COVID-19, oxidative stress, and male reproductive dysfunctions: is vitamin C a potential remedy?

Few peculiarities have been observed in the etiology of coronavirus disease 2019 (COVID-19), one such being its greater prevalence in men than women partly due to the higher expressions of angiotensin-converting enzyme-2 (ACE2) in the male reproductive tissues. Recent scientific reports are in line with some of the evidence-based hypotheses in the initial phase of the COVID-19 pandemic, regarding the involvement of oxidative stress (OS) and oxidant-sensitive pathways in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-mediated male reproductive disruptions. The seminal dissemination of SARS-CoV-2 or its components, testicular disruptions due to viral infection and oxidative damage in the testis have all been evidenced recently. High-dose of antioxidants, such as vitamin C, have been shown to be a useful treatment for COVID-19 patients, to alleviate systemic inflammation and OS. In addition, vitamin C is a major testicular antioxidant that neutralizes excess reactive oxygen species (ROS), prevents sperm agglutination, prevents lipid peroxidation, recycles vitamin E, and protects against DNA damage. Thus, the present review aims to discuss the mechanism of COVID-19-mediated male reproductive dysfunctions, based on the evidence available so far, and explore the possibility of using vitamin C in alleviating testicular OS and associated damage caused by COVID-19.

Prospective bacterial quorum sensing inhibitors from Indian medicinal plant extracts.

As virulence of many pathogenic bacteria is regulated by the phenomenon of quorum sensing (QS), the present study aimed to find the QS-inhibiting (QS-I) property (if any) in 61 Indian medicinal plants. The presence of QS-I compound in the leaf extract was evaluated by its ability to inhibit production of pigment in Chromobacterium violaceum MTCC 2656 (violacein) and Pseudomonas aeruginosa MTCC 2297 (pyocyanin) or swarming of P. aeruginosa MTCC 2297. Extracts of three plants, Astilbe rivularis, Fragaria nubicola and Osbeckia nepalensis, have shown a dose-dependent inhibition of violacein production with no negative effect on bacterial growth. Inhibition of pyocyanin pigment production and swarming motility in P. aeruginosa MTCC 2297 was also shown. Based on the results obtained by gas chromatography-mass spectroscopy (GC-MS) and thin-layer chromatography-direct bioautography (TLC-DB), it was concluded that triterpenes and flavonoid compounds found in the three plant extracts could have QS-I activity. SIGNIFICANCE AND IMPACT OF THE STUDY: A novel alternative prospect to prevent bacterial infections without inhibiting the growth is to apply chemicals that inhibit quorum sensing mechanism of the pathogens. Antiquorum property of 61 medicinal plants was evaluated by the ability of their leaf extract(s) to inhibit production of pigment (violacein in Chromobacterium violaceum MTCC 2656, pyocyanin in Pseudomonas aeruginosa MTCC 2297) or swarming in P. aeruginosa MTCC 2297. The most prospective plants (for the development of quorum sensing inhibitor), showing inhibition of violacein production without affecting bacterial growth, were Astilbe rivularis, Fragaria nubicola and Osbeckia nepalensis.

Phenotypic and antibiogram pattern of V. cholerae isolates from a tertiary care hospital in Mumbai during 2004-2013: a retrospective cross-sectional study.

