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    Microenvironmental pH modifying films for buccal delivery of saquinavir: Effects of organic acids on pH and drug release in vitro
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    To investigate the mechanism of chelate-induced phytoremediation,effects of two kinds of low molecular weight organic acids including citric acid and malic acid on chemical speciation of Pb in soil were studied.Results showed that,for different pollution levels of soil(PbⅠ-PbⅣ),percentage of the most active exchangeable Pb increased significantly as concentration of organic acids were increased.So as to achieve the objective of activating Pb;The mobilization effect of Pb would increase along with concentration of citric acid,and with higher concentration of malic acid added,the mobilization effect of Pb first increased then kept on,when malic acid concentration was 10 mmol/kg and citric acid concentration was 20 mmol/kg,activation ability of malic acid and citric acid respectively reached the maximum value.By comparison,activation ability of citric acid was better than malic acid.
    Malic acid
    Organic acid
    Genetic algorithm
    Citations (2)
    Buccal films containing a pH modifying excipient may be able to increase bioavailability of drugs with pH-dependent solubility such as saquinavir. Access to suitable in vitro drug release testing methods may facilitate buccal formulation development. This study aimed to explore two release testing methods for characterising buccal films and to elucidate the relationship between microenvironmental pH (pHM, i.e. the pH around the swelling films) and saquinavir release. The Franz diffusion cell method was applicable to investigate the effect of hydroxypropyl methylcellulose (HPMC) grade on saquinavir release. Films containing HPMC K3 LV had a faster saquinavir release than films containing HPMC K100 LV. A UV/Vis imaging method was developed to visualise saquinavir release and pHM changes during the initial dissolution. Within 5 min, the pHM decreased from 6.8 to around 5.4 for HPMC K100 LV-based films containing 11.1 % or 16.6 % (w/w) malic acid. Subsequently, the pHM increased due to increasing concentrations of saquinavir. An increase in malic acid content led to a faster saquinavir release. The combination of methods may be broadly applicable for excipient screening in development of buccal formulations. The imaging approach holds promise for characterizing other pH modifying formulation principles.
    Saquinavir
    Excipient
    Citations (18)
    The components and contents of organic acids in pineapple mature fruits from 56 germplasms were determined by high performance liquid chromatography(HPLC).The results showed that the major components of organic acids in pineapple fruits were citric acid,malic acid and quinic acid.Citric acid was ranged from 1.80 mg/g FW to 8.09 mg/g FW,with a mean of 4.82 mg/g FW,and citric acid content was the highest value,which accounted for 64.73% of the value of organic acids,followed by quinic acid and malic acid.The variation range of quinic acid was relatively stable among different germplasms,while the value of citric acid and malic acid varied greatly,showing as 33.86% and 37.92%,respectively.All the germplasms could be classified into citric acid dominant based on their organic acid composition.
    Quinic acid
    Malic acid
    Organic acid
    Germ plasm
    Citations (0)
    Significant variation in organic acid components was detected in mature fruits of 101 apple accessions using high-performance liquid chromatography. The Malus species predominantly accumulated malic acid and citric acid, whereas wild fruits exhibited significantly higher levels of organic acid content than that in cultivated fruits. Differential accumulation patterns during fruit developmental stages was detected between malic acid and citric acid, thus suggesting a complex genetic regulation mechanism of organic acid metabolism in apple fruit. A highly positive correlation was detected between fruit total organic acid content with malic acid and citric acid content, thus suggesting that malic acid and citric acid are the principal determinants of apple fruit acidity. In contrast to malic acid, citric acid was predominantly detected in partial wild apples, while extremely low to undetectable concentrations of citric acid were observed in cultivated apple fruits; this is likely due to the genetic effects of parental characters. Our results provide vital information that could be useful for future studies on genetic analysis and improvement of organic acid accumulation in apple fruits.
