[Early effectiveness of local injection of multimodal drug cocktail during anterior cruciate ligament reconstruction and its influence on cartilage].

Objective: To explore the early effectiveness and influence on cartilage of local injection of multimodal drug cocktail (MDC) during anterior cruciate ligament reconstruction (ACLR). Methods: Between February 2022 and August 2023, patients undergone arthroscopic ACLR using autologous hamstring tendons were selected as the study subjects. Among them, 90 patients met the selection criteria and were randomly divided into 3 groups ( n=30) according to the different injection drugs after ligament reconstruction. There was no significant difference in baseline data such as gender, age, body mass index, surgical side, disease duration, preoperative thigh circumference, and preoperative levels of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-1, matrix metalloproteinase 3 (MMP-3), MMP-13, and aggrecan (ACAN) in synovial fluid between groups ( P>0.05). After the ligament reconstruction during operation, corresponding MDC (consisting of ropivacaine, tranexamic acid, and betamethasone in group A, and ropivacaine, betamethasone, and saline in group B) or saline (group C) were injected into the joint and tendon site, respectively. The length of hospital stay, postoperative tramadol injection volume, incidence of complications, degree of knee joint swelling and range of motion, visual analogue scale (VAS) score, International Knee Documentation Committee (IKDC) score, Lyshlom score, and Hospital for Special Surgery (HSS) score were recorded and compared between groups. The T2 * values in different cartilage regions were detected by MRI examination and the levels of TNF-α, IL-6, IL-1, MMP-3, MMP-13, and ACAN in synovial fluid were detected by ELISA method. Results: The patients in group A, B, and C were followed up (12.53±3.24), (13.14±2.87), and (12.82±3.32) months, respectively. All incisions healed by first intention. Compared with group C, group A and group B had shorter length of hospital stay, less tramadol injection volume, and lower incidence of complications, showing significant differences ( P<0.05); there was no significant difference between group A and group B ( P>0.05). The degree of knee swelling in group A was significantly less than that in group B and group C ( P<0.05), but there was no significant difference between group B and group C ( P>0.05). At 3, 6, 12, 24, and 48 hours after operation, VAS scores of group A and group B were significantly lower than those of group C ( P<0.05); at 72 hours after operation, there was no significant difference among the three groups ( P>0.05). At 3 days, 14 days, and 1 month after operation, the range of motion of knee joint in group A were significantly better than those in group C ( P<0.05), and there was no significant difference between the other groups ( P>0.05). At 1 month after operation, the IKDC score of group A and group B was significantly higher than that of group C ( P<0.05); there was no significant difference among the three groups at other time points ( P>0.05). There was no significant difference in Lyshlom score and HSS score among the three groups at each time point ( P>0.05). At 14 days after operation, the levels of IL-1 and IL-6 in the synovial fluid in groups A and B were significantly lower than those in group C ( P<0.05). There was no significant difference in the levels of TNF-α, MMP-3, MMP-13, and ACAN between groups A and B ( P>0.05). At 1 month after operation, there was no significant difference in the above indicators among the three groups ( P>0.05). At 3, 6, and 12 months after operation, there was no significant difference in the T2 * values of different cartilage regions among the three groups ( P>0.05). Conclusion: Injecting MDC (ropivacaine, tranexamic acid, betamethasone) into the joint and tendon site during ACLR can achieve good early effectiveness without significant impact on cartilage.

A cocktail of rapamycin, acarbose, and phenylbutyrate prevents age-related cognitive decline in mice by targeting multiple aging pathways.

Aging is a primary risk factor for cognitive impairment and exacerbates multiple biological processes in the brain, including but not limited to nutrient sensing, insulin signaling, and histone deacetylation activity. Therefore, a pharmaceutical intervention of aging that targets distinct but overlapping pathways provides a basis for testing combinations of drugs as a cocktail. Our previous study showed that middle-aged mice treated with a cocktail of rapamycin, acarbose, and phenylbutyrate for 3 months had increased resilience to age-related cognitive decline. This finding provided the rationale to investigate the transcriptomic and molecular changes within the brains of mice that received this cocktail treatment or control treatment. Transcriptomic profiles were generated through ribonucleic acid (RNA) sequencing, and pathway analysis was performed by gene set enrichment analysis to evaluate the overall RNA message effect of the drug cocktail. Molecular endpoints representing aging pathways were measured using immunohistochemistry to further validate the attenuation of brain aging in the hippocampus of mice that received the cocktail treatment, each individual drug or control. Results showed that biological processes that enhance aging were suppressed, with an increased trend of autophagy in the brains of mice given the drug cocktail. The molecular endpoint assessments indicated that treatment with the drug cocktail was overall more effective than any of the individual drugs for relieving cognitive impairment by targeting multiple aging pathways.

