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Biomedical subjects

M Rinaldi

Publications and source records attributed to M Rinaldi.

At least 73 records · Page 4Linked to original sources
PubMed2001

Gene flow between natural and domestic populations of Lutzomyia longipalpis (Diptera: Psychodidae) in a restricted focus of American visceral leishmaniasis in Venezuela.

The epidemiology of the visceral leishmaniasis in the Americas is associated with both a natural and a domestic cycle. The existence of reproductively isolated populations of Lutzomyia longipalpis (Lutz & Neiva), and the scarcity of records of this species from natural habitats in areas where it has been associated with domestic habitats indicated that natural populations could be genetically distinct from domestic ones. Therefore, we compared the genetic structure and estimated the gene flow between L. longipalpis from domestic and peridomestic habitat and from an adjacent undisturbed natural environment along a 1.2-km transect. The analyses were performed on electrophoretic data from eight isozyme loci. The absence of fixed differences in the diagnostic loci Ak and Hk indicated that all specimens belonged to one of the two cryptic species identified in Venezuela. The average number of alleles per locus ranged from 2.0 to 2.9 and the average heterozygosity ranged from 7.8 to 13.4%. No differences were detected in the genetic structure of this species from domestic or peridomestic habitats and those trapped as far as 1.2 km from human dwellings. Nm, estimated from Wright's Fst, indicated that at least 208 individuals per generation migrated between the peridomestic habitat and a 1.2-km distant point to maintain the observed similarities in allelic frequencies. This high rate of gene flow indicated that this species has high migration rates between domestic and natural environments, and has the potential to transport for Leishmania from natural to domestic environments.

Adenylate Kinase↗
PubMed2001

Healing of acute myocarditis with left ventricular assist device: morphological recovery and evolution to the aspecific features of dilated cardiomyopathy.

Dilated cardiomyopathy may result from an acute myocarditis. Little is reported in vivo documenting the progression from the acute inflammatory disease to the healing phase. We describe the consecutive light and electron microscopy studies performed on five myocardial sample series in a 47-year-old female patient who was referred to our hospital with acute myocarditis. She was sustained with left ventricular assist device (LVAD) for 63 days, and then she died of cerebral hemorrhage. The first three consecutive endomyocardial biopsies (days 2, 4, 36 from onset) documented the acute and early healing phase of the inflammatory disease. In the last two biopsies (days 50 and 64 from onset) active inflammation and myocyte necrosis were absent. The histopathological features were those commonly observed in most patients diagnosed with dilated cardiomyopathy, namely myocyte hypertrophy, nuclear size and shape irregularities, and interstitial fibrosis. Overall, the myocyte morphology significantly improved and LVAD support likely contributed to the structural recovery. The major conclusions to be drawn from this case are: 1) the aspecific pathologic findings of dilated cardiomyopathy patients may result from an acute myocardial inflammation; 2) immediate endomyocardial biopsy in patients with clinically diagnosed myocarditis minimizes the risk of missing the diagnosis of inflammatory disease; to this aim a precise definition of "early onset" is especially needed; 3) LVAD support may contribute to the morphological recovery of severely damaged myocytes.

Biopsy↗
PubMed2000

How should patients with hepatocellular carcinoma be staged? Validation of a new prognostic system.

