Current Evidence for Pharmacologic Reversal Using Direct Oral Anticoagulants: What’s New?

Direct oral anticoagulants are increasingly used in clinical practice and have addressed many of the issues related to vitamin K antagonists. However, the lack of reversal in life-threatening situations raises concerns regarding patient safety. Thus, current research is aimed at developing reversal agents that can safely neutralize the effects of anticoagulants. We present the design and mechanisms of action of and the animal models, clinical trials, and current evidence supporting the use of these emerging reversal agents. Idarucizumab is approved in many countries, and andexanet alfa has been approved by the US FDA, whereas others are in clinical trials. In view of the results of clinical studies to date, the problems of safety, price and accessibility remain. Therefore, these antidotes are a significant step towards improving the field of urgent and emergency reversal. From a practical perspective, post-market surveillance will be crucial to monitor the safety and effectiveness of these agents.     

Studies of Oral Preparation of Low Molecular Weight Heparin

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Oral bioavailability of naproxen-β-cyclodextrin inclusion compound

An inclusion complex between naproxen and β-cyclodextrin was prepared by the freeze-drying method. Dissolution profiles in a pH 1.2 medium (gastric juice) of naproxen, freeze-dried naproxen, a physical mixture and 1:1 and 1:3 inclusion complexes demonstrated a faster dissolution rate of the inclusion complex. After 5 min the amount of drug dissolved was around 5% for the drug, 12% for freeze-dried naproxen, 11% for the physical mixture and 61 and 99% for the 1:1 and 1:3 inclusion complexes, respectively. The bioavailability of naproxen administered as its 1:1 inclusion complex with β-cyclodextrin has been evaluated using a new HPLC method for determining the drug and its glucuronide conjugate in urine. Renal excretion levels after oral administrations of naproxen, freeze-dried naproxen and the 1:1 inclusion complex with β-cyclodextrin, measured by this method, show no statistical differences, indicating that the three formulations assayed are bioequivalent.     

Oral bioavailability and intestinal secretion of amitriptyline: Role of P-glycoprotein?

The aim of the study was to evaluate the influence of quinidine, a P-glycoprotein inhibitor, on oral bioavailability and on intestinal secretion of amitriptyline, a tricyclic antidepressant. Amitriptyline was administrated intravenously (5 mg/kg) and orally (50 mg/kg) to rabbits, with and without quinidine. Jejunal segments of rats were mounted on diffusions chambers and the permeation of amitriptyline was measured across the tissue in luminal–serosal (LS) and serosal–luminal (SL) directions, with and without quinidine. Finally, an in situ recirculating intestinal perfusion model was performed in rabbits to study amitriptyline permeation in LS direction with and without quinidine. Absolute oral bioavailability (F) of amitriptyline was significantly increased more than three-fold in presence of quinidine (F = 0.6 ± 0.4% versus 1.9 ± 1.1%). The apparent permeability coefficients in SL direction were significantly higher than in LS direction (P_{app (SL)} = 6.01 ± 2.42 versus P_{app (LS)} = 4.90 ± 2.73 × 10⁻⁴ cm min⁻¹). In presence of quinidine, the intestinal absorption was increased (P_{app (LS)} = 4.02 ± 2.91 versus P_{app (LS)} = 5.99 ± 2.43 × 10⁻⁴ cm min⁻¹) and the intestinal secretion was decreased (P_{app (SL)} = 4.58 ± 0.54 versus P_{app (LS)} = 3.63 ± 1.46 × 10⁻⁴ cm min⁻¹) but not significantly. In conclusion, P-glycoprotein appears to be involved in oral amitriptyline absorption but other intestinal uptake and efflux transporters maybe implicated.     

Pharmacokinetics of Oral 2′,3′-Dideoxyinosine in Rats

Pharmaceutical Research -     

Oral administration of human recombinant interferon-α2 in rats

The absorption of human recombinant interferon-α₂ (IFNα₂) from the oropharynx has been investigated in the rat. We have shown that small amounts of interferon can be absorbed and measured in blood. The absorption of IFNα₂ dissolved in saline was not improved by the addition of different promoters. The practical usefulness of a small absorption of interferon has been discussed.     

Does the Intake of Ethanol Affect Oral Absorption of Poorly Soluble Drugs?

The presence of ethanol in gastrointestinal (GI) fluids may increase the solubility of poorly water-soluble drugs. This suggests that intake of ethanol with such compounds could result in increased drug absorption in the stomach and duodenum because of the greater concentration gradient present. To test this hypothesis, in vitro dissolution of 2 poorly soluble compounds (indomethacin and felodipine) was studied in simulated GI rat fluids in the presence or absence of ethanol. Results were used to predict plasma exposure of the compounds using the software PK-Sim. Finally, in vivo plasma exposure in rats was investigated after oral dosing followed by immediate administration of water or ethanol. Despite increased solubility in GI fluids in the presence of ethanol, simulations predicted a negligible effect on absorption. This was confirmed in the rat study where oral intake of indomethacin or felodipine with ethanol did not increase in vivo plasma exposure. A possible explanation for the lack of an effect may be that dilution, absorption, and transfer of ethanol upon arrival in the stomach resulted in intragastric and intraduodenal ethanol concentrations that did not reach the levels required to affect local solubility.     

