Follicular occlusion tetrad in a male patient with pachyonychia congenita: clinical and genetic analysis.

The case of a 24-year-old male patient affected by follicular occlusion tetrad (acne conglobata, hidradenitis suppurativa, pilonidal cyst and dissecting cellulitis of the scalp) associated with clinical signs of pachyonychia congenita (PC)-2 (focal palmoplantar keratoderma, plantar pain, onycodystrophy and multiple cysts) is reported. The diagnosis was supported by genetic analysis that showed heterozygous mutation within the exon 1 of KRT17 gene. This case may reflect different expressions of a phenotypic spectrum induced by a common genetic alteration.

Predictive value of assessment of disc-radicular conflict of the cervical segment by somatosensory evoked potentials.

Somatosensory evoked potentials (SSEP) of the n. medianus, with clinically significant neurological findings helps in diagnosing a number of different cervical spine lesions. SSEP of the n. medianus and neurological observations also aid in diagnosticis of the disc-radicular conflict. A final diagnosis is set by the computerised tomography (CT). The tested positive predictive value of assessment of disc-radicular conflict of the cervical spine by means of SSEP is 87%. The 95% confidence interval (CI) is 0.87 (0.81-0.93) (Tab. 3, Fig. 4, Ref. 23). Full Text (Free, PDF) www.bmj.sk.

Adhesion and proliferation of fibroblasts on cluster-assembled nanostructured carbon films: the role of surface morphology.

We have investigated the influence on adhesion and proliferation of NIH 3T3 fibroblasts of the surface morphology of cluster assembled carbon films deposited by Supersonic Cluster Beam Deposition. Nanostructured carbon films exhibit a multi-scale morphology, which resembles the surface structure of the extracellular matrix, and possess a high specific area, while being relatively smooth at all scales. Correlations between measured morphological parameters and adaptive cell response have been brought out. High specific area and smoothness appear to conceivably favour both the early attachment of plated cells and the long-term survival of adherent cells. Moreover, nano-structured carbon films affect the cells morphology as well as the extension and the number of the focal contacts.

Pharmacological and toxicological aspects of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548): a novel antineoplastic agent.

4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548) belongs to a novel class of antitumor compounds (termed alkycyclines) and is currently undergoing Phase II clinical trial. In the present study, we investigated the in vitro and in vivo antitumor activity, the pharmacokinetics, and the toxicological profile of this compound. PNU-159548 showed good cytotoxic activity in murine and human cancer cells growing in vitro, with an average concentration for 50% growth inhibition of 15.8 ng/ml. The drug showed strong antitumor efficacy in vivo after i.v. and p.o. administration against rapidly proliferating murine leukemias and slowly growing transplantable human xenografts. At non-toxic doses, PNU-159548 produced complete regression and cures in ovarian, breast, and human small cell lung carcinomas. Fourteen of 16 models studied, including colon, pancreatic, gastric, and renal carcinomas, astrocytoma and melanoma, were found to be sensitive to PNU-159548. In addition, PNU-159548 was effective against intracranially implanted tumors. Toxicological studies revealed myelosuppression as the main toxicity in both mice and dogs. The maximum tolerated doses, after a single administration, were 2.5 mg/kg of body weight in mice, 1.6 mg/kg in rats, and 0.3 mg/kg in dogs. In the cyclic studies, the maximum tolerated doses were 0.18 mg/kg/day (cumulative dose/cycle: 0.54 mg/kg) in rats and 0.05 mg/kg/day (cumulative dose/cycle: 0.15 mg/kg) in dogs. PNU-159548 showed minimal cardiotoxicity, when compared with doxorubicin in the chronic rat model at a dose level inducing similar myelotoxicity. Animal pharmacokinetics, carried out in mice, rats, and dogs, was characterized by high volumes of distribution, plasma clearance of the same order of the hepatic blood flow, and short terminal half-life. These findings support the conclusion that PNU-159548 is an excellent candidate for clinical trials in the treatment of cancer.

Management of multidrug-resistant tuberculosis in Italy.

