT (bone marrow-liver-thymus) mice and rhesus macaques. Raltegravir concentration in peripheral blood and tissue was analysed. Suppression of HIV replication was assessed in infected BLT mice. Two high-dose HIV vaginal challenges were used to evaluate protection from HIV transmission in BLT mice. Two weeks after a single subcutaneous injection of long-acting raltegravir in BLT mice (7.5 mg) and rhesus macaques (160 mg), the plasma concentration of raltegravir was comparable to 400 mg orally, twice daily in humans. Serum collected from mice 3 weeks post-administration of long-acting raltegravir efficiently blocked HIV infection of TZM-bl indicator cells in vitro. Administration of long-acting raltegravir suppressed viral RNA in plasma and cervico-vaginal fluids of infected BLT mice, demonstrating penetration of active raltegravir into the female reproductive tract. Using transmitted/founder HIV we observed that BLT mice administered a single subcutaneous dose of long-acting raltegravir were protected from two high-dose HIV vaginal challenges 1 week and 4 weeks after drug administration. These preclinical results demonstrated the efficacy of long-acting raltegravir in preventing vaginal HIV transmission.

Efficacy of Extended-Interval Dosing of Micafungin Evaluated Using a Pharmacokinetic/Pharmacodynamic Study with Humanized Doses in Mice.

The pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the echinocandins favor infrequent administration of large doses. The in vivo investigation reported here tested the utility of a range of humanized dose levels of micafungin using a variety of prolonged dosing intervals for the prevention and therapy of established disseminated candidiasis. Humanized doses of 600 mg administered every 6 days prevented fungal growth in prophylaxis. Humanized doses of 300 to 1,000 mg administered every 6 days demonstrated efficacy for established infections.

Active immunization therapies for Parkinson's disease and multiple system atrophy.

Vaccination is increasingly being investigated as a potential treatment for synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies associated with α-synuclein pathology. All lack a causal therapy. Development of novel, disease-altering treatment strategies is urgently needed. Vaccination has positioned itself as a prime strategy for addressing these diseases because it is broadly applicable, requires infrequent administration, and maintains low production costs for treating a large population or as a preventive measure. Current evidence points to a causal role of misfolded α-synuclein in the development and progression of synucleinopathies. In the past decade, significant progress in active immunization against α-synuclein has been shown both in preclinical animal models and in early clinical development. In this review, we describe the state-of-the-art in active immunization approaches to synucleinopathies, with a focus on advances in Parkinson's disease (PD) and multiple-system atrophy (MSA). We first review preclinical animal models, highlighting their progress in translation to the clinical setting. We then discuss current clinical applications, stressing different approaches taken to address α-synuclein pathology. Finally, we address challenges, trends, and future perspectives of current vaccination programs.

Vav1 controls T cell polarization and susceptibility to central nervous system autoimmunity

cells with a naive phenotype decreased from baseline to Month 1 (36.7% to 2.3%), whereas the percentage of CD4 memory cells increased (62.5% to 97.4%). The percentages of both cell types then gradually returned toward baseline levels, but did not reach baseline levels by Month 12. The proportion of CD4 T cells with a regulatory phenotype increased from baseline to Month 1 (3.8% to 12.5%), and remained elevated at Month 12. A similar pattern was observed for CD8 T-cell subsets. The proportion of B cells with a mature naive phenotype decreased from 56.4% to 5.4% from baseline to Month 1, whereas the immature cell fraction increased from 4.7% to 36.8%; relative proportions then approached baseline levels by Month 6. Conclusions:Alemtuzumab-induced lymphocytedepletionwasselective andresulted inanincreasedproportionofmemoryandregulatoryTcells. A distinctive pattern of lymphocyte repopulation was observed within weeks. These effects may explain alemtuzumab's sustained benefit despite infrequent (yearly) administration. Study Supported by: Genzyme, a Sanofi Company, and Bayer Healthcare Pharmaceuticals.

