The Use of Global Sensitivity Analysis to Assess the Oral Absorption of Weakly Basic Compounds: A Case Example of Dipyridamole.

OBJECTIVE: To utilize the global system analysis (GSA) in oral absorption modeling to gain a deeper understanding of system behavior, improve model accuracy, and make informed decisions during drug development. METHODS: GSA was utilized to give insight into which drug substance (DS), drug product (DP), and/or physiological parameter would have an impact on peak plasma concentration (Cmax) and area under the curve (AUC) of dipyridamole as a model weakly basic compound. GSA guided the design of in vitro experiments and oral absorption risk assessment using FormulatedProducts v2202.1.0. The solubility and precipitation profiles of dipyridamole in different bile salt concentrations were measured. The results were then used to build a mechanistic oral absorption model. RESULTS: GSA warranted further investigation into the precipitation kinetics and its link to the levels of bile salt concentrations. Mechanistic modeling studies demonstrated that a precipitation-integrated modeling approach appropriately predicted the mean plasma profiles, Cmax, and AUC from the clinical studies. CONCLUSIONS: This work shows the value of GSA utilization in early development to guide in vitro experimentation and build more confidence in identifying the critical parameters for the mathematical models.

Centriolin interacts with HectD1 in a cell cycle dependent manner.

OBJECTIVE: The centrosome is universally recognized as the microtubule organizing center of animal cells, but emerging evidence suggests that it has other important functions including primary cilia formation, DNA damage checkpoints, and cell cycle progression. Despite this, the role of individual components of the centrosome remains unclear. Previous studies suggest that one component, centriolin, has an important function in cytokinesis and cell cycle progression, although its exact role in these processes is not known. To determine how centriolin influences the progression through the cell cycle, we sought to identify interacting partners that may be involved in regulating its function. RESULTS: This study provides evidence that the ubiquitin E3 ligase HectD1 binds to centriolin and that this association likely accounts for our observation that HectD1 co-localizes with centriolin at the centrosome during mitosis. In addition to its centrosomal localization, we also show that the expression of HectD1 fluctuates throughout the cell cycle, with the highest levels during mitosis, coinciding with a marked reduction in centriolin expression. We propose that the interaction between HectD1 and centriolin may be necessary for normal cell cycle progression and we speculate that this function may involve HectD1-mediated degradation of centriolin.

CD73 deficiency does not aggravate angiotensin II-induced aortic inflammation in mice.

Vascular inflammation plays a key role in the development of aortic diseases. A potential novel target for treatment might be CD73, an ecto-5'-nucleotidase that generates anti-inflammatory adenosine in the extracellular space. Here, we investigated whether a lack of CD73 results in enhanced aortic inflammation. To this end, angiotensin II was infused into wildtype and CD73-/- mice over 10 days. Before and after infusion, mice were analyzed using magnetic resonance imaging, ultrasound, flow cytometry, and histology. The impact of age and gender was investigated using female and male mice of three and six months of age, respectively. Angiotensin II infusion led to increased immune cell infiltration in both genotypes' aortae, but depletion of CD73 had no impact on immune cell recruitment. These findings were not modified by age or sex. No substantial difference in morphological or functional characteristics could be detected between wildtype and CD73-/- mice. Interestingly, the expression of CD73 on neutrophils decreased significantly in wildtype mice during treatment. In summary, we have found no evidence that CD73 deficiency affects the onset of aortic inflammation. However, as CD73 expression decreased during disease induction, an increase in CD73 by pharmaceutical intervention might result in lower vascular inflammation and less vascular disease.

A Combined In-Vitro and GastroPlus® Modeling to Study the Effect of Intestinal Precipitation on Cinnarizine Plasma Profile in a Fasted State.