OBJECTIVES: Cholera is a major gastroenteric disease with reports on fluctuation and resistance. Hence, the objective is to determine the trend in seasonality, resistance pattern, prevalent biotypes, serotypes and phage types between 2004 and 2013 among Vibrio cholerae isolates. DESIGN: A retrospective cross-sectional study. SETTINGS: A single-centre study was carried out at a tertiary care hospital in a metropolitan city (Mumbai) of a developing country (India). METHODS: Records of stool specimen cultures of patients with suspected cholera from January 2004 to December 2013 were analysed. The organisms were identified as per standard protocol. Antimicrobial susceptibility testing was performed as per Clinical Laboratory Standard Institute. Biotyping, serotyping and phage typing were carried out. From the confirmed cases of cholera, demographic and laboratory details were noted. Descriptive analysis was used and the data were presented in the form of percentages. RESULTS: Vibrio cholerae was predominant in males and was isolated from 9.41% (439/4664) of stool specimens. Variability was found in terms of the gross appearance of stool specimens, seasonal trend and antibiotic resistance pattern. The antimicrobial susceptibility showed a waxing and waning pattern for most of the antibiotics (ampicillin, cefuroxime, chloramphenicol, tetracycline) tested, while for a few others the strains were either uniformly sensitive (gentamicin, norfloxacin) or resistant (trimethoprim-sulfamethoxazole, nalidixic acid). All isolates belonged to subgroup O1 and biotype El Tor. The most common serotype was Ogawa. The predominant phage type was T2 (old scheme) and T27 (new scheme). CONCLUSIONS: The predominant biotype, serotype and phage type were El Tor, Ogawa and T27 phage, respectively. The changing trends in antimicrobial resistance pattern over the years necessitate continued epidemiological and microbiological surveillance of the disease.

In vitro acaricidal activity of ethanolic and aqueous floral extracts of Calendula officinalis against synthetic pyrethroid resistant Rhipicephalus (Boophilus) microplus.

Detection of resistance levels against deltamethrin and cypermethrin in Rhipicephalus (Boophilus) microplus collected from Jammu (India) was carried out using larval packet test (LPT). The results showed the presence of resistance level II and I against deltamethrin and cypermethrin, respectively. Adult immersion test (AIT) and LPT were used to evaluate the in vitro efficacy of ethanolic and aqueous floral extracts of Calendula officinalis against synthetic pyrethroid resistant adults and larvae of R. (B.) microplus. Four concentrations (1.25, 2.5, 5 and 10 %) of each extract with four replications for each concentration were used in both the bioassays. A concentration dependent mortality was observed and it was more marked with ethanolic extract. In AIT, the LC50 values for ethanolic and aqueous extracts were calculated as 9.9 and 12.9 %, respectively. The egg weight of the live ticks treated with different concentrations of the ethanolic and aqueous extracts was significantly lower than that of control ticks; consequently, the reproductive index and the percent inhibition of oviposition values of the treated ticks were reduced. The complete inhibition of hatching was recorded at 10 % of ethanolic extract. The 10 % extracts caused 100 % mortality of larvae after 24 h. In LPT, the LC50 values for ethanolic and aqueous extracts were determined to be 2.6 and 3.2 %, respectively. It can be concluded that the ethanolic extract of C. officinalis had better acaricidal properties against adults and larvae of R. (B.) microplus than the aqueous extract.

Metaphase arrest and delay in cell cycle kinetics of root apical meristems and mouse bone marrow cells treated with leaf aqueous extract of Clerodendrum viscosum Vent.

OBJECTIVES: To study cell cycle delay and metaphase arresting activity of leaf aqueous extract of Clerodendrum viscosum Vent. (LAECV) in root apical meristems and mouse bone marrow cells. MATERIALS AND METHODS: Cell cycle delay and metaphase arresting activities of LAECV were analysed, in root apical meristems of onion and wheat, and in mouse bone marrow cells, by scoring mitotic index, metaphase frequency and transition of cells from metaphase to anaphase. Colchicine was used as the standard metaphase arresting drug. Phytochemicals present in LAECV were detected and their phytotoxic activity was evaluated by analysing green-gram (Vigna radiata) seedling's root growth retardation and branch root swelling phenomenon. RESULTS: LAECV treatment resulted in dose-dependent root growth retardation of green-gram seedling root length (P < 0.01) and half maximal growth inhibitory concentration (IC(50) ) of LAECV was 0.87 mg/ml at 144 h. In onion and wheat root meristem cells the mitotic index decreased, metaphase frequency increased and transition from metaphase to anaphase reduced. Experimentation with mouse bone marrow cells indicated that LAECV induced metaphase arrest (164.3% increase in arrested metaphases per 300 mg/kg body weight, over 2.5 h). Phytochemicals like carbohydrates, glycosides, saponins, terpenoids, triterpenoids, tannins and trace amounts of alkaloids were detected in LAECV. CONCLUSION: It may be said that LAECV contains mitostatic and metaphase arresting components that are able to induce significant metaphase arrest in root apical meristems and also in mouse bone marrow cells.