Role of meningeal lymphoid follicle-like structures in the CNS inflammatory disorders

cells with a naive phenotype decreased from baseline to Month 1 (36.7% to 2.3%), whereas the percentage of CD4 memory cells increased (62.5% to 97.4%). The percentages of both cell types then gradually returned toward baseline levels, but did not reach baseline levels by Month 12. The proportion of CD4 T cells with a regulatory phenotype increased from baseline to Month 1 (3.8% to 12.5%), and remained elevated at Month 12. A similar pattern was observed for CD8 T-cell subsets. The proportion of B cells with a mature naive phenotype decreased from 56.4% to 5.4% from baseline to Month 1, whereas the immature cell fraction increased from 4.7% to 36.8%; relative proportions then approached baseline levels by Month 6. Conclusions:Alemtuzumab-induced lymphocytedepletionwasselective andresulted inanincreasedproportionofmemoryandregulatoryTcells. A distinctive pattern of lymphocyte repopulation was observed within weeks. These effects may explain alemtuzumab's sustained benefit despite infrequent (yearly) administration. Study Supported by: Genzyme, a Sanofi Company, and Bayer Healthcare Pharmaceuticals.

Therapeutic effect of a multi-targeted imidazolium compound in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed lethal cancers in the world. We previously showed two imidazolium salts (IBN-1 and IBN-9) with a moderate efficacy for HCC. Here we report a more potent imidazolium compound IBN-65 (1-benzyl-2-phenyl-3-(4-isopropyl)-benzyl-imidazolium chloride) and the associated mechanisms of action in a mouse model of HCC. The IC50 of this compound in various liver cancer cell lines was around 5 μm. IBN-65 dose-dependently arrested cell cycle at G1 phase and was associated with the down-regulation of the cyclin-dependent kinase-4, -6, cyclin D1, and cyclin E. In addition, IBN-65 induced apoptosis by down-regulating Survivin, Bcl-2 and up-regulating Bax, leading to sequential activation of Caspase-3, Caspase-9 and the cleavage of poly(ADP-ribose) polymerase (PARP). Dysregulation of the epidermal growth factor receptor (EGFR) signaling network has been frequently reported in HCC. We found that IBN-65 displayed a profound inhibitory effect on the EGFR/Raf/MEK/ERK signaling at the phosphorylation level. In Huh7 or Hep3B cells, pretreatment with IBN-65 attenuated EGF-induced phosphorylation of both EGFR and the downstream p44/42 MAPK. A siRNA knockdown of EGFR also proved that IBN-65 induced apoptosis mostly through inhibiting downstream EGFR pathway signaling, much less at the receptor level. Infrequent administration of IBN-65 (i.p., 5 mg/kg once weekly for four weeks) to mice bearing the Huh7 cells significantly reduced the tumor volume by 65% without affecting the body weight. Critically, many of the anti-tumor signaling features observed in the HCC cell lines were recaptured in the xenografted tissues. Thus, the metal-free imidazolium compound IBN-65 could be a potential candidate towards therapeutic development for HCC.

Portosplenomesenteric Venous Thrombosis in Patients With Acute Pancreatitis Is Associated With Pancreatic Necrosis and Usually Has a Benign Course

Although there are some data on prevalence of portosplenomesenteric venous thrombosis (PSMVT) in patients with acute pancreatitis (AP), the progression of PSMVT in patients who have and have not received anticoagulants has not been studied systematically. We evaluated the prevalence and natural history of PSMVT in a well-defined cohort of individuals with AP. In a retrospective study, we analyzed data from the University of Pittsburgh Medical Center on 162 patients with a sentinel attack of AP from 2003-2010. Data were collected on patient demographics, clinical presentation, etiology, clinical course, and outcomes. One hundred twenty-two patients underwent contrast-enhanced computed tomography; the scans were reviewed to identify thromboses and/or narrowing of splanchnic veins (splenic, superior mesenteric, and portal). PSMVT was detected in 22 patients overall (14%; 18% among patients who underwent contrast-enhanced computed tomography). Median time to detection of PSMVT was 17 days (interquartile range, 11-40 days). PSMVT formed most frequently in the splenic vein (19 of 22, 86%), followed by portal (8 of 22, 36%) and superior mesenteric (6/22, 27%) veins. Development of PSMVT was associated with presence (21 of 22, 95%), location, and extent of pancreatic necrosis. Fifty-three percent of patients (21 of 40) with necrosis developed PSMVT. Anticoagulants were administered infrequently (6 of 22, 27%) and always for indications unrelated to PSMVT. Most patients with PSMVT developed collateral veins (19 of 22, 86%), and 27% (6 of 22) were found to have varices during endoscopic evaluation, but clot resolution was infrequent (2 of 22, 9%). No patient developed complications directly related to PSMVT. PSMVT develops in about half of patients with necrotizing AP and is rare in the absence of necrosis. Despite infrequent administration of anticoagulants, complications directly related to PSMVT are rare.