SETTING: SMIRA (Italian Study on Anti-Tuberculosis Drug Resistance) network, 46 major clinical units and 22 laboratories nationwide in Italy. OBJECTIVES: To determine the main features, adherence to WHO guidelines and the outcomes of multidrug-resistant tuberculosis (MDR-TB) patients enrolled from January 1995 to December 1999. DESIGN: Observational study, preceded by proficiency testing, according to WHO recommendations. Results were stratified by appropriate and inappropriate regimens (< three active drugs). Analysis of the outcomes was performed according to adequacy of treatment. Analysis of risk factors and factors predicting treatment outcomes was performed using univariate and multivariate analysis (level of significance P < 0.05). RESULTS: One hundred and twenty-seven MDR patients were diagnosed. The overall success rate was low (39%). Seventy per cent of cases were treated with at least three active drugs. Factors predicting treatment success were new MDR-TB cases (OR 3.45; 95% CI 1.22-9.78; P < 0.05) and treatment for > or = 12 months (OR 5.03; 95% CI 1.65-15. 31; P < 0.05). Immigration and HIV infection were the main risk factors among new MDR-TB cases. CONCLUSION: The best available treatment should be provided to all newly diagnosed MDR-TB patients, avoiding the use of poorly modified regimens. MDR-TB patients should be referred to highly specialised centres.

Phase I and pharmacokinetic studies of PNU-159548, a novel alkycycline, administered intravenously to patients with advanced solid tumours.

PNU-159548 (4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin) is the lead compound of a novel class of cytotoxic agents (alkycyclines) with a unique mechanism of action combining DNA intercalation with alkylation of guanines in the DNA major groove. The objectives of two phase I studies were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to study the pharmacokinetics (PKs) of PNU-159548 and its active metabolite PNU-169884 when administered intravenously (i.v.) over 10 or 60 min to patients with advanced solid tumours. Patients were treated with escalating doses of PNU-159548, courses repeated every 21 days at doses ranging from 1.0 to 16 mg/m(2). For pharmacokinetic analysis, plasma sampling was performed during the first course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. 69 patients received a total of 161 courses. The MTD was reached at 14 and 16 mg/m(2) in heavily (HP) and minimally pretreated/non-pretreated (MP) patients, respectively, with thrombocytopenia as the DLT. A hypersensitivity reaction was observed in 8 patients across all dose levels, characterised by fever with chills, erythema, facial oedema and dyspnoea. The PKs of PNU-159548 and PNU-169884 were linear over the dose range studied. A significant correlation was observed between the percentage decrease in platelet count and the AUC of PNU-159548. In these studies, the DLT of PNU-159548 was thrombocytopenia. The recommended dose for phase II studies of PNU-159548 is 12 and 14 mg/m(2) administered i.v. over 10 min, once every 21 days, in HP and MP patients, respectively.

Mixed 5-HT1A/D-2 activity of a new model of arylpiperazines: 1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines. 1. Synthesis and structure-activity relationships.

A new model of 4-alkyl-1-arylpiperazines containing a terminal dihydronaphthalene fragment on the alkyl chain was synthesized in order to have mixed serotonergic and dopaminergic activity and to pursue the recent alternative approaches to the discovery of novel antipsychotic and anxiolytic agents. Title compounds were evaluated for in vitro activity on dopamine D-2 and serotonin 5-HT1A and 5-HT2 receptors by radioreceptor binding assays. They show high nanomolar affinity for 5-HT1A, moderate affinity for D-2, and low affinity for 5-HT2 receptors, and in particular, two compounds, 4-[3-(1,2-dihydro-6-methoxynaphthalen-4-yl)-n-propyl]-1-(2- methoxyphenyl)piperazine (8) and 4-[3-(1,2-dihydro-8-methoxynaphthalen-4-yl)-n-propyl]-1-(2- pyridyl)piperazine (15), show values (nM) of IC50 = 2.0 and 1.4 for 5-HT1A and IC50 = 90.6 and 119.3 for D-2, respectively. Some in vivo behavioral studies show compound 8 to be an antagonist on 5-HT1A receptors. These first findings place the new arylpiperazines on the same level as that of the azaspirone class, e.g., 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)-n-butyl]piperazine (NAN-190) and buspirone.

High affinity and selectivity on 5-HT1A receptor of 1-aryl-4-[1-tetralin)alkyl]piperazines. 2.

Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines). Several synthetic procedures were followed to obtain the final products, depending on the presence or absence of a double bond, as well as of a heteroatom on the side chain. In the first case versatile use of Grignard reaction was made, whereas in the second one usual synthetic ways were applied. Final compounds were evaluated for in vitro activity on dopamine D-1 and D-2, serotonin 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2, alpha 1 adrenergic, and sigma receptors by radioreceptor binding assay. For the 2-MeO-Ph, 2-pyridyl, and unsubstituted phenyl N-piperazine derivatives, low IC50 values (0.3 nM) on 5-HT1A receptors and high selectivity values were observed.