What do the suffixes--XR, ER, Chrono, Chronosphere--really mean as it pertains to modified-release antiepileptic drugs?

BACKGROUND: Epilepsy is a disease requiring chronic therapy with antiepileptic drugs (AEDs). Many conventional AEDs currently available have either too rapid an absorption or elimination, requiring the patient to take multiple doses per day, which may adversely impact adherence or cause peak-related side-effects. Consequently, some AEDs with immediate-release characteristics have been modified to prolong absorption and/or reduce peak serum concentration, enabling dosage regimen simplification. Modified-release (MR) AED formulations have been labelled with various suffixes or names ('XR, ER, -Chrono, -Chronosphere'), but such labelling may not adequately distinguish those MR AEDs with the most prolonged absorption or unique formulation characteristics. Such suffixes lack precise definition. OBJECTIVE: We identified the formulation characteristics of currently available MR AEDs, attempting to distinguish them by suffix designation. DESIGN/METHODS: Nine MR AED formulations, representing six different AEDs, were characterized, utilizing information from FDA-approved inserts (2001 +) and published literature. RESULTS: The formulation characteristics of commercially available MR AEDs are quite variable and do not appear to correlate with their brand name suffix. CONCLUSIONS: When all MR AEDs are compared, suffix designations do not provide distinguishable information about formulation characteristics. Clarification of MR AED suffix terminology may be warranted.

Expanded safety study of Praneem polyherbal vaginal tablet among HIV-uninfected women in Pune, India: a phase II clinical trial report.

BACKGROUND: Praneem, a candidate vaginal microbicide with reported anti-HIV and contraceptive properties was evaluated for its long-term safety through a double-blind, placebo-controlled, randomised phase II trial. METHODOLOGY: 142 women were screened and 100 HIV-uninfected, eligible women were enrolled, after obtaining written informed consents. Of these, 50 were randomly assigned to the study product arm and 50 to the placebo arm. Participants were requested to use the study product at least half an hour before each sexual act for 6 months. RESULTS: Participants in both treatment groups contributed 601 person-months of follow-up and 95% of the participants completed the last follow-up. Although transient genital discomfort was the main reported adverse experience, none of the study participants discontinued product use. Most of the adverse events were mild and there were no serious adverse events related to study product use and no HIV seroconversions. DISCUSSION: Praneem polyherbal tablet was safe for vaginal use up to 6 months with each act of sex among low-risk women. In light of the failure of Nonoxynol-9, cellulose sulphate and Carraguard in preventing HIV infections among women, additional preclinical evaluations should be undertaken urgently before moving into effectiveness studies.

Municipal wastewater treatment using novel constructed soil filter system.

The study gives a new approach for contaminant removal from municipal wastewater using constructed soil filter (CSF) and presents performance of two CSF units located in Mumbai, India. In this system, natural weathered rock is formulated which combines sedimentation, infiltration and biochemical processes to remove suspended solids and oxidisable organics and inorganics of the wastewater. Results show elevated dissolved oxygen (DO) levels, removal of COD (136-205 to 38-40 mg l(-1)) and BOD (80-125 to less than 12 mg l(-1)) suspended solids from 135-203 to 13-18 mg l(-1) and turbidity from 84-124 to 8-11 NTU, bacterial removal of 2.4-3.1 log order for Total coliform and Fecal coliform from site I which is almost 8 years old facility, and site II which is 3 years old. Estimated hydraulic retention time of 0.5-1.0 h, hydraulic loading of 0.036-0.047 m(3)m(-2)h(-1), no pretreatment, high DO levels in the effluent, no bio-sludge production, no mechanical aeration, low energy requirement (0.04 kW h m(-3)) and green aesthetic ambience are its unique features.

Evaluation of dimethoxydop-NU as a novel anti-tumor agent.