BACKGROUND: The life expectancy of a patient with hepatocellular carcinoma (HCC) in cirrhosis is hard to predict, making it difficult to decide whether a certain treatment is indicated and what to say to the patient regarding prognosis. A new score recently has been proposed, which includes the parameters involved in the Child-Pugh stage, plus macroscopic tumor morphology, alpha-fetoprotein levels, and the presence or absence of portal thrombosis. The score has been validated in internal control series, but its general applicability has yet to be confirmed. The authors compared the discriminatory ability of the Cancer of the Liver Italian Program (CLIP) score with those of the Okuda and TNM staging systems and the Child-Pugh classification in a group of cirrhotic patients with HCC, diagnosed and followed up by their unit. METHODS: One hundred fifty-four patients with histologically ascertained HCC in cirrhosis were recruited (median age, 62.5 years; male/female ratio, 122/32) and prospectively followed up. Staging was performed at the baseline using the Child-Pugh, Okuda, TNM, and CLIP systems. RESULTS: The CLIP score was able to predict survival better than the Okuda or TNM staging system, as confirmed by the Kaplan-Meier comparison of survival curves and by the Cox regression analysis, with a median survival rate of 31, 27, 13, 8, 2, and 2 months in patients with CLIP Stages 0, I, II, III, IV, and V-VI, respectively. The Child-Pugh classification performed as well as the Okuda. The predictive capacity of CLIP score was confirmed in the subgroup of patients undergoing chemoembolization. Overall, the survival rate in the authors' series was higher than predicted on the basis of previous reports. CONCLUSIONS: The CLIP score, which is based on simple features of the patient and of the tumor, can accurately identify patients with different prognoses, particularly in the early phases of HCC, thus representing a useful tool in the management of the disease and of the affected patient.

Adult↗
PubMed2000

The effects of transdermal estradiol on the response to mental stress in postmenopausal women: a randomized trial.

PURPOSE: Estrogens inhibit adrenomedullary catecholamine release and catecholamine-mediated responses to stress. We examined whether estrogen supplementation reduces the sympathoadrenal response to mental stress in postmenopausal women. MATERIALS AND METHODS: We compared the effects of 3-week treatment with transdermal 17-beta-estradiol and placebo in 10 postmenopausal women using a randomized, blinded, crossover design. We measured plasma catecholamine levels and the cardiovascular and metabolic responses to a 15-minute stress with mental arithmetic. Treatments were compared using repeated measures analysis of variance. RESULTS: During placebo treatment, mean (+/- SD) epinephrine levels reached a peak of 431 +/- 135 pmol/liter after 15 minutes of stress; the epinephrine response was blunted during estradiol treatment, with a peak of 357 +/- 77 pmol/liter (P <0.05). Estradiol also blunted the diastolic blood pressure response to stress (baseline levels of 78 +/- 15 mm Hg vs peak of 90 +/- 6 mm Hg during placebo; baseline of 80 +/- 8 mm Hg vs peak of 84 +/- 6 mm Hg during estradiol; P <0.05). Estradiol treatment also blunted the decrease in the standard deviation of the mean of the electrocardiographic RR intervals and the increase in the ratio between the low-frequency and high-frequency bandwidths. CONCLUSION: We observed a moderate, although significant, reduction in markers of the stress response to mental arithmetic in postmenopausal women treated with transdermal 17-beta-estradiol.

Administration, Cutaneous↗
PubMed2000

Orthotopic heart transplantation: standard versus bicaval technique.

We compared orthotopic heart transplantation (HT) by bicaval technique with the standard technique. Between January 1995 and December 1997, 117 patients underwent 118 HTs; 71 patients (15 women and 56 men) had 72 HTs by standard technique and 46 patients (9 women, 37 men) underwent HT using bicaval procedures. Preoperative parameters were similar in both groups; 5 patients who underwent the standard technique and no patients who underwent bicaval procedures required permanent pacemakers (p = NS). Isoproterenol infusion was significantly longer in the standard technique. Major perioperative arrhythmias (ventricular tachycardia and fibrillation, asystole) appeared in 8.2% and 7.0% of standard and bicaval HTs, respectively; atrial fibrillation appeared in 13.1% and 4.6%, respectively (p = NS). At 1 month, mitral and tricuspid regurgitation rates were higher in the standard group (p = NS); at 1 year only tricuspid regurgitation was still higher (p = NS). Right atrial pressure, Wood units, cardiac output, and cardiac index were examined (p = NS). At multivariate analysis, interaction between preoperative Wood units and transplant type was elicited for Wood units at 1 month and for right atrial pressure at 1, 3, and 6 months. In the high resistance subgroup, the patients who underwent bicaval procedures had higher resistances at 1 month. In the low resistance subgroup, right atrial pressure was higher in patients who underwent standard techniques at 1, 3, and 6 months follow-up. Thus, bicaval HT was found to be safe, without surgically related complications, it provoked significantly less blood loss, and required less isoproterenol use. No significant advantages were observed in conduction disturbances and major arrhythmias or regarding the need for temporary or permanent pacemakers.