Poorly water-soluble weak base molecules such as cinnarizine often exhibit pH-dependent solubility within the gastrointestinal tract. This means that their solubility can be influenced by the pH of the surrounding environment, and this can affect their oral absorption. The differential pH solubility between the fasted-state stomach and intestine is an important consideration when studying the oral absorption of cinnarizine. Cinnarizine has moderate permeability and is known to exhibit supersaturation and precipitation in fasted-state simulated intestinal fluid (FaSSIF), which can significantly impact its oral absorption. The present work is aimed at studying the precipitation behavior of cinnarizine in FaSSIF using biorelevant in vitro tools and GastroPlus® modeling, to identify the factors contributing to the observed variability in clinical plasma profiles. The study found that cinnarizine demonstrated variable precipitation rates under different bile salt concentrations, which could impact the concentration of the drug available for absorption. The results also showed that a precipitation-integrated modeling approach accurately predicted the mean plasma profiles from the clinical studies. The study concluded that intestinal precipitation may be one of the factors contributing to the observed variability in Cmax but not the AUC of cinnarizine. The study further suggests that the integration of experimental precipitation results representing a wider range of FaSSIF conditions would increase the probability of predicting some of the observed variability in clinical results. This is important for biopharmaceutics scientists, as it can help them evaluate the risk of in vivo precipitation impacting drug and/or drug product performance.

Monkeypox-Associated Central Nervous System Disease: A Case Series and Review.

OBJECTIVE: Monkeypox virus (MPXV) disease has been declared a public health emergency by the World Health Organization, creating an urgent need for neurologists to be able to recognize, diagnosis, and treat MPXV-associated neurologic disease. METHODS: Three cases of MPXV-associated central nervous system (CNS) disease occurring during the 2022 outbreak, and their associated imaging findings are presented, with 2 cases previously published in a limited capacity in a public health bulletin. RESULTS: Three previously healthy immunocompetent gay men in their 30s developed a febrile illness followed by progressive neurologic symptoms with presence of a vesiculopustular rash. MPXV nucleic acid was detected by polymerase chain reaction (PCR) from skin lesions of 2 patients, with the third patient having indeterminate testing but an epidemiologic link to a confirmed MPXV disease case. Cerebrospinal fluid demonstrated a lymphocytic pleocytosis, elevated protein, and negative MPXV-specific PCR. In 2 patients, magnetic resonance imaging of the brain and spine demonstrated partially enhancing, longitudinally extensive central spinal cord lesions with multifocal subcortical, basal ganglia, thalamic, cerebellar, and/or brainstem lesions. The third patient had thalamic and basal ganglia lesions. All patients received 14 days of tecovirimat, and 2 patients also received multiple forms of immunotherapy, including intravenous immunoglobulin, pulsed high-dose steroids, plasmapheresis, and/or rituximab. Good neurologic recovery was observed in all cases. INTERPRETATION: MPXV can be associated with CNS disease. It is unclear whether this is from a parainfectious immune-mediated injury or direct CNS viral invasion. ANN NEUROL 2023;93:893-905.

Primary fibular grafting combined with double plating in distal femur fractures in elderly patients.

PURPOSE: To report functional and radiological outcomes of using primary fibular graft together with double plating in distal femoral fractures in the elderly. METHODS: A retrospective study on 30 elderly patients with comminuted distal femoral fractures managed by primary fibular grafting and double plating through an anterior midline approach has been conducted. Only isolated distal femoral fractures type 33-A3, 33-C2, and 33-C3 were included. The patient's mean age was 75.3 years. Evaluation included operative time, blood loss, time to union, knee range of motion, Sanders scoring, and presence of complications. RESULTS: The average follow-up period was 26.6 months. Mean intraoperative blood loss was 401 ml, and mean operative time was 216 min. All patients had a knee range of motion (90-120°) during follow-up. Time for union ranged from 16 to 23 weeks with a mean of 18.4 weeks, with no cases of non-union. A total of 22 patients (73.3%) showed excellent functional outcomes, and the remaining eight (26.7%) showed good functional outcomes according to the Sanders scoring system. Only two cases (6.6%) had superficial wound infections managed conservatively. No post-operative deformity, loss of reduction, or implant failure was observed until the end of follow-up period. CONCLUSION: Primary fibular grafting combined with double plating of comminuted distal femur fractures in patients above 70 years is an effective technique with higher rates of union and lower re-operation rates compared to other fixation modalities.

