Showing papers in "Drugs Under Experimental and Clinical Research in 1987"

NE-19550: a novel, orally active anti-inflammatory analgesic

Abstract: NE-19550, N-(3-methoxy-4-hydroxybenzyl)oleamide, is a capsaicin analogue that has been shown to possess oral activity in the 55 degrees C rat hot-plate and mouse phenylquinone abdominal constriction analgesia tests. The compound also displayed anti-inflammatory activity orally in the carrageenan-inflamed rat-paw test and topically in the croton oil-inflamed mouse-ear test. NE-19550 activity in the thermal analgesia assay was not blocked by the opioid antagonist naloxone, and no inhibition of prostanoid synthesis in rat platelets or tissues was seen following a high analgesic and anti-inflammatory oral dose (300 mg/kg). A wide variety of known neuronal antagonists (adrenergic, serotonergic, dopaminergic, cholinergic, GABA-ergic, histaminergic) were found not to inhibit NE-19550 analgesia, further indicating a lack of involvement of known drug receptors mediating analgesic responses. Analgesic doses of NE-19550 were also found to lack the acute toxicity and thermoregulatory desensitization characteristics of the parent natural product capsaicin. It appears to represent a new class of potent-acting, non-narcotic, anti-inflammatory analgesic agents.

L-acetylcarnitine in depressed elderly subjects. A cross-over study vs placebo

Abstract: An open, cross-over study was performed on a population of 24 geriatric patients hospitalized because of depressive syndrome. They were subdivided, according to Hamilton's Scale as modified for the aged, into low- and high-score subgroups. The study period covered 2 months. Half the patients received acetylcarnitine for 1 month and placebo thereafter (Group A); the other half received placebo and acetyl-carnitine thereafter (Group B). Statistical evaluation was twofold: parametrical analysis of variance was carried out on 4 subgroups (A1, A2, B1 and B2) and analysis of the score percentage modifications before and after treatment was performed on Groups A and B. The experimental results showed that acetylcarnitine treatment was highly effective and statistically significant in subgroups A1/B1, A2/B2, A1, B1 and B2. In particular, it should be noted that depressive tendencies were significantly modified in most groups, whereas general somatic symptoms as well as anxiety, asthenia and sleep disturbances proved to be little affected. Clinical evaluation, carried out by calculation of modifications in pre- and post-treatment score percentages, provided clear evidence that acetylcarnitine was particularly effective in patients showing more serious clinical symptoms. The drug caused no side-effects at the doses and regimens used.

Inhibitory mechanism of acarbose and 1-deoxynojirimycin derivatives on carbohydrases in rat small intestine

Abstract: The inhibitory action and mechanism of inhibition of two types of alpha-glucosidase inhibitors, acarbose (Bay-g-5421) and 1-deoxynojirimycin derivatives (Bay-m-1099 and Bay-o-1248), on small intestinal carbohydrases (sucrase, isomaltase, glucoamylase, trehalase and lactase) and pancreatic alpha-amylase were compared in vitro using small intestinal brush border membranes and pancreatic homogenates from adult Sprague-Dawley rats. Acarbose at a low (4 microM) concentration strongly inhibited the activities of glucoamylase, alpha-amylase and sucrase (98, 68, and 63%, respectively). At a high (200 microM) concentration, isomaltase activity was also inhibited (28%); effects on trehalase and lactase activities were negligible. Both the 1-deoxynojirimycin derivatives were even more potent inhibitors of sucrase (Ki = 8.6 x 10(-8) M for Bay-m-1099;Ki = 5.0 X 10(-8) M for Bay-o-1248) than acarbose (Ki = 9.9 x 10(-7) M). Whereas glucoamylase activity was strongly inhibited by the 1-deoxynojirimycin derivatives, alpha-amylase activity was not. In contrast to acarbose, the 1-deoxynojirimycin derivatives at high concentrations (20-200 microM) inhibited considerably trehalase and lactase (a beta-galactosidase) activities. The inhibition of lactase activity was stronger by Bay-m-1099 (Ki = 4.9 X 10(-6) M) than by Bay-o-1248 (Ki = 6.7 X 10(-5) M). Where inhibition was seen, kinetic analysis showed fully competitive inhibition of sucrase, isomaltase, trehalase, glucoamylase and lactase by all three inhibitors.

