Physiologically Based Pharmacokinetic Models Can Be Used to Predict the Unique Nonlinear Absorption Profiles of Vismodegib.

Predicting human pharmacokinetics (PK) during the drug discovery phase is valuable to assess doses required to reach therapeutic exposures. For orally administered compounds, however, this can be especially difficult, since the absorption process is complex. Vismodegib is a compound with unique nonlinear oral PK characteristics in humans. Oral physiologically based pharmacokinetic (PBPK) models were built using preclinical in vitro and in vivo data and successfully predicted the oral PK profiles in rats, dogs, and monkeys. Simulated drug exposures (area under the concentration-time curve from time 0 to infinity and Cmax) following oral administration were within twofold of observed values for dogs and monkeys, and close to twofold for rats, providing validation to the model structure. Adaptation of this oral PBPK model to humans, using human physiologic parameters coupled with predicted human PK, resulted in underpredictions of vismodegib exposure following both single and multiple doses. When observed human PK was used to drive the oral PBPK model, oral PK profiles in humans were well predicted, with fold errors in predicted versus observed drug exposures being close to 1. Importantly, the oral PBPK model captured the unique nonlinear, nondose-dependent PK of vismodegib at a steady state. The mechanism responsible for nonlinearity was consistent with oral absorption being influenced by nonsink permeation conditions. We introduce a new parameter, the permeation gradient factor, to characterize the effect of nonsink conditions on permeation. Using vismodegib as an example, we demonstrate the value of using oral PBPK models in drug discovery to predict the oral PK of compounds with nonlinear absorption characteristics in human. SIGNIFICANCE STATEMENT: A physiologically based pharmacokinetic (PBPK) model was built to demonstrate the value of these models early in the drug discovery stage for the prediction of human pharmacokinetics for compounds with unusual oral pharmacokinetics. In this study, our PBPK model could successfully capture the unique steady-state oral pharmacokinetics of our model compound, vismodegib. The mechanism for nonlinearity can be attributed to nonsink permeation conditions in vivo. We introduce the permeation gradient factor as a parameter to assess this effect.

A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is a common cause of end-stage renal disease, and no approved treatment is available in the United States to slow disease progression. The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in renal cysts, and while mTOR inhibitors are highly effective in rodent models, clinical trials in ADPKD have been disappointing due to dose-limiting extrarenal side effects. Since mTOR is known to be regulated by nutrients and cellular energy status, we hypothesized that dietary restriction may affect renal cyst growth. Here, we show that reduced food intake (RFI) by 23% profoundly affects polycystic kidneys in an orthologous mouse model of ADPKD with a mosaic conditional knockout of PKD1. This mild level of RFI does not affect normal body weight gain, cause malnutrition, or have any other apparent side effects. RFI substantially slows disease progression: relative kidney weight increase was 41 vs. 151% in controls, and proliferation of cyst-lining cells was 7.7 vs. 15.9% in controls. Mice on an RFI diet maintained kidney function and did not progress to end-stage renal disease. The two major branches of mTORC1 signaling, S6 and 4EBP1, are both suppressed in cyst-lining cells by RFI, suggesting that this dietary regimen may be more broadly effective than pharmacological mTOR inhibition with rapalogs, which primarily affects the S6 branch. These results indicate that polycystic kidneys are exquisitely sensitive to minor reductions in nutrient supply or energy status. This study suggests that a mild decrease in food intake represents a potential therapeutic intervention to slow disease progression in ADPKD patients.

Histological observations of pulpal replacement tissue in immature dog teeth after revascularization of infected pulps.

BACKGROUND AND AIM: Many studies have examined the nature of tissue formed in the canals of immature necrotic teeth, following revascularization in animals and humans. While speculations have been made that regeneration of the pulp tissue might take place in the canal, the tissue has been found to be cementum-like, bone-like, and periodontal ligament-like. The purpose of this study was to histologically examine the tissue in the root canals in immature dog teeth that had been artificially infected and then revascularized. METHODS: Two 4- to 5-month-old mongrel dogs with immature teeth were used in the study. In one dog, four maxillary and four mandibular anterior teeth, and in another dog, four maxillary and five mandibular anterior teeth were used in the experiment. Pulp infection was artificially induced in the immature teeth. Revascularization was performed on all teeth by disinfecting the root canals with sodium hypochlorite irrigation and triple antibiotic intracanal dressing, completed with induction of intracanal bleeding, and sealed with an MTA plug. The access cavity was restored with silver amalgam. The animals were sacrificed 3 months after revascularization procedures. The revascularized teeth and surrounding periodontal tissues were removed and prepared for histological examination. RESULTS: Besides cementum-like, bone-like, and periodontal ligament-like tissues formed in the canals, residual remaining pulp tissue was observed in two revascularized teeth. In four teeth, ingrowth of alveolar bone into the canals was seen; presence of bone in the root canals has the potential for ankylosis. CONCLUSIONS: Within the limitation of this study, it can be concluded that residual pulp tissue can remain in the canals after revascularization procedures of immature teeth with artificially induced pulp infection. This can lead to the misinterpretation that true pulpal regeneration has occurred. Ingrowth of apical bone into the root canals undergoing revascularization can interfere with normal tooth eruption if ankylosis occurs.

