Elevated CD4+/CD25+ T cell frequency and function during acute hepatitis C presage chronic evolution.
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Acute Disease↗
Biomedical subjects
G Morelli
Publications and source records attributed to G Morelli.
Comparative bioavailability of a generic capsule formulation of the reverse transcriptase inhibitor efavirenz and the innovator product.
OBJECTIVE: Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that has been used successfully for more than a decade to treat human immunodeficiency virus (HIV) infection. The objective of the current study was to determine the bioequivalence between a generic capsule formulation of efavirenz and the innovator product. MATERIAL AND METHODS: A total of 41 healthy subjects (34 males and 8 females) received a single 200 mg oral dose of efavirenz as the generic (Ranbaxy-Efavirenz, Ranbaxy Laboratories Ltd.) and innovator (Sustiva, Bristol-Myers Squibb) capsule formulations under fasting conditions in a randomized, 2-way crossover study. Multiple blood samples were collected over 72 hours and plasma concentrations of efavirenz were assayed using an LC/MS/MS method. Pharmacokinetic (PK) parameters were calculated using non-compartmental methods. RESULTS: Plasma concentrations of efavirenz peaked within 2.5 hours and then declined in a multi-exponential manner for both formulations. At 72 hours post dose, all plasma concentrations of efavirenz were above the LOQ of the assay (10 ng/ml). Mean area under the curve from 0 - 72 hours (AUC0-72) and maximum plasma concentrations (Cmax) of efavirenz for the generic capsule formulation were 22,840 ng x h/ml and 1,199 ng/ml, respectively. Ratios and 90% confidence intervals of PK parameters between the two formulations were within 80.0 - 125.0%, suggesting that the two capsule formulations resulted in similar rate and extent of bioavailability under fasting conditions. Adverse events were similar in nature and frequency for the two formulations. CONCLUSIONS: Based on the above results, the generic capsule formulation of efavirenz developed by Ranbaxy should be as effective as the innovator product.
Administration, Oral↗
Comparative bioavailability study of zidovudine administered as two different tablet formulations in healthy adult subjects.
AIM: Zidovudine is a synthetic nucleoside analogue of thymidine with activity against the human immunodeficiency virus type 1 (HIV-1). In patients with HIV infections or the acquired immunodeficiency syndrome (AIDS), zidovudine is a first-line therapy that was shown to reduce morbidity, mortality, and hospitalization. A generic formulation of zidovudine offers the possibility of considerable savings to HIV/AIDS patients in developed and Third World countries. The objective of the current study was to characterize the pharmacokinetic and safety profiles of zidovudine administered as a generic tablet formulation relative to the innovator product. VOLUNTEERS AND METHODS: A total of 68 healthy adult volunteers received a 300 mg oral dose of zidovudine as the generic formulation (AVIRO-Z 300 mg tablet, Ranbaxy Laboratories Limited) and as the innovator product (Retrovir tablet, GlaxoSmithKline) in a randomized, 2-way crossover study. Multiple blood samples were collected over 12 hours and plasma concentrations of zidovudine were assayed using an LC/MS/MS method with an analytical range of 5.00 to 2,000 ng/ml. Pharmacokinetic parameters were calculated using non-compartmental methods. RESULTS: Mean plasma concentrations of zidovudine declined in a mono-exponential manner, with mean concentration values falling below the limit of quantitation 12 hours after administration of both formulations. Mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), mean area under the curve from time 0 to infinity (AUC(0-infinity)) and peak plasma concentrations (C(max)) of zidovudine for the generic tablet formulation (2,220.6 ng x h/ml, 2,236.0 ng x h/ml and 1,087.9 ng/ml, respectively) were very similar to those observed for the innovator product (2,139.7 ng x h/ml, 2,158.6 ng x h/ml and 1,066.5 ng/ml, respectively). Ratios of least-squares means and 90% confidence intervals of AUC(0-t) AUC(0-infinity) and C(max) between the 2 formulations were within 80-125%, suggesting that the two tablet formulations displayed similar rate and extent of bioavailability. The oral clearance (CL/F) of zidovudine for the generic and innovator formulations were 2.11 1/h/kg and 2.16 1/h/kg, respectively. For the two formulations, adverse events were similar in nature and frequency. CONCLUSION: Since the two formulations displayed similar in vivo delivery rate of zidovudine in the bloodstream, the generic tablet formulation of zidovudine developed by Ranbaxy should be equally effective as the innovator product and is expected to produce considerable cost-savings in AIDS patients worldwide.