Treatment of Raynaud's phenomenon with captopril

Abstract: Antineoplaston A5 is a mixture of small peptides and amino acid derivatives isolated from human urine which show a unique pattern of growth inhibition in the tissue culture of human neoplastic cells and no significant animal toxicity. Clinical trials described in this paper involved 15 patients diagnosed with advanced neoplastic diseases. The patients' diagnoses included: lung cancer, stage III (4 cases); breast, stages III and IV (3); colorectal, stage IV (2); bladder (2); and single cases of adenocarcinoma of the jejunum, stage IV; adenocarcinoma of the prostate, stage IV; adenocarcinoma of the ovary, stage IV and astrocytoma, grade IV. Antineoplaston A5 was administered daily in divided doses intravenously through a subclavian vein catheter. The formulation was given from 47 to 130 days. The highest dosage attained was 153 mg/kg/24 h. Adverse effects included febrile reaction in five patients, arthralgia in one patient and premature beats and pressure in the chest in one patient. The side-effects were very mild and usually experienced only once during the entire course of treatment. Desirable side-effects included increase of platelet count, increase of white blood cell count and hypertrophy of epidermis. Nine patients (60%) had objective response to the treatment. They were diagnosed with cancer of the lung (3 patients), breast (2), colorectal (2) and bladder (2). Four patients had increasing disease and two patients were classified as having stable disease without objective improvement.

In vitro antibacterial activity of rifaximin against Clostridium difficile, Campylobacter jejunii and Yersinia spp.

Abstract: Fifty-four isolates of Campylobacter jejunii, 91 isolates of Yersinia spp. and 56 isolates of Clostridium difficile, recovered from stools of patients with diarrhoea or other intestinal disturbances and from stools of asymptomatic patients receiving antibiotic therapy, were tested in vitro for susceptibility to rifaximin, rifampicin and neomycin. The in vitro antibacterial activities were found to be comparable against the aerobic bacterium; on the contrary, against microaerophilic and anaerobic bacteria rifaximin and rifampicin were much more effective than neomycin.

A sulphonamido-indanone derivative CGP 28237 (ZK 34228), a novel non-steroidal anti-inflammatory agent without gastro-intestinal ulcerogenicity in rats.

Abstract: CGP 28237 (5-methylsulphonylamino-6-phenoxy-1-indanone) belongs to a series of structurally novel indanones. The compound is a weak acid (pK = 6.98), but it does not contain a carboxylic group. CGP 28237 exhibits potent anti-inflammatory activity in developing and established adjuvant arthritis in rats (ED40 approximately 0.5 mg/kg p.o.) and good activity in carrageenin oedema (ED40 approximately 3 mg/kg p.o.). It inhibits yeast-induced fever in rats with ED50 values of 1, 2 and 10 mg/kg p.o. at 1, 3 and 5 hours after drug administration. The antinociceptive activity in mice (phenyl-p-benzoquinone writhing) and rats (acetic-acid writhing) is weak. CGP 28237 has been shown to be non-ulcerogenic in rats under acute and chronic test conditions: it does not cause mucosal lesions in the stomach at 2 X 400 mg/kg p.o., it does not enhance gastro-intestinal blood loss during 10 days' oral treatment with 400 mg/kg p.o., and it did not induce gastro-intestinal lesions in a 4-week toxicity study up to 1000 mg/kg p.o. Although CGP 28237 is not a cyclooxygenase inhibitor in bovine seminal vesicle microsomes, it inhibits prostaglandin synthesis in zymosan-stimulated murine macrophages (IC50 approximately 3 X 10(-6) mol/l) and protects rabbits against arachidonic acid-induced lung embolism with 10 mg/kg p.o. CGP 28237 may represent a novel anti-inflammatory drug with excellent gastro-intestinal tolerability.

Cytostatic activity of naturally isolated isomers of secalonic acids and their chemically rearranged dimers.

Abstract: Six different secalonic acids were tested for cytostatic activity against cultured mouse leukaemia L1210 cells. Secalonic acids B and E showed rather weak activity but the other four isomers showed quite strong activity, especially secalonic acids A and D which were slightly more active than adriamycin. The chemically rearranged 2,4'-dimer of secalonic acid A showed almost the same activity as the naturally isolated 2,2'-dimer, but the activity of the 4,4'-dimer was much stronger than that of both the 2,2'-dimer and adriamycin. Interestingly, in a mouse bone marrow stem cell assay, secalonic acids F and G showed almost the same toxicity as adriamycin, but secalonic acids A and D showed rather weak toxicity. Similarly, the 2,2'-dimer of secalonic acid A showed almost the same toxicity as adriamycin, but the toxicity of the 2,4'- and 4,4'-dimers was weaker than that of the 2,2'-dimer and also that of adriamycin.

The post-antimicrobial suppressive effect of quinolone agents.