    Malic acid
    Malus
    Organic acid
    Citations (67)
    Citric acid is a regular ingredient in many vase solution formulations but pre-harvest use of citric acid is a novel method in vase life extension of cut flowers, which is reported on tuberose earlier. In order to verify previous result, and check for possible substitution of citric acid by malic acid, the current research was designed. Citric acid (0, 0.075, 0.15% w/v) and malic acid (0, 0.075, 0.15% w/v) were used in a factorial design with three replications. Foliar sprays were applied two times during growth period of Lilium plants. The results point out that 0.15% citric acid alone had increased vase life from 11.8 in control treatment to 14 days (α < 0.05). The interesting finding was the effect of citric acid on bulbil weight, which was decreased from 9 g in control to 1.5 g in treatment containing combination of 0.075% citric acid and 0.075% malic acid. Malic acid while having no direct effect on pre-mentioned traits surprisingly increased the chlorophyll content significantly. The interaction effect between citric acid and malic acid on vase life and chlorophyll content proved significant and was evident in results, both as antagonistic and synergistic in various traits.
    Malic acid
    Vase life
    Citations (47)
    Saquinavir belongs to the class of HIV protease inhibitors, and is a potent inhibitor of HIV-1 replication in vitro and in vivo. Saquinavir (Invirase) displays a limited and variable oral bioavailability of approximately 4%[1] The affinity of saquinavir for P-glycoprotein may play a significant role in this respect [2] Saquinavir must be taken with food, because its oral bioavailability when administered on an empty stomach is substantially lower [1] Because of its limited oral bioavailability and the extensive metabolism of the drug by the cytochrome P450 enzyme system (CYP450), some patients exhibit low exposure to saquinavir, putatively leading to an increased risk of virological failure [3] The addition of ritonavir (an inhibitor of CYP450 and P-glycoprotein) to a saquinavir-containing regimen is a widely applied strategy to increase the exposure to saquinavir. The increase in the concentration of saquinavir by the concomitant use of ritonavir is in the range of 20-fold or more. This allows for a reduced dose and dosing frequency of saquinavir (e.g. 400 mg twice a day of both saquinavir and ritonavir), while a high exposure to saquinavir is achieved [4] Currently, ritonavir is temporarily only available as a liquid formulation (because of stability problems with the capsule formulation), which is generally not well tolerated because of its taste. Many patients using ritonavir (including those who also use saquinavir) are thus confronted with a serious problem that has a negative influence on compliance. During our routine therapeutic drug monitoring programme of antiretroviral drugs, we noted that two patients had a greater than five-fold higher exposure to saquinavir than anticipated. Their antiretroviral regimen consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and saquinavir. Further investigation ascertained that these patients concomitantly used itraconazole, an antifungal drug and an inhibitor of CYP450 and P-glycoprotein [5] This prompted us to perform a pilot pharmacokinetic study to investigate in more detail the effect of the addition of itraconazole on the exposure to saquinavir as part of a triple antiretroviral drug regimen with two NRTI. In three HIV-1-infected male patients who used saquinavir (Invirase 1200 mg three times a day) for at least 3 months in combination with two NRTI, but without the concomitant use of other drugs, the pharmacokinetics of saquinavir were determined. Patients were admitted to the hospital after an overnight fast and ingested their drugs during a meal. Over an 8 h interval a total of 12 venous blood samples were drawn, plasma was isolated by centrifugation and immediately stored at −30°C until analysis. Itraconazole was subsequently added to the regimen (200 mg a day, after a loading dose of 200 mg twice a day for 3 days), and the patients returned to the hospital after 14 days and underwent the same procedure to assess the pharmacokinetics of saquinavir, itraconazole and its active metabolite, hydroxyitraconazole. Plasma concentrations of saquinavir, itraconazole and hydroxyitraconazole