Administration, Oral↗
Bioequivalence of abacavir generic and innovator formulations under fasting and fed conditions.
OBJECTIVE: Abacavir sulfate is a synthetic carbocyclic nucleoside analogue indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. The objective of the current study was to determine the bioequivalence between a generic formulation of abacavir and the innovator product. MATERIAL AND METHODS: A total of 80 subjects were randomly assigned to receive a single 300 mg oral dose of abacavir sulfate as the generic (Ranbaxy-Abacavir, Ranbaxy Laboratories Ltd., equivalent to 300 mg of abacavir) and innovator (Ziagen, GlaxoSmithKline) tablet formulations in 2-way crossover studies performed under fasting (n=40) and fed (n=40) conditions. Multiple blood samples were collected over 14 hours and plasma concentrations of abacavir were assayed using an LC/MS/MS method with a limit of quantitation of 25.0 ng/ml. Pharmacokinetic (PK) parameters were calculated using noncompartmental methods. RESULTS: Under fasting conditions, geometric mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), area under the curve extrapolated to infinity (AUC(0-infinity) and maximum plasma concentrations (Cmax) of abacavir for the generic (5565 ng x h/ml, 5668 ng x h/ml and 2526 ng/ml, respectively) and innovator (5675 ng x h/ml, 5770 ng x h/ml and 2528 ng/ml, respectively) products were very similar. Under fed conditions, mean values of AUC(0-t) AUC(0-infinity) and Cmax for the generic (4487 ng x h/ml, 4571 ng x h/ml and 1841 ng/ml, respectively) and innovator (4574 ng x h/ml, 4654 ng x h/ml and 1781 ng/ml, respectively) formulations were also very similar. Ratios of LSM and 90% confidence intervals of PK parameters between the 2 formulations were within 80.0 - 125.0% under fasting and fed conditions, suggesting that the 2 tablet formulations resulted in similar rate and extent of bioavailability. Adverse events for the generic and innovator products were similar in nature and frequency in the fasting and fed studies. CONCLUSIONS Based on the above results, the generic tablet formulation of abacavir developed by Ranbaxy should be equally effective as the innovator product.
Adult↗
Fluoroquinolone resistance in hematopoietic stem cell transplant recipients with infectious complications.
The infectious complications are an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. Our retrospective study has the objective to evaluate the incidence, clinical and bacteriologic features of documented infections in these patients. The frequency of infectious complications was analysed in 42 patients with hematologic malignancies who received HSCT from January to December 2002 at Pisa General Hospital. Thirty-three patients underwent autologous HSCT and 9 received allogeneic HSCT. All patients received acyclovir, fluconazole and fluoroquinolones as prophylactic regimen. A total of 38 infectious episodes were recognized in 22 patients during the early post-HSCT period (N=27) and in the late post-HSCT period (N=11). Infectious complications rate correlated positively with the deepness and length of neutropenia in the early period. There were 21 episodes of sepsis (the majority by coagulase negative staphylococci), 2 pneumonias and 1 vertebral osteomyelitis. All staphylococcus strains were, in vitro, resistant to oxacillin and ciprofloxacin and 8 out of 15 gram negative rods were resistant to ciprofloxacin. Most of the infectious complications were cured with appropriated antimicrobial therapy and/or with engraftment and, in 4 cases, with central catheter removal. One patient developed a positive CMV antigenemia; a pre-core mutant form of HBV reactivation was diagnosed in another patient. No cases of invasive fungal infections were recognised. Five patients died but only one from infection (septic shock). Pneumonia was a coexisting cause of death in 2 patient in the late period. We can conclude that most of infectious complications, that occurred in the early period post-HSCT were due to coagulase negative staphylococci and gram negative rods resistant to ciprofloxacin. For this reason, the usefulness of fluoroquinolone prophylaxis in HSCT recipients should be reevaluated.
