LitCovid-sentences  

PMC:7204663 / 1488-16090 JSONTXT 12 Projects

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T11 0-165 Sentence denotes Recent reports identified significant reduction or disappearance of viral load in COVID-19 patients given a combination of hydroxychloroquine and azithromycin [1,2].
T12 166-323 Sentence denotes However, other clinical studies could not confirm these early findings [3] and there are considerable concerns about the safety of this drug combination [4].
T13 324-518 Sentence denotes The present communication discusses some common pharmacokinetic properties of these two drugs that may be linked to a potential underlying mechanism of action for their pharmacological activity.
T14 520-542 Sentence denotes 1 Chemical structures
T15 543-619 Sentence denotes Fig. 1 shows the chemical structures of hydroxychloroquine and azithromycin.
T16 620-760 Sentence denotes Although the two compounds are from two chemically distinct classes, they have a structural similarity that is pharmacokinetically relevant.
T17 761-880 Sentence denotes Both compounds are multibasic amines with pKa values that are susceptible to protonation in the physiological pH range.
T18 881-947 Sentence denotes Azithromycin has two nitrogens with pKa values of 8.1 and 8.8 [5].
T19 948-1027 Sentence denotes Hydroxychloroquine has three nitrogens with pKa values of 4.0, 8.3 and 9.7 [6].
T20 1028-1158 Sentence denotes However, only the two nitrogens with the higher values (shown in circles in Fig. 1) are protonated under physiological conditions.
T21 1159-1225 Sentence denotes Fig. 1 Chemical structures of hydroxychloroquine and azithromycin.
T22 1226-1280 Sentence denotes The circles indicate the pH-sensitive basic nitrogens.
T23 1282-1307 Sentence denotes 2 Lysosomal ion-trapping
T24 1308-1473 Sentence denotes If the pH of the molecular environment is lower (more acidic), more nitrogens are protonated, which in turn hinders the now-charged moieties from crossing membranes.
T25 1474-1594 Sentence denotes This is particularly relevant for the intracellular distribution of basic drugs crossing between the cytosol (pH approx.
T26 1595-1642 Sentence denotes 7.4) and the acidic lysosomal space (pH approx.
T27 1643-1648 Sentence denotes 5.0).
T28 1649-1693 Sentence denotes Fig. 2 shows this distribution conceptually.
T29 1694-1869 Sentence denotes Basic compounds are in an equilibrium of a less polar unionized form (B) that can easily cross membranes, and a polar protonated form (BH+) that cannot easily cross membranes.
T30 1870-2062 Sentence denotes As the unionized drug enters the acidic environment of the lysosome, it will be protonated and ‘trapped’ in the lysosome as the protonated form BH+ cannot easily diffuse back into the cytosol.
T31 2063-2140 Sentence denotes As a result, high concentrations of the compound can accumulate in lysosomes.
T32 2141-2210 Sentence denotes This concept of “ion-trapping” has been described and reviewed [7,8].
T33 2211-2440 Sentence denotes The magnitude of this accumulation depends on the mathematical relationship of the pKa of the compound of interest, its permeability, and the pH gradient between the two environments (e.g. cytosol [pH 7.4] and lysosome [pH 5.0]).
T34 2441-2603 Sentence denotes If there is no permeability limitation, the expected ratio or concentration gradient can be calculated based on the well-known Henderson-Hasselbalch equation [8].
T35 2604-2875 Sentence denotes If the compound of interest has only one basic group, the ratio between the concentrations will be:(1) R=C1C2=H1+KaH2+Kawhere H1 and H2 are the respective proton concentrations (=10−pH) of the two environments (pH 5 and 7.4) and Ka is the dissociation constant (=10−pKa).
T36 2876-2982 Sentence denotes Fig. 3 A shows the magnitude of the resulting accumulation as a function of the pKa value of the compound.
T37 2983-3093 Sentence denotes Accumulation of up to 250-fold higher concentrations in lysosomes can be explained by the described mechanism.
T38 3094-3135 Sentence denotes Fig. 2 Concept of lysosomal ion-trapping.
T39 3136-3311 Sentence denotes Basic compounds are in an equilibrium of a less polar unionized form (B) that can easily cross membranes, and a polar protonated form (BH+) that cannot easily cross membranes.
