Design and experimental validation of the oxazole and thiazole derivatives as potential antivirals against of human cytomegalovirus.

QSAR studies of a set of previously synthesized azole derivatives tested against human cytomegalovirus (HCMV) were performed using the OCHEM web platform. The predictive ability of the classification models has a balanced accuracy (BA) of 73-79%. The validation of the models using an external test set proved that the models can be used to predict the activity of newly designed compounds with a reasonable accuracy within the applicability domain (BA = 76-83%). The models were applied to screen a virtual chemical library with expected activity of compounds against HCMV. The five most promising new compounds were identified, synthesized and their antiviral activities against HCMV were evaluated in vitro. Two of them showed some activity against the HCMV strain AD169. According to the results of docking analysis, the most promising biotarget associated with HCMV is DNA polymerase. The docking of the most active compounds 1 and 5 in the DNA polymerase active site shows calculated binding energies of -8.6 and -7.8 kcal/mol, respectively. The ligand's complexation was stabilized by the formation of hydrogen bonds and hydrophobic interactions with amino acids Lys60, Leu43, Ile49, Pro77, Asp134, Ile135, Val136, Thr62 and Arg137.

Atypical autonomic regulation, auditory processing, and affect recognition in women with HIV.

This study examined the effect of HIV on visceromotor (i.e., heart rate and heart rate variability) and somatomotor (i.e., auditory processing and affect recognition) components of a Social Engagement System defined by the Polyvagal Theory (Porges, 1995) that links vagal regulation of the heart with brainstem regulation of the striated muscles of the face and head. Relative to at risk HIV-seronegative women, HIV-seropositive women had less heart rate variability (i.e., respiratory sinus arrhythmia) and had poorer performance on auditory processing and affect recognition tasks. CD4 was negatively correlated with the accuracy to detect specific emotions. The observed indices of atypical autonomic and behavioral regulation may contribute to greater difficulties in social behavior and social communication between HIV-infected women and other individuals in their social network.

The effects of cerebral white matter changes on cardiovascular responses to cognitive and physical activity in a stroke population.

Autonomic nervous system (ANS) control may be disrupted by cerebrovascular disease. We investigated the relationship between alterations in white matter integrity and regulation of the ANS in 23 participants who sustained a stroke within 5 years. These participants underwent diffusion tensor imaging, and fractional anisotropy values were calculated (DTI-FA) for each hemisphere and lobe. Cognitive and physical exertion tasks were performed while recording an electrocardiogram. Respiratory sinus arrhythmia (RSA) decreased more during a verbal fluency task with lower left hemisphere DTI-FA. Further, the physical stressor yielded decreases in RSA with lower frontal DTI-FA and higher temporal lobe DTI-FA, p < .05 (perhaps a release effect on the central autonomic network). Decrements in ANS regulation may have functional consequences that alter behavior, as well as potentially increasing the risk for further vascular disease.

In vitro activities of methylenecyclopropane analogues of nucleosides and their phosphoralaninate prodrugs against cytomegalovirus and other herpesvirus infections.

Human cytomegalovirus (HCMV) infection does not generally cause problems in the immunocompetent adult but can result in severe clinical disease in the fetus, neonate, and immunocompromised host. Ganciclovir (GCV), the agent currently used to treat most HCMV infections, has resulted in much therapeutic success; however, efficacy remains suboptimal. Therefore, there is still a need to develop new compounds for use against HCMV infections. In the present study, several Z- and E-series methylenecyclopropane analogues and their phosphoroalaninate prodrugs were tested initially for activity against HCMV, strain AD169, and murine cytomegalovirus (MCMV) in vitro. Many were found to exhibit efficacy comparable to that of GCV against HCMV in plaque assays and were active against MCMV as well. The compounds were also tested for efficacy against herpes simplex virus types 1 and 2, varicella-zoster virus, and Epstein-Barr virus, and some had levels of activity that were comparable to that of acyclovir. In addition, the compounds synguanol (QYL-438) and 2-amino-6-cyclopropylamino analogue (QYL-769) were chosen for further evaluation and were found to be effective against additional laboratory and clinical isolates of HCMV and GCV-resistant isolates. QYL-438 and QYL-769 were found to be nontoxic in human and mouse fibroblasts and were considerably less toxic than GCV in granulocyte macrophage CFUs and erythroid burst-forming units. These results provide evidence for the high activity of some of these methylenecyclopropane analogues against various herpesviruses, particularly HCMV, in tissue culture and suggest that further evaluation is warranted to determine their potential for use in future clinical studies.

