Acute hypopyon uveitis in a patient with acquired immunodeficiency syndrome treated for systemic Mycobacterium avium complex (MAC) infection with rifabutin

Background: Hypopyon-uveitis has been identified as a dosage-dependent side effect in patients with acquired immunodeficiency syndrome who are treated for Mycobacterium avium complex (MAC) infection with systemic rifabutin. Patients and methods: We report a 38-year-old female AIDS patient with bilateral hypopyon uveitis under therapy with rifabutin in combination with clarithromycin and indinavir. Results: At the time of presentation of the bilateral hypopyon uveitis the patient was treated with rifabutin (300 mg/day), clarithromycin (1000 mg/day) and ethambutol (1000 mg/day) for an M. avium complex infection. Also, the patient received the protease inhibitor indinavir. The rifabutin dose was reduced to 150 mg/day. Hypopyon and inflammation resolved under therapy with steroids. Conclusions: The concomitant use of rifabutin, clarithromycin, and protease inhibitors may lead to hypopyon uveitis. Reduction of dosage of rifabutin (150 mg/day) and treatment with topical steroids are required.      

Therapeutic Drug Monitoring of Indinavir in HIV-Infected Patients Undergoing HAART

Background: Therapeutic drug monitoring (TDM) of protease inhibitors (PI) is gaining increasing importance for the management of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). The PI indinavir (IDV) is widely used in HAART regimens. Combinations of IDV with ritonavir (RTV) have been used to increase the plasma concentration of IDV. However, the desirable IDV concentration range in clinical practice remains to be elucidated. Patients and Methods: To study the value of TDM for IDV in clinical practice, a retrospective analysis of 501 plasma samples of patients treated with IDV in various dosages was performed. IDV levels were determined during routine outpatient visits. Analysis was performed by high pressure liquid chromatography (HPLC) with UV detection. Results: A widespread range of IDV plasma concentrations was seen both within and between patients. The mean IDV level during therapy with IDV 2.4 g/d was 3,260 ng/ml (95% CI: 2,903 ng/ml; 3,618 ng/ml). IDV levels at a dose of IDV 1.6 g/d in combination with RTV resulted in a mean IDV plasma concentration of 4,191 ng/ml (95% CI: 3,356 ng/ml; 5,016 ng/ml). There was no significant difference between plasma levels at the doses of 2.4 g/d and 1.6 g/d. 35 of all 130 patients treated with IDV reached only suboptimal IDV plasma concentrations below the limit of 150 ng/ml. There was no statistically significant difference between the number of patients below an IDV plasma concentration of 150 ng/ml in the various dosage regimens. Conclusion: During therapy with IDV in a b.i.d. scheme, similar IDV plasma concentrations and a comparable number of patients with subinhibitory plasma concentrations were observed when compared to a therapeutic regimen with t.i.d. dosing. In this study, even at various times of plasma sampling after oral ingestion, TCM facilitated the surveillance of patients compliance. Received: August 07, 2000 · Revision accepted: August 27, 2001     