T40 3312-3502 Sentence denotes As the unionized drug enters the acidic environment of a lysosome, it will be protonated and ‘trapped’ in the lysosome as the protonated form BH+ cannot easily diffuse back into the cytosol.
T41 3503-3584 Sentence denotes As a result, high concentrations of the compound can accumulate in the lysosomes.
T42 3585-3677 Sentence denotes Fig. 3 Magnitude of lysosomal ion-trapping depending on the pKa of the compound of interest.
T43 3678-3775 Sentence denotes For a monobasic compound (A), up to 250-fold higher concentrations are possible depending on pKa.
T44 3776-3845 Sentence denotes For a dibasic compound (B), the accumulation can be over 60 000-fold.
T45 3846-3922 Sentence denotes These simulations assume a pH gradient of 5.0 (lysosomes) and 7.4 (cytosol).
T46 3923-4032 Sentence denotes However, in cases where there are two basic centers in the molecule, this effect is considerably potentiated.
T47 4033-4217 Sentence denotes There are two different monobasic species that are produced by protonation of the respective nitrogens, and neither of these can easily diffuse from the lysosome back into the cytosol.
T48 4218-4332 Sentence denotes Furthermore, both species are in equilibrium with the biprotonated species, which is also trapped in the lysosome.
T49 4333-4481 Sentence denotes Therefore, there are three different forms of the molecule (two monoprotonated and one biprotonated) that cannot easily diffuse back to the cytosol.
T50 4482-4534 Sentence denotes This tremendously magnifies the ion-trapping effect.
T51 4535-4823 Sentence denotes The expected accumulation ratio under these conditions is calculated as follows:(2) R=C1C2=H12+Ka1*H1+Ka1*Ka2H22+Ka1*H2+Ka1*Ka2where H1 and H2 are the respective proton concentrations (=10−pH) of the two environments (pH 5 and 7.4) and Ka1 and Ka2 are the dissociation constant (=10−pKa).
T52 4824-4970 Sentence denotes Fig. 3B shows the magnitude of the resulting accumulation as a function of the pKa value of the compound, assuming equal values for pKa1 and pKa2.
T53 4971-5088 Sentence denotes Accumulation of up to 60 000-fold higher concentrations in the lysosomes can be explained by the described mechanism.
T54 5090-5111 Sentence denotes 3 Hydroxychloroquine
T55 5112-5361 Sentence denotes When the above described concepts are applied to hydroxychloroquine, the expected accumulation ratio in lysosomes compared with cytosol is calculated as 56 000-fold; therefore, after drug intake a large fraction of the dose will reside in lysosomes.
T56 5362-5478 Sentence denotes This is confirmed by the known pharmacokinetic parameters for hydroxychloroquine derived from plasma concentrations.
T57 5479-5693 Sentence denotes After intravenous administration to healthy volunteers (average weight 63.5 kg), the volume of distribution of hydroxychloroquine was reported to be over 44 000 L, which is equivalent to approximately 700 L/kg [9].
T58 5694-5852 Sentence denotes This means that most of the drug in the body resides in the tissues, which is consistent with the predicted extraordinarily high lysosomal accumulation ratio.
T59 5853-5953 Sentence denotes Furthermore, it explains the very long half-life (approximately 40 days) reported in the same study.
T60 5954-6085 Sentence denotes In this study, hydroxychloroquine could still be detected in blood more than 6 months after a single dose administration of 310 mg.
T61 6087-6102 Sentence denotes 4 Azithromycin
T62 6103-6317 Sentence denotes When the same ion-trapping concepts are applied to azithromycin, the expected accumulation ratio in lysosomes compared with cytosol is calculated as 52 000-fold, which is very similar to that of hydroxychloroquine.
T63 6318-6477 Sentence denotes After administration of azithromycin, a large fraction of the dose will reside in lysosomes where it also binds to acidic phospholipids [10], [11], [12], [13].
T64 6478-6545 Sentence denotes A clinical study supports azithromycin lysosomal accumulation [14].
T65 6546-6699 Sentence denotes In this study, the experimentally measured average total azithromycin concentrations in polymorphonuclear white blood cells (PMLs) was over 14 000 ng/mL.