Adolescent↗
PubMed2000

4-Hydroxynonenal-induced MEL cell differentiation involves PKC activity translocation.

4-Hydroxynonenal (HNE) is a highly reactive aldehyde, produced by cellular lipid peroxidation, able to inhibit proliferation and to induce differentiation in MEL cells at concentrations similar to those detected in several normal tissues. Inducer-mediated differentiation of murine erythroleukemia (MEL) cells is a multiple step process characterized by modulation of several genes as well as by a transient increase in the amount of membrane-associated protein kinase C (PKC) activity. Here we demonstrate that a rapid translocation of PKC activity from cytosol to the membranes occurs during the differentiation induced by HNE. When PKC is completely translocated by phorbol-12-myristate-13-acetate (TPA), the degree of HNE-induced MEL cells differentiation is highly decreased. However, if TPA is washed out from the culture medium before the exposition to the aldehyde, HNE gradually resumes its differentiative ability. The incubation of cells with a selective inhibitor of PKC activity, bisindolylmaleimide GF 109203X, partially prevents the HNE-induced differentiation in MEL cells. In conclusion, our results demonstrate that HNE-induced MEL cell differentiation is preceded by a rapid translocation of PKC activity, and that the inhibition of this phenomenon prevents the onset of terminal differentiation.

Aldehydes↗
PubMed2000

Glyceryl trinitrate for chronic anal fissure--healing or headache? Results of a multicenter, randomized, placebo-controled, double-blind trial.

PURPOSE: Internal anal sphincterotomy for treating chronic anal fissure can irreversibly damage anal continence. Reversible chemical sphincterotomy may be achieved by anal application of glyceryl trinitrate ointment (nitric oxide donor), which has been reported to heal the majority of patients with anal fissure by inducing sphincter relaxation and improving anodermal blood flow. This trial aimed to further clarify the role of glyceryl trinitrate in the treatment of chronic anal fissure. METHODS: A total of 132 consecutive patients from nine centers were randomly assigned to receive 0.2 percent glyceryl trinitrate ointment or placebo twice daily for at least four weeks. The severity of pain and maximum anal resting pressure were measured before and after one week of treatment. Anodermal blood flow was measured before and after application of glyceryl trinitrate or placebo in ten patients. RESULTS: The study was completed by 119 patients (59 glyceryl trinitrate and 60 placebo), matched for gender, age, duration of symptoms, duration of treatment, site of fissure, previous attempts to treat, pain score, and maximum anal resting pressure. Twenty-nine patients (49.2 percent) healed after glyceryl trinitrate and 31 patients (51.7 percent) healed after placebo (P = not significant). Pain score fell significantly in both groups, in addition to maximum anal resting pressure. Anodermal blood flow improved significantly in seven patients receiving glyceryl trinitrate, but not in the three receiving placebo. Twenty-three patients (33.8 percent) experienced headache and 4 (5.9 percent), orthostatic hypotension after glyceryl trinitrate. CONCLUSION: This trial fails to demonstrate any superiority of topical 0.2 percent glyceryl trinitrate treatment vs. a placebo, although the effects of glyceryl trinitrate on anodermal blood flow and sphincter pressure are confirmed. This finding, together with the high incidence of side-effects, should discourage the use of this treatment as a substitute for surgery in chronic anal fissure.

Adult↗
PubMed2000

Serum ECP and MPO are increased during exacerbations of chronic bronchitis with airway obstruction.