Abstract: A post-antimicrobial effect (PAE) was seen with all of the new 4-quinolones studied: ciprofloxacin, ofloxacin, Cl-934, Ro 23-6240, A-56619 and S-25930. The post-antimicrobial suppression of growth was for 4-8 h in the case of Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Pseudomonas aeruginosa. PEA was demonstrated both in Mueller-Hinton broth at pH 7.4 and in urine at pH 5.5 with a Mg2+ concentration of 9.5 mM. Resistant organisms, with MICs greater than 4 micrograms/ml, showed a PAE after a 2-h exposure to 200 micrograms/ml of 4-quinolones. This demonstrates that PAE is seen for 4-quinolones even under conditions in which they are less active.

Antiproliferative activity of picolinic acid due to macrophage activation.

Abstract: Activation and subsequent enhancement of cytotoxicity of mouse peritoneal macrophages (M phi) by picolinic acid (PLA) in vivo have been reported previously by the authors' group. The optimum dose was found to be 100 mg/kg. PLA-stimulated M phi lysed different tumor targets in vitro, MBL-2 lymphoma cells and Madison 109 lung carcinoma cells, with equal efficiency. Treatment with PLA was performed daily for 5 consecutive days with a dose of 100 mg/kg intraperitoneally in C57/BL mice, which previously had been inoculated with MBL-2 tumor cells. Treatment was initiated on the first day after tumor inoculation. Oral treatment with PLA (200 mg/kg) dissolved in the drinking water was also performed for 7 days. In addition, some groups received PLA treatment 1 or 2 days before tumor implantation but not afterwards, to elucidate the in vivo efficacy of M phi activation. Intraperitoneal therapy with PLA after tumor inoculation resulted in a highly significant increase in lifespan (46%); intraperitoneal pretreatment caused a significant increase (15%); orally administered PLA was without effect. Thus intraperitoneal treatment with PLA was found to have protective and therapeutic effects against the MBL-2 ascites tumor in vivo. These effects are most likely caused by macrophage activation.

A comparison of the efficacy and safety of cefuroxime axetil and augmentin in the treatment of upper respiratory tract infections.

Abstract: Cefuroxime axetil (CAE), an orally absorbed prodrug of cefuroxime, was evaluated for its efficacy and safety in the treatment of upper respiratory tract infections (tonsillitis, pharyngitis, sinusitis and otitis media) in general practice in the United Kingdom. A total of 385 patients aged 14 or over were enrolled in a randomized study to compare cefuroxime axetil 250 mg b.d. for 5 days with amoxycillin/clavulanate (Augmentin, AUG) 375 mg t.d.s. for 5 days. Of 175 clinically assessable patients treated with cefuroxime axetil, 136 were cured and 33 improved (97% success rate). Of 188 assessable patients given Augmentin, 155 were cured and 29 improved (98% success rate). Sixty-four patients treated with cefuroxime axetil were evaluable for bacteriological response: 47 (73%) of the causative pathogens were eradicated, as compared with 62 of 86 (72%) in patients treated with Augmentin. Thirteen out of 181 (7%) patients treated with cefuroxime axetil experienced drug-related adverse events, including 4% with diarrhoea. In the Augmentin group 24 out of 204 (12%) patients had a drug-related adverse event, including 5% with diarrhoea. In conclusion, cefuroxime axetil at a dose of 250 mg b.d. appears to be as safe and effective as Augmentin at the higher dose of 375 mg t.d.s. in the treatment of upper respiratory tract infections.

Protective action of acetylcarnitine on NADPH-induced lipid peroxidation of cardiac microsomes.

Abstract: Rat cardiac microsomes treated with NADPH generated a chemiluminescence, detected by the chemilumigenic probe lucigenin. The chemiluminescent signal, which is an index of lipid peroxidation, was found to be inhibited by acetylcarnitine in a dose-dependent way. Superoxide dismutase (SOD) and inhibitors of arachidonate metabolism were also effective in preventing light emission. The combined action of acetylcarnitine plus SOD and acetylcarnitine plus indomethacin suggested a possible common target for the compounds. When tested on superoxide production from isolated human neutrophils detected both by luminol-amplified chemiluminescence and cytochrome C reduction, acetylcarnitine did not show any inhibitory effect. The results of these experiments demonstrate the antioxidant properties of acetylcarnitine, even if they cannot clarify the specific target of the drug action.