Adult↗
Catheter-associated urinary tract infections (CAUTI): distribution of uropathogens and patterns of antimicrobial resistance in an Italian hospital (1996-2003).
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Aged↗
Role of pharmacologic rehabilitation in the recovery of sexual function following radical prostatectomy.
AIM: The aim of the present study is to evaluate the role of pharmacological postoperative sexual rehabilitation in the recovery of erectile function following radical retropubic prostatectomy. METHODS: Following radical retropubic prostatectomy 113 patients were divided into 2 groups: 77 (group 1) underwent pharmacologic rehabilitation with intracavernous PGE1 starting with 5 mg once or twice weekly beginning 1 month after surgery, followed by oral sildenafil 50-100 mg twice a week after recovery of spontaneous erections, while 36 (group 2) acted as controls. The 2 groups were homogeneous for age and preoperative IIEF5 score, while nerve-sparing techniques were used more frequently in group 1. RESULTS: With 1 year follow-up 42% of group 1 patients have recovered sexual function, versus 8% of group 2 (P < 0.001). The mean recovery time was 7 months, and 56% of rehabilitated patients with bilateral preservation of the neurovascular bundles recovered sexual function, compared to 37.5% of those with unilateral preservation and 28.5% of those operated with non nerve-sparing technique. Intracavernous PGE1 caused pain in 27% of cases. CONCLUSIONS: Pharmacologic rehabilitation significantly impacts on the recovery of sexual function following radical prostatectomy, and the optimal treatment schedule is still to be defined.
Aged↗
In vitro and in vivo characterization of Indium-111 and Technetium-99m labeled CCK-8 derivatives for CCK-B receptor imaging.
Cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with 111In or 99mTc for CCK-B receptor imaging. Derivatives of CCK8 were obtained by addition at the N-terminus in solid phase of a DTPA derivative (DTPAGlu) linked through a glycine spacer (DTPAGlu-G-CCK8) or cysteine, glycine and a diphenylphosphinopropionyl moiety (PhosGC-CCK8) for labeling with 111In and 99mTc, respectively. CCK-BR overexpressing A431 cancer cell lines were utilized to characterize in vitro properties of the two compounds as well as for generating xenografts in nude mice for in vivo characterization. Both 111In-DTPAGlu-G-CCK8 and 99mTcPhosGC-CCK8 showed similar binding affinities for CCK-BR with dissociation constants of 20-40 nM, were internalized after interaction with the receptor and displayed prolonged cellular retention times. Specific in vivo interaction with the receptor of both CCK8 analogs was observed in our animal model. 111In-DTPAGlu-G-CCK8 showed better target to non-target ratios, although it appeared to be rapidly metabolized after injection and activity cleared through the kidneys. 99mTc-PhosGC-CCK8 was more stable in vivo but showed marked hepatobiliary clearance with resulting high background activity in the bowel. The rapid clearance and lower background obtained with 111In-DTPAGlu-G-CCK8 make this a better candidate for further development.
Animals↗
Design, synthesis and preclinical evaluation of radiolabeled peptides for diagnosis and therapy.