A drug cocktail of rapamycin, acarbose, and phenylbutyrate enhances resilience to features of early-stage Alzheimer's disease in aging mice.

The process of aging is defined by the breakdown of critical maintenance pathways leading to an accumulation of damage and its associated phenotypes. Aging affects many systems and is considered the greatest risk factor for a number of diseases. Therefore, interventions aimed at establishing resilience to aging should delay or prevent the onset of age-related diseases. Recent studies have shown a three-drug cocktail consisting of rapamycin, acarbose, and phenylbutyrate delayed the onset of physical, cognitive, and biological aging phenotypes in old mice. To test the ability of this drug cocktail to impact Alzheimer's disease (AD), an adeno-associated-viral vector model of AD was created. Mice were fed the drug cocktail 2 months prior to injection and allowed 3 months for phenotypic development. Cognitive phenotypes were evaluated through a spatial navigation learning task. To quantify neuropathology, immunohistochemistry was performed for AD proteins and pathways of aging. Results suggested the drug cocktail was able to increase resilience to cognitive impairment, inflammation, and AD protein aggregation while enhancing autophagy and synaptic integrity, preferentially in female cohorts. In conclusion, female mice were more susceptible to the development of early stage AD neuropathology and learning impairment, and more responsive to treatment with the drug cocktail in comparison to male mice. Translationally, a model of AD where females are more susceptible would have greater value as women have a greater burden and incidence of disease compared to men. These findings validate past results and provide the rationale for further investigations into enhancing resilience to early-stage AD by enhancing resilience to aging.

Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice.

Rationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult. Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12 months. A cocktail of six drugs was administered, and parent compounds as well as phase I and II metabolites were quantified in blood, bile, and urine in a time-dependent manner. Pharmacokinetics were modeled in relation to the altered expression of metabolizing enzymes. In discrepancy with computational predictions, a strong increase of glucuronides in blood was observed in cirrhotic mice compared to vehicle controls. Results: The deviation between experimental findings and computational simulations observed by analyzing different hypotheses could be explained by increased sinusoidal export and corresponded to increased expression of export carriers (Abcc3 and Abcc4). Formation of phase I metabolites and clearance of the parent compounds were surprisingly robust in cirrhosis, although the phase I enzymes critical for the metabolism of the administered drugs in healthy mice, Cyp1a2 and Cyp2c29, were downregulated in cirrhotic livers. RNA-sequencing revealed the upregulation of numerous other phase I metabolizing enzymes which may compensate for the lost CYP isoenzymes. Comparison of genome-wide data of cirrhotic mouse and human liver tissue revealed similar features of expression changes, including increased sinusoidal export and reduced uptake carriers. Conclusion: Liver cirrhosis leads to increased blood concentrations of glucuronides because of increased export from hepatocytes into the sinusoidal blood. Although individual metabolic pathways are massively altered in cirrhosis, the overall clearance of the parent compounds was relatively robust due to compensatory mechanisms.

Drug Cocktail Formulation via Circuit Design.

Electronic circuits intuitively visualize and quantitatively simulate biological systems with nonlinear differential equations that exhibit complicated dynamics. Drug cocktail therapies are a powerful tool against diseases that exhibit such dynamics. We show that just six key states, which are represented in a feedback circuit, enable drug-cocktail formulation: 1) healthy cell number; 2) infected cell number; 3) extracellular pathogen number; 4) intracellular pathogenic molecule number; 5) innate immune system strength; and 6) adaptive immune system strength. To enable drug cocktail formulation, the model represents the effects of the drugs in the circuit. For example, a nonlinear feedback circuit model fits measured clinical data, represents cytokine storm and adaptive autoimmune behavior, and accounts for age, sex, and variant effects for SARS-CoV-2 with few free parameters. The latter circuit model provided three quantitative insights on the optimal timing and dosage of drug components in a cocktail: 1) antipathogenic drugs should be given early in the infection, but immunosuppressant timing involves a tradeoff between controlling pathogen load and mitigating inflammation; 2) both within and across-class combinations of drugs have synergistic effects; 3) if they are administered sufficiently early in the infection, anti-pathogenic drugs are more effective at mitigating autoimmune behavior than immunosuppressant drugs.

Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents.

BACKGROUND: Cardiac arrest (CA) can lead to neuronal degeneration and death through various pathways, including oxidative, inflammatory, and metabolic stress. However, current neuroprotective drug therapies will typically target only one of these pathways, and most single drug attempts to correct the multiple dysregulated metabolic pathways elicited following cardiac arrest have failed to demonstrate clear benefit. Many scientists have opined on the need for novel, multidimensional approaches to the multiple metabolic disturbances after cardiac arrest. In the current study, we have developed a therapeutic cocktail that includes ten drugs capable of targeting multiple pathways of ischemia-reperfusion injury after CA. We then evaluated its effectiveness in improving neurologically favorable survival through a randomized, blind, and placebo-controlled study in rats subjected to 12 min of asphyxial CA, a severe injury model. RESULTS: 14 rats were given the cocktail and 14 received the vehicle after resuscitation. At 72 h post-resuscitation, the survival rate was 78.6% among cocktail-treated rats, which was significantly higher than the 28.6% survival rate among vehicle-treated rats (log-rank test; p = 0.006). Moreover, in cocktail-treated rats, neurological deficit scores were also improved. These survival and neurological function data suggest that our multi-drug cocktail may be a potential post-CA therapy that deserves clinical translation. CONCLUSIONS: Our findings demonstrate that, with its ability to target multiple damaging pathways, a multi-drug therapeutic cocktail offers promise both as a conceptual advance and as a specific multi-drug formulation capable of combatting neuronal degeneration and death following cardiac arrest. Clinical implementation of this therapy may improve neurologically favorable survival rates and neurological deficits in patients suffering from cardiac arrest.

Pharmaceutical interventions to slow human aging. Are we ready for cocktails?

Slowing human aging with pharmaceuticals is now recognized as a feasible strategy. However, the design of clinical trials is still focused on single drug approaches. The process of aging has multiple pathways, which no current drug has been shown to effectively target. Therefore, it is of interest to study combinations, or cocktails, of drugs. A recently published article reported that a drug cocktail of rapamycin, acarbose and phenylbutyrate slowed aging in middle-aged mice treated for three months. The impact of this report is discussed, with the implications for determining endpoints in humans for testing drug cocktails as well as testing other drug combinations.

Suicide committed by a paramedic using a cocktail of drugs: Morphine, etomidate, diazepam and rocuronium. Case report and review of literature.

Suicide is still an important issue in developed countries. The problem affects all age groups and both sexes, although usually more commonly middle-aged men. Attempted suicides committed by taking drugs ended in death are rare (regardless of gender, age, social group) except among health professionals who have easy access to medications and the knowledge of their use. This paper describes a case of a paramedic's suicide and discusses the literature on the issue of suicides in terms of statistics. The paramedic, who is the subject of this case story suffered from depression and alcohol dependence and committed suicide at work using the medicines available in the Medical Air Rescue service: morphine, diazepam, etomidate and rocuronium. Toxicological studies revealed that the man had also been taking sertraline, a commonly used antidepressant. The reasons for suicide among healthcare professionals are the same as for the general population; however, given the extremely high work-related stress and easy availability of drugs that can be effectively used to commit suicide, a special approach to the issue is necessary.

Quantitative self-assembly of pure drug cocktails as injectable nanomedicines for synergistic drug delivery and cancer therapy.