Many studies have demonstrated that, in asthma, serum levels of eosinophil cationic protein (ECP) are related to the activity and severity of the disease and can be used to evaluate the response to steroid treatment. During exacerbations of chronic bronchitis, airway inflammation shows some features of asthmatic inflammatory processes, with recruitment of eosinophils and recovery of significant amounts of ECP in bronchial lavage fluid (BAL). Involvement of neutrophils, with high levels of myeloperoxidase (MPO), is, on the contrary, typical of this latter disease, and not shared with asthma. In spite of the information collected with BAL and bronchial biopsy studies, few data still exist on serum levels of these proteins in chronic bronchitis. The objective of this study was to assess if serum levels of ECP and MPO are specifically increased in exacerbations of chronic bronchitis, as compared to other non-asthmatic acute respiratory disturbances. Serum ECP, MPO and immunoglobulin E (IgE) levels were measured in 17 non-atopic patients with exacerbation of chronic bronchitis with airway obstruction (COPD) and in 11 control subjects seeking emergency medical treatment for unrelated acute respiratory problems. Spirometry was performed in patients able to give the necessary collaboration. All the subjects of this study were recruited from the emergency department. Both ECP and MPO were significantly increased in serum from patients with exacerbated COPD (22.2 +/- 4.1 vs 9.5 +/- 1.4 mcg/L and 853 +/- 168 vs 375 +/- 41 mcg/L) and a strong correlation existed between these two variables (r = 0.782). A further control group was made of 11 patients with stable COPD. These subjects had levels of both ECP (13.1 +/- 2.7 mcg/L) and MPO (469 +/- 71) significantly lower than patients with exacerbated disease and higher than those without COPD. We conclude that serum ECP and MPO are increased during the exacerbations of COPD. These observations can give a basis for further studies aimed to evaluate the utility of these two proteins as markers of activity and severity of COPD.

Aged↗
PubMed2000

A three-week schedule of gemcitabine-cisplatin in advanced non-small-cell lung cancer with two different cisplatin dose levels: a phase II randomized trial.

BACKGROUND: To explore a new schedule of gemcitabine-cisplatin (GP) combination therapy using two different cisplatin doses in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: From May to December 1997, 92 chemonaive patients entered the study and 88 (28 with locally advanced and 60 with disseminated NSCLC) were evaluable for response and toxicity (45 in arm A and 43 in arm B). Patients were randomly assigned to arm A or arm B. Gemcitabine 1000 mg/m2 was given on days 1-8 plus cisplatin 100 mg/m2 in arm A and cisplatin 70 mg/m2 in arm B on day 2 of every 21-day cycle. RESULTS: The overall response rates in arms A and B were 42% (95% confidence interval (CI): 27.8%-56.7%) and 47% (95% CI: 31.6%-61.5%), respectively. Median duration of response was 9.7 months (range 1.8 to 30.9 months; 13.1 and 9.5 months for arm A and B, respectively), and median survival was 12 months (range 0.2 to 31.1 months; 15.4 and 11.5 months for arm A and B, respectively). Major WHO grade 3-4 toxicities in arm A vs. arm B included: thrombocytopenia (23% vs. 17% of courses), leukopenia (15%, vs. 4% of courses), anemia (7% vs. 6% of courses), and nausea-vomiting (20% vs. 7% of patients). Grade 1-2 nephrotoxicity occurred in 20% of patients in arm A and in 7% of patients in arm B, with one grade 4 episode in arm A. Six patients discontinued treatment because of toxicities, 5 in arm A and I in arm B. CONCLUSIONS: Results of this trial indicate that both schedules are feasible and active, with a milder toxicity in the arm with the lower cisplatin dose.

Adult↗
PubMed2000

Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by intramuscular injection of plasmid DNA.

We report on systemic delivery and long-term biological effects of apolipoprotein E (apoE) obtained by intramuscular (i.m.) plasmid DNA injection. ApoE plays an important role in lipoprotein catabolism and apoE knock-out mice develop severe hypercholesterolemia and diffuse atherosclerosis. We have injected apoE-deficient mice with 80 microg of a plasmid vector (pCMV-E3) encoding the human apoE3 cDNA under the control of the CMV promoter-enhancer in both posterior legs. Local expression of the transgene was demonstrated throughout 16 weeks. Human apoE3 recombinant protein reached 0.6 ng/ml serum level. After i.m. injection of pCMV-E3 expression vector the mean serum cholesterol concentrations decreased from 439 +/- 57 mg/dl to 253 +/- 99 mg/dl (P < 0.05) 2 weeks after injection and persisted at a significantly reduced level throughout the 16 weeks observation period (P < 0.005). Serum cholesterol was unaffected and reached an absolute level of 636 +/- 67 mg/dl in control groups. Finally, injection of pCMV-E3 into apoE-deficient mice resulted in a redistribution of cholesterol content between lipoprotein fractions, with a marked decrease in VLDL, IDL and LDL cholesterol content and an increase in HDL cholesterol. These results demonstrate that severe hypercholesterolemia in apoE-deficient mice can be effectively reversed by i.m. DNA injection, and indicate that this approach could represent a useful tool to correct several hyperlipidemic conditions resulting in atherosclerosis.

