The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has occasioned worldwide alarm. Globally, the number of reported confirmed cases has exceeded 84.3 million as of this writing (January 2, 2021). Since there are no targeted therapies for COVID-19, the current focus is the repurposing of drugs approved for other uses. In some clinical trials, antiviral drugs such as remdesivir (Grein et al., 2020), lopinavir/ritonavir (LPV/r) (Cao et al., 2020), chloroquine (Gao et al., 2020), hydroxychloroquine (Gautret et al., 2020), arbidol (Wang et al., 2020), and favipiravir (Cai et al., 2020b) have shown efficacy in COVID-19 patients. LPV/r combined with arbidol, which is the basic regimen in some regional hospitals in China including Zhejiiang Province, has shown antiviral effects in COVID-19 patients (Guo et al., 2020; Xu et al., 2020). A retrospective cohort study also reported that this combination therapy showed better efficacy than LPV/r alone for the treatment of COVID-19 patients (Deng et al., 2020).
Animals ; COVID-19/drug therapy* ; Drug Interactions ; Drug Therapy, Combination ; Female ; Indoles/pharmacokinetics* ; Lopinavir/pharmacokinetics* ; Male ; Rats ; Retrospective Studies ; Ritonavir/pharmacokinetics* ; SARS-CoV-2

Cardiovascular disease (CVD) is the most common cause of death in patients with non-alcoholic fatty liver disease (NAFLD). New therapeutic strategies which have the potential for slowing down the evolution of NAFLD and reducing CVD-related mortality are urgently needed. Statins are well recognized in the treatment of dyslipidemia, but their use in the treatment of NAFLD is limited due to the safety concerns. Ilexgenin A (IA) is one of the main bioactive compounds in 'Shan-lv-cha', an herbal tea commonly used in China. In the present study, we investigated the possible synergistic therapeutic effects of IA and simvastatin (SV) on NAFLD. IA or SV showed beneficial effects on the rats with NAFLD by lowering the liver weight, liver index and plasma levels of alanine aminotransferase and aspartate aminotransferase, regulating abnormal metabolism of lipids and ameliorating steatosis in liver. IA significantly enhanced the hypolipidemic and anti-inflammation effects of SV. Furthermore, a sensitive, accurate, convenient and reproducible LC-MS method was developed to investigate the effects of IA on the pharmacokinetics of SV. No significant changes were observed in pharmacokinetic parameters of SV and simvastatin hydroxy acid in the IA plus SV co-treated group in comparison with those in the group treated with SV alone. The mRNA levels and activity of CYP3A1 were not altered by IA. In conclusion, the results obtained from the present study should be helpful for further clinical application of SV and IA alone or in combination.
Alanine Transaminase ; metabolism ; Animals ; Aspartate Aminotransferases ; metabolism ; Cytochrome P-450 CYP3A ; genetics ; metabolism ; Diet, High-Fat ; Disease Models, Animal ; Drug Synergism ; Drug Therapy, Combination ; Lipids ; blood ; Liver ; metabolism ; pathology ; physiopathology ; Male ; Molecular Structure ; Non-alcoholic Fatty Liver Disease ; blood ; drug therapy ; Rats ; Rats, Sprague-Dawley ; Simvastatin ; analogs & derivatives ; pharmacokinetics ; therapeutic use ; Transcription, Genetic ; Triterpenes ; chemistry ; therapeutic use

It is very common to use Chinese medicine (CM) combined with Western medicine (WM) in clinical practice. The appropriate combination of CM with WM can reduce toxicity and enhance effects in order to make the best use of advantages and bypass the disadvantages. However, an inappropriate combination can not only affect the curative effect but even cause death. Therefore, strengthening the complementary advantages of the CM and WM to improve the therapeutic efficacy and reduce side effects has become an important research topic of clinical medicine and pharmacy. Many researchers try to clarify the effects of combining CM with WM on therapeutic efficacy and absorption, distribution, metabolism and excretion by pharmacodynamics and pharmacokinetics studies, providing evidence for clinical application. This review focuses on the new developments in the pharmacodynamics and pharmacokinetics of the combination of CM with WM in order to give references for clinical treatment.
Anti-Bacterial Agents ; pharmacology ; Blood Circulation ; drug effects ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; pharmacokinetics ; pharmacology ; Humans ; Medicine, Chinese Traditional

Herbal medicines (HMs) are often used in combination with Western medicines (WMs) to improve therapeutic efficacies of orthodox medicines. This review discussed the current status of combination treatment with HMs and WMs in clinical practices. The influence of HMs on bioavailability of WMs was also discussed from the pharmacokinetic point of view. In addition, benefits and considerations of combination treatment were discussed using data obtained from clinical trials and randomized controlled trials of HMs treatment in skin diseases.
Adrenal Cortex Hormones ; pharmacokinetics ; Dermatitis, Atopic ; drug therapy ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; adverse effects ; therapeutic use ; Herbal Medicine ; Humans ; Syndrome ; Treatment Outcome