New strategies to fabricate nanomedicines with high translational capacity are urgently desired. Herein, a new class of self-assembled drug cocktails that addresses the multiple challenges of manufacturing clinically useful cancer nanomedicines was reported. Methods: With the aid of a molecular targeted agent, dasatinib (DAS), cytotoxic cabazitaxel (CTX) forms nanoassemblies (CD NAs) through one-pot process, with nearly quantitative entrapment efficiency and ultrahigh drug loading of up to 100%. Results: Surprisingly, self-assembled CD NAs show aggregation-induced emission, enabling particle trafficking and drug release in living cells. In preclinical models of human cancer, including a patient-derived melanoma xenograft, CD NAs demonstrated striking therapeutic synergy to produce a durable recession in tumor growth. Impressively, CD NAs alleviated the toxicity of the parent CTX agent and showed negligible immunotoxicity in animals. Conclusions: Overall, this approach does not require any carrier matrices, offering a scalable and cost-effective methodology to create a new generation of nanomedicines for the safe and efficient delivery of drug combinations.

Current state and future perspective of drug repurposing in malignant glioma.

Malignant gliomas are still extremely difficult to treat because complete surgical resection is biologically not feasible due to the invasive nature of these diseases and the proximity of tumors to functionally sensitive areas. Moreover, adjuvant therapies are facing a strong therapeutic resistance since the central nervous system is a highly protected environment and the tumor cells display a vast intra-tumoral genetic and epigenetic variation. As a consequence, new therapeutics are urgently needed but the process of developing novel compounds that finally reach clinical application is highly time-consuming and expensive. Drug repurposing is an approach to facilitate and accelerate the discovery of new cancer treatments. In malignant glioma, like in other cancers, pre-existing physiological pathways that regulate cell growth, cell death or cell migration are dysregulated causing malignant transformation. A wide variety of drugs are clinically used to treat non-cancerous diseases interfering with these malignancy-associated pathways. Repurposed drugs have key advantages: They already have approval for clinical use by national regulatory authorities. Moreover, they are for the most part inexpensive and their side effect and safety profiles are well characterized. In this work, we provide an overview on current repurposing strategies for the treatment of malignant glioma.

Physical performance is enhanced in old mice fed a short term diet medicated with rapamycin, acarbose, and phenylbutyrate.

Loss of physical performance, as seen in humans by decreased grip strength and overall physical fitness, is generally accepted to be a consequence of aging. Treatments to delay or reduce these changes or increase resilience to them are generally not available. In this preliminary study, 20-month-old male and female C57BL/6 mice were given either a standard mouse diet or a formulated mouse diet containing rapamycin (14 ppm), acarbose (1000 ppm), and phenylbutyrate (1000 ppm), or a diet containing one half dose of each drug, for 3 months. At the end of the study, performance on a rotarod and grip strength test was compared. In general, mice fed the full dose drug cocktail diet performed better on these assays, with significant improvements in rotarod performance in females fed the full dose cocktail and in grip strength in males fed the full dose cocktail, and females fed the low dose cocktail. These observations provide support for the concept that short term treatment with a cocktail of drugs that targets multiple aging pathways can increase resilience to aging, and suggests that this prototype cocktail could be part of a clinical therapeutic strategy for delaying age-related loss of physical performance in people.

A Geroscience Approach to Preventing Pathologic Consequences of COVID-19.

The essential scope of the coronavirus infectious disease 2019 (COVID-19) pandemic is focused on developing effective treatments and vaccines for acute SARS-CoV-2 infection. There is also a critical need to develop interventions to prevent the complications of COVID-19, which occur with an alarming frequency in older adults. Since severe pathologic effects of infection occur with increasing age, COVID-19 falls under the geroscience concept that all diseases in older adults have a common and major underlying cause of declining function and resilience. Geroscience posits that manipulation of aging will simultaneously delay the appearance or severity of major diseases because they share the same risk factor: aging and the multiple processes involved in aging. Drug combinations that target multiple aging processes and the cytokine networks associated with them would not necessarily limit SARS-CoV-2 infection rates but would prevent severe pathologic consequences of the disease in older adults by maintaining a more youthful-like resilience to infection-related complications. A drug cocktail aimed at controlling cytokine actions would complement current clinical treatments and vaccine effectiveness for COVID-19 and serve as a prototype for future age-related infectious disease pandemics wherein the elderly population is especially vulnerable.

A refined cocktailing of pro-apoptotic nanoparticles boosts anti-tumor activity.