N,N'-disubstituted L-isoglutamines as novel cancer chemotherapeutic agents

Abstract: Previous studies carried out in the authors' Institute revealed that one of the active metabolites of Antineoplaston A10 is phenylacetylisoglutamine. The objective of this study is screening of N,N'-disubstituted L-isoglutamine derivatives for selection of novel anticancer agents. A series of seven derivatives of L-isoglutamine was synthesized as potential chemotherapeutic agents. Antitumor activity studies were performed in tissue culture of breast carcinoma cells HBL-100. The acute toxicity study was carried out on a group of 60 HA/ICR Swiss mice. Among the compounds tested N alpha-(phenylacetylamino)-gamma-(4-amino-N-benzyl-piperidinyl)-L-g lutamyl amide was found to have the best anticancer activity and no significant acute toxicity. The LD50 was calculated by the moving average method and determined as 4.5 g/kg i.p. in mice. It is concluded that the important structural features for good antineoplastic activity are lipophilic groups on both amine and amide nitrogen of isoglutamine. The activity is also increased when the phenyl group present at the side chain is at least two carbon atoms away from the amide nitrogen.

Determination of MICs of conventional and experimental drugs in liquid medium by the radiometric method against Mycobacterium avium complex.

Abstract: The aim of this study was to search for new drugs active against the Mycobacterium avium complex and to re-examine the activity of some conventional antituberculosis drugs against these species. This progress report describes the protocol and phases of in vitro experiments in a search which included 57 different compounds tested against numerous strains of M. avium clinical isolates. The preliminary screening and MIC determination of these drugs were conducted in 7H12 broth by the radiometric method (BACTEC system). Of the total of 57 drugs, 23 were discarded after preliminary screening and 17 after MIC determination. The remaining 17 drugs were considered sufficiently promising for more detailed in vitro studies. These, now in progress, include MIC determination by two additional methods (in broth by sampling and plating and in 7H11 agar plates), MBC determination and drug combination studies. The following drugs are currently undergoing these detailed studies: isoniazid, rifampin, rifabutine (ansamycin LM427), amikacin, streptomycin, ethambutol, ethionamide, cycloserine, clofazimine (CF), CF derivative B746, CF derivative B1865, ofloxacin, ciprofloxacin, cephalosporin BMY 28142, trimethoprim-sulfamethoxazole, spectinomycin derivative U6633F(B), and dihydromycoplanecin.

Headache in association with sleep disorders in children: a psychodiagnostic evaluation and controlled clinical study--L-5-HTP versus placebo.

Abstract: Forty-eight elementary and junior high school students presenting the association of recurring headache and sleep disorders were selected for this study on the basis of a questionnaire filled out by the entire school population. The selected students had normal intellectual capacity but often showed inadequate progress in school, attentive-mnemonic deficiencies, and psychopathological elements of a depressive nature. The clinical characteristics predicted that this group would be responsive to treatment with L-5-hydroxytryptophan. The results of a double-blind, cross-over trial with placebo confirmed these expectations for headache and some sleep disorders, in particular frequent awakenings and some parasomnias.

Determination of teicoplanin concentration in serum using a bioassay technique.

Abstract: An accurate and sensitive bioassay for determining concentrations of teicoplanin in serum has been developed using modifications of procedures described for assaying vancomycin A linear relationship (r = 09983) was obtained between the diameter of the zone of inhibition and log10 teicoplanin concentration over the range 025-32 micrograms/ml The medium used was Antibiotic Medium No 1 (Oxoid, UK) adjusted to pH 55-57 by the addition of hydrochloric acid and containing sodium chloride to a final concentration of 3% The indicator organism used was a Bacillus subtilis ATCC 6633 (NCTC 10400) Teicoplanin was assayed: (i) in the presence of beta-lactams and cephalosporins, including ceftazidime, by prior treatment of serum with broad-spectrum beta-lactamase mixtures (Genzyme Laboratories, UK); (ii) in the presence of aminoglycosides by prior treatment of serum with cellu-ion phosphate (100 mg/ml) followed by centrifugation; (iii) in the presence of sulphamethoxazole and/or trimethoprim by the addition of p-aminobenzoic acid and/or thymidine to the assay medium Teicoplanin was assayed in the presence of either rifampicin or erythromycin by using a rifampicin-resistant, erythromycin-resistant clinical isolate of Staphylococcus aureus as indicator organism The lower limit of sensitivity of this assay was 1 microgram/ml The presence of undeclared, broad-spectrum antimicrobials was detected by screening serum samples for antimicrobial activity using an assay plate seeded with Escherichia coli NCTC 10418

Intestinal microflora changes induced by ciprofloxacin and treatment of portal-systemic encephalopathy (PSE).

