Search

The spotted or bean pod borer, Maruca vitrata Fabricius is an important pest of major pulses and vegetable legumes in India and are mostly managed by chemical pesticides. Exploring other alternative management tools, here, we carried out on the availability of parasitoids and its genetic variation to control this major pest. Totally, four larval parasitoids viz., Bassus sp., Trathala flavoorbitalis Cameron, Phanerotoma hendecasisella Cameron and an undetermined Braconid wasp were recorded on M. vitrata larva. The occurrence of P. hendecasisella was reported for the first time from Tamil Nadu, India. The Bassus sp. was found to be dominant with the parasitism of 3.0 to 12.7% in different pulses and total parasitism of four parasitoids was maximum in pigeonpea (16.1%). Total parasitism had a positive relationship with number of webbings on cowpea. The larval parasitoids Bassus sp. and braconid wasp (undetermined) yielded specific fragments (~800 bp) with mitochondrial COI primer. Presence of Wolbachia was confirmed in all four larval parasitoids with the amplicons size between 600 and 650 bp. The results clearly indicate the close proximity of Bassus sp. on M. vitrata than other parasitoids studied, and suggestfor further insights on suitability, mass culturing and development for sustainable management of this insect pest. [ABSTRACT FROM AUTHOR]

The Legume pod borer Maruca vitrata (Fabricius) is a serious pest in most common pulses affecting their yield. In the present investigation, genetic diversity among larval population of Maruca vitrata from five locations of India was assessed using 23 RAPD primes and 6 SSR primers. RAPD primers produced 364 (98.9% polymorphism) polymorphic alleles with the mean number of 18.2 alleles/primer while SSR primers produced 45 polymorphic alleles with 68% polymorphism. The mean number of alleles detected per primer ranged from 4 to 46 and 5 to 12 with RAPD and SSR primers, respectively in different larval samples. Dendrogram constructed using similarity index values for RAPD and SSR primers differentiated the larval samples. In all three types of Maruca larval samples, Polymorphism information content (PIC) value observed for RAPD primers ranged from 0.019 (OPC 08) to 0.375 (OPAF 12). Similarly, SSR primers showed PIC value of 0.061 (C32008E) to 0.781 (C3393E,1) irrespective of larval samples. [ABSTRACT FROM AUTHOR]

Maruca vitrata (Fabricius), commonly known as legume pod borer, is a serious pest in pulses affecting the yield. Liberal use of chemical insecticides to control has resulted in diverse array of insect detoxification enzymes produced by the pest to metabolize these toxic chemicals and develop resistance. Here, we studied the gut hydrolytic enzymes of M. vitrata up on its field exposure to different insecticides in order to have an idea about level of adaptation. Among the larval samples collected from different pulses, the maximum protein content of 547.14 mg was recorded per g of gut sample of legume pod borer, M. vitrata collected from green gram. Total trypsin activity was insignificant in gut samples of larvae collected from different samples. The total chymotrypsin and aminopeptidase activities were found maximum in cowpea of 0.5655 and 0.1184 mM/mL/min/g, respectively. Whereas, the maximum GST activity in lablab populations of M. vitrata (2.3335 mM/mL/min/g). The specific activity of trypsin was maximum in Maruca larval populations from lablab (0.0050 nM/mL/min/mg of protein) and red gram or pigeonpea (0.0049 nM/mL/min/mg of protein) and chymotrypsin activity in cowpea (0.0098 nM/mL/min/mg of protein). The larval samples collected from lablab (0.0052 nM/mL/min/mg of protein) and cowpea (0.0037 nM/mL/min/mg of protein) showed the maximum specific activity of aminopeptidase. Maximum specific GST activity of 0.0325 and 0.0294 nM/mL/min/mg of protein was recorded in larvae collected from lablab and red gram, respectively. Larval samples from black gram ranked the last with respect to the activity of gut enzymes. [ABSTRACT FROM AUTHOR]