Chemically engineering the drug release rate of a PEG-paclitaxel conjugate using click and steric hindrance chemistries for optimal efficacy.

A small molecule drug with poor aqueous solubility can be conjugated to a hydrophilic polymer like poly(ethylene glycol) (PEG) to form an amphiphilic polymer-drug conjugate that self-assembles to form nanoparticles (NPs) with improved solubility and enhanced efficacy. This strategy has been extensively applied to improve the delivery of several small molecule drugs. However, very few reports have succeeded to tune the rate of drug release from these NPs. To the best of our knowledge, there have been no reports of utilizing click and steric hindrance chemistry to modulate the drug release of self-assembling polymer-drug conjugates. In this study, we utilized click chemistry to conjugate methoxy-PEG (mPEG) to an anti-tumor drug, paclitaxel (PTX). A focused library of PTX-Rx-mPEG (x = 0, 1, 2) conjugates were synthesized with different chemical modalities next to the cleavable ester bond to study the effect of increasing steric hindrance on the self-assembly process and the physicochemical properties of the resulting PTX-NPs. PTX-R0-mPEG had no added steric hindrance (x = 0; minimal), PTX-R1-mPEG consisted of two methyl groups (x = 1: moderate), and PTX-R2-mPEG consisted of a phenyl group (x = 2: significant). Drug release studies showed that PTX-NPs released PTX at a decreased rate with increasing steric hindrance. Pharmacokinetic studies showed that the AUC of released PTX from the moderate-release PTX-R1-NP was approximately 20-, 6-, and 3-fold higher than that from free PTX, PTX-R0-NP and PTX-R2-NP, respectively. As a result, among these different PTX formulations, PTX-R1-NP showed superior efficacy in inducing tumor regression and prolonging the animal survival. The tumors treated with PTX-R1-NP displayed the lowest tumor progression markers (Ki68 and CD31) and the highest apoptotic marker (TUNEL) compared to the others. This work emphasizes the importance of taking a systematic approach in designing self-assembling polymer drug conjugates and highlights the potential of utilizing steric hindrance as a tool to tune the drug release rate from such systems.

Regenerative Endodontic Procedures for Traumatized Immature Permanent Teeth with Severe External Root Resorption and Root Perforation.

External root resorption (ERR) is often a complication of traumatic injury to the teeth. Traditionally, external inflammatory root resorption is treated with calcium hydroxide. The outcome of ERR, especially replacement resorption, is unpredictable. The purpose of the present case report was to describe regenerative endodontic procedures (REPs) for 1 replanted avulsed tooth with severe external root resorption and root perforation (tooth #9) and 1 extruded tooth (tooth #8). A 9-year-old girl was referred for the treatment of teeth #8 and #9 4 months after the initial trauma. Clinical examination showed that tooth #9 had a sinus tract present near the periapical area, was tender to percussion and palpation, and did not respond to pulp sensibility tests. Tooth #8 responded to pulp sensibility tests. Periapical radiographic and cone-beam computed tomographic examination showed that tooth #9 had a periapical radiolucent lesion and severe ERRs with a root perforation. Tooth #9 was diagnosed with a necrotic pulp and symptomatic apical periodontitis. Regenerative endodontic procedures (REPs) were initiated. Tooth #8 became nonresponsive to pulp sensibility tests and developed a periapical lesion 12 months after REPs of tooth #9 and was also treated with REPs. The clinical symptoms and apical lesions resolved for both teeth after REPs. The severe ERRs were arrested, and root perforation was repaired for tooth #9. Teeth #8 and #9 underwent canal obliteration by hard tissue formation after REPs and were in function at 18 months and 30 months, respectively. REPs may be used to manage traumatized immature permanent teeth with a necrotic pulp and apical periodontitis associated with severe ERR and root perforation.

Modified Apexification Procedure for Immature Permanent Teeth with a Necrotic Pulp/Apical Periodontitis: A Case Series.

