Pharmacokinetic Interaction between Voriconazole and Methadone at Steady State in Patients on Methadone Therapy

ABSTRACT This trial was aimed to estimate the pharmacokinetic interaction between voriconazole and methadone at steady state in male patients on methadone therapy and to characterize the safety and tolerability profile during the coadministration. Twenty-three patients on individualized methadone therapy (30 to 100 mg once daily) were enrolled into this randomized, patient- and investigator-blind, placebo-controlled, parallel-group study. Methadone pharmacokinetic samples were collected from patients receiving methadone alone as the baseline before they were randomized to coadminister either 200 mg voriconazole twice daily (BID) (400-mg BID loading doses on the first day) (n = 16) or matching placebo (n = 7) for the next 5 days. Pharmacokinetic samples for methadone and voriconazole were collected on the last day of voriconazole dosing. The safety data were collected throughout the study. Voriconazole increased the steady-state exposure of pharmacologically active enantiomer (R)-methadone: the mean area under the concentration-time curve from 0 to 24 h (AUC0-24) was increased by 47.2% (90% confidence intervals [CI]: 37.7%, 57.4%), and the mean peak concentration (C max) was increased by 30.7% (90% CI: 22.2%, 39.8%). The magnitude of increase in (S)-methadone exposure was greater than that of (R)-methadone: the AUC0-24 was increased by 103.4% (90% CI: 85.0%, 123.6%), and the C max was increased by 65.4% (90% CI: 52.6%, 79.2%). Methadone appeared to have no effect on the steady-state voriconazole pharmacokinetics compared to the historical data for voriconazole alone. Methadone patients receiving voriconazole showed no signs or symptoms of significant opioid withdrawal or overdose. Coadministration of 200 mg voriconazole BID with methadone was generally safe and well tolerated. Nevertheless, caution should be exercised when voriconazole is coadministered with methadone due to the increase in (R)-methadone exposure, which in turn may require a dose reduction of methadone.

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Steady-State Pharmacokinetic and Safety Profiles of Voriconazole and Ritonavir in Healthy Male Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00526-07 ◽

2007 ◽

Vol 51 (10) ◽

pp. 3617-3626 ◽

Cited By ~ 46

Author(s):

Ping Liu ◽

Grover Foster ◽

Kuan Gandelman ◽

Robert R. LaBadie ◽

Mark J. Allison ◽

...

Keyword(s):

Steady State ◽

Low Dose ◽

Safety Data ◽

Fold Increase ◽

High Dose ◽

Time Curve ◽

Period 2 ◽

Parallel Group ◽

Male Subjects ◽

Parallel Group Trial

ABSTRACT Since there is a likelihood of coadministration of voriconazole and ritonavir, two studies were conducted to evaluate the potential of drug interaction. Study A was a randomized, placebo-controlled, two-period, parallel-group trial (n = 34). Study B had the same design without the placebo group (n = 17). In period 1, subjects received 200 mg voriconazole or placebo twice daily (BID) for 3 days (400 mg BID on day 1). In period 2, following a 7-day washout, subjects received ritonavir alone at 400 mg BID (study A) or 100 mg BID (study B) for 10 days (days 11 to 20), and then ritonavir was coadministered with 200 mg BID voriconazole or placebo for the next 10 days (days 21 to 30). Serial plasma samples were collected on days 3, 20, and 30, and safety data were collected throughout the study. High-dose (400 mg BID) ritonavir substantially reduced the steady-state mean voriconazole exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12], −82%; maximum concentration [C max], −66%). However, the effect of low-dose (100 mg BID) ritonavir was less pronounced (AUC0-12, −39%; C max, −24%). The decrease in voriconazole exposure was probably due to the induction of CYP2C19 and CYP2C9 by ritonavir. It is interesting that one subject in each study exhibited the opposite effect of ritonavir on voriconazole exposure (a 2.5- to 3-fold increase), probably due to lack of CYP2C19. Voriconazole had no apparent effect on the exposure of high-dose ritonavir but slightly decreased the exposure of low-dose ritonavir (AUC0-12, −14%; C max, −24%). The safety profile of combination therapy was not notably different from that of voriconazole or ritonavir alone. Due to the significant effect of ritonavir on voriconazole exposure, coadministration of voriconazole with 400 mg BID ritonavir is contraindicated; coadministration with 100 mg BID ritonavir should be avoided, unless an assessment of the benefit/risk to the patient justifies the use.