An Enabling Formulation of a Weakly Basic Compound Guided by Physiologically Based Biopharmaceutics Modeling (PBBM).

Weakly basic compounds propose biopharmaceutics risks due to the possibility of precipitation out of solution when passing from the stomach to the intestine. This behavior would limit the available drug for absorption and in turn reduces the plasma exposure at dose escalation scenarios in phase 1 clinical trials. In vitro precipitation studies along with computational models are often used to assess the risks of intestinal precipitation and provide insights about the parameters that should be controlled to minimize the risks of low absorption at high doses. In this work, both parameter sensitivity analysis and pH shift precipitation methods were used to guide the formulation approach and select excipients to reduce the risks associated with intestinal absorption of a weakly basic model compound. The simulations showed that absorption is sensitive to gastric pH and precipitation time which could be manipulated by formulation approaches. Other factors such as particle size and gastric residence time showed no impact. Precipitation studies using pH shift method were used to screen acidic excipients and polymers that will be added in a combination to boost supersaturation and retard precipitation. Hydroxy propyl methyl cellulose acetate succinate (HPMCAS) polymer middle grade was selected along with para-toluene sulfonic acid as the two excipients that would provide the highest supersaturation among the tested excipients. Merging both in vitro testing and computational models showed great merit in reducing time for selecting excipient for enabling formulation by focusing on the most influential formulation parameter for drug absorption.

Total cementless unconstrained hip arthroplasty in Crowe type IV hip dysplasia with subtrochentric derotation osteotomy.

Developmental hip dysplasia is a common cause for secondary osteoarthritis and in the past it was considered impossible to do hip arthroplasty surgery for this group of patients. We aim at introducing our results and arthroplasty technique in management of such technically demanding and challenging cases. 22 patients with 25 hips suffer from hip dysplasia Crowe type IV were operated by total cementless unconstrained hip arthroplasty with subtrochentric derotation osteotomy without fixation of osteotomy site, The mean age group was 37.9. All patients were operated through lateral approach. The acetabular component is located in the true acetabulum. Postoperatively the patient can weight bear fully unaided within 3 months. The preoperative limb length discrepancy improved from a mean 46.36 mm to 7.3 mm. One case of stem subsidence occurred and underwent revision to cemented stem 1years later. The Harris hip score improved to 85.9 at end of follow up in comparison to38.09 preoperatively. The osteotomy site healed within 5.1months in average .No cases of osteotomy non union occurred. The mean follow up was 28.3 months. We concluded that hip arthroplasty in patients with hip dysplasia Crowe type IV is technically demanding surgery. Recreation of normal biomechanics and anatomy through implantation of acetabular component in the true acetabulum and femoral shortening and derotation offers the patient painless and adequately functioning hip.

Intracranial Hemorrhage in Hospitalized SARS-CoV-2 Patients: A Case Series.

The SARS-CoV-2 virus causing Coronavirus Disease 2019 (COVID-19) is a global pandemic with almost 30 million confirmed worldwide cases. Prothrombotic complications arising from those affected with severe symptoms have been reported in various medical journals. Currently, clinical trials are underway to address the questions regarding anticoagulation dosing strategies to prevent thrombosis for these critically ill patients. However, given the increasing use of therapeutic anticoagulation in patients admitted with COVID-19 to curtail this prothrombotic state, our institution has witnessed six cases of devastating intracranial hemorrhage as well as thrombosis leading to five fatalities and we examine their hospital course and anticoagulation used.

Transverse process osteotomy for surgical drainage of primary iliopsoas abscess and secondary cases combined with spondylodiscitis.