The current American Association of Endodontists clinical considerations for a regenerative endodontic procedure state that a regenerative procedure is suitable for immature permanent teeth with necrotic pulp when the pulp space is not needed for a post/core in the final restoration. Therefore, many immature permanent teeth with necrotic pulp that have sustained a substantial loss of coronal tooth structure either from caries or trauma are treated by apexification or mineral trioxide aggregate/Biodentine (Septodent, Lancaster, PA) apical barrier techniques in which no further root maturation would occur. This case series presents 10 immature permanent teeth with necrotic pulp in which a post/core was likely required in the future for adequate coronal restoration because of loss of substantial coronal tooth structure and a modified apexification procedure was used. All 10 cases after the modified apexification procedure showed no clinical symptoms/signs and showed radiographic evidence of healed/healing of periapical lesion after a 2-year review. Eight cases showed increased thickness of the apical root canal walls, increased apical root length, and apical closure. The overall percentage change in root length was 7.52%, in root width at the apical one third it was 18.89%, and in radiographic root area it was 15.04% at the 24- to 72-month follow-up period. This modified apexification procedure allows for the tooth to be restored with a post/core if required for the final restoration in the future as well as continued root development.

Vital pulp therapy of mature permanent teeth with irreversible pulpitis from the perspective of pulp biology.

The American Association of Endodontists (AAE) Consensus Conference Recommended Diagnostic Terminology states that mature permanent teeth clinically diagnosed with irreversible pulpitis are treated with pulpectomy and root canal filling because inflamed vital pulp is not capable of healing. Histological studies have demonstrated that clinically diagnosed irreversible pulpitis does not involve the entire pulp. A recent International Endodontic Journal Editorial suggested clinical diagnosis of pulp disease should be reassessed because of the poor correlation between clinical symptoms and pulp sensibility testing and the actual histological status of the pulp. This review identified studies in a PubMed search that provide evidence for vital pulp therapy (VPT) of mature permanent teeth with irreversible pulpitis is predictable if correctly diagnosed and properly treated. A narrative review was undertaken to outline the correlation between the clinical symptoms/signs and pulp sensibility testing and the histological findings of the pulp. Treatment procedures for permanent teeth are outlined.

Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease.

The rate of disease progression in autosomal-dominant (AD) polycystic kidney disease (PKD) exhibits high intra-familial variability suggesting that environmental factors may play a role. We hypothesized that a prevalent form of renal insult may accelerate cystic progression and investigated tubular crystal deposition. We report that calcium oxalate (CaOx) crystal deposition led to rapid tubule dilation, activation of PKD-associated signaling pathways, and hypertrophy in tubule segments along the affected nephrons. Blocking mTOR signaling blunted this response and inhibited efficient excretion of lodged crystals. This mechanism of "flushing out" crystals by purposefully dilating renal tubules has not previously been recognized. Challenging PKD rat models with CaOx crystal deposition, or inducing calcium phosphate deposition by increasing dietary phosphorous intake, led to increased cystogenesis and disease progression. In a cohort of ADPKD patients, lower levels of urinary excretion of citrate, an endogenous inhibitor of calcium crystal formation, correlated with increased disease severity. These results suggest that PKD progression may be accelerated by commonly occurring renal crystal deposition which could be therapeutically controlled by relatively simple measures.

Epilepsy and dental procedures. A review.

This paper is a review of the dental management of patients with epilepsy. It includes discussion of the effects anti-epileptic drugs have on dental procedures and addresses complications and side effects of these drugs. A clinical case photo is presented to show gingival hyperplasia, along with four tables on which common antiepileptic medications are enumerated.

Revascularization-associated Intracanal Calcification: A Case Report with an 8-year Review.

Revascularization-associated intracanal calcification (RAIC) is a common finding in immature teeth managed with regenerative endodontic treatment (RET). The aim of this report was to illustrate a case in which 2 mandibular premolar teeth developed complete canal obliteration and have been reviewed for 8 years. The 3 primary outcome goals as defined by the American Association of Endodontists after RET are resolution of signs and symptoms of pulp necrosis, further root maturation, and achievement of responses to pulp vitality testing. The teeth had been included in an earlier quantitative study in which an increase in root canal width of 72.1% and 39.6% and an increase in root length of 1.7% and 0% were reported for teeth #20 and #29, respectively. Qualitative assessments over the 8-year review period showed no pathosis and a response to electric pulp testing at the final review. A quantitative assessment at the 8-year review showed an increase of 100% for canal width because complete calcification had occurred and no substantive change in root length (-0.17% and 0.68% for teeth #20 and #29, respectively). In this report, complete RAIC occurred in both teeth over time. RAIC has the potential to complicate future endodontic or prosthodontic treatment if necessary. Therefore, it is recommended that the American Association of Endodontists clinical considerations for a regenerative endodontic procedure be updated to include the incidence of RAIC after RET.