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Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00766-12 ◽

2012 ◽

Vol 56 (10) ◽

pp. 5076-5081 ◽

Cited By ~ 39

Author(s):

Keith A. Rodvold ◽

Mark H. Gotfried ◽

J. Gordon Still ◽

Kay Clark ◽

Prabhavathi Fernandes

Keyword(s):

Steady State ◽

High Performance ◽

Healthy Adult ◽

Plasma Concentrations ◽

Epithelial Lining ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Once Daily ◽

Drug Concentrations ◽

The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

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Steady-State Pharmacokinetics of Amprenavir Coadministered with Ritonavir in Human Immunodeficiency Virus Type 1-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.1.118-123.2003 ◽

2003 ◽

Vol 47 (1) ◽

pp. 118-123 ◽

Cited By ~ 26

Author(s):

Cecile Goujard ◽

Isabelle Vincent ◽

Jean-Luc Meynard ◽

Nathalie Choudet ◽

Diane Bollens ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Steady State ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Time Curve ◽

Concentration Time ◽

Immunodeficiency Virus ◽

The Mean ◽

Hiv 1

ABSTRACT The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (C min,ss) was 1.92 μg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 μg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (C max,ss) was 7.12 μg/ml, the area under the concentration-time curve from 0 to 10 h (AUC0-10) was 32.06 μg · h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUCss) was 35.74 μg · h/ml. Decreases in the mean values of C min,ss (29%), C max,ss (42%), AUC0-10 (42%), and AUCss (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir C min,ss markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir C min,ss above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.

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Analysis of the Pharmacokinetic Interaction between Cephalexin and Quinapril by a Nonlinear Mixed-Effect Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.6.1463 ◽

1998 ◽

Vol 42 (6) ◽

pp. 1463-1469 ◽

Cited By ~ 22

Author(s):

C. Padoin ◽

M. Tod ◽

G. Perret ◽

O. Petitjean

Keyword(s):

Competitive Inhibition ◽

Pharmacokinetic Interaction ◽

Angiotensin Converting Enzyme Inhibitors ◽

Oral Route ◽

Elimination Kinetics ◽

Time Curve ◽

Converting Enzyme Inhibitors ◽

Mixed Effect ◽

Nonlinear Mixed Effect ◽

The Mean

ABSTRACT Oligopeptidic drugs such as β-lactams and angiotensin-converting enzyme inhibitors share the same carriers in humans and animals, which results in possible pharmacokinetic interactions. To model such interactions, the effects of quinapril on cephalexin pharmacokinetics were investigated in rats. Blood cephalexin concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method and by fitting a bicompartmental model by a nonlinear mixed-effect modeling approach. Five groups of eight rats were examined. In the first three groups, cephalexin elimination kinetics after intra-arterial administration alone or in combination with quinapril given by the parenteral or the oral route were studied, and the occurrence of a pharmacokinetic interaction was not revealed. The absence of an effect of quinapril on cephalexin elimination after parenteral administration might be explained either by the higher affinity of cephalexin for the renal anionic transport system than that of quinapril or by the much higher concentrations of cephalexin than those of quinapril. In the last two groups, cephalexin was administered by the oral route alone or in combination with quinapril. The mean area under the concentration-time curve (AUC) for cephalexin was increased by ca. 30% by coadministration of quinapril (40.1 versus 31.4 mg · h/liter;P = 0.04). The mean elimination clearance of cephalexin was significantly decreased by quinapril, from 0.81 to 0.64 liter/h/kg of body weight (P < 0.05), probably by competitive inhibition of cephalexin secretion at the tubular level. The mean absorption rate constant of cephalexin was significantly lowered by quinapril (from 0.249 to 0.177 h−1;P < 0.01), without modification of the extent of absorption (89%). This pharmacokinetic interaction could be explained by competitive inhibition of cephalexin active transport by quinapril at the intestinal level.