Optimal timing for intravascular administration set replacement.

The tubing (administration set) attached to both venous and arterial catheters may contribute to bacteraemia and other infections. The rate of infection may be increased or decreased by routine replacement of administration sets. This review was originally published in 2005 and was updated in 2012. The objective of this review was to identify any relationship between the frequency with which administration sets are replaced and rates of microbial colonization, infection and death. We searched The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (1950 to June 2012), CINAHL (1982 to June 2012), EMBASE (1980 to June 2012), reference lists of identified trials and bibliographies of published reviews. The original search was performed in February 2004. We also contacted researchers in the field. We applied no language restriction. We included all randomized or controlled clinical trials on the frequency of venous or arterial catheter administration set replacement in hospitalized participants. Two review authors assessed all potentially relevant studies. We resolved disagreements between the two review authors by discussion with a third review author. We collected data for seven outcomes: catheter-related infection; infusate-related infection; infusate microbial colonization; catheter microbial colonization; all-cause bloodstream infection; mortality; and cost. We pooled results from studies that compared different frequencies of administration set replacement, for instance, we pooled studies that compared replacement ≥ every 96 hours versus every 72 hours with studies that compared replacement ≥ every 48 hours versus every 24 hours. We identified 26 studies for this updated review, 10 of which we excluded; six did not fulfil the inclusion criteria and four did not report usable data. We extracted data from the remaining 18 references (16 studies) with 5001 participants: study designs included neonate and adult populations, arterial and venous administration sets, parenteral nutrition, lipid emulsions and crystalloid infusions. Most studies were at moderate to high risk of bias or did not adequately describe the methods that they used to minimize bias. All included trials were unable to blind personnel because of the nature of the intervention.No evidence was found for differences in catheter-related or infusate-related bacteraemia or fungaemia with more frequent administration set replacement overall or at any time interval comparison (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.67 to 1.69; RR 0.67, 95% CI 0.27 to 1.70). Infrequent administration set replacement reduced the rate of bloodstream infection (RR 0.73, 95% CI 0.54 to 0.98). No evidence revealed differences in catheter colonization or infusate colonization with more frequent administration set replacement (RR 1.08, 95% CI 0.94 to 1.24; RR 1.15, 95% CI 0.70 to 1.86, respectively). Borderline evidence suggested that infrequent administration set replacement increased the mortality rate only within the neonatal population (RR 1.84, 95% CI 1.00 to 3.36). No evidence revealed interactions between the (lack of) effects of frequency of administration set replacement and the subgroups analysed: parenteral nutrition and/or fat emulsions versus infusates not involving parenteral nutrition or fat emulsions; adult versus neonatal participants; and arterial versus venous catheters. Some evidence indicates that administration sets that do not contain lipids, blood or blood products may be left in place for intervals of up to 96 hours without increasing the risk of infection. Other evidence suggests that mortality increased within the neonatal population with infrequent administration set replacement. However, much the evidence obtained was derived from studies of low to moderate quality.

O.9 First-in-human phase I study to assess safety, tolerability and dose for intrathecal injection of ISIS-SMNRx in SMA patients