Continued root maturation despite persistent apical periodontitis of immature permanent teeth after failed regenerative endodontic therapy.

Three immature permanent teeth with pulp necrosis and apical periodontitis were treated with regenerative endodontic therapy (RET), which included root canal disinfection with sodium hypochlorite irrigation, intra-canal medication with calcium hydroxide paste, 17% EDTA rinse, induction of periapical bleeding into the canal, collagen matrix and MTA coronal seal, and composite resin restoration of access cavities. After different periods of follow-up, it was observed that continued root maturation, especially apical closure occurred despite persistent apical periodontitis of immature permanent teeth after failed RET. This finding is of interest as the secondary goal of further root maturation occurred despite failure of the primary goal of elimination of clinical symptom/sign and periapical inflammation. The possible biological mechanisms that could allow for further root maturation to occur in spite of persistent root canal infection of immature permanent teeth are discussed. Based on these observations, the biology of wound healing of immature permanent teeth after injury is not fully understood and should be further investigated. This case report demonstrates that whilst further root maturation is considered a successful outcome for teeth treated with RET, the primary objective must be the resolution of the signs and symptoms of apical periodontitis.

Comparison of 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine when used as a supplemental anesthetic.

A randomized, double-blind trial was conducted to compare the efficacy of 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine when used as a supplemental anesthetic. Forty-eight patients with irreversible pulpitis requiring supplemental buccal infiltration for endodontic therapy were given either 4% articaine with 1:100,000 epinephrine or 2% lidocaine with 1:100,000 epinephrine in a double-blind manner. A standard VAS pain scale was used to evaluate the patient's response to pain after a supplemental injection. The mean VAS score after supplemental anesthesia was 15.28 for 4% articaine with 1:100,000 epinephrine and 19.70 for 2% lidocaine with 1:00,000 epinephrine. The mean percentage change in VAS score was 70.5 and 62.2% for articaine and lidocaine, respectively. There was no statistically significant difference in the VAS pain score between 4% articaine with 1:00,000 epinephrine and 2% lidocaine with 1:00,000 epinephrine as a supplemental anesthetic.

Proliferation of epithelial cell rests, formation of apical cysts, and regression of apical cysts after periapical wound healing.

There is continuing controversy regarding the potential for inflammatory apical cysts to heal after nonsurgical endodontic therapy. Molecular cell biology may provide answers to a series of related questions. How are the epithelial cell rests of Malassez stimulated to proliferate? How are the apical cysts formed? How does the lining epithelium of apical cysts regress after endodontic therapy? Epithelial cell rests are induced to divide and proliferate by inflammatory mediators, proinflammatory cytokines, and growth factors released from host cells during periradicular inflammation. Quiescent epithelial cell rests can behave like restricted-potential stem cells if stimulated to proliferate. Formation of apical cysts is most likely caused by the merging of proliferating epithelial strands from all directions to form a three-dimensional ball mass. After endodontic therapy, epithelial cells in epithelial strands of periapical granulomas and the lining epithelium of apical cysts may stop proliferating because of a reduction in inflammatory mediators, proinflammatory cytokines, and growth factors. Epithelial cells will also regress because of activation of apoptosis or programmed cell death through deprivation of survival factors or by receiving death signals during periapical wound healing.

One-appointment endodontic therapy: biological considerations.

BACKGROUND: The authors conducted a literature review to present the best available biological evidence concerning one-appointment endodontic therapy for asymptomatic teeth with apical periodontitis. TYPES OF STUDIES REVIEWED: Because of recent advances in technology, such as rotary engines and nickel-titanium instruments, some practitioners are performing one-appointment endodontic therapy for asymptomatic teeth with apical periodontitis. The authors reviewed the literature, which revealed only a small number of randomized, controlled clinical trials that have been conducted on one-appointment versus multiple-appointment endodontic therapy. RESULTS: As the apical canal preparation is enlarged, a greater percentage of bacteria is eradicated from infected root canals. In addition, sufficiently large apical root canal enlargement facilitates the delivery of antimicrobial irrigant to the apical portion of the canal. However, an association between positive or negative preobturation root canal culture results and the outcome of endodontic treatment has not been well-established. CLINICAL IMPLICATIONS: The best available evidence, based on a systematic literature review, indicates that one-appointment endodontic therapy may be feasible in selected cases of apical periodontitis in asymptomatic teeth. However, additional randomized, controlled clinical trials are required.

