To study the bioequivalence of Clavulanate Potassium and Amoxicillin (1:7) dispersible tablets, a randomized cross-over study was conducted in 18 healthy volunteers. A single oral dose of 1,000 mg Clavulanate Potassium and Amoxicillin (1:7) dispersible tablets (Tested formulation, T) or Augmentin syrup (Reference formulation, R). Concentrations in plasma were determined with high-performance liquid chromatography. The main parameters of T were: for Clavulanate Potassium and Amoxicillin, Cmax: 2.46 +/- 1.11 micrograms/ml and 18.81 +/- 7.26 micrograms/ml, Tmax: 1.12 +/- 0.23 h and 1.30 +/- 0.34 h, AUC(0-6 h): 5.18 +/- 2.24 micrograms.h/ml and 45.09 +/- 14.53 micrograms.h/ml, t1/2: 1.43 +/- 0.44 h and 1.09 +/- 0.22 h., respectively. The relative bioavailability of T to R were 96.5 +/- 19.2% and 98.4 +/- 26.1%, respectively. Statistical analysis showed that the two formulations were bioequivalent.
Amoxicillin-Potassium Clavulanate Combination/*pharmacokinetics ; Drug Therapy, Combination/*pharmacokinetics ; Tablets ; Therapeutic Equivalency

To study the bioequivalence of Clavulanate Potassium and Amoxicillin (1:7) dispersible tablets, a randomized cross-over study was conducted in 18 healthy volunteers. A single oral dose of 1,000 mg Clavulanate Potassium and Amoxicillin (1:7) dispersible tablets (Tested formulation, T) or Augmentin syrup (Reference formulation, R). Concentrations in plasma were determined with high-performance liquid chromatography. The main parameters of T were: for Clavulanate Potassium and Amoxicillin, Cmax: 2.46 +/- 1.11 micrograms/ml and 18.81 +/- 7.26 micrograms/ml, Tmax: 1.12 +/- 0.23 h and 1.30 +/- 0.34 h, AUC(0-6 h): 5.18 +/- 2.24 micrograms.h/ml and 45.09 +/- 14.53 micrograms.h/ml, t1/2: 1.43 +/- 0.44 h and 1.09 +/- 0.22 h., respectively. The relative bioavailability of T to R were 96.5 +/- 19.2% and 98.4 +/- 26.1%, respectively. Statistical analysis showed that the two formulations were bioequivalent.
Adult ; Amoxicillin-Potassium Clavulanate Combination ; pharmacokinetics ; Drug Therapy, Combination ; pharmacokinetics ; Humans ; Male ; Tablets ; Therapeutic Equivalency

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

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

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

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

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

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

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

OBJECTIVETo investigate the effect of Shengmai Injection (SMI) on serum concentration and pharmacokinetic parameters of digoxin in patients with congestive heart failure.

METHODSForty in-patients with congestive heart failure were selected and randomly divided into 4 groups, the three treated groups I, II and III treated with digoxin combined with 20 ml, 40 ml and 60 ml of SMI respectively, and the control group, 10 patients in each group. The serum concentration of digoxin at different time points was determined with radioimmunoassay and the pharmacokinetical parameters were calculated with 3P97 pharmacokinetic software.

RESULTSThe serum concentration of digoxin in the treated group I was significantly lower than that in the control group (P < 0.05), with the pharmacokinetical parameters, including the elimination half-life time (T1/2), elimination rate constant (Ke), apparent volume of distribution (Vd), plasma clearance (CL) and area under curve (AUC), significantly different to those in the control group (P < 0.05 or P < 0.01). But the serum concentration of digoxin with its pharmacokinetical parameters in the other two treated groups were not different significantly to those in the control group respectively (P > 0.05).

CONCLUSIONSMI could influence the metabolism of digoxin in patients with congestive heart failure. This study has provided an important reference for safe and rational combined use of digoxin and SMI in clinical practice.

Adult ; Aged ; Coronary Disease ; complications ; Digoxin ; administration & dosage ; blood ; pharmacokinetics ; Drug Combinations ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Heart Failure ; blood ; drug therapy ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Phytotherapy