ISIS-SMNRx is an antisense oligonucleotide designed to enhance inclusion of SMN2 exon 7 mRNA and increase the amount of functional SMN protein. A first-in-human, open-label, escalating-dose clinical study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ISIS-SMNRx in patients with SMA. A single dose was delivered by intrathecal injection to medically stable SMA patients 2-14 years of age. Four dose levels (1, 3, 6, 9 mg) were examined in cohorts of 6-10 subjects (n = 28). Subjects were followed for 29 days or 85 days post-dosing and monitored for drug safety and tolerability. Plasma drug levels were measured over the first 24 hours and CSF drug levels were assessed at 7 or 28 days post-dose. Exploratory endpoints including the Hammersmith Motor Function Scale - Expanded (HFMSE) in all subjects, and electrophysiological measures in cohort 4 only, were performed to gain further experience with these measures. Overall, ISIS-SMNRx was well tolerated in this study. No serious adverse events or dose-limiting toxicities were reported. All adverse events were mild or moderate in severity and none were related to dose level of ISIS-SMNRx. No drug-related changes in neurological exams, CSF laboratory assessments, or systemic evaluations were reported. Intrathecal injections were also well tolerated in SMA children and shown to be feasible. Pharmacokinetics in plasma and CSF indicate that drug levels in SMA patients were dose-dependent; observations were consistent with preclinical data and thus support infrequent administration (i.e. every 6-9 months). Although the study was not designed to provide evidence of functional improvement, an increase in the HFMSE was observed in the highest dose cohort at 3 months (mean increase = 3.1 points or 17.6%; 6/10 subjects with a >4 point change). Results from this study support continued development of ISIS-SMNRx and thus we have initiated multiple-dose clinical studies of ISIS-SMNRx in patients with SMA.

Biodistribution of the GATA-3-specific DNAzyme hgd40 after inhalative exposure in mice, rats and dogs

The DNAzyme hgd40 was shown to effectively reduce expression of the transcription factor GATA-3 RNA which plays an important role in the regulation of Th2-mediated immune mechanisms such as in allergic bronchial asthma. However, uptake, biodistribution and pharmacokinetics of hgd40 have not been investigated yet.We examined local and systemic distribution of hgd40 in naive mice and mice suffering from experimental asthma. Furthermore, we evaluated the pharmacokinetics as a function of dose following single and repeated administration in rats and dogs.Using intranasal administration of fluorescently labeled hgd40 we demonstrated that the DNAzyme was evenly distributed in inflamed asthmatic mouse lungs within minutes after single dose application. Systemic distribution was investigated in mice using radioactive labeled hgd40. After intratracheal application, highest amounts of hgd40 were detected in the lungs. High amounts were also detected in the bladder indicating urinary excretion as a major elimination pathway. In serum, low systemic hgd40 levels were detected already at 5min post application (p.a.), subsequently decreasing over time to non-detectable levels at 2h p.a. As revealed by Single Photon Emission Computed Tomography, trace amounts of hgd40 were detectable in lungs up to 7days p.a. Also in the toxicologically relevant rats and dogs, hgd40 was detectable in blood only shortly after inhalative application. The plasma pharmacokinetic profile was dose and time dependent. Repeated administration did not lead to drug accumulation in plasma of dogs and rats. These pharmacokinetic of hgd40 provide guidance for clinical development, and support an infrequent and convenient dose administration regimen.

Impact of Delayed and Infrequent Administration of Vasopressors on Return of Spontaneous Circulation during Out-of-Hospital Cardiac Arrest

Introduction. Epinephrine and vasopressin are the only vasopressors associated with return of spontaneous circulation (ROSC). While current guidelines recommend rapid and frequent vasopressor administration during cardiac arrest, delays in their administration in the out-of- hospital setting remain a concern. Objective. This study evaluated delays in vasopressor administration and their effect on field ROSC. Methods. This retrospective review included all adult patients who experienced cardiac arrest of medical origin and received field resuscitative efforts among 10 emergency medical services (EMS) systems. Data were abstracted from the EMS medical record and included response time intervals, calculated first-dose and interdosing intervals of vasopressors, and ROSC. Data were analyzed using Mann-Whitney tests, chi-square tests, and t-tests, survival analysis, and logistic regression, with p ≤ 0.05 indicating significance. Results. A total of 660 cardiac arrest patients were enrolled in the study. The mean EMS response time was 8.8 minutes; 52.7% of patients had witnessed cardiac arrests, 46.2% received bystander cardiopulmonary resuscitation (CPR), 23.0% had shockable initial rhythms, and 19.5% experienced field ROSC. In total, 1,913 doses of epinephrine and 111 doses of vasopressin were administered, with mean and 90th-percentile scene arrival–to–first drug intervals of 9.5 and 17 minutes, respectively. The mean and 90th-percentile interdosing intervals were 6.1 and 10 minutes, respectively. Patients experiencing ROSC had shorter scene arrival–to–first drug intervals than those without ROSC (8.1 vs. 9.8 min, p < 0.01), but there was no difference in the mean interdosing interval (6.8 vs. 6.0 min, p = 0.57). In the logistic regression analysis of ROSC, the adjusted odds ratio for call receipt–to–first drug interval ≤10 minutes was 1.91 (p = 0.04). Patients receiving advanced airway control prior to vasopressor administration were less likely to have a call receipt–to–first drug interval within 10 minutes (4.0% vs. 17.3%, p < 0.01) and were less likely to attain ROSC (15.7% vs. 25.4%, p < 0.01). Conclusion. The interval between scene arrival and first administration of vasopressors is significantly shorter among patients who experience ROSC compared with those who do not. Airway control procedures delay vasopressor administration and reduce the likelihood of ROSC. Although the interdosing intervals of most patients were not consistent with current recommendations, there was no difference in the mean interdosing times between those who achieved ROSC and those who did not.