Dimethoxydop-NU, 1-[2-{3-(2-Chloroethyl)-3-nitrosoureido}ethyl]-3,4-dimethoxy-benzene (Compound 1), was synthesized from 3,4-dimethoxy-phenethylamine as a novel anti-tumor agent based on the structures of the clinical drug CCNU and dopamine, an important endogenous biological amine having anti-angiogenesis property. In vitro screening in two human tumor cell lines, namely promyelocytic leukemia HL-60 and histiocytic lymphoma U-937, revealed its cytotoxicity greater than that of hydroxyurea and comparable to BCNU used as standards. Its in vivo anti-tumoral potency was assessed in the murine ascites tumors Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times of drug treated (T) over untreated control (C) mice. Results revealed significant tumor regression effects in these tumors. The survival time of treated mice was markedly increased by combination of the compound 1 with dopamine hydrochloride. Its toxicity was assessed in vivo in normal and EAC bearing mice by measuring drug-induced changes in hematological parameters, femoral bone marrow and splenic cellularities as well as biochemical parameters sequentially on days 9, 14 and 19 following drug treatment at the optimum dose of 30 mg/kg from day 1 to 7. Results indicated that initial suppression in the femoral bone marrow cellularity seen on day 9 reached normalcy by day 19. Other parameters were within normal limit. Histopathological studies of liver revealed mild hepatotoxicity on day 9 in treated groups that substantially recovered on day 19. Similar studies with heart and kidney revealed no cardio toxicity or nephrotoxicity. Compound 1 comparable to standards inhibited the synthesis of DNA and RNA in S-180 tumor cells.

Evaluation of fluorenhymustine as a rationally designed novel anticancer agent.

AIM: To develop a rationally designed new nitrogen mustard namely Fluorenhymustine (compound 2), where N,N'-bis(2chloro-ethyl)amino group, the established anticancer functionality, is attached to the 2-ethyl fluorenone hydantoin moiety. MATERIALS AND METHODS: Starting from fluorenone hydantoin, a 3-step synthetic procedure was followed to obtain the title compound. 4-(4-Nitrobenzyl)pyridine was used to assess its chemical alkylating activity. Murine tumors (Ehrlich ascites carcinoma (EAC) and Sarcoma-180 (S-180)) were used to assess its in vivo activity. Its cytotoxicity was determined in vitro in MCF-7 human breast tumor cell line, toxicity - in vivo in normal and EAC bearing mice. 3H-Thymidine and 3H-Uridine were employed to study its inhibitory effect on DNA and RNA synthesis respectively in S-180 tumor cells in vitro. RESULTS: Alkylating activity of fluorenmustine exceeded that of N-di(2-chloroethyl)amine used as a standard alkylating compound. It has displayed an excellent and reproducible antitumor activity in vivo against EAC and S-180 comparable to that of 5-fluorouracil judging by the increase in median survival times of treated animals. It also significantly increased the life span of mice bearing advanced tumors for 6 days before the drug challenge. However in vitro screening in MCF-7 did not reveal any significant cytotoxicity. The compound did not adversely affect hematopoiesis at its optimum dose. Drug-induced hepatotoxicity and nephrotoxicity were also not detected. It inhibited the synthesis of DNA and RNA in S-180 tumor cells at 8 microM concentration. CONCLUSION: Results indicated promising chemotherapeutic potential of Fluorenhymustine.

Evaluation of naphthal-NU, a 2-chloroethylnitrosourea derivative of naphthalimide, as a mixed-function anticancer agent.