Rational Selection of Bio-Enabling Oral Drug Formulations – A PEARRL Commentary

New drug candidates often require bio-enabling formation technologies such as lipid-based formulations, solid dispersions, or nanosized drug formulations. Development of such more sophisticated delivery systems generally requires higher resource investment compared to a conventional oral dosage form, which might slow down clinical development. To achieve the biopharmaceutical objectives while enabling rapid cost effective development, it is imperative to identify a suitable formulation technique for a given drug candidate as early as possible. Hence many companies have developed internal decision trees based mostly on prior organizational experience, though they also contain some arbitrary elements. As part of the EU funded PEARRL project, a number of new decision trees are here proposed that reflect both the current scientific state of the art and a consensus among the industrial project partners. This commentary presents and discusses these, while also going beyond this classical expert approach with a pilot study using emerging machine learning, where the computer suggests formulation strategy based on the physicochemical and biopharmaceutical properties of a molecule. Current limitations are discussed and an outlook is provided for likely future developments in this emerging field of pharmaceutics.     

Improvement of Solubility and Oral Bioavailability of Rutin by Complexation with 2-Hydroxypropyl-β-cyclodextrin

The object of this study was to enhance the solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD). The interaction of rutin with cyclodextrins (CyDs) was evaluated by the solubility, and ultraviolet (UV) and circular dichroism (CD) spectrophotometries. The chemical and enzymatic stability of rutin was examined in an alkaline buffer solution and in rat small intestinal homogenates, respectively. Dissolution rates of rutin and its CyD complexes were measured by the dispersed amount method. In vivo absorption studies of rutin after oral administration via conventional tablet containing rutin alone or its β-CyD complexes was performed on beagle dogs. The stability constants calculated from the phase solubility method increased in the order of HP-γ-CyD < G₂-β-CyD < β-CyD < HP-β-CyD. Spectroscopic studies also revealed that HP-β-CyD and β-CyD formed a relatively more stable inclusion complex with rutin. The dissolution rates of rutin increased by the complexation with CyDs in the order of rutin alone < HP-β-CyD ≤ β-CyD. HP-β-CyD inhibited the hydrolysis of rutin in the alkaline buffer solution and the small intestinal homogenates of rats, suggesting that HP-β-CyD may stabilize rutin in a gastrointestinal tract after oral administration. When the tablet containing rutin or its β-CyD complexes was administered to beagle dogs, the plasma levels of homovanillic acid (HVA) (a major stable metabolite of rutin) after oral administration of HP-β-CyD complex were much higher than in either that of rutin alone or in its β-CyD complex. The in vivo absorption study suggests that HP-β-CyD increased the oral bioavailability of rutin from the gastrointestinal tracts of beagle dogs because of the increase in solubility, faster dissolution rate, and gastrointestinal stability. HP-β-CyD has a significant advantage with respect to providing high aqueous solubility while maintaining a lack of toxicity in oral pharmaceutical preparations of rutin.     

Which in vitro Screens Guide the Prediction of Oral Absorption and Volume of Distribution?

The development of medium to high-throughput in vitro screening of ADME (Absorption, Distribution, Metabolism, Excretion) properties has been the reply to higher demands on drug metabolism scientists to cope with progress in chemistry and biology. Two areas will be discussed here, namely screens for oral absorption and for volume of distribution. The prediction of these human pharmacokinetic parameters can be based on proper combination of simple physicochemical measurements. In the future in vitro screens most likely will be combined with in silico assessments of various ADME properties leading to the concept of in combo screening in drug discovery.     

Absolute Oral Bioavailability and Metabolic Turnover of β-Sitosterol in Healthy Subjects

The metabolic turnover, absolute oral bioavailability, clearance, and volume of distribution for β-sitosterol were measured in healthy subjects. [(14)C]β-Sitosterol was used as an isotopic tracer to distinguish pulse doses from dietary sources and was administered by both oral and intravenous routes. The administered doses of [(14)C]β-sitosterol were in the region of 3 to 4 μg, sufficiently low as not to perturb the kinetics of β-sitosterol derived from the diet. Because the plasma concentrations of [(14)C]β-sitosterol arising from such low doses were anticipated to be very low, the ultrasensitive isotope ratio analytical method of accelerator mass spectrometry was used. The limit of quantification for [(14)C]β-sitosterol was approximately 0.1 pg/ml, the oral absolute bioavailability was just 0.41%, clearance was 85 ml/h, volume of distribution was 46 L, and the turnover was 5.8 mg/day. Given the steady-state concentrations of β-sitosterol (2.83 μg/ml), then the dietary load was calculated to be approximately 1400 mg/day.     