Pharmacokinetics of single-dose reboxetine in volunteers with renal insufficiency.

Reboxetine is a new selective norepinephrine reuptake inhibitor (selective NRI) for the short- and long-term treatment of depression that is effective and well tolerated at a dose of 8 to 10 mg/day. This study assessed the pharmacokinetics of reboxetine in volunteers with renal impairment. A single 4 mg dose of reboxetine was administered to a total of 18 volunteers with mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment (creatinine clearance: 56-64, 26-51, and 9-19 ml/min, respectively), and reboxetine concentrations were measured in plasma by HPLC. Mean AUC infinity increased by 43% (mild vs. severe; p < 0.01) as renal function declined, while renal clearance and total urinary excretion of unchanged reboxetine decreased by 67% and 62%, respectively (mild vs. severe; p < 0.01 for both parameters). tmax and t1/2 were not significantly different between groups. In comparison with historical data from young healthy volunteers, AUC infinity and t1/2 are at least doubled in volunteers with renal impairment, while CLr is halved. This pharmacokinetic study has shown that increasing renal dysfunction leads to increasing systemic exposure to reboxetine, particularly in severe renal insufficiency, although reboxetine was well tolerated by all volunteers. Thus, a reduction of the starting dose of reboxetine to 2 mg twice daily would be prudent in patients with renal dysfunction.

In vivo and in vitro studies on the regulation of cholinergic neurotransmission in striatum, hippocampus and cortex of aged rats.

Young (3 months) and senescent (23 months) rats were challenged with oxotremorine both in vivo, to determine its effects on acetylcholine content in hemispheric regions, and in vitro, to assess its action on K+-evoked release of ACh from brain synaptosomes. The drug failed to inhibit KCl-induced [3H]ACh release from the P2 fraction of striatal and hippocampal homogenates of the senescent animals, whereas it was less efficient in increasing striatal ACh content. In contrast, oxotremorine was still able to stimulate an increase in ACh in the hippocampus and cerebral cortex of the aged rats to the same extent as it did in the young ones. The [3H]ACh output from striatal synaptosomes was lower in old rats with respect to young ones at low KCl depolarizing concentrations but was equal in the two groups at a high depolarizing concentration. In the hippocampus of the senescent rats, the release was significantly lower at each concentration of KCl used, resulting in a parallel downward-shift in the concentration-release plot. We also measured cholinergic muscarinic receptor binding in rat hemispheric regions using the radioligand [3H]dexetimide, a classical non-selective muscarinic receptor antagonist. It was found, in conformity with some of the literature, that receptor binding was decreased by about 32% in striatum of aged female rats as compared to younger rats. Changes were not observed in cortex and hippocampus. Analysis of the binding data indicated that the observed decrease in specific ligand binding was due to a decrease in the number of binding sites without a change in affinity. The results favor, once again, the cholinergic hypothesis for geriatric dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Frontal decortication and adaptive changes in striatal cholinergic neurons in the rat.

Interruption of the corticostriatal pathway by undercutting the cortex resulted in a reduction of glutamate uptake by 55% and in a depression of acetylcholine (ACh) synthesis by 30% in striatum after two postlesion weeks without affecting the content of ACh and choline, the specific binding of [3H]dexetimide to muscarinic receptors, the activity of choline acetyltransferase and the levels of noradrenaline, serotonin, dopamine and 3,4-dihydroxyphenylacetic acid. The influence of this excitatory pathway on striatal cholinergic neuropharmacology was investigated. It was found that the effect of a number of agonists (R-apomorphine, bromocriptine, lisuride, quinpirole, JL-14389, 2-chloroadenosine, oxotremorine and methadone), capable of depressing cholinergic activity in the striatum through receptor-mediated responses--reflected as an increase in ACh content--is operative only when the corticostriatal pathway is intact. By contrast, antagonists capable of decreasing ACh content, i.e. the typical neuroleptics pimozide, haloperidol and the atypical ones clozapine, L-sulpiride, as well as the anti-muscarinic agent scopolamine, were not influenced by the lesion. The possibility that the lesion non-specifically damaged striatal cells on which the agonists, but not the antagonists acted was excluded by results showing, firstly, that the increase in striatal ACh elicited by the ACh precursor, choline, was not blocked by decortication, and secondly, that the degeneration of the corticostriatal neurons did not prevent the ACh-increasing effect of bromocriptine, a long-acting ergot alkaloid, when sufficient time was allowed for the drug to act. It was furthermore possible to restore the inhibitory action of apomorphine on cholinergic neurons either by short-term chemical lesion of the nigrostriatal dopaminergic input or by the administration of choline.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of resistance to anti-tuberculosis drugs: results of the 1998/99 national survey in Italy.