Naphthal-NU, 2-[2-[3-(2-chloroethyl)-3-nitrosoureido]ethyl]-1H-benz[de]isoquinoline-1,3-dione (Compound 1) has been synthesized as a rationally designed new mixed-function anticancer agent from 1,8-naphthalic anhydride. Its chemical alkylating activity compared with CCNU as standard compound indicated that it possesses greater alkylating activity than the latter. Its antitumour efficacy was assessed in vivo in two murine ascites tumours namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. Three clinical drugs namely CCNU (lomustine), endoxan (cyclophosphamide) and 5-fluorouracil (5-FU) were used as positive controls for comparison. Compound 1 has displayed excellent and reproducible antitumoural activity having curative effects in these tumours comparable with CCNU and 5-FU. It has also significantly increased the life span of mice bearing highly advanced tumour for 10 days before the drug challenge. Its toxicity was also assessed in vivo in normal and in S-180 bearing mice by measuring drug-induced changes in hematological parameters, femoral bone marrow and splenic cellularity sequentially on days 9, 15 and 21 following drug treatment at the optimum dose of 50 mg/kg from day 1 to 7. The results indicated that the compound did not adversely affect hematopoiesis. Drug-induced hepatotoxicity and nephrotoxicity were also evaluated at its optimum dose on those days but no such toxicities were detected. It was further screened in vitro in 6 different human tumour cell lines but no significant activity was observed in those lines.

Ceftriaxone therapy in ciprofloxacin treatment failure typhoid fever in children.

BACKGROUND & OBJECTIVES: The rapid spread of multidrug resistant (MDR) typhoid fever has posed a great challenge for the treatment of these cases the world over. After the emergence of chloramphenicol resistant Salmonella typhi strains, ciprofloxacin has become the drug of choice for the treatment of typhoid fever even in the paediatric age group. This study evaluated the role of ceftriaxone therapy in bacteriologically confirmed MDR typhoid cases who did not respond to 12-14 days of ciprofloxacin therapy. Attempts have also been made to investigate the in vitro susceptibility of isolated S. typhi strains to chloramphenicol, ciprofloxacin and ceftriaxone. METHODS: A total of 140 children, aged 3-10 yr, clinically diagnosed as having typhoid fever, without any clinical response after 12-14 days of ciprofloxacin therapy were screened for S. typhi by blood culture. In the bacteriologically positive children the treatment was changed to intravenous ceftriaxone for 14 days. The isolated strains of S. typhi were tested for in vitro antimicrobial susceptibility. RESULTS: Clinical and bacteriological cure was observed with intravenous ceftriaxone therapy in all the 32 bacteriologically positive patients. All isolated S. typhi strains were uniformly (100%) susceptible to ciprofloxacin and ceftriaxone but 50 per cent of the strains were resistant to chloramphenicol. The MIC values of chloramphenicol, ciprofloxacin and ceftriaxone ranged between 125-500, 0.0625-0.5 and < 0.0625 microgram/ml respectively. INTERPRETATION & CONCLUSION: The study indicates that although the S. typhi strains were susceptible to ciprofloxacin in vitro, the patients did not respond clinically and bacteriologically to ciprofloxacin therapy. Hence, ciprofloxacin may not represent a reliable and useful option for treating MDR typhoid fever; ceftriaxone may be an effective alternative for the treatment of such cases.

Impact of zinc supplementation in malnourished children with acute watery diarrhoea.

A double-blind, randomized, controlled clinical trial was conducted on 80 malnourished children with acute dehydrating diarrhoea to evaluate the efficacy of oral supplementation of zinc as an adjunct therapy to oral rehydration solution (ORS). After decoding it was observed that 44 children received zinc sulphate (177 mg/kg/day in three divided doses equivalent to 40 mg elemental zinc) in a syrup form and 36 children received only syrup placebo. Clinical parameters and microbiological findings of stool samples were comparable in the two groups at the time of enrollment. All the children (100 per cent) in the zinc supplemented group and 32 (89 per cent) children in the placebo group recovered within 5 days of hospitalization (p = 0.04). The zinc supplemented group had a significantly shorter duration of diarrhoea (70.4 +/- 10.0 vs. 103.4 +/- 17.1 h; p = 0.0001), passed less liquid stool (1.5 +/- 0.7 vs. 2.4 +/- 0.7kg; p=0.0001), consumed less oral rehydration solution (2.5 +/- 1.0 vs. 3.6 +/- 0.8 litre; p = 0.0001) and other liquids (867.0 +/- 466.1 vs. 1354.7 +/- 675.6 ml; p = 0.0001) as compared to the placebo group. Our findings suggest that zinc supplementation as an adjunct therapy to ORS has beneficial effects on the clinical course of dehydrating acute diarrhoea.

