The pharmacokinetics, safety, and tolerability of posaconazole, an investigational triazole antifungal, were evaluated following the administration of rising single and multiple oral doses. A total of 103 healthy adults were enrolled in two phase I trials. Each study had a double-blind, placebo-controlled, parallel-group design with a rising single-dose (RSD) or rising multiple-dose (RMD) scheme. In the RSD study, subjects received single doses of posaconazole oral tablets (50 to 1,200 mg) or placebo. In the RMD study, subjects received posaconazole oral tablets (50 to 400 mg) or placebo twice daily for 14 days. By using model-independent methods, the area under the plasma concentration-time curve and the maximum concentration in plasma were determined and used to assess dose proportionality. In the RSD study, the levels of posaconazole in plasma increased proportionally between the 50-and 800-mg dose range, with saturation of absorption occurring above 800 mg. Dose proportionality was also observed in the RMD study. In both studies, the apparent volume of distribution was large (range, 343 to 1,341 liters) and the terminal-phase half-life was long (range, 25 to 31 h). Posaconazole was well tolerated at all dose levels, and the adverse events were not dose dependent. No clinically significant changes in clinical laboratory test values or electrocardiograms were observed. Following the administration of single and twice-daily rising doses, the level of posaconazole exposure increased in a dose-proportional manner. The long elimination-phase half-life of posaconazole supports once-or twice-daily dosing in clinical trials; however, additional studies are required to determine if further division of the dose will enhance exposure.The evolution of oral triazole antifungal agents began in the 1980s with the introduction of fluconazole and itraconazole for the treatment of systemic fungal infections. In recent years, the patterns of Candida infections have changed. Previously, Candida albicans was the most prevalent cause of Candida infections, whereas in recent times, other Candida species, such as C. glabrata and C. krusei, have become common infectioncausing pathogens (6). In addition to this shift in species, fluconazole-and itraconazole-resistant Candida strains have emerged, prompting clinicians to search for alternative treatment options. The emergence of new fungal diseases caused by fungi that were previously not thought to be pathogenic has also limited the usefulness of older triazole compounds for the treatment of invasive infections, especially in immunocompromised patients. For example, fusariosis and zygomycosis are increasingly common; however, the treatments for these infections are limited (23). In light of the need for more potent and broad-spectrum therapeutic options, posaconazole (SCH 56592), a novel oral triazole derivative structurally similar to itraconazole (Fig. 1), is in development for the treatment of invasive fungal infections.Posaconazole has enhanced activity against many old, new, and ...

Summary Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100-250 mg m -2 was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m -2 day -1 . Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean T max~1 h) and eliminated (mean t 1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m -2 day -1 for 5 days, every 28 days, is recommended for phase II studies.

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There are several clinically useful endoperoxides, mainly artemisinin derivatives available in market for the treatment of malaria. These are highly potent drugs, with fastest parasite reduction ratio, broadest parasite stage specificity and effectiveness against all species of plasmodium in human. Endoperoxides are crystalline compounds having poor aqueous solubility. Several theories have been proposed for their mechanism of action, but the understanding is still incomplete. The major limitation of this class of compounds is the short half-life, requiring frequent administration, leading to noncompliance and recrudescence. Therefore, WHO recommends their use in combination with long acting antimalarial drugs (Artemisinin based combination therapy, ACT) to manage drug resistance, recrudescence, and non compliance. Endoperoxide compounds bind selectively to malaria-infected red blood cells and moderately to human plasma proteins. Artemisinin derivatives are converted primarily to the bioactive metabolite dihydroartemisinin after parenteral, oral or rectal administration. The rate of conversion is lowest for artelinic acid and highest for the water-soluble artesunate. Such conversion occurs largely in the liver by CYP enzymes. Oral bioavailability in animals ranges between 19 to 35%. Based on their liphophilicity, they tend to cross the blood-brain barrier, causing neurotoxicity in animal models. Efforts have been made to understand and develop pharmacokinetic-pharmacodynamic (PK-PD) correlation and identify PK-PD indices of endoperoxides. In the absence of the above, the selection of doses in ACTs has been empirical. There are several reports on clinical pharmacokinetic interactions of endoperoxides and their long acting partner drugs but as on date no clinically significant interaction has been reported. This review is an update on physicochemical, pharmacokinetic and pharmacodynamic properties of the endoperoxide antimalarials.

A Randomized Controlled trial was done on 30 (CP) children of age range 6 mon to 2 y with an objective to see the efficacy of Neurofacilitation of Developmental Reaction (NFDR) approach over Neurodevelopmental Therapy (NDT) for integration / modification of early motor behavior (Primitive Reflexes) in Cerebral Palsy (CP). The baseline evaluation was done for tone, postural reactions and GMFM. The subjects were randomly allocated to two groups. With group A, NFDR and group B, conventional approach (NDT) was used for 3 mon followed by re-evaluation. Between groups analysis was done and p value was found to be significant. It was concluded that NFDR approach is more effective than NDT for integration / modification of early motor behavior in children with CP.

Introduction Cardiovascular dysautonomia comprising postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH) is one of the presentations in COVID-19 recovered subjects. We aim to determine the prevalence of cardiovascular dysautonomia in post COVID-19 patients and to evaluate an Artificial Intelligence (AI) model to identify time domain heart rate variability (HRV) measures most suitable for short term ECG in these subjects. Methods This observational study enrolled 92 recently COVID-19 recovered subjects who underwent measurement of heart rate and blood pressure response to standing up from supine position and a 12-lead ECG recording for 60 s period during supine paced breathing. Using feature extraction, ECG features including those of HRV (RMSSD and SDNN) were obtained. An AI model was constructed with ShAP AI interpretability to determine time domain HRV features representing post COVID-19 recovered state. In addition, 120 healthy volunteers were enrolled as controls. Results Cardiovascular dysautonomia was present in 15.21% (OH:13.04%; POTS:2.17%) . Patients with OH had significantly lower HRV and higher inflammatory markers. HRV (RMSSD) was significantly lower in post COVID-19 patients compared to healthy controls (13.9 ± 11.8 ms vs 19.9 ± 19.5 ms; P = 0.01) with inverse correlation between HRV and inflammatory markers. Multiple perceptron was best performing AI model with HRV(RMSSD) being the top time domain HRV feature distinguishing between COVID-19 recovered patients and healthy controls. Conclusion Present study showed that cardiovascular dysautonomia is common in COVID-19 recovered subjects with a significantly lower HRV compared to healthy controls. The AI model was able to distinguish between COVID-19 recovered patients and healthy controls.

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