A functional 29 amino acid-segment of the helix α5 from the human BAX protein has been engineered for production in recombinant bacteria as self-assembling, GFP-containing fluorescent nanoparticles, which are targeted to the tumoral marker CXCR4. These nanoparticles, of around 34 nm in diameter, show a moderate tumor biodistribution and limited antitumoral effect when systemically administered to mouse models of human CXCR4+ colorectal cancer (at 300 µg dose). However, if such BAX nanoparticles are co-administered in cocktail with equivalent nanoparticulate versions of BAK and PUMA proteins at the same total protein dose (300 µg), protein biodistribution and stability in tumor is largely improved, as determined by fluorescence profiles. This fact leads to a potent and faster destruction of tumor tissues when compared to individual pro-apoptotic factors. The analysis and interpretation of the boosted effect, from both the structural and functional sides, offers clues for the design of more efficient nanomedicines and theragnostic agents in oncology based on precise cocktails of human proteins. STATEMENT OF SIGNIFICANCE: Several human pro-apoptotic peptides (namely BAK, BAX and PUMA) have been engineered as self-assembling protein nanoparticles targeted to the tumoral marker CXCR4. The systemic administration of the same final amounts of those materials as single drugs, or as combinations of two or three of them, shows disparate intensities of antitumoral effects in a mouse model of human colorectal cancer, which are boosted in the triple combination on a non-additive basis. The superiority of the combined administration of pro-apoptotic agents, acting at different levels of the apoptotic cascade, opens a plethora of possibilities for the development of effective and selective cancer therapies based on the precise cocktailing of pro-apoptotic nanoparticulate agents.

Soft Nanohydrogels Based on Laponite Nanodiscs: A Versatile Drug Delivery Platform for Theranostics and Drug Cocktails.

A new nanohydrogel drug delivery platform based on Laponite nanodiscs, polyacrylate, and sodium phosphate salts is described. The hybrid nanohydrogel is tailored to obtain soft and flexible nanohydrogels with G' around 3 kPa, which has been proposed as the ideal stiffness for drug delivery applications. In vitro studies demonstrate that the new nanohydrogels are biocompatible, biodegradable, nonswellable, pH-responsive, and noncytotoxic and are able to deliver antineoplastic drugs into cancer cells. The IC50 of nanohydrogels containing cisplatin, 4-fluorouracil, and cyclophosphamide is significantly lower than the IC50 of the free drugs. In vivo experiments suggest that the new nanomaterials are biocompatible and do not accumulate in crucial organs. The simple formulation procedure enables encapsulation of virtually any water-soluble molecule, without the need for chemical modification of the guests. These nanohydrogels are a versatile platform that enables the simultaneous encapsulation of several cancer drugs, yielding an efficient drug cocktail delivery system, which for instance presents a positive synergistic effect against MCF-7 cells.

Chitosan encapsulation of essential oil "cocktails" with well-defined binary Zn(II)-Schiff base species targeting antibacterial medicinal nanotechnology.

The advent of biodegradable nanomaterials with enhanced antibacterial activity stands as a challenge to the global research community. In an attempt to pursue the development of novel antibacterial medicinal nanotechnology, we herein a) synthesized ionic-gelated chitosan nanoparticles, b) compared and evaluated the antibacterial activity of essential oils extracted from nine different herbs (Greek origin) and their combinations with a well-defined antibacterial Zn(II)-Schiff base compound, and c) encapsulated the most effective hybrid combination of Zn(II)-essential oils inside the chitosan matrix, thereby targeting well-formulated nanoparticles of distinct biological impact. The empty and loaded chitosan nanoparticles were physicochemically characterized by FT-IR, Thermogravimetric Analysis (TGA), Scanning Electron Microscopy (SEM), with the entrapment and drug release studies being conducted through UV-Visible and atomic absorption techniques. The antimicrobial properties of the novel hybrid materials were demonstrated against Gram positive (S. aureus, B. subtilis, and B. cereus) and Gram negative (E. coli and X. campestris) bacteria using modified agar diffusion methods. The collective physicochemical profile of the hybrid Zn(II)-essential oil cocktails, formulated so as to achieve optimal activity when loaded to chitosan nanoparticles, signifies the importance of design in the development of efficient nanomedicinal pharmaceuticals a) based on both natural products and biogenic metal ionic cofactors, and b) targeting bacterial infections and drug resistance.