T66 6700-6912 Sentence denotes However, the model-predicted unionized azithromycin concentration of 6.0 ng/mL in the cytosol of PMLs was comparable to the measured interstitial concentrations in the muscle (8.7 ng/mL) and subcutis (4.1 ng/mL).
T67 6913-7071 Sentence denotes Hence, the measured concentrations in white blood cells was approximately 2000-fold higher than the measured unbound concentrations in the interstitial space.
T68 7072-7357 Sentence denotes Considering the lysosomal volume is estimated to range between 0.5 to 5% of the cellular volume depending on cell type [14], [15], [16], [17], these concentrations are consistent with the expected magnitude of lysosomal accumulation and explain these very high cellular concentrations.
T69 7358-7483 Sentence denotes Just as for hydroxychloroquine, the pharmacokinetic parameters of azithromycin confirm these extreme distribution properties.
T70 7484-7638 Sentence denotes The volume of distribution of azithromycin was reported to be 31 L/kg and the half-life was 68 h, despite a relatively rapid clearance of 630 mL/min [18].
T71 7639-7746 Sentence denotes Furthermore, the pharmacokinetics of azithromycin have been shown to be affected by the disease state [19].
T72 7747-7896 Sentence denotes In a preclinical investigation, azithromycin was injected into rats and interstitial concentrations were measured in both thighs using microdialysis.
T73 7897-7949 Sentence denotes After 3 h, an infection was induced in only one leg.
T74 7950-8073 Sentence denotes Shortly after, the unbound interstitial tissue concentrations increased in the infected leg, without any additional dosing.
T75 8074-8207 Sentence denotes The results can be explained by macrophages loaded with lysosomal azithromycin migrating to and releasing drug at the infection site.
T76 8209-8237 Sentence denotes 5 Discussion and conclusion
T77 8238-8489 Sentence denotes Although the present paper is focused on the pharmacokinetic properties of hydroxychloroquine and azithromycin, a similar intracellular accumulation in the lysosomal space can be expected and has been reported for chloroquine as early as 1974 [20,21].
T78 8490-8587 Sentence denotes The pharmacokinetics of chloroquine and hydroxychloroquine have been described to be similar [9].
T79 8588-8701 Sentence denotes The very high accumulation of these drugs in lysosomes produces very high local concentrations of both compounds.
T80 8702-8794 Sentence denotes Furthermore, the uptake of these basic drugs into lysosomes increases the lysosomal pH [22].
T81 8795-8992 Sentence denotes However, it is difficult to estimate the magnitude and time course of this alkalization as there is continuous acidification of the lysosomal space by proton pumps that function to maintain low pH.
T82 8993-9118 Sentence denotes The combination of chloroquine and azithromycin is not new, and synergistic effect against malaria has been reported [23,24].
T83 9119-9192 Sentence denotes Hydroxychloroquine and chloroquine have similar efficacy against malaria.
T84 9193-9332 Sentence denotes Although hydroxychloroquine has a preferred safety profile, more pharmacodynamic information is available for chloroquine [25], [26], [27].
T85 9333-9436 Sentence denotes Several studies point to mechanisms for the potential antiviral action of chloroquine and azithromycin.
T86 9437-9604 Sentence denotes Chloroquine was shown to impair early stages of virus replication by interfering with the pH-dependent endosome-mediated viral entry of several different viruses [28].
T87 9605-9766 Sentence denotes Due to the alkalization of endosomes, chloroquine was an effective in vitro treatment against Chikungunya virus when added to Vero cells prior to virus exposure.
T88 9767-9872 Sentence denotes A pH-dependent mechanism of entry of coronavirus into target cells was also reported for SARS-CoV-1 [29].
T89 9873-10058 Sentence denotes The activation step that occurs in endosomes at acidic pH results in fusion of the viral and endosomal membranes, leading to the release of the viral SARS-CoV-1 genome into the cytosol.
T90 10059-10330 Sentence denotes In the absence of antiviral drug, the virus is targeted to the lysosomal compartment where the low pH, along with the action of enzymes, disrupts the viral particle, thus liberating the infectious nucleic acid and, in several cases, enzymes necessary for its replication.
T91 10331-10425 Sentence denotes Hence, the lysosomal space has been proposed as a major target site to tackle SARS-CoV-2 [30].