Cochlear function in Ménière's disease

Objective: The authors assessed the effectiveness of therapy, common features of pure-tone audiograms, and results of non-invasive electrocochleography before and after mild inhibition of peripheral vestibular function by infrequent administration of single intratympanic gentamicin injections (ITPG) in patients with Ménière's disease (MD). Study sample: Sixty-two patients with Ménière's disease. Design: Retrospective study. Results: Out of 62 patients 65% received one injection, 24% two, 6% three, 3% five, and 2% six injections. Between injections, class A vertigo control was obtained after two weeks in all cases. Before ITPG, out of 62 pure-tone threshold audiograms 37 were ‘flat’. Average hearing threshold at 2 kHz was significantly better than that of 250, 500, and 0.75 kHz on the affected side. Conclusions: Hearing threshold in advanced MD is often flat with a characteristic small peak in the high frequency range, most frequently around 2–3 kHz. Should the complaints be intolerable, single injection ITPG-therapy may be safe and effective.

Measuring motor speed through typing: a surrogate for the finger tapping test

Motor speed is an important indicator and predictor of both cognitive and physical function. One common assessment of motor speed is the finger-tapping test (FTT), which is typically administered as part of a neurological or neuropsychological assessment. However, the FTT suffers from several limitations, including infrequent in-person administration, the need for a trained assessor and dedicated equipment, and potential short-term sensory-motor fatigue. In this article, we propose an alternative method of measuring motor speed, with face validity to the FTT, that addresses these limitations by measuring the interkeystroke intervals (IKI) of familiar and repeated login data collected in the home during a subject's regular computer use. We show significant correlations between the mean tapping speeds from the FTT and the median IKIs of the nondominant (r = .77) and dominant (r = .70) hands, respectively, in an elderly cohort of subjects living independently. Finally, we discuss how the proposed method for measuring motor speed fits well into the framework of unobtrusive and continuous in-home assessment.

Results of Electrocochleography in Ménière’s Disease after Successful Vertigo Control by Single Intratympanic Gentamicin Injection

In the last several years, a promising new approach has been suggested in the therapy of Ménière’s disease (MD): the low-dose intratympanic gentamicin therapy. By titrating the desired vestibular inhibition by single injections and infrequent administration, side effects concerning hearing can be held on an acceptably low level, while disease-related symptoms are often successfully eliminated. However, it is still unclear if endolymphatic hydrops actually decreases when the patients become symptom free. In the literature, hydrops is significantly associated with an enhanced ratio of summating potential/action potential (SP/AP). Our aim in this retrospective study was to answer the question if pathologically high SP/AP ratios normalize after successful low-dose intratympanic gentamicin treatment. Twenty-eight patients with MD received one, two or three intratympanic gentamicin injections. These injections inhibited vertigo spells without causing additional hearing loss. SP/AP ratios measured by noninvasive electrocochleography did not improve statistically when patients became symptom free. This indicates that the beneficial effect of gentamicin does not depend on the improvement of SP/AP ratios. Considering the well-established correlation between increased SP/AP and active MD, it thus seems unlikely that gentamicin treatment significantly reduces hydrops.