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Tissue Penetration and Pharmacokinetics of Tigecycline in Diabetic Patients with Chronic Wound Infections Described by Using In Vivo Microdialysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01051-10 ◽

2010 ◽

Vol 54 (12) ◽

pp. 5209-5213 ◽

Cited By ~ 32

Author(s):

Catharine C. Bulik ◽

Dora E. Wiskirchen ◽

Ashley Shepard ◽

Christina A. Sutherland ◽

Joseph L. Kuti ◽

...

Keyword(s):

Steady State ◽

Protein Binding ◽

Subcutaneous Tissue ◽

Diabetic Patients ◽

Tissue Penetration ◽

Tissue Concentrations ◽

Time Curve ◽

The Mean

ABSTRACT Tissue penetration of systemic antibiotics is an important consideration for positive outcomes in diabetic patients. Herein we describe the exposure profile and penetration of tigecycline in the interstitial fluid of wound margins versus that of uninfected thigh tissue in 8 adult diabetic patients intravenously (IV) administered 100 mg and then 50 mg of tigecycline twice daily for 3 to 5 doses. Prior to administration of the first dose, 2 microdialysis catheters were inserted into the subcutaneous tissue, the first within 10 cm of the wound margin and the second in the thigh of the same extremity. Samples for determination of plasma and tissue concentrations were simultaneously collected over 12 h under steady-state conditions. Tissue concentrations were corrected for percent in vivo recovery by the retrodialysis technique. Plasma samples were also collected for determination of protein binding at 1, 6, and 12 h postdose for each patient. Protein binding data were corrected using a fitted polynomial equation. The mean patient weight was 95.1 kg (range, 63.6 to 149.2 kg), the mean patient age was 63.5 ± 9.4 years, and 75% of the patients were males. The mean values for the plasma, thigh, and wound free area under the concentration-time curve from 0 to 24 h (fAUC0-24) were 2.65 ± 0.33, 2.52 ± 1.15, and 2.60 ± 1.02 μg·h/ml, respectively. Protein binding was nonlinear, with the percentage of free drug increasing with decreasing serum concentrations. Exposure values for thigh tissue and wound tissue were similar (P = 0.986). Mean steady-state tissue concentrations for the thigh and wound were similar at 0.12 ± 0.02 μg/ml, and clearance from the tissues appeared similar to that from plasma. Tissue penetration ratios (tissue fAUC/plasma fAUC) were 99% in the thigh and 100% in the wound (P = 0.964). Tigecycline penetrated equally well into wound and uninfected tissue of the same extremity.

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Pharmacokinetic interaction between itraconazole and ceftriaxone in Yucatan miniature pigs.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.9.2029 ◽

1997 ◽

Vol 41 (9) ◽

pp. 2029-2032 ◽

Cited By ~ 10

Author(s):

A Cavalier ◽

D Levêque ◽

J D Peter ◽

J Salmon ◽

H Elkhaïli ◽

...

Keyword(s):

Antimicrobial Agents ◽

Efflux Pump ◽

Pharmacokinetic Interaction ◽

Time Curve ◽

Miniature Pigs ◽

Concentration Time ◽

P Glycoprotein ◽

Chronic Model ◽

The Mean

Since ceftriaxone and itraconazole are highly protein bound, are excreted via a biliary pathway, and are in vitro modulators of the efflux pump P glycoprotein, a pharmacokinetic interaction between these antimicrobial agents can be hypothesized. Therefore, we evaluated the pharmacokinetics of itraconazole and ceftriaxone alone and in combination in a chronic model of catheterized miniature pigs. Itraconazole does not influence ceftriaxone kinetic behavior. The mean areas under the concentration-time curve (AUC) were 152.2 microg x h/ml (standard deviation [SD], 22.5) and 129.2 microg x h/ml (SD, 41.2) and the terminal half-lives were 1.1 h (SD, 0.3) and 0.9 h (SD, 0.2) when ceftriaxone was given alone and combined with itraconazole, respectively. Regarding itraconazole kinetics, ceftriaxone was shown to alter the disposition of the triazole. Contrary to what was expected, the AUC (from 0 to 8 h) decreased from 139.3 ng h/ml with itraconazole alone to 122.7 ng h/ml with itraconazole and ceftriaxone combined in pig 1, from 398.5 to 315.7 ng x h/ml in pig 2, and from 979.6 to 716.6 ng x h/ml in pig 3 (P of <0.01 by analysis of variance).