Uncomplicated Streptococcal Bacteremia: The Era of Oral Antibiotic Step-down Therapy?

BackgroundThe purpose of this study was to compare the clinical outcomes of adults with uncomplicated streptococcal bacteremia who received either oral (PO) step-down or continued intravenous (IV) therapy.MethodsThis was a retrospective, single-center, cohort study, including adults admitted with Streptococcal bloodstream infection between January 1, 2013, and December 31, 2020. Only patients with uncomplicated Streptococcal bloodstream infections were included. Patients who transitioned to PO therapy within 5 days from bacteremia onset were compared to patients receiving continued IV therapy. The primary outcome was clinical failure, defined by either 90-day hospital readmission or mortality. Secondary outcomes included hospital length of stay (LOS) and antibiotic-related adverse events (AAEs).ResultsOf the 264 patients included, 42% were transitioned to PO therapy. Group B Streptococcus (22.7%) was the most common isolate. The most common sources of infection were skin and soft tissue (35%) and pulmonary (25%). Intensive care unit (ICU) stay was more common in the continued IV therapy group (22.2%) than in the PO step-down group (5.4%). The frequency of clinical failure was similar in the IV and PO groups (24.2% vs. 18.0%, P=0.23). The IV group had longer hospital LOS (median, [interquartile range (IQR)]) compared with the PO group (7 [5-13.5] vs. 4 [3], [4], [5] days, P<0.001). The incidence of AAEs was similar in the IV and PO groups (1.3% vs. 1.8%, P=0.74).ConclusionOral antibiotic step-down therapy may be appropriate for the treatment of uncomplicated Streptococcal bacteremia, with consideration of factors such as patient comorbidities, type of infection, source control and clinical progress.     

Oral coadministration of β-glucuronidase to increase exposure of extensively glucuronidated drugs that undergo enterohepatic recirculation

Extensive first-pass metabolism can significantly limit a drug's oral exposure levels. In this work, we introduce an innovative approach for increasing the oral bioavailability of a drug that undergoes extensive reversible glucuronidation and enterohepatic recirculation through intraduodenal coadministration of the deconjugating enzyme β-glucuronidase. Intraduodenal administration of JNJ-10198409 (10 mg/kg) with β-glucuronidase (34,000-140,000 units/kg) to catheterized rats resulted in a significant increase (p < 0.005) in the mean area under the plasma concentration versus time curve (AUC; approx. threefold) and maximum plasma concentration (C(max); approx. twofold) of JNJ-10198409. The AUC and C(max) were 60 ± 18 ng h/mL and 76 ± 29 ng/mL, respectively, with no enzyme and 177 ± 55 ng h/mL and 129 ± 41 ng/mL, respectively, with β-glucuronidase coadministered. Moreover, the AUC of the primary glucuronide metabolite increased approximately sevenfold from 1173 ± 361 (ng h)/mL with no enzyme coadministered to 8723 ± 2133 ng h/mL with coadministered enzyme. These pharmacokinetic data support the hypothesis that when the primary glucuronide is secreted into the duodenum via the bile duct, the glucuronide is converted by β-glucuronidase back to the parent compound. The parent compound is then reabsorbed and reconjugated, resulting in elevated systemic exposures to both parent and glucuronide. Potential clinical and preclinical applications and considerations for this approach are discussed.     

Preclinical Pharmacokinetic Evaluation of β-Lapachone: Characteristics of Oral Bioavailability and First-Pass Metabolism in Rats

β-Lapachone has drawn increasing attention as an anti-inflammatory and anti-cancer drug. However, its oral bioavailability has not been yet assessed, which might be useful to develop efficient dosage forms possibly required for non-clinical and clinical studies and future market. The aim of the present study was thus to investigate pharmacokinetic properties of β-lapachone as well as its first-pass metabolism in the liver, and small and large intestines after oral administration to measure the absolute bioavailability in rats. A sensitive HPLC method was developed to evaluate levels of β-lapachone in plasma and organ homogenates. The drug degradation profiles were examined in plasma to assess the stability of the drug and in liver and intestinal homogenates to evaluate first-pass metabolism. Pharmacokinetic profiles were obtained after oral and intravenous administration of β-lapachone at doses of 40 mg/kg and 1.5 mg/kg, respectively. The measured oral bioavailability of β-lapachone was 15.5%. The considerable degradation of β-lapachone was seen in the organ homogenates but the drug was quite stable in plasma. In conclusion, we suggest that the fairly low oral bioavailability of β-lapachone may be resulted from the first-pass metabolic degradation of β-lapachone in the liver, small and large intestinal tracts and its low aqueous solubility.     

