An open label phase 1 study evaluation safety, tolerability, and maximum tolerated dose of oral administration of irinotecan in combination with capecitabine.

PURPOSE: Oral administration of chemotherapy offers several advantages in comparison with intravenous administration. Previously, data on a new oral formulation of irinotecan have been published. The aim of the present study was to evaluate the safety, tolerability, and Maximum Tolerated Dose (MTD) of the new oral irinotecan formulation in combination with oral capecitabine. METHODS: The study was an open label, phase 1, single center, extension part in which oral irinotecan was investigated in combination with capecitabine. The MTD of irinotecan in combination with capecitabine was 17.5 mg/m2 once daily for 14 consecutive days in combination with capecitabine 800 mg/m2 twice daily. Eligible patients were adults with metastatic or unresectable solid tumors for which no standard curative or palliative therapies existed. RESULTS: 14 patients were included in the extension part. No grade 3 or 4 hematologic toxicities were observed. Non-hematological toxicities included grade 1 and 2 diarrhea, fatigue, cholinergic syndrome, vomiting, and weight loss. Totally, 3 grade 3 toxicities and no grade 4 event were reported. No objective responses were observed. Five patients had stable disease lasting median 14 weeks. CONCLUSIONS: Capecitabine in combination with oral irinotecan could be a new treatment option offering a more convenient and patient friendly treatment strategy compared to intravenous irinotecan. The combination is fairly tolerated; however, further investigations are needed to assess the efficacy of this regimen.

Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics.

BACKGROUND: Oral drug formulations have several advantages compared to intravenous formulation. Apart from patient convenience and favorable pharmacoeconomics, they offer the possibility of frequent drug administration at home. In this study, we present a new oral irinotecan formulation designed as an enteric coated immediate release tablet which in pre-clinical studies has shown good exposure with low variability. METHODS: A phase I, dose escalating study to assess safety, tolerability, pharmacokinetics and efficacy of an oral irinotecan formulation and to establish the maximum tolerated dose (MTD). Each treatment cycle was once-daily irinotecan for 14 days followed by 1 week rest. RESULTS: 25 patients were included across four cohorts; 3 patients were included in cohort 1 (20 mg/m2), 7 patients were included in cohort 2 (30 mg/m2), 3 patients were included in cohort 3 (25 mg/m2) and 12 patients were included in cohort 4 (21 mg/m2). Median age was 67 years, 52% were performance status (PS) 0 while 48% were PS 1. Median number of prior therapies was 3 (range 1-6). MTD was established at 21 mg/m2. No responses were observed. Nine patients (36%) had stable disease (SD), lasting median 19 weeks (range 7-45 weeks). Among these five patients had previously received irinotecan. No grade 3/4 hematologic toxicities were reported. Totally six patients experienced grade 1/2 anemia, three patients had grade 1/2 leucopenia and 1 patient had grade 1 thrombocytopenia. Most common non-hematological grade 1 and 2 adverse events were nausea, fatigue, diarrhea, vomiting and cholinergic syndrome. Grade 3 toxicities included diarrhea, fatigue, nausea and vomiting, no grade 4 events were reported. PK data showed consistent daily exposures during treatment at days 1 and 14 and no drug accumulation. SN-38 interpatient variability was in the same range as after infusion. CONCLUSIONS: Oral irinotecan was generally well tolerated; side effects were manageable and similar in type to those observed with intravenous irinotecan. Hematological toxicities were few and only grade 1/2. In this heavily pre-treated patient population, oral irinotecan demonstrated activity even among patients previously treated with irinotecan.

Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers.

Replication competent oncolytic herpes simplex viruses (HSV) with broad-spectrum activity against various cancers, including prostate cancer, exert a dual effect by their direct cytocidal action and by eliciting tumor-specific immunity. These viruses can deliver immunoregulatory molecules to tumors so as to enhance the cumulative antitumor response. This is particularly desirable for prostate cancers, which are usually poorly immunogenic. Initial studies described herein comparing the efficacy of three different oncolytic HSVs (G207, G47Delta, and NV1023) to inhibit the growth of the poorly immunogenic TRAMP-C2 mouse prostate tumors demonstrated that NV1023 was most effective in treating established tumors. The expression of IL-12 on an NV1023 background (NV1042), but not the expression of GM-CSF (NV1034), further enhanced the efficacy of NV1023 in two murine prostate cancer models with highly variable MHC class I levels, Pr14-2 with 91% and TRAMP-C2 with 2% of cells staining. NV1042 also inhibited the growth of distant noninoculated tumors in both prostate cancer models. NV1042 treated tumors exhibited increased immune cell infiltration and decreased levels of angiogenesis. Thus, an IL-12 expressing oncolytic herpes virus, which is capable of direct cytotoxicity and can modulate the otherwise suboptimal immune response through concomitant expression of the cytokine at the site of tumor destruction, could serve as a valuable clinical agent to seek out both overt and occult prostate cancers.