Southern green stink bug, Nezara viridula has slowly gained importance as a major pest in greengram. Conventional insecticides used in pulses ecosystem were tested against N. viridula under laboratory and field conditions. Under in vitro condition, out of three methods of insecticidal applications, the adult dip and feeding method was found to be more effective. At 1 Hour After Treatment (HAT), triazophos 40 EC (1.5 mL.L-1) and dimethoate 30 EC (2.0 mL.L-1) were highly effective against the adults of N. viridula with earliest (100%) mortality than other treatments. Under the field condition also, triazophos 40 EC (1.5 mL.L-1) and dimethoate 30 EC (2.0 mL.L-1) had 100 per cent population reduction over control and were found to be more effective than other insecticides viz., chlorantraniliprole, thiamethoxam, neemazal and imidacloprid. Results of toxicity tests concluded that triazophos 40 EC @ 1.5 mL.L-1 and dimethoate 30 EC @ 2.0 mL.L-1 were highly effective against the adults of N. viridula with high mortality than other treatments under both laboratory and field conditions. [ABSTRACT FROM AUTHOR]

The legume pod borer, Maruca vitrata (Geyer) (Lepidoptera: Crambidae), is an important pest of pulses globally. The laboratory study investigated its development, survivorship and food intake on different pulses, namely pigeon pea (CO RG 6), black gram (CO BG 6), green gram (CO GG 7), cowpea (CO 7) and lablab (Rohini) in an environment of 27.9±2.2 °C and 76.6 ± 9.1%RH. The highest food consumption was recorded in lablab flowers (433.02 mg) while the maximum larval weight gain was in pigeon pea flowers (71.85 mg). The maximum assimilation rate (375.33 mg) was in flowers of lablab. The relative growth rate wasmaximum in flowers of black gram (2.27) and whereas efficiency of conversion of digested food was 36.60 % and efficiency of conversion of ingested food was highest on green gram flowers (72.96 %).Anattempt on mass-culturing was made on its natural hosts and as per the studies, the culture could be maintained only up to first generation on all hosts except lablab. The results of the first-generation study revealed that, in lablab, the maximum number of Maruca larvae (38.2) successfully completed with the maximum pupation rate (71.1 %) and adult emergence (81.5 %). It was found that lablab was able to support four to six generations under laboratory conditions and the sex ratio (male:female) of 1:2 had themaximumnumber of eggs laid (86) on lablab. The results of significant differences among the hosts indicated that lablab was highly suitable host for rearing of M. vitrata. [ABSTRACT FROM AUTHOR]

The high yielding greengram culture COGG 973 is a cross derivative of COGG 923 x VC 6040A and matures in 55 - 60 days. This culture recorded an average yield of 845 kg/ha with a yield increase of 20 per cent over the check variety Co (Gg) 7. It has medium bold seed with a mean 100 seeds weight ranging from 3.5 to 4.0 g. It is determinate with synchronized maturity and suitable for single / mechanical harvest. The variety is suitable for closer planting and recorded a grain yield of 948 kg/ha with 25 x 10 cm spacing, which is 8.5 per cent yield increase over 30 x 10 cm spacing (874 kg/ha). It is also suitable for intercropping with maize and with drip fertigation system in redgram. Protein content of this variety is recorded as 20.21 per cent and has good organoleptic values. Co 8 greengram variety is resistant to yellow mosaic and moderately resistant to stem necrosis, root rot, aphids and stemfly. The variety is well suited for cultivation during kharif and rabi seasons in Tamil Nadu. [ABSTRACT FROM AUTHOR]

Legume pod borer, Maruca vitrata Geyer is one of the serious pests occurring during flowering and pod formation stage of pigeonpea. Relative abundance of M. vitrata studied in pigeonpea variety, CORG 7 during Kharif and Rabi seasons of 2011 and 2012 at Department of Pulses, TNAU, Coimbatore revealed that in 2011, the first peak incidence was during 34th SMW (IV week of August) and 36th (I week of September) SMW as 4.44 and 3.68 webbings/ plant respectively followed by the second peak during 50 (II week of December) and 52nd (IV week of December) SMWs as 9.38 and 5.72 webbings per plant respectively. In 2012, on 50 and 52nd SMWs (II and IV weeks of December) the peak incidence of 6.21 and 5.10 webbings per plant were recorded respectively. The larval incidence showed a significant negative correlation with maximum temperature (r=0.455*), sunshine hours (r=0.382*) and evaporation (r=402*) and positive correlation with minimum relative humidity (RH) (r=0.399*) and rainfall (r=0.463*). Regression analysis showed all abiotic factors together determine the variation in Maruca damage by 61.4 per cent (R2 = 0.614). [ABSTRACT FROM AUTHOR]