Abstract: The modifications of colon microflora in 14 patients under oral ciprofloxacin therapy for intercurrent UTIs or RTIs, at the dose of 250 mg b.i.d. or 500 mg o.d. were examined. All patients were affected by liver cirrhosis. A marked decrease in enterobacteria with both doses was noticed in the first few days, with a complete disappearance from days 3-6 of therapy and a return to normal within 2 weeks after interruption of treatment. Gram-positive and Gram-negative aerobic and anaerobic flora were not affected significantly. As a consequence of these results, the treatment of six patients affected by PSE (grade 2-3) was studied, testing the colon microflora changes, the presence of circulating endotoxins and blood ammonium levels before, during and after 12 days of therapy. A marked reduction or suppression of enterobacteria was observed, and a prompt normalization of blood ammonium levels, the disappearance of circulating endotoxins and a clear clinical improvement in 5 out of 6 patients.

L-asparaginase-induced coagulopathy in children with acute lymphoblastic leukaemia.

Abstract: Haemostatic changes induced with vincristine (VCR), prednisone (PDN) and L-asparaginase (L-ase) in 53 children with ALL were prospectively evaluated. Relative to pretreatment values, mean FG concentration diminished significantly in the first week with a minimal level in the third week and PT was prolonged during the first weeks of induction. APTT decreased significantly in the last week and after cessation of L-ase therapy. Mean concentration of factor VIII remained elevated during the entire period of L-ase therapy. Three children (5.6%) developed a cerebral thrombo/haemorrhagic complication. These data demonstrate that the tendency for thrombosis is the predominant clinical manifestation of L-ase-induced coagulopathy, when the drug is associated with VCR and PDN.

Ultrastructural aspects of ageing rat hippocampus and effects of L-acetyl-carnitine treatment.

Abstract: The ageing rat hippocampus undergoes ultrastructural changes, including the loss of axosomatic synapses of the granule cells. These synapses are supposed to take part in a feed-back regulation of granule cell activity, as they are inhibitory terminals of interneurons which receive afferences from the granules themselves via the giant synapses formed by the collaterals of the mossy fibres. In the present study the authors performed a quantitative analysis of axosomatic and giant synapses at the ultrastructural level in aged rats as compared with young animals. In aged rats a decrease both in axosomatic synapses and in giant synapsis vesicles was found, giving further support to the postulated feed-back mechanism. Both young and old rats were treated with L-acetyl-carnitine, a drug which favours the synthesis of acetylcholine, the main neurotransmitter deficient in old age. In aged rats the drug restored a normal number of both axosomatic synapses and giant bouton vesicles. The authors hypothesize that the drug, by a cholinergic-type mechanism, restores the excitatory afferences to the granule whose axon would thus form normal giant boutons with the interneuron, reestablishing the feed-back regulation. In young rats the drug induced a decrease only of the axosomatic synapses, suggesting that an "over-excitation" might impair the information to the local-circuit neurons, thus interrupting feed-back control.

Effects of subinhibitory concentrations of pefloxacin on the adherence of Staphylococcus aureus to human cells.

Abstract: The adherence of bacterial strains to eukaryotic cells can be influenced by subinhibitory concentrations of antibiotics. The effect of sub- and infra-MICs of pefloxacin, a new broad-spectrum antibacterial quinolone, on the adherence of Staphylococcus aureus to human buccal cells, was studied. Six S. aureus strains belonging to several serotypes and all sensitive to pefloxacin were pretreated with serial twofold dilutions of the drug (from 1/2 to 1/1024 the MIC). After the adhesion test, 100 buccal cells were counted in randomly chosen microscopic fields using a Nomarski interference microscope and attachment was measured as the percentage of cells with at least 50 or more adhering bacteria. Sub-MICs (1/2 and 1/4 the MIC) of pefloxacin increased the diameter of the six staphylococci. All of the strains, grown in the presence of pefloxacin, exhibited a markedly altered capacity for adhesion to buccal cells. The highest significant decrease was observed for 1/2 to 1/8 the MIC, although infra-MICs such as 1/1024 the MIC also decreased the attachment of S. aureus to buccal cells. These results were compared with those obtained with other antibiotics active against S. aureus.

Enzymatic modification of aminoglycoside antibiotics by Branhamella catarrhalis carrying an R factor.

Abstract: Fifteen out of 89 clinical strains of Branhamella catarrhalis isolated from patients at the University Hospital of Zaragoza were resistant to aminoglycosides and other antimicrobials. In two strains, B. catarrhalis 220 and B. catarrhalis 115, the resistance to aminoglycosides was associated with synthesis of aminoglycoside-modifying enzymes, namely 3"-O-phosphotransferase [APH(3")] and 3'-O-phosphotransferase [APH(3')]. B. catarrhalis 115 was resistant to ampicillin, streptomycin, kanamycin, neomycin, butirosin, lividomycin, ribostamycin, paromomycin and trimethoprim-sulfamethoxazole and harboured a 32 megadalton (Md) plasmid. The resistance determinants of the latter were transferred to Neisseria subflava by conjugation and to Escherichia coli by transformation. The transconjugant strain presented an antibiotic resistance pattern similar to the donor strain and carried the same plasmid. The transformant strain acquired the 32 Md plasmid but presented, besides the resistance pattern already mentioned, resistance to tetracycline, gentamicin and tobramycin. Resistance to gentamicin and tobramycin was mediated by the synthesis of a 3-N-acetyltransferase. This resistance and the related enzyme were expressed neither in the donor B. catarrhalis strain nor in the transconjugant N. subflava strain.