Iliopsoas abscess refers to collection of fluid in iliopsoas muscle compartment. It is well-known condition in medical history as a complication of tuberculous spine infection. Most of the cases now are due to pyogenic infection. Patient usually presents late due to delayed diagnosis. We aim to present a less invasive technique for surgical drainage of iliopsoas abscess. PATIENTS AND METHODS: It is a prospective study done between 2015 and 2018. The study included 28 patients with confirmed diagnosis of iliopsoas abscess. Laboratory investigations included CBC, ESR, and C-reactive protein that were done for all patients. MRI with contrast enhancement was gold standard for diagnosis. Ten patients underwent surgical psoas abscess drainage by transverse process osteotomy via Wiltse approach without any other spine intervention. Eighteen patients had posterior spine fixation and interbody fusion together with transverse process osteotomy and abscess drainage as treatment for spondylodiscitis. The patients were followed up for clinical improvement, and functional assessment was done by Oswestry disability index. ESR and CRP were used for laboratory follow-up of infection subsidence. Follow-up of abscess size and resolution was done by pelvic-abdominal ultrasonography. RESULTS: The mean maximum width of the abscesses in MRI axial views was 38.8 mm. Patients were divided into two groups. Group (1) included ten patients who underwent drainage only while group (2) included 18 patients who underwent spine fusion for treatment of spondylodiscitis. The amount of pus drained intra-operatively was of average 234 cc in group 1 and 191.6 in group 2. The drain was removed in average 58.6 hours post-operatively in group 1 with mean of 168.4 cc of drained fluid and in average of 74.3 hours for group 2 with mean of 350.5 cc of drained fluid. The ODI and inflammatory markers improved in all patients. The follow-up period was of average 26.7 months. The organism was isolated from 19 patients (5 patients were tuberculous and 14 patients were different pyogenic pathogens). No fluid recollection was observed in pelvic-abdominal ultrasound during follow-up in our series. CONCLUSION: Transverse process osteotomy is a safe and effective approach for drainage of psoas abscess. It can be done alone or combined with posterior spine fusion for treatment of spondylodiscitis.

Transforaminal Posterior Approach Is Effective for Treatment of Lower Thoracic Spine Spondylodiscitis.

BACKGROUND: Patients with lower-thoracic spine pathologies that affect anterior column stability and compress the neural tissues need anterior decompression and reconstruction. Anterior approaches result in long-term morbidities. Posterior laminectomy and fixation alone may not be sufficient to maintain spine stability. QUESTIONS/PURPOSES: To evaluate the results of a posterior-only transforaminal thoracic interbody fusion approach for patients with thoracic disc space infection in terms of the improvement in neurologic status, resolution of infection, correction of kyphotic deformity, and assessment of post-operative complications. METHODS: A prospective study was done on 40 patients with lower thoracic spine spondylodiscitis. All patients were assessed with pre-operative imaging. Neurologic assessment was performed using the American Spinal Injury Association (ASIA) Impairment Scale and functionally by the modified Japanese Orthopedic Association (JOA) scale. Pre-operative and post-operative white blood cell count, erythrocyte sedimentation rate, and C-reactive protein levels were compared. All patients were operated on through a posterior approach using the transforaminal thoracic interbody fusion for decompression, reconstruction, and anterior fusion. RESULTS: Mean age of patients was 49 years; mean operative period was 188 min; mean blood loss was 611 mL. Twelve patients' ASIA scores improved and only two patients' scores declined. One patient died 11 months post-operatively due to septicemia. The mean follow-up period was 27.8 months. The modified JOA score improved from 6.3 ± 1.6 to 9.5 ± 0.6. The local kyphosis angle was improved from 13.8 to 6.9° post-operatively, with insignificant loss of correction at the end of follow-up. Thirty-eight out of 40 patients had solid anterior fusion at the end of follow-up. CONCLUSION: The clinical outcomes of this study showed that the transforaminal thoracic interbody approach is effective for both decompression and anterior reconstruction of the lower thoracic spine in patients with spondylodiscitis.

Surge in Delayed Myocardial Infarction Presentations: An Inadvertent Consequence of Social Distancing During the COVID-19 Pandemic.

This case series summarizes our experience of delayed acute myocardial infarction presentations during the coronavirus disease-2019 pandemic predominantly driven by patient fear of contracting the virus in the hospital. Many presented with complications rarely seen in the primary percutaneous coronary intervention era including ventricular septal rupture, left ventricular pseudoaneurysm, and right ventricular infarction. (Level of Difficulty: Beginner.).

Visceral Artery Aneurysms: Diagnosis, Surveillance, and Treatment.