Analysis of Variance↗
PubMed2000

Effects of erythromycin on human colonic circular muscle in idiopathic chronic constipation.

BACKGROUND: Erythromycin has been shown to have profound prokinetic effects on the gastrointestinal tract of humans and animals, probably through its action on endogenous motilin receptors. The purpose of this study was to determine both the direct and indirect effects ('off contraction') of erythromycin and motilin on ex vivo circular muscle strips of the distal colon from patients with or without idiopathic chronic constipation (ICC). MATERIALS AND METHODS: Cumulative concentrations of erythromycin (1-20 microM) and motilin (0.05-1 microM) were tested in both control and ICC preparations in order to evaluate the direct drugs effect. A range doses of both erythromycin (0.5-10 microM) and motilin (0.05-0.5 microM) were tested on their ability to affect the off-contraction that follows the typical inhibitory response evoked by low frequencies of Electrical Field Stimulation (EFS) (1-5 Hz, 20 V, 1 msec pulse trains lasting 1 min). RESULTS: The direct effect of both erythromycin and motilin was a slight increase (less than 10% of the maximal ACh-induced contraction) in the basal tension, with no dose-response relationship. The off-contraction, evoked by EFS, was not affected by drugs pretreament in control preparations. Conversely, in ICC preparations both drugs significantly increased the off-contraction (about 30%). CONCLUSIONS: Erythromycin causes mainly an indirect contractile effect in circular muscle strips from ICC patients. This effect may be related to the activation of inhibitory neuronal motilin receptors. This activation might potentiate NANC relaxation, proportionally increasing the circumferential reflex contraction that follows the EFS-induced relaxation.

Adult↗
PubMed2000

Constipation after hysterectomy: fact or fiction?

Hysterectomy is responsible for numerous postoperative complications largely urological, but sometimes of sexual or colorectal function. The latter involve modifications of bowel function resulting in constipation as a result of delayed transit, infrequent evacuations and greater difficulty in expelling faeces. We have reviewed the topic, and consider the various hypotheses whereby these modifications may result from hormonal alterations, iatrogenic causes, or variations in recto-bladder sensitivity. Any of these could justify the modifications in bowel function detected in these patients. The studies carried out so far provide no clear information about the type of constipation that develops after hysterectomy, as we lack prospective studies that compare bowel function before and after operations. Nor is it clear whether we are dealing with constipation as a result of delayed transit or obstructed defaecation, nor which pathogenetic mechanisms are involved. In view of the large number of hysterectomies that are done, sometimes prophylactically, controlled prospective studies are warranted to address these issues more fully.

Constipation↗
PubMed2000

Ambamustine in the second-line treatment of patients with small-cell lung cancer: a phase II Fonicap study.

Despite a high probability of response to first-line chemotherapy, most patients with small-cell lung cancer (SCLC) will eventually have progression of their disease because of the development of resistant disease. Second-line testing of new drugs is an accepted research strategy in SCLC. In this context, the Italian Lung Cancer Task Force (FONICAP) has tested a new synthetic bifunctional alkylating agent, Ambamustine, with preliminary evidence of activity in other solid tumors. Patients with measurable SCLC, progressive after one first-line chemotherapy regimen (either "sensitive" or "refractory"), were eligible for the study. Ambamustine was administered at the dose of 2 mg/kg as a 1-hour intravenous infusion on day 1 every 21 days. The dose was to be increased to 3 mg/kg if no grade IV toxicity and complete hematologic recovery had occurred by day 22. Sample size was calculated according to a two-stage optimal Simon's design. Seventeen patients were entered into the study. Twelve patients were refractory to prior chemotherapy; 12 had extensive disease; the median age was 64 years (range: 46-75 years) and the median performance status was 1. Among 13 patients who received more than one cycle, 9 patients could increase Ambamustine dose from 2 to 3 mg/kg. No objective response was observed: one patient obtained a 50% regression of the primary tumor with contemporary disease progression in the liver and was qualified as having progressive disease. The treatment was well tolerated: grade IV leukopenia occurred in only 1 patient; grade III anemia occurred in 17.6%, grade III leukopenia in 11.8%, and grade III thrombocytopenia in 23.5%. Nonhematologic toxicity was minimal. Ambamustine, at the dose and schedule used in this study, is well tolerated in pretreated patients with SCLC but has no significant antitumor activity in this unfavorable group of patients.