Recent years have seen an increased effort in the development of peptide based radiopharmaceuticals for nuclear medicine applications in imaging and therapy. This field is of particular interest in the development of new cancer imaging and treatment strategies. Major developments in the molecular biology of cancer have brought forth the discovery of a number of receptor systems and other cell surface molecules that can be utilized as molecular targets for peptide based agents. Although such a strategy is very appealing and shows great potential for application in humans, there are as yet very few radiopharmaceuticals developed based on this scheme that have made it into clinical practice. Many different factors contribute to the generation of a successful radiopharmaceutical. Among these, a thorough and efficient pre-clinical evaluation process is necessary to single out those lead compounds that show more promise and are most likely to be winners in clinical applications. To maximize the efficacy of pre-clinical testing one must utilize currently available technology to the best extent possible. Expertise in different areas of drug development is indispensable for this type of research. This work will analyze currently available methods utilized to evaluate radiopharmaceuticals being developed, from compound design to evaluation in pre-clinical animal models.
Animals↗
Corporeal herniation after Nesbit plication with partial thickness shaving for congenital penile curvature.
A 24-year-old man with penile congenital curvature who underwent partial thickness tunical shaving and plication with absorbable suture presented 1 month after surgery with a mass at the base of the right corpus cavernosum at the level of the original plication. We believe that corporeal herniation after tunical shaving and plication must be considered a complication of the technique independent from the type of suture used for the plicatures and probably related both to the opening of plications of the albuginea before permanent adhesion of the tunical layers, and to the decreased resistance of the albuginea, probably because of excessive shaving.
Adult↗
Radiolabeling approaches for cholecystokinin B receptor imaging.
Regulatory peptides and their analogs are being extensively investigated as radiopharmaceuticals for cancer imaging. In particular, cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with (111)In or (99m)Tc for the purpose of developing radiopharmaceuticals for in vivo CCK-B receptor imaging. Labeling of CCK8 with (111)In was achieved at the N-terminus of the peptide by adding, in solid phase, a glutamate coupled diethylenetriaminepentaacetic acid (DTPA) moiety through a glycine linker, yielding DTPA-Glu-G-CCK8. For labeling with (99m)Tc, the CCK8 peptide was modified at its N-terminus by introducing, in the following order--cysteine, glycine, and a diphenylphosphinopropionyl moiety--giving a 10-residue peptide derivative, Phos-GC-CCK8. A cell culture model was developed for the purpose of evaluating the binding properties of these two ligands. The human epidermoid carcinoma cell line, A431, was transfected with a plasmid containing the full coding sequence of the human CCK-BR under a strong viral promoter, obtaining a number of receptors in the range of 2-5 x 10(6) per cell. Control cells were transfected with vector alone. An animal tumor model utilizing these two cell lines was developed to evaluate the specificity of interaction with the CCK-BR and biodistribution properties of the compounds. CCK-BR positive and control cells were subcutaneously injected in opposite flanks of CD1 female nude mice in order to obtain xenografts differing only in their ability to express CCK-B receptors. High performance liquid chromatography (HPLC) and other chromatographic methods were utilized to assess stability of the radiolabeled compounds after injection. Both (111)In-DTPA-Glu-G-CCK8 and (99m)Tc-Phos-GC-CCK8 showed similar binding affinities for cultured CCK-BR expressing cells, with dissociation constants in the range of 20-40 nM. With the two xenograft approach, we were able to demonstrate specific interaction with the receptor of both CCK analogs in our animal model. The data obtained shows rapid specific localization of both compounds on the CCK-BR overexpressing xenografts. Both tracers show rapid plasma clearance of unbound peptide. Clearance of (111)In-DTPA-Glu-G-CCK8 appears to be preferentially through the kidneys, whereas (99m)Tc-Phos-GC-CCK8 clearance occurs both through kidneys and the hepatobiliary system. Both our labeling approaches appear adequate for clinical use of peptide based radiopharmaceuticals, although (99m)Tc-Phos-GC-CCK8 shows elevated accumulation in the gastrointestinal tract, which causes high background activity.
Animals↗
The effect of a paracetamol and morphine combination on dynorphin A levels in the rat brain.