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Pharmacokinetics of Azithromycin Administered Alone and with Atovaquone in Human Immunodeficiency Virus-Infected Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.6.1516 ◽

1999 ◽

Vol 43 (6) ◽

pp. 1516-1519 ◽

Cited By ~ 5

Author(s):

Leock Y. Ngo ◽

Ram Yogev ◽

Wayne M. Dankner ◽

Walter T. Hughes ◽

Sandra Burchett ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Steady State ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Concentration Time ◽

Significant Difference ◽

Immunodeficiency Virus ◽

The Mean ◽

Clinically Significant ◽

To Receive

ABSTRACT To evaluate if atovaquone (ATQ) interacts pharmacokinetically with azithromycin (AZ) in human immunodeficiency virus-infected children, 10 subjects (ages, 4 to 13 years) were randomized in a crossover study to receive AZ (5 mg/kg/day) alone (ALONE) or AZ (5 mg/kg/day) and ATQ (30 mg/kg/day) simultaneously (SIM) prior to receiving AZ and ATQ staggered by 12 h. Despite a lack of significant difference in the mean AZ pharmacokinetic parameters, the steady-state values of AZ’s area under the concentration-time curve from 0 to 24 h and maximum concentration in serum were consistently lower (n = 7 of 7) for the SIM regimen than they were for the ALONE regimen. A larger study will be required to determine if ATQ affects AZ pharmacokinetics and efficacy in a clinically significant manner.

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Pharmacokinetic interaction between itraconazole and rifampin in Yucatan miniature pigs.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.9.2043 ◽

1996 ◽

Vol 40 (9) ◽

pp. 2043-2046 ◽

Cited By ~ 9

Author(s):

G Kaltenbach ◽

D Levêque ◽

J D Peter ◽

J Salmon ◽

H Elkhaili ◽

...

Keyword(s):

Steady State ◽

Standard Deviation ◽

Maximum Concentration ◽

Active Metabolite ◽

Pharmacokinetic Interaction ◽

Hepatic Metabolism ◽

Miniature Pig ◽

Time Curve ◽

Miniature Pigs ◽

Concentration Time

The objective of this study was to examine the effects of rifampin on itraconazole pharmacokinetics, at steady state, in three Yucatan miniature pigs. Daily for 3 weeks, the pigs received 200 mg of itraconazole orally at the beginning of each meal, and for the following 2 weeks they received itraconazole orally combined with intravenous administration of rifampin at 10 mg/kg/day. Coadministration of rifampin resulted in an 18-fold decrease in the maximum concentration of itraconazole in serum, from 113.0 (standard deviation [SD] 17.2) to 6.2 (SD, 3.9) ng/ml and a 22-fold decrease in the area under the concentration-time curve, from 1,652.7 (SD, 297.7) to 75.6 (SD, 30.0) ng.h/ml. The active metabolite of itraconazole, hydroxyitraconazole, was undetectable. This study demonstrates that rifampin affects itraconazole kinetics considerably at steady state in this miniature-pig model, probably by inducing hepatic metabolism of itraconazole.

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Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with human immunodeficiency virus infection.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.5.1231 ◽

1996 ◽

Vol 40 (5) ◽

pp. 1231-1236 ◽

Cited By ~ 15

Author(s):

B L Lee ◽

S Safrin ◽

V Makrides ◽

J G Gambertoglio

Keyword(s):