Filariasis and erisipela in Santo Domingo.

This study examined acute-convalescent changes in diagnostic anti-streptococcal antibodies by the anti-streptolysin O (ASO) and anti-DNAase B (ADAB) tests among patients (n 28) with lymphedema and recurrent erisipela of the lower limb, comparing them with endemic normal control residents (n=25). The study was based in Villa Francisca, an urban focus of Bancroftian filariasis in eastern Santo Domingo, capital of the Dominican Republic. The acute signs and symptoms of erisipela were consistent with a diagnosis of bacterial cellulitis. The ASO test was especially successful at demonstrating a rise in mean titer during convalescence, whereas the ADAB produced about the same frequency of significant increases (0.2 log titer) as did the ASO. When subjects were scored as responders if mounting a minimal titer increase by either test, patients were found more frequently positive than were controls (chi2=5.3, P=0.02). About half (54%) of all patients mounted at least a minimal antibody increase. Filaria-specific IgG4 antibodies were absent from all sera of 20 residents of a nonendemic Dominican mountain town but appeared in about two-thirds of the sampled residents of the endemic barrio. Notably however, levels did not change between the acute phase and convalescence. These findings are consistent with the hypothesis that recurrent streptococcal invasion of the lymphatics may be a significant factor triggering or amplifying lymphedema and elephantiasis in patients with chronic filariasis.

Carmustine, Ara C, cyclophosphamide and etoposide with autologous bone marrow transplantation in relapsed or refractory lymphoma: a dose-finding study.

The purpose of this study was to define the dose-limiting non-hematologic toxicity of carmustine, Ara C, cyclophosphamide and etoposide (BACE). Between October 1986 and March 1990, 37 patients with relapsed or refractory lymphoma received escalating doses of combination chemotherapy followed by autologous bone marrow transplant (ABMT). Twenty patients with Hodgkin's disease (HD) and 17 patients with intermediate or high grade non-Hodgkin's lymphoma (NHL) initially received conventional-dose therapy with either a 7 week course of modified MACOP-B or a single dose of cyclophosphamide (CY) at 2 g/m2 depending on prior therapy and response. Regardless of response, patients then received escalating doses of BACE, toxicity permitting. Ten patients obtained complete responses (CR) and 12 patients were partial responders (PR), CR+PR (75%) with modified MACOP-B and 7 (64%) patients obtained PR with CY. The maximum-tolerated dose (MTD) for BACE was determined to be carmustine 700 mg/m2, Ara C 1500 mg/m2, CY 150 mg/kg and etoposide 1500 mg/m2. When Ara C was escalated from 1500 mg/m2 to 3000 mg/m2 holding the other drugs at the prior doses, the next two patients died secondary to diffuse alveolar damage. Overall and event-free survivals are identical with 14 of 37 patients (38%) alive with a median follow-up of 61 months (range 38-79 months). Ten patients were treated at the MTD, none of whom died a toxic death and 3 (30%) are alive with a median follow-up of 42 months (range 38-52 months). We defined the MTD and BACE showing pulmonary toxicity to be the dose-limiting non-hematologic toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

The addition of mesna to hyperhydration does not decrease the incidence of hemorrhagic cystitis in patients receiving high-dose cyclophosphamide.