were quantified using validated high-performance liquid chromatography assays [6,7] Pharmacokinetic parameters were calculated using non-compartmental methods. This analysis revealed that the saquinavir area under the plasma concentration versus time curve (AUC) showed a median five-fold increase (range 2.5–6.9) after the addition of itraconazole. For the maximum and trough concentration, the median increases were 4.8-fold (range 2.0–5.4) and 3.1-fold (range 1.6–16.8), respectively. The individual saquinavir plasma concentration versus time curves before and after the addition of itraconazole are shown in Fig. 1. Saquinavir exposure was comparable to that observed when combined with ritonavir (using a dosage of 400 mg twice a day for saquinavir and ritonavir) [4]Fig. 1.: Steady-state saquinavir plasma concentration versus time curves with (•) and without (○) the co-administration of 200 mg itraconazole a day. Values for the area under the plasma concentration versus time curve (AUC)0–8 h] (in h*mg/l) with and without the co-administration of itraconazole were 8.72 and 1.27 for patient 1, 15.36 and 6.15 for patient 2, and 7.40 and 1.48 for patient 3, respectively.Itraconazole and hydroxyitraconazole pharmacokinetics were in agreement with those previously reported (the median extrapolated AUC[0–24 h] for itraconazole and hydroxyitraconazole was 13.3 and 17.1 h*mg/l, respectively) [8] The combination of itraconazole and saquinavir was well tolerated during the 2 week period. Interestingly, in patient 3 the plasma HIV-1 RNA concentration became undetectable (< 400 copies/ml) during this period for the first time after years of antiretroviral therapy. The currently reported pharmacokinetic interaction may have been caused by the inhibition of P-glycoprotein activity by itraconazole (leading to an increased absorption of saquinavir) or a decreased metabolism as a result of the inhibition of CYP450 by itraconazole (and a decreased elimination of saquinavir). It was recently reported that the combination of itraconazole and indinavir, or the combination of ritonavir and saquinavir was not tolerated because of high exposure to itraconazole and, putatively, the protease inhibitors. The use of itraconazole in combination with a pro-tease inhibitor should therefore be limited to saquinavir [9] The putatively enhanced virological effect and the safety of saquinavir when combined with itraconazole is currently being explored in a large randomized study. Although these results are not yet available, physicians may consider itraconazole as an alternative for ritonavir when combined with saquinavir, if the liquid formulation of ritonavir cannot be tolerated and further treatment with saquinavir is desired. It should be realized, however, that the antiretroviral effect of ritonavir or any synergism is lacking in this case. Furthermore, if low exposure to saquinavir is observed (or anticipated), itraconazole may be used to increase its oral bioavailability. Because the reported pharmacokinetic interaction with itraconazole appears to be smaller compared with ritonavir, the dosage of saquinavir should not be reduced when combined with itraconazole. Cornelis H.W. Koksa Rolf P.G. Van Heeswijka Agnes I. Veldkampa Pieter L. Meenhorstb Jan-Willem Mulderb J.T.M. van der Meerc Jos H. Beijnena Richard M.W. Hoetelmansa
    Saquinavir
    Ritonavir
    Protease inhibitor (pharmacology)
    Abstract A reappraisal is offered of old and new observations of substantial day‐night changes of citric‐acid levels in crassulacean acid metabolism (CAM). In contrast to malic acid, the biochemical consequences and the ecophysiological significance of nocturnal accumulation of citric acid in CAM have not received due attention. Considerations show that citric‐acid accumulation does not provide a means for nocturnal storage of CO 2 . It may, however, serve carbon retention by internal recycling and sustain the water budget affording a vacuolar osmoticum. Since citric‐acid accumulation energetically is considerably more favourable than malic‐acid accumulation, this may have important ecophysiological implications. The questions raised by these reflections can and need to be tackled experimentally.
    Malic acid
    Saquinavir
    Nelfinavir
    Ritonavir
    Protease inhibitor (pharmacology)
    Tolerability
    Reverse-transcriptase inhibitor
    Indinavir