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Synthesis and copper-dependent antimycoplasmal activity of 1-amino-3-(2-pyridyl)isoquinoline derivatives. 2. Amidines.

de Zwart MA, van der Goot H, Timmerman H.

Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, The Netherlands.

In our search for new compounds with antimycoplasmal activity, a series of aromatic amidines derived from 1-amino-3-(2-pyridyl)isoquinoline (1) was synthesized. In the presence of 40 microM copper the most active compounds show growth inhibition of Mycoplasma gallisepticum in the nanomolar range. These compounds are 3 times as active as tylosin, an antimycoplasmal therapeutic agent that is used in veterinary practice. In the presence of copper, amidines derived from 1 are 2-3 times more active than the corresponding amides. Furthermore it was established that for these compounds too, the presence of a 2,2'-bipyridyl moiety is a necessary prerequisite for antimycoplasmal activity. As for the amides, antimycoplasmal activity of amidines derived from 1 is dependent on the hydrophobic fragmental value of the aromatic nucleus of the amidine moiety. A quantitative structure-activity relationship established the optimal hydrophobic fragmental value of this part of the molecule to be zero.

Effects of copper and zinc ions on the germicidal properties of two popular pharmaceutical antiseptic agents cetylpyridinium chloride and povidone-iodine
Zeelie J.J.; McCarthy T.J.
J.J. Zeelie, Unit for Health Services, Port Elizabeth Technikon, Private Bag X6011, Port Elizabeth South Africa
Analyst (United Kingdom), 1998, 123/3 (503-507)

The effects of copper and zinc ions on the rate of killing of Gram-negative bacterium Pseudomonas aeruginosa, Gram-positive bacterium Staphylococcus aureus and fungal yeast Candida albicans by antiseptic agents cetylpyridinium chloride and povidone-iodine (Betadine) were investigated. In the 48 test cases copper and zinc ions clearly potentiated the antiseptic agents in 28 (58.3%) cases and exhibited an improved (not clear potentiation) activity in 15 (31.3%) cases. In five (10.4%) cases there was no change in the antiseptics' antimicrobial activity. In general zinc potentiated the antiseptic agents more than copper. If an 'improved activity' was the only criterion for this study, then a more rapid antimicrobial effect was observed in 43 out of the 48 test cases, i.e., 90%.

Relationship between residual metal ions in a solution and the inhibitory capability of the metal ions for pathogenic bacterial growth
Zhao Z.-H.; Sakagami Y.; Osaka T.
Z.-H. Zhao, Satosen Co., Ltd., 2-20-65 Tamadenishi, Nishinari-ku, Osaka 557 Japan
Bulletin of the Chemical Society of Japan (Japan), 1998, 71/4 (939-945)

The inhibitory capability of various low concentrations of six kinds of metal ions [silver(I), copper(II), cobalt(II), nickel(II), zinc(II), and dichromate] for pathogenic bacterial (gram-positive bacteria Staphylococcus aureus and MRSA, gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa) growth was quantitatively determined exactly. Residual metal-ion concentrations in a phosphate buffer solution after being incubated with pathogenic bacteria were then measured by an atomic-absorption spectrophotometer. We found that the inhibitory capability of metal ions correlated with the residual metal concentrations. Based on the biochemical and chemical situation, the mechanisms of the inhibitory capability of the metal ions are discussed. In addition, the determined minimum inhibitory concentration (MIC) values of metal ions on tested bacteria are considered.

A database in Rumania and on a US IBM site described links found between copper, zinc, magnesium, calcium, COX-2 enzyme, and Mycoplasma suggesting that these metals in the form of metalloenzymes (or the deficiency of the metals in the case of the enzyme production) play a role in the immune system’s reactions to microbes (certain strains of mycoplasmas). The reactions accompany the production of destructive H₂O₂ (hydrogen peroxide) in the inflamed synovial tissue where the mycoplasmas reside. Other researchers are studying the chelation actions of antibiotics vs metalloenzymes.  The puzzle is how to explain the beneficial effects of chelation, which removes metals, and the beneficial addition of certain metal ions (copper and zinc) in cases of bacterial infections.  A similar puzzle involves the beneficial effects of increases in folic acid as a nutrient vs the beneficial effect of the tetracyclenes, which inhibit folic acid synthesis in microbes, and also  perform chelation.  