To assess the efficacy of hyperhydration Versus hyperhydration plus mesna in preventing cyclophosphamide induced hemorrhagic cystitis a retrospective analysis was conducted of 110 patients who received hyperhydration alone (baseline intravenous intake of at least 3.6 1/m(2)/day) and 107 patients who received hyperhydration plus mesna (120% of daily cyclophosphamide dose) while receiving cyclophosphamide (total dose 150-200 mg/kg) as part of a dose intensive regimen. Macroscopic hematuria was noted in 17 (16%) and 9 (8%) patients who received hyperhydration with or without mesna, respectively (p=0.08). This analysis failed to demonstrate a benefit in adding mesna to hyperhydration alone in preventing cyclophosphamide induced hemorrhagic cystitis.

Reduced renal accumulation and toxicity of cisplatin in experimental galactosemia.

The kidneys of streptozotocin (STZ)-diabetic rats are resistant to certain toxic effects of the antineoplastic drug cisplatin. The mechanism is unknown. This study used the galactosemic rat model to test the hypothesis that the apparent diabetes-induced protection is due to changes in the kidney secondary to chronically elevated hexose concentrations. Galactosemic rats are normoinsulinemic and are free from many of the multiple biochemical abnormalities seen in STZ diabetics. The experiments compared renal cortical platinum (Pt) and blood urea nitrogen (BUN) levels after intraperitoneal injection of 5 mg/kg of cisplatin in galactosemic, STZ-diabetic, and age-matched nondiabetic Sprague-Dawley rats. Nephrotoxicity was defined as a BUN concentration ratio (after to before cisplatin) > 2.5. The results demonstrate that the kidneys of both galactosemic and STZ-diabetic rats became resistant to cisplatin-induced elevation of BUN and, further, that the development of the protection was related to the duration of the diabetic state. Although the protective effect developed more slowly in the galactosemic rats, the attenuation of the rise in BUN was ultimately comparable to that seen in STZ diabetics. Renal cortex [Pt] after cisplatin injection was significantly lower in galactosemics and STZ diabetics compared with age-matched nondiabetics, with the order nondiabetics > galactosemics > STZ diabetics. It was noted, however, that renal Pt accumulation was maximally depressed within 4 weeks of experimental diabetes, whereas the BUN ratio continued to decline with increasing duration of both galactosemia and STZ diabetes. Thus, reduced renal Pt accumulation cannot by itself explain the progressive attenuation of the toxicity. The results support the hypothesis and suggest that the galactosemic rat will be a useful model for mechanistic study of diabetes-induced protection from cisplatin nephrotoxicity.

Dose-related cutaneous toxicities with etoposide.

BACKGROUND: Cutaneous toxicities are seen frequently in association with administration of high doses, but not standard doses, of agents. With the increasing use of etoposide in dose-intensive regimens, cutaneous toxicities are appearing with increasing frequency. METHODS: A retrospective analysis of 145 patients treated with various doses of etoposide was conducted. RESULTS: This analysis revealed a statistically significant increase in the frequency of these toxicities at doses of 2400 mg/m2 and 4200 mg/m2, compared with doses of 1800 mg/m2. Intense, painful palmar erythema accompanied by bullae formation and desquamation occurred at the 4200 mg/m2 dose. Symptoms were controlled by a short course of corticosteroids. CONCLUSION: Although they are not dose limiting, substantial dose-related skin toxicities can be an important side effect of high-dose etoposide therapy.

Encephalopathy and seizures induced by intravesical alum irrigations.

Hemorrhagic cystitis is a significant toxic effect of cyclophosphamide therapy. Continuous bladder irrigation of a 1% alum solution is a simple and generally safe method of chemical cautery to treat the bleeding urothelium. We report four cases of encephalopathy coincident with elevated aluminum levels as well as one patient who developed seizures while receiving continuous bladder irrigations with alum. All patients had significant renal insufficiency. We recommend the cautious use of alum irrigation in patients with renal impairment and monitoring of serum aluminum levels to prevent excessive accumulation and toxicity.

Generalized seizures secondary to high-dose busulfan therapy.

