Epidemiology, clinical features and prognostic value of HIV-1 related oral lesions

Between February 1987 and February 1990, we studied 737 antibody anti HIV-1 positive (AbHIV+) subjects referred to the Infectious Diseases Institute of the University of Turin (Italy) in order to evaluate types, prevalences, relations with clinical stages, distributions in risk-groups and prognostic significances of HIV-1 related oral lesions. The study evidenced the high prevalence of oral lesions, especially mycoses, in the investigated population: 40.3% of the patients showed, in fact, HIV-1 related oral lesions. The 37 months follow-up of 55 AbHIV+ with oral hairy leukoplakia (HL) and 101 patients with oral candidiasis (OC), demonstrated that the probability of developing AIDS in patient with HL was 0.381 at 15, 0.635 at 25 and 0.824 at 37 months. In the patients with OC the probability was 0.294 at 15 months, 0.524 at 25 and 0.781 at 37 months.     

Effects of Ketoconazole on the Pharmacokinetic Properties of CG100649, A Novel NSAID: A Randomized,Open-Label Crossover Study in Healthy Korean Male Volunteers

Background

CG100649, a novel selective cyclooxygenase-2 inhibitor that also inhibits carbonic anhydrase I/II, is expected to reduce the cardiovascular risk typical of other NSAIDs. Concurrent medications may influence the activities of the cytochrome P450 (CYP) 3A enzyme through which CG100649 is metabolized.

Objectives

This study was designed to evaluate the influence of ketoconazole, a known strong inhibitor of CYP3A, on the pharmacokinetic properties of CG100649.

Methods

This randomized, open-label, 2 × 2 crossover study was conducted in healthy Korean male volunteers. Each subject received the following 2 treatments in a randomly allocated sequence, separated by a washout period of 42 days: single oral dose of CG100649 6 mg, and concurrent dosing of CG100649 6 mg and ketoconazole 400 mg followed by ketoconazole 400 mg/d over 4 days. Blood samples for pharmacokinetic analysis were collected at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 240, 384, and 480 hours after dosing of CG100649 in each sequence. Tolerability assessments were performed throughout the study.

Results

Thirty subjects participated, and 26 subjects completed the study. Seventeen adverse events (AEs) were reported in 10 subjects, and all AEs were recovered without any sequelae. No serious AEs were reported. Six subjects receiving the single dose of CG100649 had 9 AEs, and 7 subjects receiving the combination of ketoconazole and CG100649 had 8 AEs. The C_max of CG100649 with CG100649 only and with concurrent administration of CG100649 + ketoconazole were similar (10.7 and 11.0 ng/mL, respectively). The CG100649 AUC_last with concurrent ketoconazole was 1.29-fold greater than that with CG100649 only (2074.0 and 2685.8 ng · h/mL) and demonstrated a statistically significant difference (P < 0.05). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or AEs between treatments.

Conclusion

Although the AUC of CG100649 increased by 29% with the concurrent medication of ketoconazole, it is considered that concurrent administration of CG100649 with ketoconazole would not change the safety profile of CG100649. ClinicalTrials.gov identifier: NCT01154764.     

A case of sequential anti-stress medication in a patient with major depression resistant to amine-reuptake inhibitors.

One of the predictive factors of treatment-resistant depression is the syndrome of relative insulin resistance, i.e. adipositas, mild hypertension and a family history of type-2 diabetes. Such a case is here reported with a good outcome to anti-stress medication, including ketoconazole and lithium.     

A successful case of pregnancy in a woman with ACTH-independent Cushing’s syndrome treated with ketoconazole and metyrapone

Cushing’s syndrome (CS) is a rare disease caused by a chronic excess of cortisol. Hypercortisolaemia may affect reproductive system leading to infertility in women. However, some of the patients remain fertile, although pregnancy is uncommon. In our report, we describe the case of a 31-years old woman suffering from hypertension, oligomenorrhea, easy bruising, muscle weakness and elevated levels of cortisol. During hospitalization, high level of serum cortisol with stiff diurnal rhythm and undetectable plasma ACTH concentration were found. The overnight 1?mg dexamethasone (DEX) suppression test and the test with 8?mg of DEX were performed – plasma cortisol levels after both doses of DEX were over expected values. Thus, the diagnosis of ACTH independent hypercortisolaemia was established. After three weeks of ketoconazole treatment, high level of β-HCG was found corresponding to the third week of pregnancy. The ketoconazole was shift to metyrapone but afterwards ketoconazole was added again. The treatment was well tolerated and pregnancy proceeded without complications. US scan revealed a 2?cm adenoma of the left adrenal gland, confirmed by CT. An adrenalectomy was performed. Concluding, we think that medical treatment of CS in pregnant women is well tolerated and safe both for the mother and fetus.     

Abiraterone acetate for castration resistant prostate cancer

Importance of the field: Androgen deprivation therapy has been the standard of care in advanced prostate cancer for >?50 years. Although castration is initially effective, most patients eventually develop progressive disease despite low levels of testosterone (termed castration resistant prostate cancer, CRPC). Intratumor and extra-gonadal androgens (specifically adrenal androgens) represent a means for continued androgen receptor-mediated growth in CRPC and have thus become therapeutic targets. One novel therapeutic is abiraterone acetate (AA): an inhibitor of CYP17, an enzyme that catalyzes two key serial reactions in androgen and estrogen biosynthesis. Data from Phase I and II trials suggest that clinically important antitumor activity is seen in up to 70% of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies. The toxicity profile has also been found to be acceptable. Two large Phase III clinical trials are currently open to accrual and will hopefully validate the impressive Phase II data.