Pharmacognostic Profiles of Azadirachta indica A.Juss.Leaves.

The microscopic and macroscopic characters of the leaves, physical constant values, behavior on treatment with different chemical reagents, fluorescence characters under ultra violet light after treatment with different chemical reagents of the powdered leaves of Azadirachta indica A. Juss (Family-Meliaceae) were studies to fix some pharmacognostical parameters.

Randomized placebo-controlled trial of 2,3-dimercaptosuccinic acid in therapy of chronic arsenicosis due to drinking arsenic-contaminated subsoil water.

INTRODUCTION: Chronic arsenic toxicity producing various clinical manifestations is currently epidemic in West Bengal, India, Bangladesh, and other regions of the world. Animal studies have indicated that 2,3-dimercaptosuccinic acid can be used as an oral chelating agent. A prospective, double-blind, randomized controlled trial was carried out to evaluate the efficacy and safety of 2,3-dimercaptosuccinic acid for chronic arsenicosis due to drinking arsenic-contaminated (> or = 50 micrograms/L) subsoil water in West Bengal. METHOD: Twenty-one consecutive patients with chronic arsenicosis were individually randomized (random number; assignment made by individual not evaluating patients) into 2 groups: 11 patients (10 male, age 25.5 +/- 8 years) received 2,3-dimercaptosuccinic acid 1400 mg/d (1000 mg/m2) in the first week and 1050 mg/d (750 mg/m2) during the next 2 weeks with a repeat course 3 weeks later. The other 10 patients (all male, age 32.2 +/- 9.7 years) were given placebo capsules for the same schedule. The clinical features were evaluated by an objective scoring system before and after treatment. Routine investigations including liver function tests, arsenic concentrations in urine, hair, and nails, and skin biopsy evaluations were also completed. RESULTS: Though there was improvement in the clinical score of 2,3-dimercaptosuccinic acid-treated patients, similar improvement was observed in the placebo-treated group. There were no statistical differences in the clinical scores between the 2 groups at the beginning and at the end of treatment. Similarly, no differences were found for the other investigated parameters. CONCLUSION: Under the conditions of this study, 2,3-dimercaptosuccinic acid was not effective in producing any clinical or biochemical benefit or any histopathological improvement of skin lesions in patients with chronic arsenicosis.

Effect of Maharishi AK-4 on H2O2-induced oxidative stress in isolated rat hearts.

Oxidative damage to crucial biomolecules due to excess generation of reactive oxygen species has been implicated as a major cause of organ damage and hence compounds capable of negating such damage have potential benefits. Using hydrogen peroxide (H2O2) as a model pro-oxidant to induce oxidative stress, we have examined the ability of natural food supplement Maharishi Amrit Kalash (MAK-4) to decrease oxidative damage in potassium-arrested isolated rat hearts. The protocol was that hearts isolated from male Sprague-Dawley rats were retrograde-perfused with Krebs-Henseleit (K-H) solution for 30 min for equilibration. After this period, the hearts were subjected to cardioplegia with high potassium (26-30 mM), followed by reperfusion with K-H solution in the presence or absence of 200 microM H2O2. As expected, H2O2 treatment following cardioplegia induced a high degree of oxidative stress as assessed by release of lactate dehydrogenase (LDH, a marker of plasma membrane damage) and total glutathione (GSH + GSSG). H2O2 also impaired the ability of heart to regain developed tension during the testing period. However, addition of MAK-4 in the perfusate containing H2O2 decreased oxidative stress in terms of release of LDH and glutathione. In parallel with these biochemical studies, in a few experiments the cardiac function was assessed by measuring developed contractile tension. These preliminary studies also showed that in the presence of MAK-4 the H2O2-treated hearts were able to regain better developed tension. Further in vitro studies to examine the possible mechanisms of MAK-4 action reveal that this formulation contains H2O2 binding activity which resulted in the decreased availability of H2O2 itself. Our studies hence reveal that the ayurvedic food supplement MAK-4 may have potential benefits in reducing oxidative stress.