Two patients without prior histories of neurologic disorders experienced generalized seizures while receiving high-dose busulfan (total dose 16 mg/kg) as part of a preparative regimen for allogeneic bone marrow transplantation. A review of the literature revealed 14 similar occurrences. Maintenance of therapeutic blood concentrations of phenytoin in subsequent patients at our institution has resulted in no further patients experiencing generalized seizures. Prophylactic anticonvulsant therapy should be considered in patients receiving high doses of busulfan.

Marketing cardiovascular disease risk reduction programs at the workplace. The Pawtucket Heart Health Program experience.

The workplace offers a unique setting in which to offer CVD risk reduction programs. Marketing these programs involves at least two distinct processes. First, a corporation must agree to accept and support workplace health programming. Second, workplace programs must be effectively marketed to eligible employees, dependents, and retirees. After identifying critical barriers to the effective marketing of workplace programs, a stepwise approach used by the Pawtucket Heart Health Program to successfully overcome these obstacles is used. Using real world examples and practical tips, a discussion of implications for marketing future programs to the corporate and employee audience is shared.

High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy.

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.

Hodgkin's lymphoma of the uterus presenting as refractory pelvic inflammatory disease. A case report.

Lymphoma rarely presents with initial involvement of the uterine corpus, though disseminated disease may well involve the pelvic organs secondarily. We treated a patient for Hodgkin's lymphoma presenting as pelvic serositis found at hysterectomy for refractory pelvic pain. Nodules consistent with Hodgkin's lymphoma were found within the uterine serosa and muscularis as well as throughout the uterine and tubal lymphatics, but no visible or palpable adenopathy was noted in the pelvis or abdomen or peripherally. Following surgery the patient developed signs and symptoms of widespread lymphoma, which developed fulminantly but responded well initially to standard chemotherapy. This is the first reported case of systemic Hodgkin's lymphoma presenting de novo in the uterine corpus and associated with clinical symptoms referable to the female reproductive tract.

Demonstration of phenotypic abnormalities of thymic epithelium in thymoma including two cases with abundant Langerhans cells.

A panel of monoclonal antibodies that phenotypically define stages of normal human thymic epithelial (TE) cell maturation was used to compare thymic epithelium of nine thymomas with hyperplastic thymic epithelium in myasthenia gravis (MG) and thymic epithelium of normal thymuses. It has been shown previously that normal thymic epithelial cells express antigens of early TE cell maturation (A2B5, TE-4) throughout thymic ontogeny and acquire antigens 12/1-2, TE8, and TE-15 at 14 to 16 weeks of fetal gestation. Hyperplastic MG thymic epithelial cells expressed TE antigens in phenotypic patterns similar to that seen in normal postnatal thymus, ie, TE in subcapsular cortex and medulla was TE4+, A2B5+, and 12/1 - 2+ and Hassall's bodies were reactive with antibodies TE8 and TE15. In contrast, thymic epithelium in primary mediastinal thymomas was TE4+, A2B5+, TE8-, and greater than 75% of thymoma epithelium was 12/1 - 2-, a thymic epithelial phenotype similar to that seen on normal fetal thymic epithelium at 14 to 16 weeks fetal gestation. In one subject with a mature epithelial histologic pattern, thymoma epithelium was found to be strongly TE8+, a phenotype suggestive of a later stage of TE maturation. Lymphocytes in five of seven thymomas with immature thymic epithelial cells predominantly expressed immature thymocyte phenotype while two thymomas with immature epithelial phenotype showed a predominance of Langerhans cells and surrounding lymphocytes expressing a mature phenotype. Lymphocytes in the thymoma with differentiated epithelial cells expressed a mature thymocyte phenotype. Thus, in thymomas of varying histologic types, phenotypic abnormalities of thymic epithelium are present; these phenotypic abnormalities may reflect abnormal thymic epithelial maturation.

Acute neurologic dysfunction after high-dose etoposide therapy for malignant glioma.

Etoposide (VP-16-213) has been used in the treatment of many solid tumors and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose etoposide therapy. Significant clinical manifestations have included confusion, papilledema, somnolence, exacerbation of motor deficits, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous dexamethasone therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose etoposide therapy for malignant glioma.