The purpose of this study was to find out whether the combination of inactive doses of paracetamol (PARA) and morphine was able to change dynorphin (DYN) A levels, evaluated by radioimmunoassay, and whether naloxone or [(-)-2-(3 furylmethyl)-normetazocine] (MR 2266), a kappa-opioid antagonist, modifies or prevents the activity of this combination on nociception and on DYN levels. The work was suggested by our previous findings which demonstrated that inactive doses of PARA and morphine, when given in combination, share an antinociceptive effect, and that PARA, at antinociceptive doses, decreases DYN levels in the frontal cortex, thus indicating a selective action within the CNS. Our present results demonstrate that the combination of inactive doses of PARA (100 mg/kg) and morphine (3 mg/kg) is just as effective in decreasing the levels of DYN A as full antinociceptive doses of PARA or morphine alone in the frontal cortex of the rat. The values, expressed in pmol/g tissue, were: control = 2.83 +/- 0.20; paracetamol (100) = 2.60 +/- 0.23; morphine (3) = 2.73 +/- 0.24; paracetamol + morphine = 1.34 + 0.16 (P < 0.05). The decrease was partially antagonised by MR 2266, but not by naloxone, suggesting that the activity of PARA and morphine in combination on DYN A levels could be mediated, at least in part, through kappa-receptors, although other systems may be involved. On the other hand, both naloxone and MR 2266 prevented the antinociceptive effect of the combination in the hot plate test. All our experimental data suggest that PARA and morphine in combination exert their antinociceptive effect through the opioidergic system, which in turn may cause a decrease in DYN levels in the CNS of the rat.
Acetaminophen↗
Fit genotypes and escape variants of subgroup III Neisseria meningitidis during three pandemics of epidemic meningitis.
The genetic variability at six polymorphic loci was examined within a global collection of 502 isolates of subgroup III, serogroup A Neisseria meningitidis. Nine "genoclouds" were identified, consisting of genotypes that were isolated repeatedly plus 48 descendent genotypes that were isolated rarely. These genoclouds have caused three pandemic waves of disease since the mid-1960s, the most recent of which was imported from East Asia to Europe and Africa in the mid-1990s. Many of the genotypes are escape variants, resulting from positive selection that we attribute to herd immunity. Despite positive selection, most escape variants are less fit than their parents and are lost because of competition and bottlenecks during spread from country to country. Competition between fit genotypes results in dramatic changes in population composition over short time periods.
Alleles↗
Synthesis and solution characterization of a porphyrin-CCK8 conjugate.
In this paper we report the synthesis and a detailed NMR solution characterization of a new CCK8 analogue and its indium(III) complex, PK-CCK8 and In-PK-CCK8. The new compounds contain a porphyrin moiety covalently bound through an amide bond to the side chain of a Lys residue introduced at the N-terminus of CCK8. A molecular dynamics simulation, based on the NMR structure of the complex between CCK8 and the N-terminal extracellular arm of the CCK(A) receptor, is also reported. Both the NMR study and the molecular dynamics simulation indicate that the porphyrin-peptide conjugate might be able to bind to the CCK(A) receptor model. The results of the molecular dynamics calculations show that the conformational features of the CCK8/CCK(A) receptor model complex and of the PK-CCK8/CCK(A) receptor-model complex are similar. This evidence supports the view that the introduction of the porphyrin-Lys moiety does not influence the mode of ligand binding to the CCK(A) receptor model. The NMR structure of PK-CCK8 in DMSO consists of a well defined pseudo-helical N-terminal region, while the C-terminal region is flexible. Moreover, the absence of NOE contacts between the porphyrin and the peptide indicates that the macrocyclic ring is directed away from the peptide region involved in the binding with the receptor.
Computer Simulation↗
Deeper into attachment and culture.
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Adult↗
Negative autoregulation of the Arabidopsis homeobox gene ATHB-2.