Endophytic bacterial strains EPCO 102 and EPCO 16 were effectively reduced the aphid population under greenhouse conditions. Biochemical characterisation and 16S rRNA sequence analysis confirmed as Bacillus subtilis. Talc-based powder formulation for Bacillus subtilis strains EPCO 102, EPCO 16 and Pseudomonas fluorescens Pf1 (with and without chitin amendments) were tried and its effect in inducing systemic resistance were tested under greenhouse conditions. The combined application of bioformulation as seed, soil and foliar spray significantly reduced the aphid infestation. Chitin addition in the formulation showed additional reduction in the infestation by the aphids. Application of Pf1 culture along with chitin showed less aphid infestation and this efficacy was on par with the chemical insecticide treatment, followed by EPCO 16 + Chitin. In addition, these endophytic bacterial strains along with chitin induced the activity of peroxidase, polyphenol oxidase, phenylalanine ammonia-lyase, chitinase, β-1.3-glucanase and phenol accumulation in cotton, which favours reduction in aphid infestation. [ABSTRACT FROM AUTHOR]

The virulence of 20 isolates of Beauveria bassiana (Balsamo) Vuillemin to larvae of the leafminer, Aproaerema modicella, was tested in the laboratory. Leafminer larvae were sprayed with a standard concentration of 1×108 condia/mL of each B. bassiana isolate. All the B. bassiana isolates tested were pathogenic to A. modicella and the mortality varied between 16.7 and 68.9%. Beauveria bassiana isolate B2 was found to be the most virulent followed by isolate B4 which resulted in 59% mortality. Beauveria isolate B2 was selected for dose-response mortality studies with four different doses (1×102, 1×104, 1×106 and 1×108 conidia/mL). Among the various doses tested, 1×108 conidia/mL produced the highest mortality (70.7%). In addition, morphogenesis of the insect pest in all stages, larval, pupal and adult was greatly affected due to fungal infection. Further, B. bassiana isolate B2 and two Pseudomonas fluorescens strains, TDK1 and Pf1 were tested alone and in combination for suppression of groundnut leafminer and collar rot disease and promotion of plant growth and yield both under glasshouse and field conditions. The mixture of B. bassiana and P. fluorescens strains significantly reduced the leafminer and collar rot disease incidences when applied as talc-based formulation through seed, soil and foliar application under glasshouse and field conditions. [ABSTRACT FROM AUTHOR]

Six edible legumes, viz., green gram, black gram, chickpea, pigeonpea, pea and cowpea, were subjected to infestation by two species of bruchids, viz., Callosobruchus maculatus and Callosobruchus chinensis to study the extent of damage under single species and mixed population conditions. Green gram was found to be the most suitable host in terms of index of suitability for C. maculatus and C. chinensis under single species (0.0545 and 0.0627 respectively) and mixed population conditions (0.0556 and 0.0510 respectively). On the contrary, red gram was the least preferred host for C. maculatus and C. chinensis both under single species (0.0439 and 0.0445 respectively) and mixed population (0.0397 and 0.0389 respectively) conditions. The competition between these two species implied that though both the species coexist together, during storage C. maculatus was dominant over C. chinensis. [ABSTRACT FROM AUTHOR]