Human Immunodeficiency Virus ◽

Pneumocystis Carinii ◽

Pharmacokinetic Interaction ◽

Urinary Recovery ◽

Time Curve ◽

Concentration Time ◽

Pharmacokinetic Interactions ◽

Immunodeficiency Virus ◽

Blood And Urine Samples ◽

The Mean

Zidovudine is widely prescribed for the treatment of human immunodeficiency virus (HIV) infection. Trimethoprim and dapsone are commonly used in the management of Pneumocystis carinii pneumonia in HIV-infected patients. To examine the pharmacokinetic interactions among these drugs, eight HIV-infected patients (26 to 43 years old) with a mean CD4 count of 524.4 +/- 405.7 cells per mm3 received zidovudine (200 mg), trimethoprim (200 mg), and dapsone (100 mg) as single agents and in two- and three-drug combinations. Blood and urine samples were collected at a specified time and analyzed for zidovudine, zidovudine-glucuronide, trimethoprim, dapsone, and monoacetyl-dapsone concentrations under single-dose and steady-state conditions. Zidovudine did not influence the pharmacokinetic disposition of dapsone or trimethoprim. Dapsone had no effect on the pharmacokinetic disposition of zidovudine. Trimethoprim significantly decreased the renal clearance of zidovudine by 58% (5.0 +/- 1.8 versus 2.1 +/- 0.5 ml/min/kg of body weight [P < 0.05]). There was a concurrent 54% decrease in the mean urinary recovery of zidovudine (11.7 +/- 3.5 versus 5.4 +/- 3.0 [P < 0.05]), and the metabolic ratio was decreased by 78% (0.32 +/- 0.4 versus 0.07 +/- 0.05 [P < 0.05]). The mean area under the concentration-time curve from 0 to 6 h of the zidovudine-glucuronide/ zidovudine ratio was unchanged. We conclude that zidovudine, trimethoprim, and dapsone can be coadministered to patients with AIDS without significant pharmacokinetic interaction. However, in AIDS patients with liver impairment and impaired glucuronidation, doses of zidovudine may need to be decreased.

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Ritonavir-Enhanced Pharmacokinetics of Nelfinavir/M8 during Rifampin Use

Annals of Pharmacotherapy ◽

10.1345/aph.1c335 ◽

2003 ◽

Vol 37 (4) ◽

pp. 521-525 ◽

Cited By ~ 8

Author(s):

Alina S Bergshoeff ◽

Tom FW Wolfs ◽

Sibyl PM Geelen ◽

David M Burger

Keyword(s):

Steady State ◽

Protease Inhibitor ◽

Highly Active Antiretroviral Therapy ◽

Adult Population ◽

Plasma Concentrations ◽

Pharmacokinetic Interaction ◽

Male Infant ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Highly Active

OBJECTIVE: To describe a case of successful protease inhibitor–based highly active antiretroviral therapy (HAART) concomitant with rifampin. CASE SUMMARY: In a 7-month-old male infant with tuberculosis and HIV-1 infection, tuberculosis therapy including rifampin and HAART containing the protease inhibitor nelfinavir 40 mg/kg every 8 hours was started. Intensive steady-state pharmacokinetic sampling from baseline to 8 hours revealed very low plasma concentrations of nelfinavir: area under the plasma concentration–time curve (AUC0–24) <10% of adult population values for 750 mg every 8 hours and nonquantifiable concentrations of nelfinavir's principal metabolite (M8). Nelfinavir 40 mg/kg every 8 hours was then substituted with nelfinavir 30 mg/kg twice daily plus ritonavir 400 mg/m2 twice daily. Intensive steady-state (0–12 h) pharmacokinetic sampling was repeated. Nelfinavir concentrations had improved, but remained low when compared with adult population values of 1250 mg every 12 hours: AUC0–24 21.9 versus 47.6 mg/L•h (46%) and 12-hour trough level (C12) 0.25 versus 0.85 mg/L (29%). However, concentrations of M8 considerably exceeded population values: AUC0–24 57.5 versus 13.6 mg/L•h (443%) and C12 1.35 versus 0.28 mg/L (482%). Since M8 concentrations were highly elevated, pharmacokinetic parameters for (nelfinavir + M8) were used rather than those for nelfinavir alone. Thus, AUC0–24 (nelfinavir + M8) and C12 (nelfinavir + M8) comprised 130% and 142%, respectively of the adult population values. This, in addition to good clinical response and tolerability, favored continuation of the regimen. CONCLUSIONS: In an infant, nelfinavir-containing HAART was successfully used with rifampin after the addition of ritonavir. Ritonavir resolved the pharmacokinetic interaction between rifampin and nelfinavir by boosting nelfinavir and, especially, M8 concentrations. More research is needed to confirm these results.

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