Indinavir-Urolithiasis bei HIV-positiven Patienten

ZusammenfassungZielsetzung Indinavirsulfat (Crixivan^®) ist ein Proteaseinhibitor, der seit 1996 erfolgreich bei der Behandlung HIV-positiver Patienten eingesetzt wird. Etwa 10% aller Patienten entwickeln unter Indinavirtherapie Harnsteine aus reinem Indinavir, die röntgenologisch in der konventionellen Abdomenübersichtsaufnahme und in der Nativspiralcomputertomographie nichtschattengebend sind. Anhand 20 eigener Patienten sollen Behandlung und Prophylaxe der durch Indinavir bedingten Urolithiasis dargestellt werden.Material und Methoden 20 HIV-positive Patienten entwickelten nach 5- bis 8-monatiger (durchschnittlich 6,3 Monate) Therapie mit Indinavir (3-mal 800 mg/Tag p.o.) eine Urolithiasis. Hierbei litten 17 Patienten unter einer akuten einseitigen Nierenkolik mit sonographisch darstellbarer Obstruktion des Nierenbeckensystems. Drei Patienten bekamen eine schwere Azotämie ohne den sonographischen Befund einer Harnstauungsniere. Bei allen Patienten wurde als konservative Therapie die Flüssigkeitszufuhr gesteigert, sodass eine Urinproduktion von mindestens 2 l/Tag erreicht wurde. Der Urin wurde mit L-Methionin angesäuert, dabei war der angestrebte Urin-pH-Wert 5,3–5,8. Des Weiteren wurde das Indinavir für eine Woche abgesetzt. Einige Patienten wurden zusätzlich endoskopischen Maßnahmen (Ureteroskopie, DJ-Katheter, Nephrostomie) unterzogen.Ergebnisse Bei allen Patienten mit durch Indinavir bedingten Harnleitersteinen wurde die Obstruktion beseitigt und bei allen 3 Patienten mit beidseitiger Indinavir-Verstopfungsniere wurde die Nierenfunktion normalisiert. Die Steigerung der Flüssigkeitszufuhr, besonders während der ersten 2 h nach Medikamenteneinnahme und auch nachts, konnte als alleinige Maßnahme erfolgreich die rezidivierende Bildung von durch Indinavir bedingten Harnsteinen verhindern.Schlussfolgerung Die Trias Indinavirtherapie, Nierenkolik mit sonographisch darstellbarer Dilatation des Nierenbeckensystems, Fehlen von schattengebenden Konkrementen bei Patienten ohne Steinanamnese sollte immer Anlass zur klinischen Verdachtsdiagnose einer Indinavir-Urolithiasis geben. Dasselbe gilt, wenn statt einer Nierenbeckendilatation eine Niereninsuffizienz ohne Steinanamnese und ohne Ursache für ein prärenales Nierenversagen in Verbindung mit Indinavirtherapie und dem Fehlen von schattengebenden Konkrementen auftritt. Dies ist eine endscheidende Voraussetzung für eine erfolgreiche konservative Therapie.     

The ICH guidance in practice: stress degradation studies on indinavir sulphate and development of a validated specific stability-indicating HPTLC assay method

A sensitive, selective, precise and stability-indicating high-performance thin layer chromatography (HPTLC) method for analysis of indinavir sulphate both as a bulk drug and in formulations was developed and validated. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of carbon tetrachloride/chloroform/methanol/10% v/v ammonia (4:4.5:1.5:0.05, v/v/v/v). Densitometric analysis of indinavir sulphate was carried out in the absorbance mode at 260 nm. This system was found to give compact spots for indinavir sulphate (Rf value of 0.43 +/- 0.02, for six replicates). Indinavir sulphate was subjected to acid and alkali hydrolysis, oxidation, dry and wet heat treatment, and photo degradation. The drug undergoes degradation under acidic and basic conditions, oxidation, dry and wet heat treatment, and photo degradation. Also the degraded products were well resolved from the pure drug with significantly different Rf values. The method was validated for linearity, precision, robustness, limit of detection (LOD), limit of quantitation (LOQ), specificity and accuracy. Linearity was found to be in the range of 100-6000 ng/spot with significantly high value of correlation coefficient r2 = 0.997 +/- 0.64. The linear regression analysis data for the calibration plots showed good linear relationship with r2 = 0.999 +/- 0.002 in the working concentration range of 1000-6000 ng/spot. The LOD and LOQ were 40 and 120 ng/spot, respectively. Statistical analysis proves that the method is repeatable and specific for the estimation of the said drug. As the method could effectively separate the drug from its degradation products, it can be employed as a stability-indicating one. Moreover, the proposed HPTLC method was utilized to investigate the kinetics of acid degradation process. Arrhenius plot was constructed and activation energy was calculated.     

Novel therapeutic biosensor for indinavir—A protease inhibitor antiretroviral drug

An amperometric drug metabolism biosensor consisting of cytochrome P450-3A4 (CYP3A4) encapsulated in a didodecyldimethylammonium bromide (DDAB) vesicular system on a Pt disk electrode was developed for the determination of indinavir, a protease inhibitor antiretroviral drug. Cyclic, square wave and pulse voltammetric responses of the bioelectrode showed quasi-reversible electrochemistry of the Fe³⁺/Fe²⁺ redox species of the heme thiolate CYP3A4 enzyme under aerobic and anaerobic conditions. The biosensor exhibited excellent response to indinavir with a detection limit and response time of 6.158 × 10⁻² mg L⁻¹, and 40 s, respectively. The detection limit is well below the plasma concentration of indinavir (8 h after intake) which range from 0.13 to 8.6 mg L⁻¹.     