The same annual dose of 292000 IU of vitamin D3 (cholecalciferol) on either daily or four monthly basis for elderly women: 1‐year comparative study of the effects on serum 25(OH)D3 concentrations and renal function

Daily dosing of vitamin D supplements may be difficult among older people. Infrequent administration of 'megadoses' controlled by health care personnel may overcome adherence problem. We compared the efficacy and safety of two oral dosages (800 IU daily or 97333 IU four monthly) of vitamin D(3) resulting in the equal annual dose of 292000 IU. Randomized, double-blind, double-dummy parallel group comparison. Patients Forty women aged 69.3-78.8 years. Vitamin D(3) 400 IU twice daily (D group) or vitamin D(3) oil 97333 IU every 4 months (4 M group) for 1 year. All received 1 g of calcium daily. Serum 25-hydroxyvitamin D(3) [25(OH)D(3)] in relation to the target levels of 50-75 nmol/l, PTH, serum type I procollagen aminoterminal propeptide (PINP), serum and urine calcium, renal function. A quantity of 25OHD(3) increased more in D group than in 4 M group (P < 0.0001). All participants in D group and 67% in 4 M group had 25(OH)D(3) above 50 nmol/l at 12 months; the target level of 75 nmol/l was reached by 47% and 28% respectively. PTH did not show any seasonal perturbation in either group. PINP declined and urinary calcium rose similarly in the study groups over time (P < 0.0001). Renal function did not worsen in either group. In terms of serum 25(OH)D(3) concentrations, 800 IU daily was more efficient than a 97333 IU every 4 months. However, to increase adherence, the latter is still worth developing. Both treatments increased urinary excretion of calcium, but did not worsen renal function.

Effects of oral caffeine pretreatment on response to intravenous nicotine and cocaine.

Previous research suggests that under conditions of chronic daily caffeine administration, caffeine increases the effects of nicotine. Little is known about the effects of caffeine pretreatment on response to nicotine under infrequent caffeine administration conditions. The present study examined whether infrequent (not on consecutive days) acute oral caffeine administration alters subject-rated, physiological, and monetary value effects of intravenous nicotine in regular users of caffeine, tobacco, and cocaine. To determine the specificity of effects of caffeine on response to nicotine, the effects of caffeine administration on response to intravenous cocaine (another short-acting stimulant) were also studied. Fourteen (1 woman) volunteers participated in this 3-4 week, double-blind, inpatient study. Volunteers participated in 10 experimental conditions in pseudo-randomized order, in which oral caffeine (250 mg/70 kg) or placebo was administered 1 hr before an intravenous injection, consisting of nicotine (1 or 2 mg/70 kg), cocaine (15 or 30 mg/70 kg), or saline. Infrequent acute caffeine pretreatment attenuated the increase resulting from 2 mg/70 kg nicotine administration on ratings of "rush," "good effects," "liking," "high," and "drowsy/sleepy." Caffeine had no significant effect on physiological response to nicotine. Caffeine had no significant effect on subject-rated and physiological response to cocaine, with the exception that caffeine significantly augmented blood pressure response to cocaine. In contrast to the previous research using chronic caffeine maintenance, these data suggest that infrequent acute caffeine administration may attenuate nicotine effects.

Intracellular metabolism of the new antiviral compound 1-( S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine

1-( S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine [HPMP-5-azaC], the 5-azacytosine analogue of cidofovir (HPMPC), represents a new acyclic nucleoside phosphonate with pronounced activity against DNA viruses, and a selectivity index superior to that of cidofovir. Here we investigated the intracellular metabolic pathway of [6- 3H]-HPMP-5-azaC. By comparing the metabolism in mouse lymphosarcoma S49-wild type (S49-WT) and mutant cells deficient for dCMP deaminase, we identified the mono- and diphosphate metabolites generated from HPMP-5-azaC and its deaminated product HPMP-5-azaU. In human lung carcinoma A549 cells, the relative formation of the deaminated metabolites was only 6%, implying that deamination plays a minor role in the overall metabolism of HPMP-5-azaC. The diphosphorylated metabolite of HPMP-5-azaC accounted for 60% of the total radioactivity, and reached intracellular levels which were 60-fold higher in absolute value than the corresponding diphosphate levels obtained with cidofovir. Consequently to its increased activation, HPMP-5-azaC showed about 45-fold higher incorporation into cellular DNA than cidofovir. Herpes-, pox- or adenovirus infection had no marked influence on the metabolism of HPMP-5-azaC. The HPMP-5-azaC-diphosphate metabolite was shown to have long intracellular stability (half-life: 63 h), suggesting that infrequent administration of HPMP-5-azaC should be possible. HPMP-5-azaC represents a new acyclic nucleoside phosphonate compound with promising anti-DNA virus activity and a favorable metabolic profile that is characterized by low sensitivity to catabolic deamination and a high rate of phosphorylation and DNA incorporation.