Cefuroxime axetil in the treatment of uncomplicated UTI: a comparison with cefaclor and augmentin.

Abstract: Cefuroxime axetil (CAE) is an acetoxyethyl ester prodrug of cefuroxime. The efficacy and safety of cefuroxime axetil was studied in a randomized general practice trial in urological infections where cefuroxime axetil 250 mg b.d. was compared with amoxycillin/clavulanate (Augmentin, AUG) 375 mg t.d.s. A randomized trial was then performed in hospital outpatients, who received cefuroxime axetil 250 mg b.d. or cefaclor (CCL) 250 mg t.d.s. Of 140 clinically assessable patients, 108 were cured and 28 improved on cefuroxime axetil (97% success) compared with 75 cured and 13 improved out of 89 on Augmentin (99% success) and 31 cured and 7 improved out of 38 patients treated with cefaclor (97% success). Bacteriology was assessable in 101 patients given cefuroxime axetil (72% cleared), 61 of those given Augmentin (70% cleared) and 27 out of 28 (96%) given cefaclor. As expected, the predominant pathogen was E. coli, accounting for 61% of isolates overall. Drug-related adverse events occurred in 10% of patients given cefuroxime axetil, including diarrhoea in 4%. Eleven percent of patients given Augmentin suffered adverse events (5% diarrhoea) and 5% of those given cefaclor. Superinfections occurred in 4 cefaclor patients (2 Pseudomonas aeruginosa, 1 Candida, 1 E. coli) compared with 2 on cefuroxime axetil (1 Candida, 1 E. coli). Uncomplicated UTI accounted for 92% of cases in the G.P. trial and 82% of cases in the hospital trial. Cefuroxime axetil may be used safely and effectively to treat uncomplicated UTI at a dose of 250 mg b.d.

Stereochemical modelling studies of the interaction of antineoplaston A10 with DNA.

Abstract: Antineoplaston A10 (3-phenylacetylamino-2,6-piperidinedione), a peptide analogue originally isolated from human urine, has been demonstrated to fit between base pairs in DNA. Examination of the fit of A10 into the 10 possible sites in unwound DNA using published criteria revealed a preference, but not absolute specificity, for the sequence 5'-dTdT-3' X 5'-dAdA-3'. Good fits were also observed for the sequences 5'-dTdC-3' X 5'-dGdA-3' and 5'-dCdT-3' X 5'-dAdG-3'. In each case at least one stereospecific hydrogen bond was possible between the imino proton of the piperidinedione ring stacked between the two pyrimidines and a neighbouring phosphate oxygen of the DNA backbone. These findings support the prediction that A10 may interact reversibly with DNA and thereby compete with carcinogens that form covalent linkages with DNA (e.g., arene oxides). It follows that such interactions should prevent the growth of tumours induced by various carcinogens.

Studies on the effects of pharmacological agents on antigen-induced arthritis in BALB/c mice.

Abstract: The model of antigen-induced monoarticular arthritis in BALB/c mice, originally described by Brackertz et al. (1), has been examined with regard to disease pathogenesis and the activities of established antirheumatic agents. The acute phase of the arthritis, up to 7 days after intra-articular (IA) challenge, was characterized by intense polymorphonuclear leukocyte infiltration into the challenged joint, synovial lining cell hypertrophy and hyperplasia, accumulation of mononuclear cells within the subsynovial tissue, and pannus formation. Erosions of articular cartilage and bone commenced 7-14 days after IA challenge and progressed with time. Chronic synovitis was still evident 56 days after IA challenge. Prednisolone at 1 and 5 mg/kg, when administered against an established arthritis (dosing days 14-42), suppressed the histopathological changes. A similar level of suppression was observed when prednisolone was administered from days 0-42, indicating that the drug had no additional effect on the development phase of the arthritis. The non-steroidal anti-inflammatory agents (NSAIAs) indomethacin, ibuprofen and flurbiprofen failed to suppress either the established or developing disease. Daily treatment with D-penicillamine, tiopronin or chloroquine on days 14-42 had no significant effect on the arthritis; treatment with either D-penicillamine or chloroquine on days 0-56 was also ineffective. When administered on days 14-42 or 0-42 neither gold thiomalate nor auranofin were able to suppress the erosive changes. Sulphasalazine (10-30 mg/kg) suppressed the arthritis whereas sulphapyridine was inactive. Azathioprine (20 mg/kg) suppressed the erosive changes when administered over days 14-42 or 0-42; this activity was associated with toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Concentration and time dependence of amphotericin B-induced permeability changes across plasma membrane vesicles from Leishmania sp.