Aged↗
PubMed2000

Risk factors for candidemia in Neonatal Intensive Care Unit patients. The National Epidemiology of Mycosis Survey study group.

BACKGROUND: Candida species are important nosocomial pathogens in neonatal intensive care unit (NICU) patients. METHODS: A prospective cohort study was performed in six geographically diverse NICUs from 1993 to 1995 to determine the incidence of and risk factors for candidemia, including the role of gastrointestinal (GI) tract colonization. Study procedures included rectal swabs to detect fungal colonization and active surveillance to identify risk factors for candidemia. Candida strains obtained from the GI tract and blood were analyzed by pulsed field gel electrophoresis to determine whether colonizing strains caused candidemia. RESULTS: In all, 2,847 infants were enrolled and 35 (1.2%) developed candidemia (12.3 cases per 1,000 patient discharges or 0.63 case per 1,000 catheter days) including 23 of 421 (5.5%) babies < or =1,000 g. After adjusting for birth weight and abdominal surgery, forward multivariate logistic regression analysis demonstrated significant risk factors, including gestational age <32 weeks, 5-min Apgar <5; shock, disseminated intravascular coagulopathy, prior use of intralipid, parenteral nutrition, central venous catheters, H2 blockers, intubation or length of stay > 7 days before candidemia (P < 0.05). Catheters, steroids and GI tract colonization were not independent risk factors, but GI tract colonization preceded candidemia in 15 of 35 (43%) case patients. CONCLUSIONS: Candida spp. are an important cause of late onset sepsis in NICU patients. The incidence of candidemia might be decreased by the judicious use of treatments identified as risk factors and avoiding H2 blockers.

Candida↗
PubMed2000

The effect of acute oral erythromycin on gallbladder motility and on upper gastrointestinal symptoms in gastrectomized patients with and without gallstones: a randomized, placebo-controlled ultrasonographic study.

OBJECTIVE: Gastrectomy might be a risk factor for cholelithiasis and gallbladder stasis might play a major role. We studied fasting and postprandial gallbladder motility with 600 mg oral erythromycin or placebo in gastrectomized patients (with and without gallstones) and controls. METHODS: Seventeen patients operated on for gastric cancer (subtotal gastrectomy: n = 10, total gastrectomy: n = 7) were compared with 20 sex- and body-size matched healthy controls. Subjects randomly received erythromycin or placebo 30 min before the ingestion of a standard 200 ml liquid test meal. Gallbladder volume was estimated by ultrasonography until 120 min after test meal. A visual analog scale monitored GI perception of appetite, satiety, nausea, abdominal fullness and epigastric pain. RESULTS: Gastrectomized patients had increased fasting gallbladder volume (35.9 +/- 3.4 ml versus 21.0 +/- 1.4 ml, p = 0.0005) with faster postmeal emptying (T/2 14.8 +/- 1.1 min versus 23.5 +/- 1.5 min, p = 0.00019) than controls. Six patients developed small and asymptomatic gallstones, which did not influence gallbladder motility. In these patients, fasting gallbladder volume increased with time after surgery (r = +0.82, p = 0.047). Perception of satiety, abdominal fullness, and epigastric pain after ingestion of the test meal were all significantly greater in patients than in controls. Erythromycin significantly enhanced gallbladder emptying during fasting (p = 0.001) and postprandially in both patients and controls (0.002 < p < 0.017) and significantly reduced postmeal satiety and epigastric discomfort in gastrectomized patients. CONCLUSIONS: Increased fasting volume might be a form of stasis, predisposing patients to gallstone formation. Erythromycin improves fasting and postprandial gallbladder emptying and decreases upper GI symptoms in gastrectomized patients.