OBJECTIVE: To determine the prevalence of resistance to the main anti-tuberculosis drugs in newly and previously treated tuberculosis patients in Italy and to evaluate the contribution of foreign-born and human immunodeficiency virus (HIV) positive cases to drug resistance. METHODS: Methods and definitions were derived from the WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. Univariate and multivariate analysis was used to study prevalence rates of drug resistance in risk groups. RESULTS: In a national survey in Italy, 810 initial isolates of Mycobacterium tuberculosis (683 from new cases, 115 from retreatment cases and 12 from patients whose treatment history was unknown/dubious) were analysed. Low prevalence of drug and multidrug resistance was found in the new cases (isoniazid 2.9%; rifampicin 0.8%; multidrug resistance 1.2%; any drug resistance 12.3%). The prevalence of resistance to isoniazid and rifampicin was significantly higher in immigrants and HIV-positive subjects, respectively. A high prevalence of drug resistance was found in cases with previous treatment failure or default (isoniazid 5.2%; rifampicin 4.3%; multidrug resistance 36.5%; any drug resistance 61.7%). RECOMMENDATIONS: Special efforts are necessary to monitor trends in drug resistance and to ensure favourable treatment outcomes among immigrants and HIV-positive tuberculosis cases.

Lack of pharmacokinetic interaction between the selective dopamine agonist cabergoline and the MAO-B inhibitor selegiline.

The addition of a dopamine agonist and of a monoamine oxidase type B inhibitor to I-dopa has been suggested in the therapy of Parkinson's disease. The plasma pharmacokinetics of both cabergoline and I-dopa have previously been shown to remain unaffected when the two drugs are given concomitantly. This study aimed at examining whether the plasma pharmacokinetic parameters of cabergoline and selegiline are modified when given in combination. Selegiline is hardly detectable in plasma. Therefore, the plasma levels of its metabolites amphetamine, methamphetamine and desmetylselegiline were used to assess the effect of cabergoline co-administration. Plasma levels of the selegiline metabolites were determined first after selegiline administration (10 mg/day) for 8 days, and then after administration of both drugs for 22 additional days (day 30). Cabergoline plasma levels were measured on day 30, and then after administration of cabergoline (1 mg/day) alone for further 22 days. No statistical difference was found between the Cmax.ss, tmax.ss, AUC0-24h.ss, C0h.ss, C24h.ss values of cabergoline and of the selegiline metabolites when the two drugs were given alone or in combination, indicating the absence of pharmacokinetic interaction between cabergoline and selegiline.

Comparative evaluation of the clinical and microbiological efficacy of co-amoxiclav vs cefixime or ciprofloxacin in bacterial exacerbation of chronic bronchitis.

In an open randomized study 218 outpatients (159 males and 59 females) ranging between 18 and 85 years of age (mean 61.9) suffering from bacterial exacerbation of chronic bronchitis have been randomly treated: 79 with co-amoxiclav (amoxicillin 875 mg+clavulanic acid 125 mg) twice daily, 69 with cefixime (400 mg) once daily, and 70 with ciprofloxacin (500 mg) twice daily for an average period of 10 days. Before treatment start, 234 bacterial strains (105 Gram-positive and 129 Gram-negative) were isolated as the cause of exacerbation; the leading pathogens were Streptococcus pneumoniae and Haemophilus spp. Eradication rates at the end of treatment were 82.2% for the co-amoxiclav group, 77.6% for the cefixime group, and 81.2% for ciprofloxacin group. Clinical success (cure+improvement) was obtained in 90.8% of the cases treated with co-amoxiclav, in 80.9% for the cefixime group and in 85.7% of patients treated with ciprofloxacin. Seven adverse events (8.9%) of which 4 cases of diarrhea and 3 of itching, were recorded in the co-amoxiclav group. Eleven adverse events (14.7%) were recorded in the cefixime group including gastrointestinal disturbances in 6 patients and mild to moderate increase of liver function in 2. Nine adverse events (12.9%) occurred in the ciprofloxacin group, including insomnia in 3 patients, gastrointestinal disturbances in 2, and serious increase of liver function tests in one patient. It can be concluded that there were no statistically significant differences among the three treatment groups. However, co-amoxiclav demonstrated a higher efficacy rate than cefixime and ciprofloxacin and was better tolerated. Therefore, it can be used as a first-choice drug in the treatment of exacerbation of chronic bronchitis.

