Safety of an extended-release injectable moxidectin suspension formulation (ProHeart® 12) in dogs.

BACKGROUND: The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies. The recommended dose is 0.5 mg/kg subcutaneously once yearly. METHODS: Study 1: safety margin was evaluated as 3 treatments of PH 12 (0× (control); 1× (recommended dose); 3× (3 times recommended dose) and 5× (5 times recommended dose) in 12 months via clinical observations, body weights, food consumption, injection site observations, physical examinations, moxidectin tissue assay, pharmacokinetics, and clinical and anatomic pathology. Study 2: safety in breeding-age males was demonstrated by semen testing at 14-day intervals from Day 7 to Day 91 post-treatment (0× or 3×). Study 3: reproductive safety in females was demonstrated by monitoring dams and litters following treatments (0× or 3×) administered during breeding, gestation, or lactation. Study 4: safety in dogs surgically implanted with adult heartworms was evaluated by clinical and laboratory monitoring following treatment with 0× or 3× administered 61 days post-implantation. Study 5: safety in ivermectin-sensitive dogs (120 µg/kg SC) was by clinical monitoring for 1 week after administering 1×, 3× or 5×. RESULTS: Study 1: slight swelling clinically detectable at some 3× and 5× injection sites was characterized microscopically as granulomatous inflammation, like tissue responses to medical implants, interpreted as non-adverse. Pharmacokinetics were dose-proportional and there was little or no systemic accumulation. Residual moxidectin mean (range) at 1× injection sites after 1 year was 16.0% (0.045-37.6%) of the administered mass. Studies 2 and 3: no effects were identified in reproductive indices (females) or semen quality characteristics (males). Study 4: PH 12 produced marked reductions in circulating microfilariae and lower numbers of adult heartworms, but no adverse clinical signs were identified. Study 5: there were no abnormal clinical signs at 1×, 3× or 5× overdoses of PH 12 in ivermectin-sensitive dogs. CONCLUSIONS: PH 12 has a > 5× safety margin in both normal and ivermectin-sensitive dogs, has no effects on canine reproduction, and is well tolerated in heartworm-positive dogs. The only treatment-related finding was non-adverse, granulomatous inflammation at the injection site.

Pharmacokinetic and Metabolomic Studies with BIO 300, a Nanosuspension of Genistein, in a Nonhuman Primate Model.

Genistein is a naturally occurring phytoestrogen isoflavone and is the active drug ingredient in BIO 300, a radiation countermeasure under advanced development for acute radiation syndrome (H-ARS) and for the delayed effects of acute radiation exposure (DEARE). Here we have assessed the pharmacokinetics (PK) and safety of BIO 300 in the nonhuman primate (NHP). In addition, we analyzed serum samples from animals receiving a single dose of BIO 300 for global metabolomic changes using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (QTOF-MS). We present a comparison of how either intramuscularly (im) or orally (po) administered BIO 300 changed the metabolomic profile. We observed transient alterations in phenylalanine, tyrosine, glycerophosphocholine, and glycerophosphoserine which reverted back to near-normal levels 7 days after drug administration. We found a significant overlap in the metabolite profile changes induced by each route of administration; with the po route showing fewer metabolic alterations. Taken together, our results suggest that the administration of BIO 300 results in metabolic shifts that could provide an overall advantage to combat radiation injury. This initial assessment also highlights the utility of metabolomics and lipidomics to determine the underlying physiological mechanisms involved in the radioprotective efficacy of BIO 300.

Cardiovascular safety pharmacology studies in dogs enabled for a poorly soluble molecule using spray-dried dispersion: Impact on lead selection.