Abstract: The main purpose of this paper is to show that the polyene antibiotic amphotericin B may form two types of channels in plasma membrane vesicles from Leishmania sp.: ionic and aqueous. The experimental design was to follow the light scattering changes of a suspension of membrane vesicles under an osmotic shock. The results show that a low concentration of amphotericin B(0.2 to 0.8 microM) led to an enhancement of urea and salt permeability without affecting the total osmotic response of Leishmania vesicles. Such an increment of solute permeability induced by low concentrations of amphotericin B was 100% blocked by tetraethylammonium. Low concentrations of amphotericin B were also able to induce an enhancement of glucose permeability but only after Leishmania membrane vesicles were incubated for 15 min with the antibiotic, previous to mixing. On the other hand, high amphotericin B concentrations (greater than 0.8 microM) induced a decrease in the total extent of shrinkage of membrane vesicles immediately after its mixing with urea solutions. At this high concentration of amphotericin B the blocking of tetraethylammonium was reduced by 50%. These results support the authors' previous conclusion (1) that in ergosterol-containing membranes, amphotericin B may form two different types of channels differing in internal diameter.

Nutritional implications of high-iodine egg diet in rats: effects on lipid metabolism and thyroid function.

Abstract: This paper describes Phase I clinical studies of Antineoplaston A2 injections. The studies involved 15 patients diagnosed with advanced neoplastic diseases including cancers of the breast, bladder, lung, kidney, oesophagus, colon and liver, mesothelioma and glioma. Antineoplaston A2 was administered in divided doses daily intravenously through a subclavian vein catheter. The treatment was given from 53 to 358 days. The highest dosage administered was 147 mg/kg/24 h. Only minimal adverse effects were noticed sometime during the treatment, including fever, chills and myalgia. Desirable side-effects included increase of platelet and white blood cell counts, hypertrophy of epidermis and decrease of cholesterol and triglyceride levels. Nine patients showed objective response to the treatment. Cases of complete remission included adenocarcinoma of the lung, mesothelioma, metastatic liver and bladder cancers. In an additional case of breast cancer, the patient obtained complete remission of liver metastasis and stabilization of bone metastases. Partial remission was accomplished in cancers of the breast and oesophagus. Three patients, including cases of adenocarcinoma of the lung, mesothelioma and bladder cancer, were in complete remission for over five years.

Preclinical approaches to the treatment of metastatic disease: Therapeutic properties of RH, TNF, RM IFN-γ, and RH IL-2

Abstract: The present studies were undertaken to examine the immunotherapeutic properties of recombinant murine interferon-gamma (rM IFN-gamma), recombinant human tumour necrosis factor (rH TNF), and recombinant human interleukin-2 (rH IL-2) in preclinical metastasis models. It was observed that these cytokines have disparate mechanisms of therapeutic activity as well as different optimal therapeutic protocols. Thus, not only is the dose important to the therapeutic activity of each of the agents; so also is the route of administration, schedule of administration, duration of administration, and sequence of administration. The rM IFN-gamma has a narrow window of activity, with a bell-shaped therapeutic response with a dosage optimum at 50,000 U/animal of rM IFN-gamma administered 3 times per week. In contrast, rH IL-2 has optimal therapeutic activity for the treatment of metastatic disease after i.p. as compared to i.v. administration. This appears to be associated with the serum pharmacokinetics, since longer serum concentrations are achieved following i.p. administration although lower serum levels are also achieved. RH IL-2 has a biphasic dose-response curve for therapeutic activity with optima from 100 to 1000 U/animal and at doses greater than 100,000 U/animal. The lower doses appear to be associated with T cell augmentation whereas the higher doses are associated with NK cell or LAK cell augmentation. RH TNF has therapeutic activity for the treatment of metastatic disease after i.v. but not i.p. administration. High levels of rH TNF are readily detected in the serum following i.v. administration, with a serum half-life of approximately 30 min. In contrast, only minimal serum TNF activity is observed after i.p. administration, suggesting that this may be the origin of the increased therapeutic activity following i.v. administration. Furthermore, rH TNF has additive therapeutic activity when administered in conjunction with suboptimal doses of rM IFN-gamma. Unfortunately, the additive therapeutic activity of rM IFN-gamma and rH TNF is also associated with increased toxicity. However, in preliminary experiments it was found that the b.i.d. administration of aspirin at 25 mg/kg resulted in decreased toxicity. In summary, the recombinant cytokines provide a challenge both preclinically and clinically to the development of optimal therapeutic protocols, and suggest that close attention must be paid to the dose, route, schedule, duration, and sequence of their administration.