To investigate the effects of carbamazepine (CBZ) on the plasma concentrations of valproic acid (VPA) and its toxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in epileptic patients, the plasma concentrations of VPA and 4-ene VPA were determined, and the effect of CBZ on pharmacokinetics of VPA was evaluated. All patients had been divided into two groups (VPA group, n = 87; and VPA+CBZ group, n = 19). As compared to VPA group, the combination of CBZ significantly (P < 0.01) decreased the trough concentration of VPA [VPA group, (69.5 +/- 28.8) microg x mL(-1); VPA+CBZ group, (46.3 +/- 25.6) microg x mL(-1)] and does-adjusted VPA trough concentration [VPA group, (4.89 +/- 2.21) microg x mL(-1) x mg(-1) x kg(-1); VPA+CBZ group, (3.14 +/- 1.74) microg x mL(-1) x mg(-1) x kg(-1)]. However, the addition of CBZ did not influence the concentration of 4-ene VPA. The present study revealed that coadministration of CBZ can reduce VPA plasma concentration and may impact VPA clinical effect, therefore therapeutic drug mornitoring of VPA should be used when combined use of CBZ and VPA.
Adolescent ; Adult ; Anticonvulsants ; blood ; pharmacokinetics ; therapeutic use ; Carbamazepine ; blood ; pharmacokinetics ; therapeutic use ; Drug Interactions ; Drug Therapy, Combination ; Epilepsy ; blood ; drug therapy ; Fatty Acids, Monounsaturated ; blood ; Female ; Humans ; Male ; Valproic Acid ; blood ; pharmacokinetics ; therapeutic use ; Young Adult

BACKGROUND/AIMS: The dose of mycophenolate mofetil (MMF) has been reduced in Asia due to side effects associated with the conventional fixed dose of 2-3 g/day. We aimed to determine the pharmacokinetics of a reduced dose of MMF and to validate its feasibility in combination with tacrolimus in living-donor liver transplantation (LDLT). METHODS: Two sequential studies were performed in adult LDLT between October 2009 and 2011. First, we performed a prospective pharmacokinetic study in 15 recipients. We measured the area under the curve from 0 to 12 hours (AUC0-12) for mycophenolic acid at postoperative days 7 and 14, and we performed a protocol biopsy before discharge. Second, among 215 recipients, we reviewed 74 patients who were initially administered a reduced dose of MMF (1.0 g/day) with tacrolimus (trough, 8-12 ng/mL during the first month, and 5-8 ng/mL thereafter), with a 1-year follow-up. We performed protocol biopsies at 2 weeks and 1 year post-LDLT. RESULTS: In the first part of study, AUC0-12 was less than 30 mgh/L in 93.3% of cases. In the second, validating study, 41.9% of the recipients needed dose reduction or cessation due to side effects within the first year after LDLT. At 12 months post-LDLT, 17.6% of the recipients were administered a lower dose of MMF (0.5 g/day), and 16.2% needed permanent cessation due to side effects. The 1- and 12-month rejection-free survival rates were 98.6% and 97.3%, respectively. CONCLUSIONS: A reduced dose of MMF was associated with low blood levels compared to the existing recommended therapeutic range. However, reducing the dose of MMF combined with a low level of tacrolimus was feasible clinically, with an excellent short-term outcome in LDLT.
Adult ; Aged ; Area Under Curve ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Gastrointestinal Diseases/etiology ; Graft Rejection/prevention & control ; Humans ; Immunosuppressive Agents/blood/*pharmacokinetics ; Leukopenia/etiology ; Liver/pathology ; Liver Failure/*therapy ; *Liver Transplantation ; Male ; Middle Aged ; Mycophenolic Acid/adverse effects/*analogs & derivatives/blood/pharmacokinetics ; ROC Curve ; Retrospective Studies ; Tacrolimus/therapeutic use ; Tissue Donors

Adrenergic beta-2 Receptor Agonists ; administration & dosage ; pharmacokinetics ; therapeutic use ; Asthma ; drug therapy ; Bronchitis ; drug therapy ; Bronchodilator Agents ; administration & dosage ; therapeutic use ; Child ; Child, Preschool ; Delayed-Action Preparations ; Drug Synergism ; Drug Therapy, Combination ; Glucocorticoids ; administration & dosage ; therapeutic use ; Humans ; Infant ; Leukotriene Antagonists ; administration & dosage ; therapeutic use ; Respiratory Sounds ; drug effects ; Terbutaline ; administration & dosage ; analogs & derivatives ; pharmacokinetics ; therapeutic use ; Transdermal Patch

OBJECTIVETo evaluate the antibacterial activity of Ciprofloxacin, Amikacin in combination with beta-lactams against Pseudomonas aeruginosa strains in vitro, to optimize treatment regime for antibiotics on the basis of pharmacokinetics (PK)/pharmacodynamics (PD) and drug sensitivity tests. Methods With checkerboard titration method, the minimal inhibitory concentrations (MIC) of a combination of antibiotics in different concentrations for 33 clinically isolated Pseudomonas aeruginosa strains were determined by broth dilution. Fractional inhibitory concentrations (FIC) were calculated for judging synergic effect of antibiotics.