Dose selection is an integral part of a molecule's journey to become medicine. On top of typical challenges faced in dose selection for more common diseases, pediatric rare disease has additional unique challenges due to the combination of 'rare' and 'pediatric' populations. Using the central theme of maximizing 'relevant' information to overcome information paucity, dose selection strategy in pediatric rare diseases is discussed using a triangulation concept involving challenges, approaches and very importantly, enablers. Using actual examples, unique scenarios are discussed where specific enablers allowed certain approaches to be used to overcome the challenges. The continued need for model-informed drug development is also discussed using examples of where modeling and simulation tools have been successfully used in bridging available information to select pediatric doses in rare disease. Additionally, challenges with translation and associated dose selection of new modalities such as gene therapy in rare diseases are examined with the lens of continuous learning and knowledge development that will enable pediatric dose selection of these modalities with confidence., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The eye, which is under constant exposure to environmental pathogens, has evolved various anatomic and immunological barriers critical to the protection of tissues lacking regenerative capacity, and the maintenance of a clear optic pathway essential to vision. By bypassing the ocular barriers, intravitreal (IVT) injection has become the mainstay for the delivery of drugs to treat conditions that affect the back of the eye. Both small molecules and biotherapeutics have been successfully administered intravitreally, and several drugs have been approved for the treatment of (wet) age-related macular degeneration and diabetic macular edema. However, IVT injection is an invasive procedure, which requires sufficient technical expertise from the healthcare professional administering the drug. Potential side effects include bleeding, retinal tear, cataracts, infection, uveitis, loss of vision, and increased ocular pressure. Pharmaceutical companies often differ in their drug development plan, including drug administration techniques, collection of ocular tissues and fluids, ophthalmology monitoring, and overall conduct of nonclinical and clinical studies. The present effort, under the aegis of the Innovation & Quality Ophthalmic Working Group, aims at understanding these differences, identifying pros and cons of the various approaches, determining the gaps in knowledge, and suggesting feasible good practices for nonclinical and early clinical IVT drug development., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aim: This phase I study investigated talazoparib pharmacokinetics (PK) and safety in patients with advanced solid tumours and varying degrees of hepatic function., Methods: Patients with advanced solid tumours and normal hepatic function or varying degrees of hepatic impairment (mild, moderate or severe, based on National Cancer Institute Organ Dysfunction Working Group classification) received talazoparib 0.5 mg once daily for 22 calendar days. Plasma and urine samples after single and multiple doses were collected and analysed for talazoparib using validated assays. Plasma PK data from all patients were analysed using the population PK method. Plasma and urine PK parameters in PK-evaluable patients were calculated using noncompartmental analysis (NCA). Safety was monitored in all enrolled patients., Results: Thirty-eight patients were enrolled; 37 had ≥1 PK concentration, among which 17 were evaluable for NCA. Population PK analysis (n = 37) indicated no significant impact of hepatic function on apparent clearance (CL/F) of talazoparib. Baseline creatinine clearance was the only significant covariate on CL/F (α = 0.05). NCA of data (n = 17) showed no clear trend for increase in exposure on day 22 with worsening hepatic function. Talazoparib protein binding was comparable in patients with varying hepatic function. Talazoparib was generally well tolerated, and the safety profile observed in this study was consistent with the known safety profile of the drug., Conclusions: Hepatic impairment (mild, moderate or severe) has no impact on the PK of talazoparib. No dose modification is recommended for patients with advanced solid tumours and various degrees of hepatic impairment, and this labelling language has been approved by the US Food and Drug Administration and the European Medicines Agency., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Pharmacokinetic (PK) studies suggest that talazoparib is primarily eliminated unchanged via renal excretion. The current study investigated how varying degrees of renal impairment may affect the PK of talazoparib, and evaluated the safety and tolerability of talazoparib, in patients with advanced solid tumors with/without renal impairment., Methods: Patients with advanced solid tumors and normal renal function or different degrees of renal impairment measured by estimated glomerular filtration rate (eGFR: mild = 60-89, moderate = 30-59, severe = 15-29 mL/min/1.73 m 2 ) were enrolled in this open-label, non-randomized, phase I study. Talazoparib was administered orally at 0.5 mg/day for 22 days. Primary PK parameters included the area under the plasma concentration-time curve from 0 to 24 h (AUC 0-24 ) and maximum observed plasma concentration (C max ) at steady state (Day 22). Safety and tolerability were also investigated., Results: Thirty-four patients were enrolled. At Day 22, compared with patients with normal renal function (n = 9), patients with mild (n = 9), moderate (n = 8), or severe (n = 8) renal impairment had a 12.2%, 43.0%, and 163.3% increase in talazoparib AUC 0-24 , and a 11.1%, 31.6%, and 89.3% increase in talazoparib C max , respectively. Talazoparib was generally well tolerated, and overall there were no notable differences in the treatment-emergent adverse event profile across renal function groups., Conclusions: Exposure to talazoparib increased with worsening renal impairment. Overall, this study confirms current dosing recommendations in patients with mild and moderate renal impairment (1 mg/day and 0.75 mg/day, respectively) and indicates that a lower starting dose of 0.5 mg/day should be considered for patients with severe renal impairment., Clinical Trials Registration: NCT02997163.