[Use of miocamycin in infections of the oral cavity]. / L'uso della miocamicina nelle infezioni del cavo orale.

The results of clinical experimental with a new antibiotic, Miocamycin (Macroral Zambeletti), are reported. 300 patients suffering from the most varied infections of the oral cavity were treated. In view of its utility and the lack of side-effects, it is concluded that this antibiotic may be used with peace of mind in odontostomatological pathology.

[Di George's syndrome with neutropenia in an adult patient]. / Sindrome di Di George con neutropenia in un paziente adulto.

The clinical data of a thirty-nine old inpatient woman are reported, whose main complaints were non-operable vulvo-vaginal condylomata, recurrent bacterial infections, complicated chickenpox and prominent lymphopenia. The peculiar facies get us to suggest the diagnosis of a case of the Di George syndrome in an adult patient. Was probably the associated neutropenia congenital and combined with immunodeficiency syndrome?

[Clinico-statistical features of perinatal and early neonatal mortality]. / Rilievi clinico-statistici sulla mortalità perinatale e neonatale precoce.

Perinatal and neonatal mortality rates are considered to be among the most sensitive measures available for monitoring the health of population and consequently have been assumed, too, to reflect primarily the capacity of the obstetricians and pediatricians. Perinatal mortality is here defined as stillbirths (or late fetal deaths) plus early neonatal deaths, that is, it includes fetuses born dead after 28 completed weeks of pregnancy and liveborn infants who died before the completion of the first week after birth. This report is concerned with the variation in neonatal mortality observed at the Istituto Clinico di Puericultura, Bologna University in a period from 1971 to 1981 and in perinatal mortality from 1976 to 1981 only. In this period reductions in stillbirths (from 12.5% to 7.8%) and early neonatal mortality (from 13.2% to 7.0%) are recorded. The decrease in the perinatal mortality rate, which occurred at the Obstretic-Neonatal Unit of Bologna University (dropping from 25.6% in 1976 to 14.8% in 1981) may be attributed to a comparable reduction in stillbirths and early neonatal mortality due to better health services and a more modern pattern of medical care. More attention must be given to that particular group of newborn babies weighing 1,500 gm or less (VLBW Infants) which accounted for about 40% of all the neonatal deaths.

Anti-tumour efficacy on glioma models of PHA-848125, a multi-kinase inhibitor able to cross the blood-brain barrier.

BACKGROUND AND PURPOSE: Malignant gliomas, the most common primary brain tumours, are highly invasive and neurologically destructive neoplasms with a very bad prognosis due to the difficulty in removing the mass completely by surgery and the limited activity of current therapeutic agents. PHA-848125 is a multi-kinase inhibitor with broad anti-tumour activity in pre-clinical studies and good tolerability in phase 1 studies, which could affect two main pathways involved in glioma pathogenesis, the G1-S phase progression control pathway through the inhibition of cyclin-dependent kinases and the signalling pathways mediated by tyrosine kinase growth factor receptors, such as tropomyosin receptors. For this reason, we tested PHA-848125 in glioma models. EXPERIMENTAL APPROACH: PHA-848125 was tested on a panel of glioma cell lines in vitro to evaluate inhibition of proliferation and mechanism of action. In vivo efficacy was evaluated on two glioma models both as single agent and in combination with standard therapy. KEY RESULTS: When tested on a subset of representative glioma cell lines, PHA-848125 blocked cell proliferation, DNA synthesis and inhibited both cell cycle and signal transduction markers. Relevantly, PHA-848125 was also able to induce cell death through autophagy in all cell lines. Good anti-tumour efficacy was observed by oral route in different glioma models both with s.c. and intracranial implantation. Indeed, we demonstrate that the drug is able to cross the blood-brain barrier. Moreover, the combination of PHA-848125 with temozolomide resulted in a synergistic effect, and a clear therapeutic gain was also observed with a triple treatment adding PHA-848125 to radiotherapy and temozolomide. CONCLUSIONS AND IMPLICATIONS: All the pre-clinical data obtained so far suggest that PHA-848125 may become a useful agent in chemotherapy regimens for glioma patients and support its evaluation in phase 2 trials for this indication.