Areas covered in the review: The chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy and safety/tolerability of AA.

What the reader will gain: Readers will understand the function of non-gonadal androgens, the importance of continued androgen deprivation in advanced prostate cancer and the role/clinical efficacy of AA.

Take home message: The recent realization that non-gonadal sources of androgens (adrenal and intracrine de novo synthesis) may be a major mediator of disease progression forms the biological rationale behind the development of abiraterone acetate and related drugs. Abiraterone acetate is an orally administered, specific inhibitor of CYP17A1, a rate-limiting enzyme in androgen biosynthesis. Preliminary data from Phase I and II trials suggest that prostate specific antigen declines occur in a large proportion of patients and that the toxicity profile is acceptable. Two large Phase III clinical trials are currently open to accrual and, if proven to be efficacious, will result in widespread use of a drug specifically developed to suppress adrenal androgens.     

In Vitro Release—In Vivo Microbiological and Toxicological Studies on Ketoconazole Lipid Granules

In some multidrug therapy programs, ketoconazole (KTZ) may be administered with some antacids that could modify its dissolution rate and reduce its absorption, thus leading to therapeutic failures. The primary aim of this study was to evaluate the influence of Compritol HD5 ATO and Compritol 888 ATO on this interaction in comparison with commercial KTZ tablets. The second aim was to prepare lipid granules of KTZ that could be an alternative to the commercial formulation. Therefore, six KTZ sustained-release granules were prepared with different lipid concentrations, because they were found to be more suitable than tablets that are dissolved only in gastric medium. The results confirmed that the dissolution rate of KTZ granules was significantly reduced in the presence of antacids. The ideal formulation was selected as granules including 5% of Compritol lipids in relation to the suitability of the target profile. Therapeutic effects of orally administered, ideal KTZ granule formulations, and commercial tablets were evaluated in vivo by the experimental model of murine vulvo-vaginal candidiasis (VVC) with and without antacids. It was found that formulations were very effective on VVC, and the therapeutic effect decreased significantly in the presence of antacids. Histopathological studies were carried out for vagina, stomach, and liver tissues and hepatoxicity was also examined. The levels of reduced glutathione (GSH) were measured to assess the oxidative stress induced by KTZ and function of the liver. It was observed that orally administered formulations of KTZ were successful in treating candidiasis in mice without irritancy in stomach. However, liver tissues were damaged. The decreased GSH levels indicated toxicity in our study. This study suggested that in vitro release and in vivo microbiological-toxicological properties of KTZ were affected by antacids and drug-excipient interactions. Lipid granules of KTZ prepared with Compritol 888 ATO could be proposed as a new KTZ solid dosage form with optimum dissolution and therapeutic characteristics.     

Ketoconazole ion-exchange fiber complex: a novel method to reduce the individual difference of bioavailability in oral administration caused by gastric anacidity

Water insoluble faintly alkaline drugs often have potential absorption problem in gastrointestinal tract in oral administration for patients with gastric anacidity. The purpose of the present study is to develop a novel method to improve the absorption of the water insoluble faintly alkaline drug in peroral administration. This method is based on ion exchange of ion-exchange fibers. Water-insoluble faintly alkaline drug ketoconazole was used as a model drug. Ketoconazole and the active groups of the ion-exchange fibers combined into ion pairs based on the acid-base reaction. This drug carrier did not release drugs in deionized water, but in water solution containing other ions it would release the drugs into the solution by ion exchange. Confirmed by the X-ray diffraction and the differential scanning calorimetry (DSC), the ketoconazole combined onto the ion-exchange fibers was in a highly molecular level dispersed state. The improved dissolution of ketoconazole ion-exchange fiber complexes is likely to originate from this ketoconazole’s highly dispersed state. Furthermore, due to this ketoconazole’s highly dispersed state, ketoconazole ion-exchange fiber complexes significantly decreased the individual difference of absorption in oral administration of ketoconazole caused by the fluctuation of the acid degree in the gastric fluid.     

Emerging drugs for Cushing’s disease

Introduction: Considering the effects of uncontrolled hypercortisolism on morbidity and mortality, there is a clear need for effective medical therapy for patients with Cushing’s disease (CD). Therefore, the search for new medical effective tools remains active, and already promising results have been obtained.

Areas covered: The importance of the design and conduct of trials to validate old drugs or to test new compounds is discussed. The results of the ongoing clinical trials, targeting the specific properties of drugs, such as ketoconazole, LCI699, mifepristone, etomidate and pasireotide, are also reported. The authors also emphasise the advantages and drawbacks of each particular drug, and the potential combined use of agents with complementary mechanisms of action.

Expert opinion: CD is an excellent example of a situation where effective therapy is essential, but where the balance of risk and benefit must be carefully judged. Metyrapone is the drug of choice when rapid control of the hypercortisolaemia is required, ketoconazole represents a good second-line drug, although in the future LCI699 may be a better alternative. Mifepristone can also be used in the rare situation when previous drugs are inappropriate. Etomidate is useful where immediate parenteral action is required. For drugs working directly on the pituitary, cabergoline is occasionally effective and pasireotide can be attempted in patients with mild CD.