The aim of this study was to identify an adequate formulation for a poorly soluble lead molecule (BI-A) that would achieve sufficiently high plasma concentrations after oral administration in dogs to enable a robust cardiovascular safety pharmacology assessment in telemetry-instrumented conscious dogs during lead optimization in drug discovery. A spray-dried dispersion of BI-A (BI-A-SDD) containing a 1:2 ratio of BI-A and hydroxypropyl methylcellulose acetate succinate-LF was prepared using a Büchi spray dryer B-90 (B-90). Physical form characterization, an in vitro dissolution test and a preliminary pharmacokinetic (PK) study following oral administration of BI-A-SDD were performed. Thereafter, effects on cardiovascular parameters in conscious, chronically-instrumented dogs were investigated for 24h after a single oral dose (5, 10, and 50mg/kg) using a modified Latin square cross-over study design. The BI-A-SDD powder was confirmed to be amorphous and was stable as an aqueous suspension for at least 4h. The BI-A-SDD suspension provided a greater rate and extent of dissolution than the crystalline BI-A suspension and the supersaturation was maintained for at least 4h. In PK studies the Cmax of the BI-A-SDD formulation (25.4µM; 77-fold the projected efficacious Cmax of 0.33µM) was 7.5-fold higher than the Cmax observed using oral administration of a 10% hydroxypropyl-ß-cyclodextrin formulation at 100mg/kg in dogs (3.4µM). In conscious, chronically-instrumented dogs, the doses tested and plasma concentrations achieved were sufficient to enable a robust safety pharmacology evaluation. Multiple off-target hemodynamic effects were detected including acute elevations in aortic blood pressure (up to 22% elevation in systolic and diastolic blood pressure) and tachycardia (68% elevation in heart rate), results that were confirmed in other in vivo models. These results led to a deprioritization of BI-A. The study demonstrated that a spray-dried dispersion, prepared using the B-90 in drug discovery, enhanced the oral exposure of a poorly water-soluble molecule, BI-A, and thereby enabled its evaluation in safety pharmacology studies that ultimately resulted in deprioritization of BI-A from a pool of lead compounds.

Activity and Safety of Inhaled Itraconazole Nanosuspension in a Model Pulmonary Aspergillus fumigatus Infection in Inoculated Young Quails.

Pulmonary aspergillosis is frequently reported in parrots, falcons, and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but its administration requires repeated oral dosing, and the safety margin is narrow. To investigate the efficacy of inhaled ITRA, six groups of ten young quails (Coturnix japonica) were inoculated intratracheally with 5 × 10(6) spores (3 groups) or 5 × 10(7) spores (3 groups). Animals were exposed to nebulized ITRA nanosuspension as 10 % suspension or 4 % suspension, once daily for 30 min, starting 2 h after inoculation for 6 days. Control groups were exposed to nebulized saline for the same period of time. Survival and clinical scores were evaluated, and animals were subjected to gross pathology. In control animals, aspergillosis resulted in systemic disease without pulmonary or air sac granulomas. Animals died from multiple organ failure. Inhalation of 10 % ITRA nanosuspension blocked lethality and prevented disease-related symptoms in the quails exposed to the low dose of spores, while the disease course in quails inoculated with the high-spore dose was retarded. Inhalation of 4 % ITRA nanosuspension was less effective. Both inhalations were well tolerated, and gross pathology did not reveal signs of local toxicity. The data indicate that inhaled administration of 10 % ITRA nanosuspension is capable of alleviating an acute A. fumigatus infection in quails. A lower ITRA concentration may be only active in chronic pulmonary aspergillosis.

Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.

BACKGROUND & AIMS: No treatment has been approved by the U.S. Food and Drug Administration for eosinophilic esophagitis (EoE). We investigated the efficacy and safety of a new formulation of oral budesonide suspension (OBS), a corticosteroid, in a prospective, placebo-controlled, dose-ranging study. METHODS: Subjects 2-18 years old with symptoms of EoE and peak eosinophil counts ≥20/high-power field at ≥2 levels of the esophagus were randomly assigned to groups given placebo or low-dose, medium-dose, or high-dose OBS for 12 weeks. Doses and volumes were adjusted on the basis of patients' age to cover the entire esophagus. The primary efficacy end point was compound response to therapy (peak eosinophil counts ≤6/high-power field at all levels of the esophagus and ≥50% reduction in EoE symptom score). Multiple safety parameters were evaluated. RESULTS: Data from 71 subjects who completed all efficacy assessments were included in the primary efficacy analysis. At the end of 12 weeks, there were significantly greater percentages of responders in groups given medium-dose OBS (52.6%, P = .0092) and high-dose OBS (47.1%, P = .0174) than in the group given placebo (5.6%); there was no significant difference in percentages of responders between the low-dose OBS (11.8%) and placebo groups (P = .5282). The significant compound responses noted in the medium-dose and high-dose OBS groups were accounted for by the significant histologic responses; in contrast, all 4 groups (including the placebo group) had large symptom responses, and there was no significant difference in the percentage of subjects with a symptom response in either OBS group compared with the placebo group (P ≥ .1235). There were no unexpected safety concerns or signals. CONCLUSIONS: Peak eosinophil counts were significantly reduced throughout the esophagus in pediatric patients with EoE who were given medium-dose and high-dose OBS. There was a large symptom response to placebo that was similar to symptom responses in the OBS groups; symptom response did not distinguish OBS from placebo. ClinicalTrials.gov number, NCT00762073.

Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity.

We evaluated posaconazole serum concentrations and hepatotoxicity in 12 leukemia patients who transitioned from posaconazole suspension to tablets. Patients who switched to tablets had significantly increased posaconazole concentrations (median: suspension, 748 ng/ml; tablet, 1,910 ng/ml; P < 0.01) without clinically relevant hepatotoxicity.

Rat chronic glaucoma model induced by intracameral injection of microbeads suspended in sodium sulfate-sodium hyaluronate.

PURPOSE: To establish a rat glaucoma model with chronic intraocular pressure (IOP) elevation induced by microbeads suspended in sodium sulfate-sodium hyaluronate. METHODS: Chronic elevation of IOP was induced unilaterally by injecting polystyrene microbeads, suspended in 4 % sodium sulfate and 3 % sodium hyaluronate, into the anterior chamber. The microbead suspension was injected through either the clear corneal (CC) or sclerocorneal (SC) tunnel. IOP changes were monitored up to 8 weeks after injection. The loss of retinal ganglion cells (RGCs) was assessed using fluorogold retrograde labeling of RGCs. RGC axons were evaluated by immunohistochemistry and immunoblotting. RESULTS: The resulting IOP elevation was maintained up to 3 weeks after the intracameral injection of microbeads through the CC route and up to 4 weeks after injection through the SC route. The density of RGCs was significantly reduced at 4 weeks after injection, with the SC route leading to more RGC loss than the CC route (p = 0.037). The neurofilament immunoreactivity and protein levels in the optic nerve were also significantly reduced at 4 weeks after injection. Some eyes in the SC route cohort received re-injection of the microbead suspension at 4 weeks after the initial injection, which led to an elevated IOP more than 8 weeks after the initial injection, and eventually a 27.5 % loss of RGC density compared with the control eyes. CONCLUSION: The intracameral injection of microbeads suspended in hyaluronate effectively produced chronic IOP elevation and subsequent RGC degeneration in rat eyes. The sclerocorneal tunnel approach yielded a longer period of IOP elevation than the clear corneal approach. Our modified microbead injection offers a reliable high-pressure glaucoma model.

Chronic ocular hypertensive rat model using microbead injection: comparison of polyurethane, polymethylmethacrylate, silica and polystyene microbeads.

PURPOSE: To establish and assess an ocular hypertensive rat model using intracameral injection with various microbeads of different sizes and materials. METHODS: Chronic elevation of intraocular pressure (IOP) was induced by the injection of various microbeads into the anterior chamber of Sprague-Dawley rat eyes. We compared the IOPs induced by the injection of different microbeads [7- and 17-µm polyurethane (PU), 7- and 15-µm polymethylmethacrylate (PMMA), 13-µm silica, and 15-µm polystyrene (PS)] and selected the appropriate microbeads for a chronic ocular hypertensive model in terms of IOP elevation and adverse events. IOP changes were observed for 4 weeks after microbead injections. Axonal degeneration was assessed with transmission electron microscopic photographs and RGC loss was assessed with retrograde labeling. RESULTS: Seventy-eight rats were included. Three days after a single injection of microbeads, IOPs were increased by 24.0% by 7-µm PU microbeads, 101.8% by 17-µm PU microbeads, 56.6% by 7-µm PMMA microbeads, 22.0% by 15-µm PMMA microbeads, 153.0% by 13-µm silica microbeads, and 34.7% by 15-µm PS microbeads. 17-µm PU microbeads produced constant IOP elevation with good reproducibility (standard deviation of <6.5 mmHg). Silica injected eyes showed severe inflammation. Sustained IOP elevation by two injections of 17-µm PU microbeads resulted in a 42% axon loss and 36.5% RGC loss (p < 0.05, Mann-Whitney U test). CONCLUSIONS: PU microbead injections offer an applicable and versatile model for a chronic ocular hypertensive model in rats. Among several biomaterials, PU microbeads produced a more stable IOP elevation without adverse events.