Halothane anesthesia enhances the effect of dopamine uptake inhibition on interstitial levels of striatal dopamine.

The anesthetic, isoflurane, has been shown to potentiate the ability of the dopamine (DA)-uptake inhibitor, nomifensine, to increase the brain interstitial dopamine level ([DA]e). Since the effect of the more commenly used anesthetic, halothane, on this system is unknown, we determined [DA]e by microdialysis in the striatum of rats, conscious or anesthetized with halothane, in the presence of the more selective DA uptake inhibitor, vanoxerine (GBR 12909), or the DA releaser, d-amphetamine. Basal [DA]e was not changed by halothane. However, in halothane-anesthetized rats, the vanoxerine (3 mg/kg i.v.)-induced DA response increased severalfold compared to the response in conscious rats. The initial peak response to d-amphetamine (1 mg/kg i.v.) did not change, but the late response (1-3 h after injection) was augmented in anesthetized rats. Halothane is believed to increase firing of DA neurons in the substantia nigra and, hence, to release striatal DA. We hypothesize that [DA]e is maintained at a normal level during the increased firing by equally increased activity of the DA transporter. However, when the DA transporter is blocked by vanoxerine, the increased DA release is unimpaired and [DA]e rises.

Hereditary palmoplantar keratoderma and dermatophytosis in the northernmost county of Sweden (Norrbotten).

Clinical reports of hereditary palmoplantar keratoderma are generally based on a limited number of patients. In 1967 the prevalence in the northernmost county of Sweden (Norrbotten) was shown to be 0.55%. In 1982 it was possible to trace half of the original propositi from that study. Among these families, a severe clinical form with a presumed recessive inheritance could be distinguished. The clinical pictures in relatives of the original propositi were described, and other diseases were listed together with those in patients from previously performed studies. The frequency of dermatophytosis was 36.2%, which was equal to a prevalence of 37.6%. T. mentagrophytes occurred significantly more often and immunological factors, such as increased presence of blood group A, specific dermatophyte IgG antibodies, precipitating antibodies and an immunological in vitro reaction to keratin, supported differences in the distribution of dermatophytes. However, the amount of keratin was considered the most important factor for the affinity of dermatophytes to the palms and soles. A vesicular eruption along the hyperkeratotic border and a mononuclear cell infiltrate were often reported. Such reactions were interpreted as immunological reactions to dermatophytosis. Scaling and fissuring were considered clinical signs of dermatophyte infections and not a part of the originally reported clinical picture. Results of the histopathological study corresponded to previously reported descriptions of the Unna-Thost variety. However, it has recently been reported that the histopathological picture of this variety was based on histopathological features of epidermolytic palmoplantar keratoderma. The existence on the Continent of the Unna-Thost variety was therefore questioned. Histopathological features of epidermolytic palmoplantar keratoderma were not found in the County of Norrbotten and the designation "Diffuse HPPK type Norrbotten" has therefore been proposed. The histopathological picture of the presumed recessive variety did not differ from that of the dominant variety but ultrastructural characteristics differentiated it from Mal de Meleda and the dominant variety. It was therefore concluded that a new variety with a presumed recessive inheritance was found.

The gamma-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats.

