The bioavailability of griseofulvin from microsized and ultramicrosized tablets in nonfasting volunteers

Tablets of either microsized or ultramicrosized griseofulvin (2 x 125 mg), were administered to 6 healthy volunteers of either sex just before a breakfast containing 4o g. of butter. The plasma concentration of griseofulvin were determined 1, 3, 5, 7, 9, 24, and 32 h. after dosing using a spectrofluorometric method, and pharmacokinetic parameters (Cp max, t max, AUC 0 - greater than 32) were calculated. These parameters were found to be; Cp max = 0.0.681 +/- 0.1 mu/ml, t max. = 2.51 +/- 0.33 h. and AUC = 14.14 +/- 2.33 micrograms h/ml for microsized tablets and Cp max = 0.80 +/- 0.08 +/- g/ml, t max = 2.44 +/- 0.54 and AUC = 16.25 +/- 1.16 microgram h/ml for ultramicrosized tablets. Our results show that mean peak plasma level and AUC (0 - greater than 32) are only slightly higher for the ultramicrosized preparation and the time to peak plasma level is similar in two preparations. Therefore, it is concluded that coadministration of griseofulvin with food will tend to reduce the difference between the bioavailability of the two type of preparations.     

Aortic responsiveness to nitric oxide is affected by seasonal variation.

Cardiac attacks and sudden cardiac deaths are more common in cold seasons. Up to now the underlying pathophysiologic mechanism of the seasonal variation in cardiovascular accidents is scarcely known. There are many physiological mechanisms which exhibit seasonal variation (e.g. blood pressure). Nitric oxide (NO) is a potent vasodilator, and impaired responsiveness to its physiological effects has been reported in many pathological situations including cardiovascular accidents. The aim of the present study was to evaluate the role of NO-dependent mechanisms on seasonal variation in aortic relaxation in vitro in rats. Male Sprague-Dawley rats grown up in different seasons in natural light/dark situation were used in the study, while the temperature and humidity were kept constant throughout the study (22+/-1 degrees C). The in vitro aortic ring responsiveness to an NO donor was studied in different seasons. Intact and denuded rings were pre-contracted with phenylephrine and vaso-relaxatory response to sodium isosorbide dinitrate (10(-8) to 10(-4)M) was recorded in vitro. The vaso-relaxatory response to isosorbide dinitrate (10(-6)M) was higher in aortic rings obtained in summer compared with those in winter and fall. There was a significant difference in EC(50) of sodium isosorbide dinitrate-induced vaso-relaxation of rings obtained from rats which were grown up in summer and winter (EC(50): 2.23+/-0.069 versus 4.31+/-0.088, P<0.05). The maximum response (R(max)) to isosorbide dinitrate was, however, identical in rings obtained from these rats. In conclusion, the in vitro responsiveness of aorta to NO is affected by seasonal light/dark periods the rats are exposed. This might be one of the reasons why more sudden cardiac deaths occur also in humans during winter.     

Natural low- and high-density lipoproteins as mighty bio-nanocarriers for anticancer drug delivery

Cancer Chemotherapy and Pharmacology - Lipoproteins (LPs) are a set of naturally occurring bio-nanoparticles consisting of Apo-LPs, phospholipids, a highly hydrophobic core of cholesteryl esters...     

Human Cytomegalovirus Infection Leads to Elevated Levels of Transplant Arteriosclerosis in a Humanized Mouse Aortic Xenograft Model