1,6-Dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido (1,2-a)-pyrimidine 3-carboxamide (CH-127) protects against the intestinal damage in rats caused by two weeks' daily administration of indomethacin

Abstract: 1,6-Dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido 1,2-a pyrimidine-3-carboxamide (Ch-127) significantly inhibited the intestinal ulceration induced by a single dose of indomethacin (15 mg/kg p.o.). Moreover, indomethacin produced 75% lethality in the dose of 3.5 mg/kg p.o. administered daily for 2 weeks. The concurrent daily administration of Ch-127 (50 mg/kg p.o. +25 mg/kg s.c.) with indomethacin prevented the gastrointestinal mucosa from histologically detectable changes, and none of the animals died. The 80% lethality following the daily administration of naproxen (60 mg/kg p.o.) for two weeks was also significantly decreased by combining it with Ch-127 (50 mg/kg p.o.).

Haematotoxicity of doxorubicin and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and of their association in rats

Abstract: Doxorubicin is an anthracycline widely used in the treatment of leukaemias, lymphomas and solid tumors Doxorubicin cannot pass into the cerebrospinal fluid Nitrosoureas are known to be lipophilic and to be able to penetrate the blood-brain barrier CCNU is a nitrosourea used to treat Hodgkin's disease, brain tumors and other solid tumors The authors have previously reported on the nephrotoxicity and hepatotoxicity of these drugs; the present paper reports their findings on haematotoxicity in female Wistar rats In one group 40 rats received 10 mg/kg doxorubicin In a second group 40 rats received 20 mg/kg CCNU, and a further 40 rats received 50 mg/kg CCNU In a third group 60 rats received the association doxorubicin 10 mg/kg plus CCNU 20 mg/kg Blood counts were performed on days 4, 8, 15, 21 and 28 after treatment Leucopenia and severe thrombocytopenia were noted after doxorubicin administration A biphasic decrease in the leucocyte count was observed after CCNU treatment More severe alterations were observed when doxorubicin and CCNU were combined Very few data on haematological abnormalities following treatment of human patients have been published Similarities can be seen between the haematological side-effects noted in rats and those occurring in humans treated with these cytotoxic drugs Female Wistar rats seemed to be a good model to evaluate the haematological tolerance of anthracycline, nitrosoureas or of their association If multiple courses of these drugs have to be administered, the evolution of haematological alterations must be known: the decrease phase of blood cells is followed by a rebound phase The drug should be avoided during this phase of granulocyte activation

Comparative in vitro evaluation of BMY-28142, a new broad-spectrum cephalosporin, versus other beta-lactams against multiresistant gram-negative isolates.

Abstract: The in vitro activity of the new parenteral cephalosporin BMY-28142 was compared with that of cephalothin, cefoxitin, cefotaxime, ceftriaxone, moxalactam, aztreonam and ceftazidime, against a total of 374 recent multiresistant Gram-negative microorganisms of nosocomial origin. Against all species of Enterobacteriaceae resistant to the first- and second-generation cephalosporins, BMY-28142 had superior inhibitory activity than the newer beta-lactams tested, with intrinsic activity against E. coli and Pr. mirabilis slightly less than that of cefotaxime and ceftriaxone. BMY-28142 differed from the other beta-lactams mainly in being at least 16-fold more active against E. cloacae, while BMY-28142 and ceftazidime showed comparable activity against Ps. aeruginosa strains. Against strains of Ps. aeruginosa resistant to both BMY-28142 and amikacin, the combination of the two antibiotics proved to be synergistic in vitro.

Comparative in vitro activity, serum binding and binding activity interactions of the macrolides A-56268, RU-28965, erythromycin and josamycin.

Abstract: The minimal inhibitory concentrations of macrolide antibiotics against staphylococci, streptococci and Haemophilus influenzae were determined in vitro. A-56268 was the most active and RU-28965 was the least active of the macrolides tested. The interaction at erythromycin binding sites in serum and at alpha 1-acid glycoprotein was studied. RU-28965 exhibited the highest binding affinity. The effect of binding on antimicrobial potencies was evaluated by measurements of the first-order generation rate constants and by determination of MICs of staphylococci in broth and in human serum. The activity of each of the macrolides was lowered by serum binding, but only that of RU-28965 was dramatically decreased.