The effect of systemic administration of the gamma-aminobutyric acid (GABA) uptake inhibitor, R(-)N-(4,4-di(3-methyl-thien-2-yl)-but-3-enyl) nipecotic acid, hydrochloride (tiagabine) (previously NO-328), on extracellular GABA levels in the globus pallidus, ventral pallidum and substantia nigra of awake Sprague-Dawley rats was investigated using in vivo microdialysis. Tiagabine was administered in doses of 11.5 or 21.0 mg/kg i.p. (ED50 and ED85 doses, respectively, for inhibiting pentylenetetrazole-induced tonic seizures). Tiagabine increased the extracellular concentrations of GABA in globus pallidus with peak values 310% of basal level (after 21 mg/kg) and 240% of basal level (after 11.5 mg/kg). A significant increase in extracellular GABA levels was also found in the ventral pallidum (280% increase after 11.5 mg/kg and 350% increase after 21 mg/kg) and in the substantia nigra where the ED85 dose of tiagabine (21 mg/kg) produced a peak value of 200% compared to the basal level. Thus, tiagabine acts as a GABA uptake inhibitor in vivo also.

Identification of the major metabolites of [3H]-(+)-8-chloro-5-(2,3- dihydrobenzofuran-7-yl)-7-methoxymethyloxy-3-methyl-2,3,4,5-tetrahydro- 1H-3- benzazepine in rats.

1. The in vivo urinary metabolites of 3H(+)-8-chloro-5(2,3- dihydrobenzofuran-7-yl)-7-methoxymethyloxy-3-methyl-2,3,4,5-tetrah ydro-1H-3- benzazepine isolated from Wistar rats have been characterized by mass spectrometry and n.m.r. spectroscopy. 2. Metabolites are formed by N-demethylation, hydroxylation of the dihydrobenzofuran moiety, and elimination of the methoxymethyl group followed by glucuronidation. All combinations of these metabolic pathways were found in the metabolites in urine. 3. In the faeces metabolites formed by hydroxylation of the dihydrobenzofuran moiety and elimination of the methoxymethyl moiety dominate, while N-demethylated metabolites are present only in small amounts. 4. The major plasma metabolite was formed by elimination of the methoxymethyl group followed by glucuronidation. Only minute amounts of other metabolites were present.

Diffuse palmoplantar keratoderma associated with acrocyanosis. A family study.

Four members of a family, in which 8 suffered from diffuse palmoplantar keratoderma associated with an uncommon form of acrocyanosis, are reported. Acrocyanosis and palmoplantar keratoderma do not always occur together and, therefore, an autosomal dominant inheritance for this association is suggested.

PCDDs, PCDFs, and metals in selected Danish soils.

Topsoil samples from five locations in Denmark were collected and analyzed for polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and selected heavy metals. The upper soil layers contained elevated concentrations of PCDDs, PCDFs, Pb, Zn, and Cu compared to the lower layers. The soil contents of PCDDs plus PCDFs were closely related to Pb contents. Higher concentrations were found near urban areas relative to strictly rural locations. From the presented data the provisional Danish background content of PCDDs plus PCDFs is estimated to be 4-7 micrograms m-2 in the topsoil of coniferous forests.

Amino acid analysis of the horny layer of the soles of patients with hereditary palmoplantar keratoderma.

The amino acid composition of keratin from soles of patients suffering from hereditary palmoplantar keratoderma of the Unna Thost variety was investigated. Patients were divided into two groups: those without dermatophytosis and those whose hereditary palmoplantar keratoderma was complicated with a dermatophyte infection. The amino acid composition of the horny layer was compared to that of control individuals and to a previously performed analysis of mammalian hair. However, no difference was found between the groups nor was any explanation as to why Trichophyton mentagrophytes occurred significantly more often in soles of patients with hereditary palmoplantar keratoderma made apparent.

Congenital pernicious anemia: report of seven patients, with studies of the extended family.

Seven children ages 1 1/2 to 12 years with congenital pernicious anemia were detected in an extended Mexican family. All affected children had megaloblastic anemia accompanied by low serum B12 and normal serum folate levels. Gastric fluid analysis in six patients revealed normal gastric acidity and absent intrinsic factor. Serum antibodies to intrinsic factor or parietal cells were also absent. Schilling tests performed in six of the seven patients yielded abnormal results. Of the three patients in whom gastric biopsy was done, two had normal histologic findings (including examination by electron microscopy) and one had mild atrophy. All patients responded rapidly to parenterally administered vitamin B12 therapy. In addition, 170 family members were screened for the defect with complete blood counts and serum B12 levels. Such screening detected pernicious anemia in two of the children, but no other abnormalities that could be attributed to pernicious anemia were found in other family members. Based on the family pedigree, autosomal recessive inheritance is likely. The variability of age of presentation in this family is noteworthy and suggests that expression may be modified by still undefined factors.