Phase I/II trial of combined 131I anti-CEA monoclonal antibody and hyperthermia in patients with advanced colorectal adenocarcinoma.

BACKGROUND: This pilot project was undertaken to evaluate the toxicity of and tumor response to combined 131I anti-carcinoembryonic antigen monoclonal antibody (131I anti-CEA RMoAb) and hyperthermia in patients with metastatic colorectal adenocarcinoma. METHODS: Nine patients who had colorectal carcinoma with liver metastases were enrolled in this study. Intact 131I anti-CEA RMoAb was used (the specific antibody was IMMU-4, provided by Immunomedics, Inc., Morris Plains, NJ). During the diagnostic phase, dosimetry revealed that the tumor site received a higher radiation dose than the surrounding normal tissues in only six patients. These six, who were treated with radioimmunotherapy and hyperthermia, were the basis of this study. The first three patients were treated with 30 mCi/m2 of 131I anti-CEA RMoAb, and the next three received 60 mCi/m2. Pharmacokinetic clearance data were reported for all nine patients. RESULTS: Thermometry data revealed an average T90 of 40.3 (+/- 1.4 degrees C) and T50 of 41.1 (+/- 1.2 degrees C). The average thermal dose equivalent at 42.5 degrees C was 34.5 (+/- 21.5) minutes. The average Tmin, Tmax, and Tmeam were 40 (+/- 1.2 degrees C), 42.4 (+/- 0.7 degrees C), and 41.1 (+/- 1.1 degrees C), respectively. The pharmacokinetic clearance data of antibody showed monoexponential plasma clearances in all patients except one, in whom a biexponential plasma clearance was observed. In general, similar plasma and whole-body clearances as well as similar urinary excretions were observed when diagnostic and therapeutic phases for each patient were compared. Two of the six patients showed a marked improvement in their symptoms; five patients showed a drop in carcinoembryonic antigen levels. A follow-up computed tomography scan one month after treatment showed no change in tumor volume in five patients; one patient showed a partial response. Three patients developed toxicity, two developed moderate thrombocytopenia (39,000 and 58,000), and the other patient developed hematoma resulting from the insertion of a catheter for thermometry. CONCLUSIONS: It is feasible to combine hyperthermia and radiolabeled monoclonal antibodies, and the combination was well tolerated by these patients. The interaction between hyperthermia and low dose rate radioimmunotherapy is complex. Further studies are necessary to explore the use of this combined modality in the management of maligancies.

Effect of sepsis and 3,5,3'-triiodothyronine replacement on myocardial integrity during oxidant challenge.

OBJECTIVE: To determine whether sepsis, with or without thyroid hormonal augmentation, induces myocardial tolerance to an oxidant challenge. DESIGN: A prospective, randomized, controlled animal trial. SETTING: University research laboratory. SUBJECTS: Twenty male Sprague-Dawley rats. INTERVENTIONS: After anesthesia, animals underwent cecal ligation and puncture, with or without 3,5,3'-triiodothyronine replacement (3 ng/hr), or sham surgery. Twenty-four hours later, the heart was rapidly excised for retrograde Langendorff perfusion. Oxyradical challenge consisted of the addition of 200 microM of hydrogen peroxide to the perfusate for 60 mins. MEASUREMENTS AND MAIN RESULTS: Myocardial contractility and relaxation were continuously recorded. Perfusate glutathione and lactate dehydrogenase concentrations were determined enzymatically at 30-min intervals for 90 mins. Oxyradical perfusion alone significantly increased glutathione efflux and decreased myocardial contractility when compared with control animals. Prior cecal ligation and puncture decreased oxidant-mediated glutathione efflux and maintained myocardial contractility. 3,5,3'-triiodothyronine supplementation appeared to increase late cardiac contractility and cellular integrity during oxidant challenge. However, this increase was not statistically significant. CONCLUSIONS: Antecedent septic challenge appears to induce tolerance to further myocardial oxyradical exposure and improves myocardial functional and biochemical integrity. Thyroid hormonal supplementation may provide a modest additional benefit in septic animals.