T92 10426-10616 Sentence denotes Macrolides such as azithromycin are very commonly used antibacterial agents; however, they have also received considerable attention for their anti-inflammatory and immunomodulatory actions.
T93 10617-10722 Sentence denotes These two properties may ensure some efficacy in a wide spectrum of respiratory viral infections [31,32].
T94 10723-10904 Sentence denotes Both in vitro and in vivo studies indicate efficacy of macrolides in respiratory viral infections, including rhinovirus (RV), respiratory syncytial virus (RSV), and influenza virus.
T95 10905-11086 Sentence denotes Macrolides also reduced the release of proinflammatory cytokines, which were induced by RSV infection, viral titers, RNA of RSV replication, and the susceptibility to RSV infection.
T96 11087-11250 Sentence denotes Similar effects of macrolides on influenza virus infection and augmentation of IL-12 by macrolides, which is essential in reducing virus yield, were reported [32].
T97 11251-11368 Sentence denotes As with the use of any drug or drug combination, the potential benefit has to be weighed against any safety concerns.
T98 11369-11472 Sentence denotes Prolongation of QT interval and cases of torsades de pointes have been reported for both drugs [18,33].
T99 11473-11667 Sentence denotes Hydroxychloroquine prolongs the QT interval and, according to its prescribing information, should not be administered with other drugs that have the potential to induce cardiac arrhythmias [33].
T100 11668-11805 Sentence denotes There may be an increased risk of inducing ventricular arrhythmias if the drug is used concomitantly with other arrhythmogenic drugs [4].
T101 11806-11884 Sentence denotes Most relevant interaction data with azithromycin is available for chloroquine.
T102 11885-12134 Sentence denotes QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 mg once daily) [18].
T103 12135-12242 Sentence denotes Co-administration of azithromycin increased the QTc interval in a dose- and concentration-dependent manner.
T104 12243-12465 Sentence denotes Compared with chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.
T105 12466-12589 Sentence denotes Furthermore, studies in pigs revealed that azithromycin/chloroquine combinations did not increase cardiac instability [34].
T106 12590-12726 Sentence denotes In a clinical interaction study between azithromycin and chloroquine, no clinically relevant pharmacokinetic changes were observed [23].
T107 12727-12771 Sentence denotes However, increases in QTc values were noted.
T108 12772-12961 Sentence denotes Although mean increases were numerically greater for the azithromycin plus chloroquine group compared with the chloroquine alone group, these differences were not statistically significant.
T109 12962-13066 Sentence denotes Administered alone and together, chloroquine and azithromycin were well tolerated overall in this study.
T110 13067-13263 Sentence denotes More investigations with hydroxychloroquine are needed as well as finetuning the optimum dosing regimen to get a clearer picture of the expected risk-benefit assessment in these severe infections.
T111 13264-13469 Sentence denotes These dose optimization attempts will have to utilize ways to estimate the respective infection site concentration; this is very challenging due to the tremendous differences in subcellular concentrations.
T112 13470-13641 Sentence denotes Average tissue concentrations based on lung/blood ratios obtained from animal studies have been proposed and applied but may not be appropriate for dose optimization [35].
T113 13642-13837 Sentence denotes The unusual pharmacokinetic properties of these two drugs may make them suitable partners for an ion-trapping-mediated mechanism of action where lysosomal drug accumulation delivers local action.
T114 13838-13894 Sentence denotes These two drugs have very large volumes of distribution.
T115 13895-14095 Sentence denotes In a widely used long list of pharmacokinetic properties of the most commonly used drugs, chloroquine and azithromycin have the largest volumes of distribution (hydroxychloroquine is not listed) [36].
T116 14096-14213 Sentence denotes Short-term use of hydroxychloroquine with azithromycin may have clinical impact early in the progress of COVID [1,2].
T117 14214-14339 Sentence denotes An early diagnosis combined with a safe and effective treatment before more serious symptoms occur would be highly desirable.
T118 14340-14533 Sentence denotes Both of these low-cost drugs have been widely used for decades with acceptable safety that could expedite rapid use if a clinical benefit is established in rigorous safety and efficacy studies.
T119 14534-14602 Sentence denotes These studies are currently ongoing and will provide solid guidance.