Visceral artery aneurysms (VAAs) are a rare, but serious clinical entity as rupture confers a high rate of mortality. Data regarding the prevalence, treatment, and prognosis of VAAs is largely from case series, as true randomized trials are lacking. The incidence of VAAs has risen over the decades with advances in imaging technology, availability, and utilization. Even in the presence of symptoms, the prompt diagnosis of VAAs may be challenging as symptoms are often nonspecific and varied. Although there are no definitive treatment guidelines, asymptomatic VAAs require treatment in the following scenarios: when the aneurysm diameter is greater than 2 cm, when identified during pregnancy, when multiple aneurysms are present, and in the case of hepatic transplant. Similar to therapeutic trends in other vascular beds, advances in endovascular devices and techniques have driven an "endovascular first" approach for the treatment of VAAs. However, although the success rates of endovascular repair are impressive, surgical intervention is still necessary in treating centers. This paper reviews the pathophysiology, clinical features, anatomic characteristics, and management strategies required for the effective diagnosis and treatment of VAAs.

Mono segmental fixation of selected types of thoracic and lumbar fractures; a prospective study.

AIM OF STUDY: A prospective study to evaluate the results of monosegmental fixation; fixation of the fractured level with the adjacent vertebra sharing the same disc, in selected types of lumbar and thoracic fractures. This technique aims at saving motion levels by fusion of the only affected motion segment without sacrificing other levels. METHODS: Forty patients enrolled in this study between August 2011 and October 2013. The inclusion criteria were recent thoracic or lumbar vertebral fractures (less than 2 weeks). The fracture involves only one of the end plates of the vertebrae (either the superior or the inferior). The other end plate and both pedicles should be intact. The exclusion criteria were cervical fractures, fractures that include both end plates or pedicles of the vertebra, fracture dislocation, and load sharing classification score more than seven. All patients underwent monosegmental fixation with pedicle screw fixation. Eight patients were supplemented with interbody grafts. Radiological evaluation was done to assess local kyphosis angle, degree of compression of the anterior column, the degree of comminution, retropulsed fragment, neural canal compromise, integrity of the affected end plate, exclusion of pedicle fracture, and most important to assure that only one end plate is affected. All patients were assessed neurologically according to Frankel grading system. Patient were assessed by Denis pain scale and Denis work scale. RESULTS: The age of the patients was of a mean of 34.5 years old. All patients were Frankle E at time of presentation and remained the same post-operative. The mean operative time from incision time to end of skin closure was 74.2 min. The mean blood loss was 230 ml. The pre-operative degree of local kyphosis; was of a mean 8.22°. This was improved to 2.25° at the immediate postoperative x-rays. At two years follow up, the loss of correction was of a mean 0.85° which was insignificant. The pre-operative percentage of height lost improved from a mean of 56.05 % to post-operative mean of 90.125 %. At the end of follow up, no pseudoarthrosis cases or metal failure were noticed. DISCUSSION: Thoracic and lumbar fractures are common in young adults. Surgical treatment offers early rehabilitation and preserves spine alignment. Monosegmental fixation technique in selected types of dorsal and lumbar fractures offers spine stability and preserves motion segments. It fuses only one motion segment that is prone for later instability or deformity. Reconstrcution of the anterior column can be achieved through TLIF approach in combination of monosegmental fixation to achieve 360° fusion. CONCLUSION: Monosegmental fixation is an effective technique. It can save motion segments in young patients with adequate spine stability and good functional outcomes.

Effect of variations in treatment regimen and liver cirrhosis on exposure to benzodiazepines during treatment of alcohol withdrawal syndrome.