RESULTSThe combination of Amikacin and Ceftazidime showed synergic effects (accounting for 57.6%). The combinations of Ciprofloxacin with Ceftazidime, Cefepime, Imipenem/Cilastatin, Meropenem showed synergic or additive effect. In the study with PK/PD, C(max)/MIC was the principal parameters for evaluation of aminoglycoside and fluoroquinolone antibiotics, while T > MIC was the principal parameter to be used to evaluate beta-lactams antibiotics.

CONCLUSIONWhen antibiotics are used in combination, MICs can be reduced significantly and antibacterial activities are enhanced remarkably. The combination of antibiotics results mainly in synergic or additive effect, and no inhibitory effect is observed. PK/PD analysis plays an important role in planning optimal combination regime to raise clinical efficacy.

Amikacin ; pharmacokinetics ; pharmacology ; Anti-Bacterial Agents ; pharmacokinetics ; pharmacology ; Burn Units ; Ciprofloxacin ; pharmacokinetics ; pharmacology ; Drug Therapy, Combination ; Humans ; Intensive Care Units ; Microbial Sensitivity Tests ; Pseudomonas aeruginosa ; drug effects ; isolation & purification ; beta-Lactams ; pharmacokinetics ; pharmacology

The disposition kinetics of levofloxacin was investigated in six male crossbred calves following single intravenous administration, at a dose of 4 mg/kg body weight, into the jugular vein subsequent to a single intramuscular injection of paracetamol (50 mg/kg). At 1 min after the injection of levofloxacin, the concentration of levofloxacin in plasma was 17.2 +/- 0.36 microgram/ml, which rapidly declined to 6.39 +/- 0.16 microgram/ml at 10 min. The drug level above the MIC90 in plasma, was detected for up to 10 h. Levofloxacin was rapidly distributed from blood to the tissue compartment as evidenced by the high values of the distribution coefficient, alpha (17.3 +/- 1.65 /h) and the ratio of K12/K21 (1.83 +/- 0.12). The values of AUC and Vdarea were 12.7 +/- 0.12 microgram.h/ml and 0.63 +/- 0.01 l/kg. The high ratio of the AUC/MIC (126.9 +/- 1.18) obtained in this study indicated the excellent antibacterial activity of levofloxacin in calves. The elimination half-life, MRT and total body clearance were 1.38 +/- 0.01 h, 1.88 +/- 0.01 h and 0.32 +/- 0.003 l/kg/h, respectively. Based on the pharmacokinetic parameters, an appropriate intravenous dosage regimen for levofloxacin would be 5 mg/kg repeated at 24 h intervals when prescribed with paracetamol in calves.
Acetaminophen/administration & dosage/*pharmacokinetics ; Animals ; Anti-Bacterial Agents/administration & dosage/blood/*pharmacokinetics ; Area Under Curve ; Cattle/*metabolism ; Drug Therapy, Combination ; Half-Life ; Hybridization, Genetic ; Injections, Intravenous/veterinary ; Male ; Ofloxacin/administration & dosage/blood/*pharmacokinetics ; Time Factors

OBJECTIVESeizure is a common emergency in children with complicated pathogeny. Seizures are usually caused by complicated etiology and fever and febrile seizure are the commonest causes. Repeated and permanent seizures can damage the brain. So it is important to take active and effective measures to control seizure and high fever. Because most seizures and fever take place at home or out of hospital and it is difficult to administer drugs intravenously, it is important to explore an easy, safe, quick and effective way to control and prevent both seizure and fever. The present study aimed to explore the efficacy and safety of rectal administration of mixed ibuprofen and diazepam (IBU-DZP) solution.

METHODS(1) Animal study on the pharmacokinetics in rabbits and pharmacodynamics in rats after rectal administration with the mixed solution and on the irritability of the mixed solution to rectum. (2) Clinical study: Pharmacokinetics of the mixed solution in children after rectal administration were investigated.

RESULTS(1) Animal study: IBU and DZP were both rapidly absorbed from rectum with a peak blood level of (11.7 +/- 1.2) min and (9.4 +/- 2.7) min in rabbits, respectively. The mixed solution could effectively prevent the severity of seizures induced by pentetrazole and significantly suppressed fever induced by yeast. There were no remarkable pathological changes in rectal tissues after repeated rectal administration of the mixed solution. (2) Clinical study: IBU and DZP rapidly reached their peak blood levels at about 30 min and 15 min respectively after rectal administration to the children. The peak values were (57.8 +/- 7.9) mg/L and (450.1 +/- 158.7) microg/L, respectively. In fact, both of them reached levels that were much higher than their therapeutic levels in serum just at 5 min after administration, their blood levels were (41.4 +/- 5.5) mg/L and (321.8 +/- 53.9) microg/L, respectively.

CONCLUSIONSIBU-DZP mixed solution administered rectally is an easy, safe, quick and effective way to control and prevent both seizure and fever.

Administration, Rectal ; Animals ; Child ; Child, Preschool ; Diazepam ; administration & dosage ; pharmacokinetics ; Drug Therapy, Combination ; Humans ; Ibuprofen ; pharmacokinetics ; therapeutic use ; Infant ; Rabbits ; Rats ; Rats, Wistar ; Seizures, Febrile ; drug therapy