Papillary Necrosis Associated with the HIV Protease Inhibitor Indinavir

The HIV protease inhibitor indinavir may cause nephrolithiasis and interstitial nephritis. The renal consequences of indinavir-associated nephrotoxicity are uncertain. We report a case of papillary necrosis in a patient treated with indinavir. An asymptomatic HIV-infected woman experienced right-sided renal colicky pain during treatment with indinavir. She passed a non-solid stone and continued indinavir treatment. Intravenous pyelogram performed 20 months later following an episode of left-sided colicky pain showed right-sided papillary necrosis. Indinavir-associated nephrolithiasis and chronic interstitial nephritis were the only possible causes identified in this patient. Physicians should be aware that indinavir nephrolithiasis may cause papillary necrosis. Received: July 25, 2000 · Revision accepted: March 2, 2001     

Novel protease inhibitor-loaded Nanoparticle-in-Microparticle Delivery System leads to a dramatic improvement of the oral pharmacokinetics in dogs

With the advent of the Highly Active Antiretroviral Therapy, the morbidity and the mortality associated to HIV have been considerably reduced. However, 35–40 million people bear the infection worldwide. One of the main causes of therapeutic failure is the frequent administration of several antiretrovirals that results in low patient compliance and treatment cessation. In this work, we have developed an innovative Nanoparticle-in-Microparticle Delivery System (NiMDS) comprised of pure drug nanocrystals of the potent protease inhibitor indinavir free base (used as poorly water-soluble model protease inhibitor) produced by nanoprecipitation that were encapsulated within mucoadhesive polymeric microparticles. Pure drug nanoparticles and microparticles were thoroughly characterized by diverse complementary techniques. NiMDSs displayed an encapsulation efficiency of approximately 100% and a drug loading capacity of up to 43% w/w. In addition, mucoadhesiveness assays ex vivo conducted with bovine gut showed that film-coated microparticles were retained for more than 6 h. Finally, pharmacokinetics studies in mongrel dogs showed a dramatic 47- and 95-fold increase of the drug oral bioavailability and half-life, respectively, with respect to the free unprocessed drug. These results support the outstanding performance of this platform to reduce the dose and the frequency of administration of protease inhibitors, a crucial step to overcome the current patient-incompliant therapy.     

国产硫酸茚地那韦胶囊人体药动学及生物等效性研究

目的研究国产与进口硫酸茚地那韦胶囊的生物等效性。方法20名健康男性志愿者采用随机交叉给药方案,分别单剂量口服800mg的国产硫酸茚地那韦胶囊(受试制剂)与进口硫酸茚地那韦胶囊(参比制剂),以高效液相色谱法测定茚地那韦的血药浓度。结果受试制剂与参比制剂的Cmax分别为(13·51±3·23)、(13·14±3·92)mg/L,tmax分别为(0·63±0·17)、(0·63±0·18)h,AUC0～8分别为(23·62±7·27)、(23·02±6·24)(mg·h)/L,t1/2分别为(1·2±0·5)、(1·2±0·4)h;受试制剂的相对生物利用度为(99·2±13·9)%。结论国产与进口硫酸茚地那韦胶囊的主要药动学参数均无显著性差异(P>0·05),二者具有生物等效性。     

Severe Impairment of Endothelial Function with the HIV-1 Protease Inhibitor Indinavir is not Mediated by Insulin Resistance in Healthy Subjects

Endothelial dysfunction may contribute to increased cardiovascular events among HIV-1-infected patients receiving antiretroviral therapy. The HIV-1 protease inhibitor indinavir causes both vascular dysfunction and insulin resistance, but the relationship between the two disturbances is not established. Endothelium-dependent vasodilation (EDV), insulin-mediated vasodilation (IMV), and whole body and leg glucose uptake during a euglycemic hyperinsulinemic clamp (40 mU/m²/min) were measured before and after four weeks of indinavir in nine healthy men. EDV fell from 270 ± 67% above basal to 124 ± 30% (P = 0.04) and IMV from 56 ± 14% above basal to 8 ± 8% (P = 0.001) with indinavir. During the clamp, arteriovenous glucose difference and leg glucose uptake were not significantly different after indinavir and whole-body glucose uptake was only modestly reduced (8.0 ± 0.8 vs. 7.2 ± 0.8 mg/kg/min, P = 0.04). The change in EDV did not correlate with the change in whole-body glucose uptake after indinavir (r = 0.21, P = 0.6). Despite marked impairment of endothelial function and IMV with indinavir, only modest, inconsistent reductions in measures of insulin-stimulated glucose uptake occurred. This suggests that indinavir’s effects on glucose metabolism are not directly related to indinavir-associated endothelial dysfunction. Studies of the vascular effects of newer protease inhibitors are needed.