Effects of zinc oxide on the attachment of Staphylococcus aureus strains
Akiyama H.; Yamasaki O.; Kanzaki H.; Tada J.; Arata J.
H. Akiyama, Department of Dermatology, Okayama University Medical School, Shikata-cho 2-5-1, Okayama 700-0914 Japan
Journal of Dermatological Science (Ireland), 1998, 17/1 (67-74)

We examined the attachment of Staphylococcus aureus to plastic tissue- culture coverslips after incubation for 24 h. The attachment to coverslips was weaker in rabbit plasma with 5% zinc oxide (ZnO) than in the control rabbit plasma without ZnO (P < 0.01). Plasma coagulation by S. aureus strains was not detected in plasma with 5% ZnO after incubation for 24 h. The membranous structure (an immature biofilm) was formed on the coverslips by S. aureus cells in plasma after incubation for 24 h. The colony counts of S. aureus cells on the membranous structures were lower in plasma with 5% ZnO, plasma with 0.2% hinokitiol, plasma with 5% ZnO + 0.2% hinokitiol, plasma with cefdinir at 4 minimum inhibitory concentration (MIC) and plasma with levofloxacin at 4 MIC, than in the control plasma after incubation for 24 h (P < 0.01). The colonies on the membranous structures completely disappeared in the case of plasma with 5% ZnO and 0.2% hinokitiol. The colony counts on membranous structures were lower in plasma with cefdinir at 4 MIC or levofloxacin at 4 MIC containing 5% ZnO than in plasma with cefdinir at 4 MIC or levofloxacin at 4 MIC only, (P < 0.05). The MICs of hinokitiol against S. aureus strains peaked at an MIC distribution of 16-32 microg/ml. The peak shifted to below 1 microg/ml by adding 5% ZnO in agar plate method. The results suggest that the attachment of S. aureus cells to the coverslips is suppressed in the presence of 5% ZnO and that antistaphylococcal activities of cefdinir, levofloxacin and hinokitiol increase in the presence of 5% ZnO.

Small bowel bacterial overgrowth syndrome
Bjorneklett A.
Med. Dep. A, Rikshosp., Oslo Norway
Scand. J. Gastroenterol. Suppl. (Norway), 1983, 18/85 (83-93)

Different aspects of the small bowel bacterial overgrowth syndrome are reviewed. Special emphasis is put on the newly recognized structural and functional abnormalities of the small intestinal mucosa, abnormalities that may not be fully reversed by effective antimicrobic therapy. The pathogenetic mechanisms involved in the malabsorption of different substances are discussed and the available diagnostic tests are briefly presented. The current therapy, surgical, medical and supportive, are outlined. It is pointed out that abnormal overgrowth flora of the small intestine can occur unassociated with malabsorption. Thus, the clinician must assess the potential benefit to be derived from treatment, once the presence of absorptive abnormalities is documented.

Am Surg. 2000 Nov;66(11):1004-10.
Zinc, copper, and metallothionein metabolism after jejunoileal bypass surgery or small bowel resection in rats.

Rodriguez JA, Sandoval M, Udall JN, O'Leary JP, Hempe JM.

Department of Surgery, Louisiana State University School of Medicine, New Orleans, USA.