Highly sensitive LC-MS/MS methods for the determination of seven human CYP450 activities using small oral doses of probe-drugs in human.

Cocktails composed of several Cytochrome P450 (CYP450)-selective probe drugs have been shown of value to characterize in vivo drug-metabolism activities. Our objective was to develop and validate highly sensitive and selective LC-MS/MS assays allowing the determination of seven major human CYP450 isoenzyme activities following administration of low oral doses of a modified CYP450 probe-drug cocktail in patients. The seven-drug cocktail was composed of caffeine, bupropion, tolbutamide, omeprazole, dextromethorphan, midazolam (all administered concomitantly) and chlorzoxazone (administered separately) to phenotype for CYP1A2, 2B6, 2C9, 2C19, 2D6, 3A4/5 and 2E1, respectively. Serial plasma and urine samples were collected over an 8h period. The probe-drugs and their respective metabolites were measured in both human plasma and urine, except for omeprazole (plasma only) and chlorzoxazone (urine only). Samples were analyzed by high performance liquid chromatography with heated electrospray ionization tandem mass spectrometry (HPLC-HESI-MS/MS) using a Phenomenex Luna PFP (2) analytical column (3µm PFP(2) 150×3mm) for chromatographic separation. Optimal detection was achieved based on 3 different analytical methods; (1) isocratic elution with a mobile phase consisting of acetonitrile and water both fortified with 0.01% formic acid for the analysis of bupropion, tolbutamide, chlorzoxazone and their respective metabolites; (2) isocratic elution with a mobile phase composed of acetonitrile and ammonium formate (pH 3; 10mM) for omeprazole, dextromethorphan, midazolam and their metabolites; (3) for caffeine and paraxanthine, gradient elution using acetonitrile and 0.01% formic acid in water was used. All calibration functions were linear for all probe drugs and metabolites in both matrices over wide analytical ranges. The main advantages of our methods are the use of specific probe drugs available in most countries, the administration of small doses of probe drugs, small volume of plasma required for the analyses and simple and rapid extraction procedures. The methods met all requirements of specificity, sensitivity, linearity, precision and accuracy and stability generally accepted in bioanalytical chemistry. Determination of CYP450 phenotype in patients will permit characterization of their capacities to metabolize drugs through CYP450 under specific conditions at a definite time. This tool will be highly clinically relevant since wide intersubject variability observed in drug response is largely explained by variation in drug metabolism; it will be particularly useful in polymedicated patients with multiple comorbidities. So far, our CYP450 cocktail assays have been successfully applied to phenotype CYP450 activities in patients.

Impact of Tetrahydropalmatine on the Pharmacokinetics of Probe Drugs for CYP1A2, 2D6 and 3A Isoenzymes in Beagle Dogs.

Tetrahydropalmatine (Tet) exhibit multiple pharmacological activities and is used frequently by clinical practitioners. In this study, we evaluate the in vivo effects of single and repeated oral Tet administrations on CYP1A2, 2D6 and 3A activities in six beagle dogs in a randomized, controlled, open-label, crossover study. A cocktail approach, with dosages of the probe drugs caffeine (3.0 mg/kg), metoprolol (2.33 mg/kg) and midazolam (0.45 mg/kg), was used to measure cytochrome P450 (CYP) metabolic activities. The cocktail was administered orally as a single dose (12 mg/kg) 1 day prior to and 4 days after repeated oral Tet administrations (12 mg/kg three times daily). The probe drugs and their metabolites in plasma were quantified simultaneously by a validated HPLC technique, and non-compartmental parameters were used to evaluate metabolic variables for assessment of CYP inhibition or induction. Tet had no or minor impact on the pharmacokinetics and metabolism of the probe drugs caffeine and metoprolol, CYP1A2 and CYP2D6 substrates, respectively. However, Tet increased AUC0-24 h and decreased AUCratio(0-24 h) (1-hydroxymidazolam/midazolam ratio) for midazolam statistically significant, both in single or multiple dosing of Tet, with up to 39 or 57% increase for AUC0-24 h and 29% or 22 decrease for AUCratio(0-24 h), respectively, in line with previous in vitro findings for its CYP3A4 inhibition. The extensive use of Tet and herbal medicines containing Tet makes Tet a candidate for further evaluation of CYP3A-mediated herb-drug interactions. Copyright © 2016 John Wiley & Sons, Ltd.