Background: Palbociclib is indicated for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC)., Objective: Exposure-response analyses were conducted to evaluate efficacy in Asian versus non-Asian patients and in patients with versus without dose reduction in PALOMA-2., Patients and Methods: PALOMA-2 compared palbociclib plus letrozole versus placebo plus letrozole in patients with ABC. Population pharmacokinetic analysis provided apparent palbociclib clearance (CL/F) for each patient. The time-varying exposure metric, C avg,t , was calculated using average dose intensity and CL/F at the time of each progression-free survival (PFS) event. A Cox proportional model characterized PFS and palbociclib C avg,t relationships. Significant prognostic factors for PFS were identified by univariate analysis, which were subsequently included in multivariate analyses, in addition to the C avg,t effect on PFS. PFS profiles in Asian/non-Asian patients and patients with/without dose reduction were simulated and compared using observed palbociclib exposures and established exposure-response relationships., Results: Patients (n = 421) received palbociclib plus letrozole (Asian = 64, non-Asian = 357; no dose reduction = 272, dose reduction = 149). Based on univariate analyses, significant prognostic factors were Ki67 score, age, and baseline aspartate aminotransferase (BAST), tumor size, alkaline phosphatase, and albumin levels. In multivariate analysis, only Ki67 and BAST remained significant. Palbociclib exposure did not significantly affect PFS in either univariate (P = 0.12) or multivariate (P = 0.44) analyses., Conclusions: This analysis suggests that palbociclib exposure has no impact on PFS when the dose reduction algorithm from palbociclib clinical trials is used. There is no difference in efficacy between Asians and non-Asians, despite the higher level of dose reductions in Asians., Pfizer: NCT01740427.

Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to treat cancers associated with somatic BRCA mutations and germline genetic aberrations involved in the DNA damage response. The efficacy, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profile of talazoparib, a potent small-molecule PARP inhibitor, was established in 4 clinical studies in cancer patients (2 phase 1 studies PRP-001 and PRP-002, the phase 2 ABRAZO trial, and the phase 3 EMBRACA trial). The current study aimed to describe the population PK of talazoparib and identify covariates that affect talazoparib PK in patients with advanced cancers using pooled data from these 4 studies. Talazoparib PK was well characterized by a 2-compartment model with first-order absorption and absorption lag time. Based on covariate analysis, no dose adjustment for talazoparib is required based on a patient's age, sex, baseline body weight, Asian race, the presence of mild renal or hepatic impairment, or use of acid-reducing agents. A reduced 0.75-mg daily dose is recommended for patients taking a potent P-glycoprotein inhibitor and those with moderate renal impairment. Insufficient data were available to establish dosing recommendations for patients with severe renal and moderate or severe hepatic impairment. The PK of a single 1-mg talazoparib capsule is comparable with 4 0.25-mg capsules. Talazoparib can be taken with or without food. These data provide support for dosing recommendations and labeling information for talazoparib., (© 2019, The American College of Clinical Pharmacology.)

In this open-label study (NCT02142920), we investigated the distribution, pharmacokinetics, and metabolism of the pan-class-I isoform phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor gedatolisib (PF-05212384), following a single intravenous administration in healthy male subjects. A single, 89-mg, intravenous dose of gedatolisib was associated with a favorable safety profile in the 6 healthy subjects evaluated. Peak plasma concentrations for unchanged gedatolisib and total radioactivity were observed at the end of the 30-minute infusion. The only observed drug-related material in plasma was the parent drug, gedatolisib. Terminal half-life for plasma gedatolisib was ∼37 hours. Following the dose, 66%-73% of drug-related material was recovered in the feces. Metabolism of gedatolisib was trace; only 1 oxidative metabolite, M5, was identified in feces (<1% of total dose). Identification of gedatolisib in feces suggests that biliary and/or intestinal secretion of unchanged parent drug significantly contributes to gedatolisib clearance., (© 2018, The American College of Clinical Pharmacology.)

The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.