Effects of weekly exposure to anatoxin-a and nicotine on operant performance of rats

This study examined the effects of acute and weekly administration of anatoxin-a and nicotine on operant performance. Anatoxin-a is a potent nicotinic receptor agonist produced by cyanobacteria, which are found in fresh waters throughout the world. Anatoxin-a is a potential human health hazard and has been responsible for numerous deaths of wildlife, livestock and domestic animals. Remarkably little is known, however, about the effects of anatoxin-a on behavior. Nicotine, the psychomotor stimulant in tobacco, has many well-documented behavioral effects, which often diminish (i.e. tolerance develops) when it is given daily. Male Long Evans rats initially were trained to respond under a multiple variable-ratio 30-response variable-interval 60-s (mult VR-30 VI 60-s) schedule of food reinforcement. They were then divided into 12 groups of 8 that received four weekly subcutaneous injections of anatoxin-a (0.05–0.2 mg/kg), nicotine (0.125–1.8 mg/kg), or vehicle 5-min prior to testing. When initially administered, each compound decreased response rates and reinforcement rates in both components of the multiple schedule. Substantial tolerance developed to the disruptive effects of nicotine with weekly administration. Tolerance also developed to the effects of anatoxin-a, although to a lesser degree; the highest dose severely decreased performance with little evidence of recovery. In conjunction with prior findings, these results suggest the behavioral effects of anatoxin-a and nicotine are similar, but not identical, and that relatively infrequent (episodic) administration can produce tolerance.

Prolonged Efficacy of a Single Dose of the Bisphosphonate Zoledronic Acid

Bisphosphonates play a central role in the management of bone loss due to a range of disorders, including metastatic bone disease, cancer treatment-induced bone loss, and postmenopausal osteoporosis. With potent bisphosphonates, such as zoledronic acid, it may be possible to maintain efficacy with relatively infrequent administration. Sixty-six patients who were osteopenic at >1 year following curative cancer therapy received a single i.v. 4 mg dose of the bisphosphonate zoledronic acid. Bone mineral density (BMD) was measured using double-beam X-ray absorptiometry scan and the bone resorption marker N-telopeptide of type II collagen was determined using a chemiluminescence ELISA assay. The single dose of zoledronic acid induced mean increases in bone BMD at the lumbar spine of 3.1%, 5.2%, and 5.3% and at the total hip of 2.7%, 3.5%, and 4.3% after 12, 24, and 36 months of follow-up, respectively (P < 0.001 at all time points). By 36 months, 84% of patients had achieved increase in BMD at the spine and 90% at the hip. The mean percentage decrease in the bone resorption marker N-telopeptide was approximately 58% at 6 weeks and 42%, 33%, and 31% at 12, 24, and 36 months, respectively (P < 0.001). A single dose of zoledronic acid in patients with low BMD results in a sustained increase in BMD and a corresponding decrease in bone resorption. Very infrequent administration of zoledronic acid may have clinical benefits in terms of convenience, reduced toxicity, improved compliance, and cost.

Back to the Future: Using Aminoglycosides Again and How to Dose Them Optimally

Gram-negative organisms have become increasingly resistant to both beta-lactam antibiotics and fluoroquinolones. Consequently, aminoglycoside antibiotics have undergone a resurgence in use. Because of the known toxicities of aminoglycoside antibiotics, clinicians have avoided their use, unless no other alternatives were extant. Over the past 2 decades, we have learned much about the relationship between aminoglycoside exposure and the likelihood of a good clinical outcome or the occurrence of nephrotoxicity. For example, minimum inhibitory concentration values > or = 2.0 mg/L lead to unacceptably low probabilities of a good clinical outcome, and infrequent administration of doses (i.e., intervals of 24 h and longer intervals for patients with compromised renal function) plays a central role in minimizing the likelihood of toxicity. Using these new insights, we suggest ways of evaluating the dose and schedule of administration of aminoglycosides in empirical therapy to obtain the highest likelihood of an efficacious and nontoxic therapy.