Therapeutic protein-drug interaction assessment for daclizumab high-yield process in patients with multiple sclerosis using a cocktail approach.

AIMS: To characterize the potential effect of daclizumab high-yield process (DAC HYP), a monoclonal antibody that blocks the high-affinity interleukin-2 receptors for treatment of multiple sclerosis, on activity of cytochrome P450 (CYP) enzymes. METHODS: Twenty patients with multiple sclerosis received an oral cocktail of probe substrates of CYP1A2 (caffeine 200 mg), CYP2C9 (warfarin 10 mg/vitamin K 10 mg), CYP2C19 (omeprazole 40 mg), CYP2D6 (dextromethorphan 30 mg) and CYP3A (midazolam 5 mg) on two sequential occasions: 7 days before and 7 days after subcutaneous administration of DAC HYP 150 mg every 4 weeks for three doses. Serial pharmacokinetic blood samples up to 96 h post dose and 12-h urine samples were collected on both occasions. Area under the curve (AUC) for caffeine, S-warfarin, omeprazole and midazolam, and urine dextromethorphan to dextrorphan ratio were calculated. Statistical analyses were conducted on log-transformed parameters using a linear mixed-effects model. RESULTS: The 90% confidence intervals (CIs) for the geometric mean ratio (probe substrate with DAC HYP/probe substrate alone) for caffeine AUC from 0-12 h (0.93-1.15), S-warfarin AUC from 0 to infinity (AUC[0-inf]) (0.95-1.06), omeprazole AUC(0-inf) (0.88-1.13) and midazolam AUC(0-inf) (0.89-1.15) were within the no-effect boundary of 0.80-1.25. The geometric mean ratio for urine dextromethorphan to dextrorphan ratio was 1.01, with the 90% CI (0.76-1.34) extending slightly outside the no-effect boundary, likely due to high variability with urine collections and CYP2D6 activity. CONCLUSIONS: DAC HYP treatment in patients with multiple sclerosis had no effect on CYP 1A2, 2C9, 2C19, 2D6 and 3A activity.

Drugs indicated for mitochondrial dysfunction as treatments for acute encephalopathy with onset of febrile convulsive status epileptics.

We studied the efficacy of drugs indicated for mitochondrial dysfunction in the treatment of 21 patients with acute encephalopathy with onset of febrile convulsive status epilepticus at our hospital from January 2006 to December 2014. Among them, 11 patients had been treated with a mitochondrial drug cocktail consisting of vitamin B1, vitamin C, biotin, vitamin E, coenzyme Q10, and l-carnitine (prescription group) and 10 patients were not treated with the cocktail (non-prescription group). We retrospectively reviewed age, trigger, clinical form, treatment start time, and sequelae. Clinical form was classified into a biphasic group presenting acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and a monophasic group. Sequelae were classified as (A) no sequelae group or (B) sequelae group, and differences in the interval between diagnosis and treatment were also evaluated. The sequelae were not different between the mitochondrial drug cocktail prescription and non-prescription groups, but significantly better in the group administered the mitochondrial drug cocktail within 24h (P=0.035). We expect that early treatment with a mitochondrial drug cocktail could prevent sequelae in acute encephalopathy with onset of febrile convulsive status epilepticus.

Personalized Cancer Therapy Considering Cytochrome P450 Variability.

The individual variability of pharmacokinetics is underestimated and few systematic studies exist in this field. In most cases, this leads to unwanted side effects or toxicity. In polychemotherapy, prodrugs (like ifosfamide), which have to be activated by cytochrome P450 enzymes (CYPs), play an important role. If patients are poor metabolizers for these drugs, the therapy will be ineffective. Furthermore, CYPs and transporters can be (over)expressed in target tissues, which is also not examined and considered in clinical routine. Here, we present a body map showing relevant enzymes in some organs and tissues. Finally, a typical case of a Caucasian chemotherapy patient with breast cancer is presented and discussed regarding a personalized cancer therapy considering the single nucleotide polymorphisms found via genotyping.