Although the fundamental concepts of pharmacokinetics remain the same, ocular pharmacokinetics has its own challenges due to the uniqueness of barrier properties posed by various ocular tissues and its growing complexity with different routes of ocular administration. A thorough understanding of the barrier nature will aid in tailoring a drug or its carrier's physicochemical properties to its advantage. In order to deliver the right payload of a drug at the target site, various approaches can be taken to leverage the pharmacokinetics that includes molecular design based on desirable physicochemical properties, formulation approaches, and alternative routes of administration. In this chapter, a brief overview of the barrier properties with respect to various routes of administration is presented along with the physicochemical properties that influence the pharmacokinetics of ocular drugs. Recent advances in ocular pharmacokinetics are discussed in addition to new perspectives in interpreting existing data.

Background and Objective: Effective control of intraocular pressure (IOP) is essential for the successful management of glaucoma. IOP exhibits diurnal variation, yet continuous monitoring is impractical. To date, no clear evidence exists on the number of sampling timepoints required to characterize diurnal IOP and when those measurements should be collected. The objective of this study was to develop an optimized sampling scheme to estimate diurnal IOP and to provide sampling windows for practicality., Methods: Baseline IOP values for glaucoma patients were collected from the published literature. A population model-based meta-analysis was performed to develop a model for diurnal IOP that accounts for covariates and inter-study variability. Optimization was performed using the D-optimality criteria to determine optimal sampling times. In addition, various reduced sampling designs were tested to investigate the minimum number of sampling timepoints to precisely estimate diurnal IOP. Also, sampling windows were calculated around the final optimal sampling times to allow flexibility in data collection. The final reduced optimized model was validated by simulating and estimating 500 datasets with reduced optimal sampling times., Results: The final baseline IOP model included type of glaucoma as a covariate. Bootstrap analysis and visual predictive check plots revealed the adequacy of the model to describe the observed IOP data. Optimization results indicated an increasing trend in bias with decreasing sampling timepoints. A reduced model with four sampling times resulted in acceptable precision (<40 %). Restricting the sampling time between 8 a.m. and 4 p.m. underestimates the fluctuation in diurnal IOP. Sampling windows with ≥95 % efficiency were calculated around the optimized sampling times. Validation results indicated acceptable precision and relative bias for model estimates in the reduced optimized model., Conclusion: A physiologically based mechanistic model was developed to describe the diurnal variation in baseline IOP and inter-study variability was estimated on key diurnal model parameters. Optimization of the final covariate model indicated a reduced sampling time of at least four samples should be collected at 5:45 a.m., 2:15 p.m., 8:00 p.m., and 12:00 a.m. for reliable estimation of diurnal IOP variation.

Purpose: To develop a mechanism based translational pharmacokinetic-pharmacodynamic (PKPD) model in preclinical species and to predict the intraocular pressure (IOP) following drug treatment in patients with glaucoma or ocular hypertension (OHT)., Methods: Baseline diurnal IOP of normotensive albino rabbits, beagle dogs and patients with glaucoma or OHT was collected from literature. In addition, diurnal IOP of patients treated with brimonidine or Xalatan® were also obtained from literature. Healthy normotensive New Zealand rabbits were topically treated with a single drop of 0.15% brimonidine tartrate and normotensive beagle dogs were treated with a single drop of Xalatan®. At pre-determined time intervals, IOP was measured and aqueous humor samples were obtained from a satellite group of animals. Population based PKPD modeling was performed to describe the IOP data and the chosen model was extended to predict the IOP in patients., Results: Baseline IOP clearly depicts a distinctive circadian rhythm in rabbits versus human. An aqueous humor dynamics based physiological model was developed to describe the baseline diurnal IOP across species. Model was extended to incorporate the effect of drug administration on baseline IOP in rabbits and dogs. The translational model with substituted human aqueous humor dynamic parameters predicted IOP in patients following drug treatment., Conclusions: A physiology based mechanistic PKPD model was developed to describe the baseline and post-treatment IOP in animals. The preclinical PKPD model was successfully translated to predict IOP in patients with glaucoma or OHT and can be applied in assisting dose and treatment selection and predicting outcome of glaucoma clinical trials.