The Arabidopsis homeobox gene ATHB-2 is tightly regulated by light signals, and is thought to direct morphological changes during shade avoidance responses. To understand how ATHB-2 mediates light signals in plant morphogenesis, we investigated its transcriptional network. We constructed a gene encoding a chimeric transcription factor (HD-Zip-2-V-G) that is expected to activate target genes of ATHB-2 in a glucocorticoid-dependent manner. In transgenic Arabidopsis plants expressing HD-Zip-2-V-G, glucocorticoid treatment activates the ATHB-2 gene itself, independent of de novo protein synthesis. An in vitro DNase I-footprinting experiment showed that recombinant ATHB-2 protein specifically bound to an ATHB-2 promoter region. These complementary results indicate that ATHB-2 recognizes its own promoter. Consistent with the fact that ATHB-2 itself has been shown to act as a repressor, expression of the endogenous ATHB-2 gene was repressed in transgenic plants overexpressing an ATHB-2 transgene. Moreover, target-gene analysis using the HD-Zip-2-V-G suggested that ATHB-2 recognizes other HD-Zip II subfamily genes. We conclude that ATHB-2 has a negative autoregulatory loop and may be involved in a complicated transcriptional network involving paralogous genes, as is the case with animal homeobox genes.
Arabidopsis↗
Regional lymph node dissection in the treatment of renal cell carcinoma: is it useful in patients with no suspected adenopathy before or during surgery?
OBJECTIVES: To evaluate the role of regional lymph node dissection (LND) in a series of patients with renal cell carcinoma (RCC) with no suspicion of nodal metastases before or during surgery. PATIENTS AND METHODS: A series of 167 patients with RCC, free from distant metastases at diagnosis, and who underwent radical nephrectomy at our hospital between January 1990 and October 1997, was reviewed. The mean (median, range) follow-up was 51 (45, 19-112) months. Of the 167 patients, 108 underwent radical nephrectomy alone and 59 had radical nephrectomy with regional LND limited to the anterior, posterior and lateral sides of the ipsilateral great vessel, from the level of the renal pedicle to the inferior mesenteric artery. Of these 59 patients, 49 had no evidence of nodal metastases before or during surgery. The probability of survival was estimated by the Kaplan-Meier method, using the log-rank test to estimate differences among levels of the analysed variables. RESULTS: The overall 5-year survival was 79%; the 5-year survival rate for the 108 patients who underwent radical nephrectomy alone was 79% and for the 49 who underwent LND was 78%. Of the 49 patients with no suspicion of lymph node metastases, one (2%) was found to have histologically confirmed positive nodes. CONCLUSION: These results suggest that there is no clinical benefit in terms of overall outcome in undertaking regional LND in the absence of enlarged nodes detected before or during surgery.
Adult↗
The effect of paracetamol on nociception and dynorphin A levels in the rat brain.
Male Wistar rats were administered with naloxone (1 mg/kg i.p.) or MR 2266 (5 mg/kg i.p) 15 min before paracetamol (400 mg/kg i.p.) treatment and the pain threshold was evaluated. Rats were subjected to the hot-plate and formalin tests and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in the hypothalamus, hippocampus, striatum, brainstem, frontal and parietal-temporal cortex by radioimmunoassay. Pretreatment with naloxone abolished paracetamol antinociceptive activity both in hot-plate and in the first phase, but not in the second phase of the formalin test, while MR 2266 pretreatment was able to antagonise paracetamol effect either in the hot-plate test or in both phases of the formalin test. Among different brain areas investigated paracetamol significantly decreased ir-dynorphin A levels only in the frontal cortex. MR 2266 but not naloxone reversed the decrease in ir-dynorphin A levels elicited by paracetamol. Paracetamol seems to exert its antinociceptive effect also through the opioidergic system modulating dynorphin release in the central nervous system (CNS) of the rat, as suggested by the decrease in the peptide levels.
Acetaminophen↗