Administration, Oral↗
PubMed2000

A head-on comparison of the in vitro antifungal activity of conventional and lipid-based amphotericin B: a multicenter study.

A comparative study of conventional amphotericin B, Abelcet and AmBisome was performed using a microdilution format of the NCCLS M27-A methodology for susceptibility testing against 300 fungal isolates (152 yeasts, 148 filamentous fungi) in both RPMI-1640 and antibiotic medium #3 (AB3). The clinical isolates included Candida albicans (n=54), Candida glabrata (n=25), Candida parapsilosis (n=23), Candida krusei (n=19), Candida lusitaniae (n=14), Cryptococcus neoformans (n=5), Candida tropicalis (n=12), Aspergillus flavus (n=34), Aspergillus fumigatus (n=46) and 68 other filamentous fungi encompassing 22 different genera. The minimal inhibitory concentrations (MIC) for all drugs were defined as the lowest concentrations in which there was no visible growth. MICs were determined after 48 h for yeasts and 72 h for filamentous fungi. The mean MICs +/- standard error (microg/ml) for yeasts and filamentous fungi, respectively, were: Abelcet, 0.51+/-0.21, 4.34+/-0.61; AmBisome, 1.28+/-0.24, 5.68+/-0.57; amphotericin B, 0.29+/-0.11, 1.12+/-0.19, respectively. Overall, against both yeasts and filamentous fungi Abelcet proved to have more potent antifungal activity than AmBisome. Using AB3 as opposed to RPMI-1640 generally produced lower MIC values but did not have any effect on the order of relative activity with all of the antifungal agents tested. In conclusion, our data shows that Abelcet is more active than AmBisome against pathogenic yeast and filamentous fungi when assayed in AB3 in vitro. Comparison of the activities of these antifungals in experimental animal models is necessary to determine whether these in vitro findings are correlated with in vivo efficacy.

Amphotericin B↗
PubMed1999

Phthalein derivatives as a new tool for selectivity in thymidylate synthase inhibition.

A new set of phthalein derivatives stemming from the lead compound, phenolphthalein, were designed to specifically complement structural features of a bacterial form of thymidylate synthase (Lactobacillus casei, LcTS) versus the human TS (hTS) enzyme. The new compounds were screened for their activity and their specificity against TS enzymes from different species, namely, L. casei (LcTS), Pneumocystis carinii (PcTS), Cryptococcus neoformans (CnTS), and human thymidylate synthase (hTS). Apparent inhibition constants (Ki) for all the compounds against LcTS were determined, and inhibition factors (IF, ratio between the initial rates of the enzymatic reaction in the presence and absence of each inhibitor) against each of the four TS species were measured. A strong correlation was found between the two activity parameters, IF and Ki, and therefore the simpler IF was used as a screening factor in order to accelerate biological evaluation. Compounds 5b, 5c, 5ba, and 6bc showed substantial inhibition of LcTS while remaining largely inactive against hTS, illustrating for the first time remarkable species specificity among TSs. Due to sequence homology between the enzymes, several compounds also showed high activity and specificity for CnTS. In particular, 3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H, 3H-naphtho[1,8-c,d]pyran-1-one (6bc) showed an IF < 0.04 for CnTS (Ki = 0.45 microM) while remaining inactive in the hTS assay at the maximum solubility concentration of the compound (200 microM). In cell culture assays most of the compounds were found to be noncytotoxic to human cell lines but were cytotoxic against several species of Gram-positive bacteria. These results are consistent with the enzymatic assays. Intriguingly, several compounds also had selective activity against Cr. neoformans in cell culture assay. In general, the most active and selective compounds against the Gram-positive bacteria were those designed and found in the enzyme assay to be specific for LcTS versus hTS. The original lead compound was least selective against most of the cell lines tested. To our knowledge these compounds are the first TS inhibitors selective for bacterial TS with respect to hTS.

Anti-Bacterial Agents↗