In vivo toxicological evaluation of polymeric nanocapsules after intradermal administration.

Polymeric nanocarriers have shown great promise as delivery systems. An alternative strategy has been to explore new delivery routes, such as intradermal (i.d.), that can be used for vaccines and patch-based drug delivery. Despite their many advantages, there are few toxicity studies, especially in vivo. We report a safety assessment of biodegradable poly(ɛ-caprolactone) lipid-core nanocapsules (LNC) with a mean size of 245±10nm following single and repeated intradermal injections to Wistar rats. Suspensions were prepared by interfacial deposition of polymer. The animals (n=6/group) received a single-dose of saline solution (1.2ml/kg) or LNC (7.2×10(12)LNC/kg), or repeated-doses of two controls, saline solution or Tween 80 (0.9ml/kg), or three different concentrations of LNC (1.8, 3.6, and 5.4×10(12)LNC/kg) for 28 consecutive days. Clinical and physiological signs and mortality were observed. Samples of urine, blood, and tissue were used to perform toxicological evaluation. There were no clinical signs of toxicity or mortality, but there was a slight decrease in the relative body weights in the Tween 80-treated group (p<0.01) after repeated administration. No histopathological alterations were observed in tissues or significant changes in blood and urinary biomarkers for tissue damage. Mild alterations in white blood cells count with increases in granulocytes in the Tween-80 group (p<0.05) were found. Genotoxicity was evaluated through the comet assay, and no statistical difference was observed among the groups. Therefore, we conclude that, under the conditions of these experiments, biodegradable LNC did not present appreciable toxicity after 28 consecutive days of intradermal administration and is promising for its future application in vaccines and patch-based devices for enhancing the delivery of drugs.

Anaphylactoid reaction to paliperidone palmitate extended-release injectable suspension in a patient tolerant of oral risperidone.

PURPOSE: A probable anaphylactoid reaction to the injectable formulation of the atypical antipsychotic paliperidone in a patient with established tolerability to oral risperidone is reported. SUMMARY: A 19-year-old man with schizophreniform disorder was admitted to the emergency department experiencing command hallucinations and persecutory delusions. The patient was treated with oral risperidone during which time his presenting symptoms improved; no risperidone-related adverse effects were noted. Due to concerns about long-term adherence to daily risperidone use, it was decided to initiate once-monthly injections of paliperidone palmitate extended-release suspension. Within 15 minutes of the first paliperidone injection, the patient developed flushing of the face, neck, and head, and he soon developed chills, rigors, and difficulty breathing; after treatment to resolve those symptoms, oral risperidone was restarted. No further drug-related problems occurred during the man's hospital stay. The pharmacy subsequently received notice that the medication lot from which the patient had received the paliperidone dose had been recalled due to reports of cracked syringes, but a possible link between the syringe defect and the man's anaphylactoid symptoms could not be determined. The temporal relationship between paliperidone palmitate administration and the onset of the man's symptoms, as well as application of the Naranjo nomogram, indicated a probable anaphylactoid reaction associated with the paliperidone formulation. CONCLUSION: A man who had tolerated oral risperidone developed an anaphylactoid reaction after receiving an injection of paliperidone palmitate extended-release suspension. After recovering from the reaction, the patient again received oral risperidone without adverse effects.

Solid lipid nanoparticles suspension versus commercial solutions for dermal delivery of minoxidil.