CHF5074 Reduces Biomarkers of Neuroinflammation in Patients with Mild Cognitive Impairment: A 12-Week, Double-Blind, Placebo-Controlled Study.

As neuroinflammation is an early event in the pathogenesis of Alzheimer's disease, new selective anti-inflammatory drugs could lead to promising preventive strategies. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of CHF5074, a new microglial modulator, in a 12-week, double-blind, placebo-controlled, parallel groups, ascending dose study involving 96 MCI patients. Subjects were allocated into three successive study cohorts to receive ascending, titrated doses of CHF5074 (200, 400 or 600 mg/day) or placebo. Vital signs, cardiac safety, neuropsychological performance and safety clinical laboratory parameters were assessed on all subjects. Plasma samples were collected throughout the study for measuring drug concentrations, soluble CD40 ligand (sCD40L) and TNF-α. At the end of treatment, cerebrospinal fluid (CSF) samples were optionally collected after the last dose to measure drug levels, ß-amyloid1-42 (Aß42), tau, phospho-tau181, sCD40L and TNF-α. Ten patients did not complete the study: one in the placebo group (consent withdrawn), two in the 200-mg/day treatment group (consent withdrawn and unable to comply) and seven in the 400-mg/day treatment group (five AEs, one consent withdrawn and one unable to comply). The most frequent treatment-emergent adverse events were diarrhea, dizziness and back pain. There were no clinically significant treatment-related clinical laboratory, vital sign or ECG abnormalities. CHF5074 total body clearance depended by gender, age and glomerular filtration rate. CHF5074 CSF concentrations increased in a dose-dependent manner. At the end of treatment, mean sCD40L and TNF-α levels in CSF were found to be inversely related to the CHF5074 dose (p=0.037 and p=0.001, respectively). Plasma levels of sCD40L in the 600-mg/day group were significantly lower than those measured in the placebo group (p=0.010). No significant differences between treatment groups were found in neuropsychological tests but a positive dose-response trend was found on executive function in APOE4 carriers. This study shows that CHF5074 is well tolerated in MCI patients after a 12-week titrated treatment up to 600 mg/day and dose-dependently affects central nervous system biomarkers of neuroinflammation.

Phase I dose-escalation study of brostallicin, a minor groove binder, in combination with cisplatin in patients with advanced solid tumors.

PURPOSE: Brostallicin is a DNA minor groove binder which shows enhanced antitumor activity in cells which are resistant to several anticancer agents due to their high glutathione S-transferase (GST)/glutathione content. Phase I and II clinical trials of single-agent brostallicin have shown that myelotoxicity is the dose-limiting toxicity (DLT), while hints of antitumor activity were mainly observed in soft tissue sarcoma. Preclinical studies showing a more than additive antitumor effect of the cisplatin-brostallicin combination paved the way to clinical combination studies. In particular, we set up the first clinical combination study of brostallicin and cisplatin in patients with advanced solid tumors. This study was to be followed by a phase II study in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). METHODS: Escalating doses of brostallicin were administered in combination with a fixed dose of cisplatin (75 mg/m(2)) in patients with recurrent or metastatic advanced solid tumors who had previously received a cumulative dose of cisplatin not higher than 475 mg/m(2). The recommended dose of brostallicin was expanded in order to have a better estimate of antitumor activity and to better define the safety profile of the combination. RESULTS: Twenty-one patients were treated. Two DLTs (grade 3 fatigue and febrile neutropenia) were observed at dose level 3 (brostallicin 9 mg/m(2)). Dose level 2 (brostallicin 7 mg/m(2) and cisplatin 75 mg/m(2)) was recommended for future phase II studies. Main toxicity was hematologic; in fact, only 1 patient out of 21 did not develop neutropenia and only 2 patients did not have thrombocytopenia. Grade 3-4 neutropenia was observed in 90.5% of patients, grade 3-4 thrombocytopenia in 38.1%, grade 3-4 anemia in 23.8%. The cycle 1 nadir (ANC < 500 x 10(9)/L) for neutrophils was Day 14 (median; range 11-17) with recovery to an ANC of >1,500 3.5 days after nadir (median; range 2-4) at dose level 3. The cycle 1 nadir (median of 51,000 x 10(9)/L) for platelets occurred on Day 13 (median; range 10-15) with recovery to a platelet count of >100,000 4 days after nadir (median; range 2-8). No objective responses were observed, but seven patients had a long lasting (>18 weeks) stable disease. CONCLUSIONS: Further studies of the combination of brostallicin and cisplatin are warranted.