Purpose: We compared ocular and systemic pharmacokinetics of brimonidine and dexamethasone following a single intravitreal dose in animals with blood-retinal barrier (BRB) breakdown and in healthy controls., Methods: We induced BRB breakdown in rabbits by intravitreal injection of recombinant human VEGF165 and choroidal neovascularization (CNV) in monkeys with laser. Control and disease animals then received single intravitreal injections of brimonidine alone, dexamethasone alone, or brimonidine in combination with dexamethasone. Ocular tissues and plasma were collected and quantified for drug concentration using LC-MS/MS assays. Statistical analysis was performed to compare the pharmacokinetic parameters between the control and disease animal models., Results: In rabbits, brimonidine and dexamethasone exposure, as assessed by area under the drug concentration-time curve (AUC) in aqueous humor, retina, and choroid, was lower in disease than control animals, with a greater difference observed for dexamethasone than brimonidine. In monkeys, dexamethasone exposure was lower in disease than control animals for the central retina/choroid and peripheral choroid, whereas brimonidine exposure was lower in disease animals only in the central retina/choroid. Plasma exposure to both drugs was comparable between control and disease animals in both species., Conclusions: In animal models with a breakdown of the blood-retina barrier, drug clearance could be increased, resulting in lower drug concentration in ocular tissues compared to normal animals. However, the extent of difference may be compound- and disease model-specific. Therefore, extrapolation of ocular pharmacokinetic data obtained in normal animals to disease models for the purpose of pharmacokinetic/pharmacodynamic data analysis should be performed with caution.

The purpose of this study was to quantify the melanin pigment content in sclera, choroid-RPE, and retina, three tissues encountered during transscleral drug delivery to the vitreous, in human, rabbit, monkey, minipig, and dog models. Strain differences were assessed in NZW × NZR F1 and Dutch belted rabbits and Yucatan and Gottingen minipigs. The choroid-RPE and retina tissues were divided into central (posterior pole area) and peripheral (away from posterior pole) regions while the sclera was analyzed without such division. Melanin content in the tissues was analyzed using a colorimetric assay. In all species the rank order for pigment content was: choroid-RPE >retina ≥ sclera, except in humans, where scleral melanin levels were higher than retina and central choroid. The melanin content in a given tissue differed between species. Further, while the peripheral tissue pigment levels tended to be generally higher compared to the central regions, these differences were significant in human in the case of choroid-RPE and in human, monkey, and dogs in the case of retina. Strain difference was observed only in the central choroid-RPE region of rabbits (NZW × NZR F1 >Dutch Belted). Species, strain, and regional differences exist in the melanin pigment content in the tissues of the posterior segment of the eye, with Gottingen minipig being closest to humans among the animals assessed. These differences in melanin content might contribute to differences in drug binding, delivery, and toxicity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: The objective of this study was to compare the reduction in size of experimentally induced choroidal neovascularization (CNV) in rat eyes treated with bevacizumab, poly(ethylene-glycol) (PEG)-bevacizumab conjugate (b-PEG), and poly(lactic-co-glycolic acid) (PLGA)-encapsulated bevacizumab (b-PLGA)., Methods: Forty-eight eyes from 24 rats were divided into 4 groups of 12 eyes. In each group, 3 eyes were assigned to a treatment subgroup, each receiving a different injection-control, bevacizumab, b-PEG, and b-PLGA. In all eyes, laser photocoagulation was used to rupture Bruch's membrane. In group 1, laser was followed by injection, which was then followed by harvesting the rats to assess the CNV area. All 3 steps were separated by a 2-week interval. In groups 2, 3, and 4, injection preceded laser photocoagulation by a variable interval and all rats were harvested 2 weeks postlaser treatment. In group 2, laser and injection were separated by 2 weeks. In group 3, laser followed injection by 4 weeks. In group 4, laser followed injection by 6 weeks. The CNV area was measured for each subgroup and compared against its control. Pairwise comparisons were conducted to assess for statistically significant differences between subgroups., Results: All subgroups in groups 1, 2, and 4 showed statistically significant reduction of CNV area (P<0.05). In group 3, the b-PEG and b-PLGA subgroups showed a 9.0% (P=0.384) and 20.3% (P=0.077) reduction in CNV area versus control, whereas there was no reduction in CNV area in the bevacizumab subgroup. However, this was not found to be statistically significant. In group 4, b-PEG was more effective than bevacizumab and b-PLGA., Conclusion: The reduction in CNV area in all treatment subgroups, with the exception of those in group 3, suggests successful creation of the 2 bevacizumab formulations while retaining its active antiangiogenic properties. Further studies varying in dosages and timing of injection and laser are needed to evaluate the formulations' long-acting efficacy.