Solid lipid nanoparticles have been reported as possible carrier for skin drug delivery. Solid lipid nanoparticles are produced from biocompatible and biodegradable lipids. Solid lipid nanoparticles made of semi-synthetic triglycerides stabilized with a mixture of polysorbate and sorbitan oleate were loaded with 5% of minoxidil. The prepared systems were characterized for particle size, pH and drug content. Ex vivo skin penetration studies were performed using Franz-type glass diffusion cells and pig ear skin. Ex vivo skin corrosion studies were realized with a method derived from the Corrositex(®) test. Solid lipid nanoparticles suspensions were compared to commercial solutions in terms of skin penetration and skin corrosion. Solid lipid nanoparticles suspensions have been shown as efficient as commercial solutions for skin penetration; and were non-corrosive while commercial solutions presented a corrosive potential. Solid lipid nanoparticles suspensions would constitute a promising formulation for hair loss treatment.

The Movat pentachrome stain as a means of identifying microcrystalline cellulose among other particulates found in lung tissue.

CONTEXT: Microcrystalline cellulose (MCC) is extensively used as a filler material in pharmaceutical tablets. When injected intravenously in aqueous tablet suspensions, MCC may contribute to embolic pulmonary hypertension and be identified histologically in lung tissue samples. In this study, we evaluated a modified Russell Movat pentachrome stain (MMPS) as a means of recognizing MCC and distinguishing it from other birefringent crystals in lung specimens. OBJECTIVE: To study the staining properties of MCC versus other crystalline materials using the MMPS stain. DESIGN: Archival, formalin-fixed, paraffin-embedded lung specimens that contained birefringent crystals, including MCC (3 cases of intravenous drug abuse), talc (2 cases of intravenous drug abuse, 1 talc pleurodesis), mixed silicates (1 case of silicate pneumoconiosis), and calcium oxalate (1 case of aspergillosis from Aspergillus niger infection), were evaluated with MMPS. Crystal identification was confirmed by morphology, other histochemical stains, infrared spectroscopy (1 case), and cellulose controls. RESULTS: The MMPS stained the MCC bright yellow in tissue and control specimens. Talc stained light greenish-blue; mixed silicates appeared either greenish-blue or unstained. Oxalate crystals stained sea-green. Crospovidone, a nonbirefringent tablet filler substance, stained yellow to dark green with MMPS and was easily distinguished from MCC. Starch granules were unstained by MMPS. CONCLUSIONS: The MMPS is an excellent method for the histochemical identification of MCC in tissue and its separation from other birefringent crystals with which MCC might be confused. The MMPS is especially useful in the evaluation of pulmonary foreign body embolization in cases of suspected intravenous substance abuse.

Complications of transforaminal cervical epidural steroid injections.

STUDY DESIGN: A comprehensive literature review. OBJECTIVES: To review and critically evaluate the past literature focusing on incidence and clinical presentation of complications associated with transforaminal cervical epidural steroid injection (TFCESI) and techniques employed to avoid them. The overall goal is to guide the direction of future research and improve clinical care by increasing awareness of complications and measures that may be undertaken to increase safety. SUMMARY OF BACKGROUND DATA: TFCESI is a component in the diagnosis and management of cervical radicular syndromes in patients who have failed conservative management. There has been much discussion and also controversy in the recent literature. Considerable attention has been paid to reports of catastrophic complications and proposed measures to avoid them. METHODS: Medical databases were searched for studies of TFCESI. The bibliographies of these articles were then searched as well. Thoracic and lumbar articles were discarded as were any non-transforaminal cervical procedures or those that did not involve injection into the epidural space. Particular attention was paid to serious neurologic sequelae after TFCESI and its mechanism, as well as techniques being employed to avoid complications. RESULTS: There are a limited number of studies looking at complications of TFCESI. One retrospective study reported an overall rate of complications of 1.64%. There are reports of serious neurologic sequelae in the literature including brain and spinal cord infarction due to embolic phenomenon of particulate steroids. Cadaveric dissection revealed ascending and deep cervical arterial branches entering the external opening of the posterior intervertebral foramen, the classic target site for TFCESI. Measures to avoid complications mentioned in the literature include the use of nonparticulate steroids, test dose of local anesthetic before injection of steroids, live fluoroscopy, digital subtraction, no to light sedation, use of true lateral view to supplement frontal and oblique views in fluoroscopy, use of blunt needles, and computed tomography guidance. CONCLUSION: The literature reveals a number of rare, potentially catastrophic neurologic sequelae including brain and spinal cord infarction. Most of these are thought to be due to intravascular uptake of particulate steroids. The true overall incidence remains obscure due to the lack of blinded controlled studies. Injectionists, referring physicians, and patients should be aware of the nature and potential consequences of these complications. Additionally, it is imperative for injectionists to standardize techniques to minimize complications, especially by using a test dose of local anesthetic before injection of preferably nonparticulate corticosteroid.