PURPOSE: Benzodiazepines (BDZs) are the drugs of choice to prevent the symptoms of alcohol withdrawal syndrome (AWS). Various treatment protocols are published and have been shown to be effective in both office-managed and facility-managed treatment of AWS. The aim of this scientific commentary is to demonstrate the differences in the expected exposure to BDZs during AWS treatment using different treatment regimens available in the literature, in patients with or without alcoholic liver cirrhosis. METHODS: Diazepam and lorazepam AWS protocols were examined and reviewed in the literature, and blood plasma levels were examined and compared, respectively. RESULTS: Considerable variation in the blood levels with the different dosing schedules was found. Because the drugs are metabolized differently, we have also shown that liver disease affects the blood levels of diazepam, but not of lorazepam. CONCLUSIONS: Differences in treatment regimens, the choice of BDZ, as well as the presence of liver cirrhosis can substantially alter the exposure of patients to drugs used for AWS treatment. Outpatient treatment of AWS has been shown to be relatively safe and effective for the treatment of AWS but patients should be carefully monitored.

The use of the United States FDA programs as a strategy to advance the development of drug products for neglected tropical diseases.

Neglected tropical diseases (NTDs) are infections which are endemic in poor populations in lower- and middle-income countries (LMIC). Approximately one billion people have now or are at risk of getting an NTD and yet less than 5% of research dollars are focused on providing treatments and prevention of these highly debilitating and deadly conditions. The United States Food and Drug Administration (FDA) Orphan Drug Designation program (ODDP) provides orphan status to drugs and biologics, defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases and/or disorders that affect fewer than 200 000 people in the United States, or that affect more than 200 000 persons but are not expected to recover the costs of developing and marketing a treatment drug. These regulations have led to the translation of rare disease knowledge into innovative rare disease therapies. The FDA Guidance for Industry on developing drugs for the treatment and prevention of NTDs describes the following regulatory strategies: Orphan Product Designation, Fast Track Designation, Priority Review Designation, Accelerated Approval and Tropical Disease Priority Review Voucher. This paper will discuss how these regulations and especially the ODDP can improve the clinical development and accessibility of drug products for NTDs.

A simple and sensitive method for determination of vitamins D3 and K1 in rat plasma: application for an in vivo pharmacokinetic study.

PURPOSE: To develop and to validate a simple but sensitive method for determination of vitamins D3 and K1 in rat plasma. METHODS: The sample treatment included protein precipitation by cold acetonitrile, evaporation, reconstitution with methanol and filtration. The chromatography conditions included Xterra RP18 3.5 µm 4.6 × 100 mm column at ambient temperature and mobile phase consisting of methanol/water (93/7, v/v) at 0.5 mL/min flow rate. Vitamin D3 and probucol were detected at 265 nm and vitamin K1 at 239 nm. Rats were administered intravenously by 0.1 mg/kg of vitamin D3 or K1 and the blood samples were withdrawn pre-administration and at pre-determined time points post-administration. The pharmacokinetic analysis was performed using a non-compartmental approach. RESULTS: The calibration curves in rat plasma were linear up to 5000 ng/mL for both vitamins. The limit of quantification (LOQ) was 20 ng/mL for vitamin D3 and 40 ng/mL for K1. Inter- and intra-day precision and accuracy were below 15%. The pharmacokinetic parameters of vitamin D3 following intravenous administration were: AUC0-∞ = 11323 ± 1081 h × ng/mL, Vd = 218 ± 80 mL/kg, CL = 8.9 ± 0.8 mL/h/kg, t1/2 = 16.8 ± 5 h; and of vitamin K1: AUC0-∞ = 2495 ± 297 h × ng/mL, Vd = 60 ±24 mL/kg, CL = 40.5 ± 5.1 mL/h/kg, t1/2 = 1.1 ±0.5 h. CONCLUSION: The developed HPLC-UV assay is a simple and sensitive method for the determination of vitamins D3 and K1 in rat plasma. A higher dose of vitamin K1 should be used in future studies for accurate estimation of pharmacokinetic parameters. The data show the suitability of the assay for pharmacokinetic studies in rats.

Efficacy of an oral and tropically stable lipid-based formulation of Amphotericin B (iCo-010) in an experimental mouse model of systemic candidiasis.