Recent findings emphasized an important role of human cytomegalovirus (HCMV) infection in the development of transplant arteriosclerosis. Therefore, the aim of this study was to develop a human peripheral blood lymphocyte (hu‐PBL)/Rag‐2^–/–γc^–/– mouse‐xenograft‐model to investigate both immunological as well as viral effector mechanisms in the progression of transplant arteriosclerosis. For this, sidebranches from the internal mammary artery were recovered during coronary artery bypass graft surgery, tissue‐typed and infected with HCMV. Then, size‐matched sidebranches were implanted into the infrarenal aorta of Rag‐2^–/–γc^–/– mice. The animals were reconstituted with human peripheral blood mononuclear cells (PBMCs) 7 days after transplantation. HCMV‐infection was confirmed by Taqman‐PCR and immunofluorescence analyses. Arterial grafts were analyzed by histology on day 40 after transplantation. PBMC‐reconstituted Rag‐2^–/–γc^–/– animals showed splenic chimerism levels ranging from 1–16% human cells. After reconstitution, Rag‐2^–/–γc^–/– mice developed human leukocyte infiltrates in their grafts and vascular lesions that were significantly elevated after infection. Cellular infiltration revealed significantly increased ICAM‐1 and PDGF‐R‐β expression after HCMV‐infection of the graft. Arterial grafts from unreconstituted Rag‐2^–/–γc^–/– recipients showed no vascular lesions. These data demonstrate a causative relationship between HCMV‐infection as an isolated risk factor and the development of transplant‐arteriosclerosis in a humanized mouse arterial‐transplant‐model possibly by elevated ICAM‐1 and PDGF‐R‐β expression.     

Gentamicin reduces serum ACE activity in patients with normal kidney function

AIMS: We evaluated serum angiotensin-converting enzyme (ACE) as an indicator of gentamicin toxicity and compared it with N-acetyl-beta-D-glucosaminidase (NAG) and creatinine. METHODS: 20 bone fracture in-patients receiving gentamicin 80 mg TDS for 3 days. Subjects had normal kidney function and had no history or sign of hypertension. Serum and urine samples were collected before and 3 days after drug administration. Samples analyzed for ACE, NAG, BUN, creatinine, sodium, and potassium. RESULTS: Our results showed that urine NAG activity increased significantly at the 3rd day. Serum creatinine level and glomerular filtration rate (GFR) while still at a normal range showed slight but significant changes at this time. This may indicate some renal damage. Serum ACE activity decreased significantly at the 3rd day. CONCLUSION: These results indicate serum ACE can be used as a good indicator of renal damage in patients receiving gentamicin.     

Noscapine suppresses angiotensin converting enzyme inhibitors-induced cough

BACKGROUND: Dry cough is a common side-effect of the angiotensin converting enzyme inhibitors (ACEI) and is a major limiting factor of their use. It has been suggested that ACEI cause this side-effect by potentiation of the bradykinin effect. Previous work in our laboratory has shown that noscapine, an antitussive drug, inhibits the effect of bradykinin. METHODS: To investigate the effect of noscapine on ACEI-induced cough, 611 hypertensive patients who were being treated with ACEI were evaluated for the incidence of persistent dry cough. RESULTS: A cough had developed in 65 (10.6%) patients, two (3.1%) of whom also had severe respiratory distress that required hospitalisation and immediate discontinuation of the ACEI. Forty-two (64.6%) patients had developed a mild cough and 21 (32.3%) patients had developed a moderate to severe cough. The patients with moderate to severe cough received 15 mg of noscapine, orally three times daily, while they continued ACEI. Noscapine effectively resolved the cough in 19 (90%) patients within 4-9 days of starting treatment. CONCLUSION: Noscapine, possibly by inhibition of bradykinin synthesis, eliminates ACEI-induced cough in the majority of patients and allows them to continue with ACEI therapy.     

Pharmacokinetics of mebudipine, a new calcium antagonist, following single intravenous and oral administrations in rats

The pharmacokinetics of a new calcium antagonist, mebudipine, was studied after a single intravenous (0.5 mg/kg) and oral (10 mg/kg) administration to rats. After intravenous dosing, the plasma concentration of mebudipine declined biexponentially with a terminal half-life of 2.84 h. The blood clearance was 1.67 l/h/kg and the volume of distribution at steady state was found to be 6.26 l/kg. After oral dosing (10 mg/kg), the C(max) of mebudipine was 25.9+/-9.79 ng/ml. The oral bioavailability was low (< 2%) suggesting a marked first-pass effect. The distribution of mebudipine into some tissues such as brain, heart, liver and kidney following intravenous administration (0.5 mg/kg) was studied and a rapid distribution of mebudipine into these tissues was found. It was concluded that brain, heart, liver and kidney are in the same compartment as plasma (central).     