Purpose: Dendrimeric polyguanidilyated translocators (DPTs) are nanosized novel dendrimers that efficiently translocate molecules across biological barriers. The purpose of this study was to develop a DPT that could serve as an ophthalmic delivery vehicle for gatifloxacin and to evaluate its in vitro and in vivo delivery after topical application., Methods: The gatifloxacin (GFX) solubility-enhancing property of a six-guanidine group-containing dendrimer (g6 DPT) was investigated as a function of pH and dendrimer concentration. Mechanisms of drug interaction with the dendrimer were investigated by using isothermal titration calorimetry (ITC), Fourier-transformed infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR). Permeability of the dendrimer was assessed in human corneal epithelial cells (HCECs) and across isolated bovine sclera-choroid-RPE (SCRPE). In vitro efficacy of the dendrimer formulation was evaluated with a time-to-kill assay for methicillin resistant Staphylococcus aureus (MRSA). In vivo delivery of GFX in a dendrimer eye drop formulation was studied in New Zealand White rabbits after a single dose or multiple doses over 3 weeks. Drug levels in various ocular tissues were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: An optimized DPT-GFX formulation (final pH 5.9, no preservative) increased GFX solubility by fourfold. The dendrimer formed isotonically stable, nanosized (346-nm) complexes with GFX via ionic bond, hydrogen bond, and hydrophobic interactions. The dendrimer gained rapid entry into the HCECs (within 5 minutes) and increased the transport of GFX by 40% across the SCRPE in 6 hours. DPT-GFX exhibited a three times faster killing rate for MRSA when compared with GFX alone. In vivo administration of DPT-GFX (1.2% wt/vol) resulted in ∼13-fold, and ∼2-fold higher areas under the curve (AUCs) for tissue concentrations in conjunctiva and cornea, respectively, when compared with GFX (0.3%) after a single dose. Further, a single dose of DPT-GFX sustained aqueous humor and vitreous humor drug levels during the 24-hour study, with a t(1/2) of 9 and 32 hours, respectively. After multiple doses, similar advantages were seen with DPT-GFX., Conclusions: The DPT forms stable complexes with GFX and enhances its solubility, permeability, anti-MRSA activity, and in vivo delivery, potentially allowing a once-daily dose regimen.

Purpose: To evaluate the efficacy of a novel docetaxel derivative of deslorelin, a luteinizing hormone-releasing hormone (LHRH) agonist, and its combination in vivo with RGD peptide conjugated nanoparticles encapsulating an antiangiogenic, anti-vascular endothelial growth factor (VEGF) intraceptor (Flt23k; RGD-Flt23k-NP) in H1299 lung cancer cells and/or xenografts in athymic nude BALB/c mice., Experimental Design: The in vitro and in vivo efficacy of the deslorelin-docetaxel conjugate was evaluated in H1299 cells and xenografts in athymic nude mice. Coadministration of deslorelin-docetaxel conjugate and RGD-Flt23k-NP was tested in vivo in mice. Tumor inhibition, apoptosis, and VEGF inhibition were estimated in each of the treatment groups., Results: The conjugate enhanced in vitro docetaxel efficacy by 13-fold in H1299 cells compared with docetaxel at 24 hours, and this effect was inhibited following reduction of LHRH receptor expression by an antisense oligonucleotide. Combination of the conjugate with the RGD-Flt23k-NP in vivo resulted in an 82- and 15-fold tumor growth inhibition on day 39 following repeated weekly i.v. injections and a single intratumoral (i.t.) injection, respectively. These effects were significantly greater than individual targeted therapies or docetaxel alone. Similarly, apoptotic indices for the combination therapy were 14% and 10% in the i.v. and i.t. groups, respectively, and higher than the individual therapies. Combination therapy groups exhibited greater VEGF inhibition in both the i.v. and i.t. groups., Conclusions: Docetaxel efficacy was enhanced by LHRH receptor-targeted deslorelin conjugate and further improved by combination with targeted antiangiogenic nanoparticle gene therapy. Combination of novel targeted therapeutic approaches described here provides an attractive alternative to the current treatment options for lung cancer therapy.