OBJECTIVE: An oral lipid based formulation that exhibits tropical stability (iCo-010) was developed to enhance the absorption of orally administered amphotericin B (AmB). iCo-010 has previously shown high efficacy in an acute model of systemic candidiasis in rats, directing the focus of this study to be its efficacy in a chronic model of systemic candidiasis in mice. METHODS: Mice were infected with 0.6 to 1×108 CFUs of Candida albicans ATCC 18804 strain by tail vein injection and were left for three days to develop the infection after which time treatment was initiated. The infected animals were assigned to the following treatment groups: no treatment (control) or iCo-010 at 5, 10 and 20 mg/kg administered by oral gavage once daily (QD) for 5 consecutive days. The animals were sacrificed 7 days after the last dose and the concentration of AmB and the fungal burden were assessed within the liver, kidneys, heart, lungs, spleen and brain. RESULTS: Although the infection was relatively low (~ 60-100 CFUs/ 1 ml tissue homogenate) in the liver, lungs and heart, the infection level was very high (70 000 CFUs / 1 ml tissue homogenate) in the kidney tissues for the control group. The highest concentrations of AmB were recovered in the kidneys and the spleen. The fungal burden in the tissues was lowered by 69-96% in the treatment groups when compared to the control group. CONCLUSION: Oral iCo-010 is an effective treatment of systemic candidiasis in the mouse model.

Impact of co-administration of protonated nanostructured aluminum silicate (cholesterol absorption inhibitor) on the absorption of lipid soluble vitamins D3 and K1: an assessment of pharmacokinetic and in vitro intraluminal processing.

Protonated nanostructured aluminum silicate (NSAS) is a protonated montmorillonite clay that was shown to be effective as an inhibitor of intestinal cholesterol absorption. The effect of NSAS on the intestinal absorption of nutrients is unknown. An in vitro lipolysis model was adapted to test the intraluminal processing of vitamin D3 and K1 in the presence of various amounts of NSAS. Additionally, vitamin absorption was assessed in male Sprague-Dawley rats randomized in the following treatment groups: IV administration of 0.1 mg/kg vitamin D3 and 1 mg/kg vitamin K1, and a single-dose gavage of 1 mg/kg vitamin D3 and 5mg/kg of vitamin K1 in peanut oil with various doses of NSAS slurry, 2% NSAS-fortified diet, or 50 mg/kg stigmastanol. The solubilized fraction of vitamin D3 in the lipolysis medium was reduced from 70% to 46% upon the addition of 120 mg NSAS. In contrast, the solubilized fractions of vitamin K1 were not significantly affected. Although the NSAS-fortified diet did not significantly affect the absorbed fraction of both vitamins, NSAS slurry decreased the absorption of vitamin D3 as compared to the control. These results indicate that NSAS may be incorporated in diet to treat hypercholesterolemia; however, vitamin D3 monitoring may be required.

Pharmacokinetics and tissue distribution of amphotericin B following oral administration of three lipid-based formulations to rats.

The objective of this study was to assess the pharmacokinetics and tissue distribution of amphotericin B (AmB) in rats following oral administration of three lipid-based formulations (iCo-009, iCo-010 and iCo-011). The lipid-based formulations were administered to rats at a dose of 10 mg/kg and blood samples were withdrawn at predose, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 h, after which the animals were sacrificed and the body organs were collected for AmB quantification using a validated HPLC method. Plasma pharmacokinetics parameters were determined using non-compartmental analysis. The disappearance of AmB from plasma was the slowest following the administration of iCo-010 with MRT of 63 h followed by iCo-009 then iCo-011 (36 and 27 h). The AUC(0-24h) of iCo-009 and iCo-010 was 1.5-2-fold higher than that of iCo-011. The kidney exposure was comparable between iCo-009 and iCo-010 and was higher than that of iCo-011. The lung exposure was the highest following iCo-010 administration as compared to that of iCo-009. The distribution of AmB from plasma to tissues resulted in a high accumulation of AmB overtime with slow back-distribution to plasma. The pharmacokinetics profiles varied among the three formulations, despite the similarity in lipid composition between iCo-010 and iCo-011 and the presence of Peceol® as a common component in the formulations. The administration of oral iCo-010 could lead to higher steady state concentrations in the tissues after multiple dosing, which could lead to enhanced eradication of tissue borne fungal and parasitic infections.