Quantitative Structure–Activity Relationships (QSARs) of Pyrimidine Nucleosides as HIV-1 Antiviral Agents

The structural requirements for the antiviral activity of pyrimidine nucleosides against HIV-1 virus was evaluated with the Hansch SAR analysis. Antiviral activity is best related to the hydrophobicity and steric (L and B3) properties of the substituent at the C5 of pyrimidine ring. Further, the antiviral activity is related to B4 of the substituent at position 3' of the sugar ring with a positive slope. The activity of both uracil and cytosine derivatives can be related to their structure by the same equations, which indicates that the SARs are similar in these two groups of congeners. These results suggest that compounds with a small substituent at the 5 position of the pyrimidine ring and a flat substituent at the 3' position of the sugar ring will be the most active compounds against HIV-1 virus.     

Effects of mebudipine and dibudipine, two new calcium-channel blockers, on rat left atrium, rat blood pressure and human internal mammary artery.

Mebudipine and dibudipine are two new dihydropyridine calcium-channel blockers that have been synthesized in our laboratory. In a previous study, they showed considerable relaxant effect on vascular and ileal smooth muscle. Here, the pharmacological effects of mebudipine and dibudipine on isolated rat left atrium, rat blood pressure and isolated human internal mammary artery are described. Results are compared with those obtained for nifedipine. Mebudipine and dibudipine reduced contraction force of rat left atrium (pIC30 values: 5.37+/-0.13 and 5.49+/-0.15, respectively) but their negative inotropic effects were significantly weaker than that of nifedipine (pIC30 value: 6.63+/-0.11). Mebudipine and dibudipine lowered rat blood pressure. The hypotensive effect of mebudipine was similar to that of nifedipine while dibudipine was weaker than nifedipine. It was found that the half-life of the hypotensive action of dibudipine (41.91+/-3.77 min, 31.13+/-2.26 min and 28.20+/-4.37 min at 2, 4 and 8 mg kg(-1) orally administered doses, respectively) was longer than that of nifedipine (11.85+/-2.88 min, 16.65+/-2.42 min and 14.03+/-0.10 min at the same doses, respectively). Also, it appeared that mebudipine had a slower rate of absorption compared with nifedipine (the time to reach peak hypotensive action at 2, 4 and 8 mg kg(-1) orally administered doses were, respectively, 24.00+/-6.96 min, 23.75+/-2.39 min and 15.00+/-2.04 min for mebudipine and 7.80+/-0.86 min, 13.75+/-3.15 min and 833+/-0.88 min for nifedipine). The two new compounds, as well as nifedipine, relaxed KCl-treated isolated human internal mammary artery (pEC50 values; 7.87+/-0.12, 7.22+/-0.24 and 7.67+/-0.12 for mebudipine, dibudipine and nifedipine, respectively). The relaxant effects of mebudipine and dibudipine did not show any significant difference compared with that of nifedipine. It is concluded that these new compounds are weak cardiodepressants and, with due attention to its significant vasorelaxant action, mebudipine is a vasoselective compound. In addition, these two compounds have potent blood pressure lowering effects. Also, their vasorelaxant action can be reproduced in human vascular preparations.     

Frequency of paraoxonase 192/55 polymorphism in an Iranian population

Paraoxonase (PON1) is a serum enzyme that plays an important role in prevention of atherosclerosis and also protects against organophosphate-induced neurotoxicity. PON1 displays a high variability in human populations. In this study, PON1-192 and -55 polymorphisms and correlation to serum PON1 activity were investigated in 132 healthy Iranian individuals from Isfahan province. The genotype frequencies for PON1-192 were approximately 48% (QQ), 42.% (QR), and 10% (RR) and for PON1-55 17% (MM), 48% (ML), and 35% (LL). Thus, the frequencies of alleles R and L were 0.31 and 0.59, respectively. PON1 activity toward paraoxon was markedly affected in both polymorphic populations in the following order QQ < QR < RR genotype for PON1-192 and MM < ML < LL genotype for PON1-55. Neither polymorphism significantly affected PON1 activity toward phenylacetate. The RR/LL individuals had the highest PON1 activity and QQ/MM individuals the least. The QR/ML haplotype was the most frequent seen in Iranians, and the RR/MM and QR/MM haplotypes were absent in this population. In conclusion, the frequencies of PON1-192 and -55 polymorphisms in this Iranian population were different from those seen in other Asian populations from Japan and China but similar to those for European Caucasians.