Diclofenac-loaded biopolymeric nanosuspensions for ophthalmic application.

Polymeric nanoparticle suspensions (NS) were prepared from poly(lactide-co-glycolide) and poly(lactide-co-glycolide-leucine) {poly[Lac(Glc-Leu)]} biodegradable polymers and loaded with diclofenac sodium (DS), with the aim of improving the ocular availability of the drug. NS were prepared by emulsion and solvent evaporation technique and characterized on the basis of physicochemical properties, stability, and drug release features. The nanoparticle system showed an interesting size distribution suitable for ophthalmic application. Stability tests (as long as 6 months' storage at 5 degrees C or at 25 degrees C/60% relative humidity) or freeze-drying were carried out to optimize a suitable pharmaceutical preparation. In vitro release tests showed a extended-release profile of DS from the nanoparticles. To verify the absence of irritation toward the ocular structures, blank NS were applied to rabbit eye and a modified Draize test performed. Polymer nanoparticles seemed to be devoid of any irritant effect on cornea, iris, and conjunctiva for as long as 24 hours after application, thus apparently a suitable inert carrier for ophthalmic drug delivery.

Gastrointestinal effects of sorbitol as an additive in liquid medications.

Certain sugar alcohols, notably sorbitol, are widely used as a vehicle for drugs in liquid oral dosage forms. Gastrointestinal side effects due to osmotically active excipients have been described, but remain an underappreciated cause of diarrhea. Quantitating amounts of sorbitol is difficult due to a lack of compendial listings of such information. A computer search of Physicians' Desk Reference monographs was conducted to identify products that listed or potentially contained sorbitol as an inert ingredient. Standard form letters and telephone calls were used to collect information on the sorbitol content of products identified. Data were compiled for 142 products, and each value was converted to mg/mL as crystalline sorbitol. Some difficulty occurred obtaining requested information from some manufacturers in their effort to maintain product formulation confidentiality. Pharmaceutical manufacturers should recognize that technically inert ingredients are not necessarily pharmacologically inactive. Manufacturers should therefore comply with requests for, and more openly publish, quantitative information regarding such ingredients, to facilitate the assessment and treatment of patient symptoms.

Dental caries potential of liquid medications.

Cariogenicity of seven commonly prescribed liquid medications was studied. Sucrose content of the medications ranged from 0 to 70 gm/100 ml. Initial pH and buffering capacity were measured and found to vary widely among the medications. Intraoral microbial plaque pH changes were determined at intervals for 30 minutes following an oral rinse with each medication. These data were compared with plaque pH changes caused by rinsing with an established cariogenic challenge, 10% sucrose solution. Decreased plaque pH was caused by each medication tested. The extent and duration of the pH drop varied among the medications. Patterns of the pH curves are discussed in relation to sucrose content, endogenous pH, and buffering capacity of the medications. Intraoral pH response to several medications equaled or exceeded that seen when sucrose rinses alone were given. The findings are discussed in relation to dental caries-producing potential of long-term therapy with liquid medications, and two cases are presented that implicate liquid medications as a major etiologic factor leading to rampant dental decay. It is concluded that health practitioners should be aware of the sucrose content of pediatric medications. Patient education to ensure adequate oral clearance following each dose of medication is an essential first step in minimizing the risk of dental decay posed by long-term therapy with liquid medications.