Potential of Cationic-Polymeric Nanoparticles for Oral Delivery of Naringenin: In Vitro and In Vivo Investigations

The objective of the study was to improve the bioavailability and anticancer potential of naringenin (NRG) by developing a drug-loaded polymeric nanodelivery system. NRG-loaded eudragit E100 nanoparticle (NRG-EE100-NPs) system was developed and physicochemically characterized. In vivo pharmacokinetic and in vitro cytotoxicity abilities of the NRG-EE100-NPs were investigated. In vivo anticancer activity was evaluated in murine BALB/c mice-bearing colorectal tumor. The NRG-EE100-NPs had an optimum mean particle size (430.42 ± 5.78 nm), polydispersity index (0.283 ± 0.089) with percent entrapment efficiency (68.83 ± 3.45%). The NRG-EE100-NPs demonstrated significant higher bioavailability (～96-fold; p <0.05) as well as cytotoxicity (～16-fold; p <0.001) as compared to free NRG. Furthermore, NRG-EE100-NPs indicated significant tumor suppression (p <0.01) subsequently improvement in survival rate compared to free NRG in vivo. Thus, the physicochemical properties and colorectal cancer efficacy of NRG were improved by successful encapsulating in cationic-polymeric nanoparticle system.     

Oral toxicity of silver ions,silver nanoparticles and colloidal silver – A review

Orally administered silver has been described to be absorbed in a range of 0.4–18% in mammals with a human value of 18%. Based on findings in animals, silver seems to be distributed to all of the organs investigated, with the highest levels being observed in the intestine and stomach. In the skin, silver induces a blue–grey discoloration termed argyria. Excretion occurs via the bile and urine. The following dose-dependent animal toxicity findings have been reported: death, weight loss, hypoactivity, altered neurotransmitter levels, altered liver enzymes, altered blood values, enlarged hearts and immunological effects. Substantial evidence exists suggesting that the effects induced by particulate silver are mediated via silver ions that are released from the particle surface. With the current data regarding toxicity and average human dietary exposure, a Margin of Safety calculation indicates at least a factor of five before a level of concern to the general population is reached.     

Oral targeting of protein kinase C receptor: promising route for diabetic retinopathy?

In patients with diabetes, hyperglycemia is known to promote high levels of diacylglycerol which activates protein kinase C (PKC) in the vascular tissues and leads to the production of vascular endothelial growth factor (VEGF) in the retina. PKC activation and increased concentration of VEGF are likely to play a key role in diabetic microvascular complications, particularly change in vascular permeability, inflammation, fluid leakage and ischemia in the retina. PKC comprises a super family of isoenzymes that is activated in response to various stimuli. The PKC family consists of 12 isomers that possess distinct differences in structure, substrate requirement, expression and localization. PKC isomer selective inhibitors and VEGF trap are likely to be new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease. A new promising therapy for diabetic retinopathy is undergoing Phase III trials, in which they proposed to target PKC βII isomer using Ruboxistaurin by oral administration. Besides retina, PKC βII isomer is found in higher concentration in brain, spleen, etc. So, oral targeting may be a questionable approach since generalized inhibitors may prove toxic in the treatment of diabetic retinopathy and ocular delivery may be a better alternative approach.     

Comparison of Zafirlukast (Accolate®) Absorption After Oral and Colonic Administration in Humans

Purpose. This study characterized the gastrointestinal (GI) absorptionof zafirlukast after oral and colonic administration in humans. Methods. Five healthy subjects received zafirlukast solution (40 mg)orally and via an oroenteric tube into the colon in a randomized,crossover fashion. Two additional subjects were dosed into the distalileum. Serial blood samples were obtained and plasma concentrationswere quantitated by HPLC. Results. Mean ± SD pharmacokinetic parameters after oral vs. colonicadministration were: AUC of 2076 ± 548 vs. 602 ± 373 ng*h/mL,respectively, and C_max of 697 ± 314 vs. 194 ± 316 ng/mL, respectively.Mean colon:oral AUC and C_max were 0.29 and 0.30, respectively.Median t_max values were 2.0 and 1.35 hr after oral and colonicadministration. First-order absorption rate constants (K_a and K_ac) wereestimated from a two-compartment model with first-order elimination.K_ac:K_a was <0.5 in 4 of the 5 subjects dosed in the colon. Conclusions. Zafirlukast was absorbed at multiple sites in the GI tract.The rate and extent of zafirlukast absorption was less after colonicthan oral administration. Zafirlukast was significantly absorbed in thedistal ileum. This study demonstrated that gamma scintigraphy, digitalradiography, and fluoroscopy can be used to track the movement andconfirm the location of the oroenteric tube in the GI tract.