Predicting Oral Drug Absorption: Mini Review on Physiologically-Based Pharmacokinetic Models.

Most marketed drugs are administered orally, despite the complex process of oral absorption that is difficult to predict. Oral bioavailability is dependent on the interplay between many processes that are dependent on both compound and physiological properties. Because of this complexity, computational oral physiologically-based pharmacokinetic (PBPK) models have emerged as a tool to integrate these factors in an attempt to mechanistically capture the process of oral absorption. These models use inputs from in vitro assays to predict the pharmacokinetic behavior of drugs in the human body. The most common oral PBPK models are compartmental approaches, in which the gastrointestinal tract is characterized as a series of compartments through which the drug transits. The focus of this review is on the development of oral absorption PBPK models, followed by a brief discussion of the major applications of oral PBPK models in the pharmaceutical industry.

Alkaline Materials and Regenerative Endodontics: A Review.

Periapical health is the primary goal of endodontic treatment in mature and immature teeth. In addition, the goals of treatment of immature teeth with arrested root development include root growth to length and maturation of the apex, as well as thickening of the canal wall. These goals are valid for immature teeth that have been subjected to trauma and dental caries or that are the result of developmental anomalies that expose the tooth to the risk of pulp necrosis and consequently result in the cessation of root maturation. Regenerative endodontic procedures (REPs) have been described as a "paradigm shift" in the treatment of immature teeth with pulp necrosis and underdeveloped roots, as there is the potential for further root maturation and return of vitality. Treatment with REPs is advocated as the treatment of choice for immature teeth with pulp necrosis. REP protocols involve the use of alkaline biomaterials, primarily sodium hypochlorite, calcium hydroxide, mineral trioxide aggregates and Biodentine, and are the essential components of a successful treatment regimen.

A review of regenerative endodontics: current protocols and future directions.

This review outlines the biological basis and clinical protocols currently used in regenerative endodontic procedures (REPs) and discuss future directions in pulp regeneration approaches. The treatment of immature teeth with REPs has been described as a 'paradigm shift' as there is the potential for further root maturation. Clinically, REPs involve disinfection of the root canal system without damaging the endogenous stem cell potential present in the apical papilla and other tissues. These stems cells are introduced into the root canal space by inducing a blood clot followed by placement of an intracanal barrier to prevent microleakage. The biological concept of REPs involves the triad of stem cells, scaffold and signalling molecules. Currently, repair rather than true regeneration of the 'pulp-dentine complex' is achieved and further root maturation is variable. However, may clinicians consider the treatment of teeth with REPs as the optimal treatment approach for immature teeth with pulp necrosis.

An Evidence-based Review of the Efficacy of Treatment Approaches for Immature Permanent Teeth with Pulp Necrosis.

INTRODUCTION: Two fundamental assumptions for teeth treated with regenerative endodontic procedures (REPs) are (1) that the clinical outcome is comparable with the traditional techniques of calcium hydroxide apexification and mineral trioxide aggregate apical barrier techniques and (2) that REPs will result in further root maturation. METHODS: A systematic review of the electronic databases (Scopus, PubMed, and Web of Science) involved a search for studies that used quantitative assessments of root maturation. The search terms were "dental pulp," "regenerative endodontic therapy," "revascularization," and "revitalization." The identified studies were further screened for cohort studies that compared clinical outcomes between teeth treated with REPs and apexification/apical barrier approaches. The primary question under review was framed according to the population, exposure, and outcome format. RESULTS: Of the 368 studies identified by the search, 6 cohort studies used quantitative assessments of any further root maturation after REPs, and a subset of 4 of these cohort studies assessed and compared clinical outcomes between the different treatment approaches. CONCLUSIONS: Immature teeth with pulp necrosis treated with REPs generally show further root maturation although the results are variable. Clinical outcomes were similar for both groups. Patient-based criteria such as tooth discoloration, indications for changing the treatment option, and number of treatment appointments are all important for discussion before electing the appropriate treatment plan for the management of immature teeth with pulp necrosis.

Endodontic Treatment Outcomes.

The primary goal of conventional endodontic treatment is prevention and/or elimination of apical periodontitis for both mature permanent teeth and immature teeth with an open apex. Besides these goals, the objectives of endodontic treatment of immature teeth include preservation of pulp vitality and often further root maturation. Robust criteria for outcome assessment are an essential determinant for any measure of treatment success for both mature and immature teeth.