Liver dysfunction is a frequent complication of jejunoileal bypass (JIB) surgery, a procedure commonly used until recently to treat morbid obesity. It has been suggested that liver failure in JIB patients is due to bacterial overgrowth and translocation from the bypassed intestine. Because invading microorganisms cause hepatic inflammation these experiments evaluated zinc, copper, and metallothionein (MT) in two experimental rat models of intestinal surgery to determine whether their distribution in plasma and tissues was similar to the highly characteristic pattern observed during an inflammatory response. In the JIB rat model 90 per cent of the small intestine was isolated from the flow of digesta but remained viable in the abdominal cavity. In the small bowel resection (SBR) model 90 per cent of the small intestine was removed and the remaining intestine was resected. Data collected 21 days after surgery showed decreased growth rate and plasma zinc in the SBR and JIB rats that was significantly improved by supplemental zinc. All other measures of zinc, copper, and MT metabolism in the SBR rats were similar to those of controls. In JIB rats, however, liver copper, MT protein, and MT mRNA were significantly elevated, and a high proportion of the intracellular zinc and copper was associated with MT. The pattern of zinc, copper, and MT distribution in systemic circulation and liver of JIB rats suggests hepatic inflammation superimposed on low zinc and copper status. Lack of a similar response in the SBR rats confirms the involvement of the bypassed intestinal segment and supports the hypothesis that bacterial overgrowth and translocation are responsible for liver inflammation and dysfunction in JIB patients.


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11090006&dopt=Abstract

Nutrition and immunity with emphasis on infection and autoimmune disease. Harbige LS, Nutr Health, 1996, 10:4, 285-312

(Address: Division of Immunology, United Medical School of Guy's and St. Thomas's Hospital, Rayne Institute, London, UK. 1.harbige@umds.ac.uk)

Abstract: Nutrition and nutritional status can have profound effects on immune functions, resistance to infection and autoimmunity in man and other animals. Nutrients enhance or depress immune function depending on the nutrient and level of its intake. Protein-energy malnutrition and vitamin A deficiency are strongly associated with impaired immunity and infectious disease. The essential role vitamin A plays in infection and maintenance of mucosal surfaces has long been known. Recent evidence shows that T-cell subpopulations, cytokines and antibody subclasses are all affected by vitamin A. In animal studies supplementation with vitamin E protects against infection and is linked to stimulatory effects on the immune system. In man vitamin E and other anti-oxidants increase the number of CD4+ cells. Dietary lipids and zinc have a substantial impact on autoimmunity from protective to potentiation of immuno-pathological processes in animals. There is considerable potential to modify human autoimmune disease by manipulation of lipid nutrition. Deficiency of pyridoxine induces atrophy of lymphoid organs, marked reduction in lymphocyte numbers, impairs antibody responses and IL-2 production. Dietary copper is important in the prevention of infection in some animal species and T-cell function is defective under deficiency states due to an inability to produce IL-2. Selenium has been linked to viral infection, enhanced T-cell functions and TNF beta induced increase in natural killer cell activity. Understanding the molecular and cellular immunological mechanisms involved in nutrient-immune interactions will increase our applications for nutrition of the immune system in health and in disease

High amount of zinc such as 270 µg/kg/day has been reported to be lost through stool during persistent diarrhoea in Bangladeshi children 7. In Bangladesh the overall diarrhoeal incidence rate is 3-4 episodes per child per year 8 and about 9% of the acute diarrhoeal episodes become persistent in this country 9. A significant proportion of children who suffer from diarrhoea are malnourished which may further contribute to increased severity and duration of diarrhoea in such children. Studies conducted in Bangladesh have shown that supplementation of 20 mg elemental zinc/day for two weeks during acute 10 and persistent 11 diarrhoea reduced diarrhoeal duration (14%, P=NS and 33%, P<0.03 respectively) and stool out put in malnourished children. Zinc supplementation significantly reduced diarrhoeal duration (22%, P<0.04) and median stool weight (279 vs. 326 g/kg, P<0.04) in children with a lower serum zinc (<14 µmol/l) with acute diarrhoea 10 . Zinc supplemented children with acute diarrhoea gained weight (P=0.03)10 and children with persistent diarrhoea maintained their body weight and serum zinc level whereas there was a reduction in both body weight (P<0.05) and serum zinc level (P<0.03) in the un-supplemented group during hospitalization11. Studies from India showed that supplementation of 40 mg elemental zinc/kg/day resulted in significantly shorter duration of diarrhoea (P<0.0001), zinc supplemented children passed less liquid stool (P<0.0001), consumed less ORS (P<0.0001) and other liquids (P<0.0001) compared to the placebo group 12. Roy et al. have found that supplementation of 30 mg elemental zinc/day for 7 days in children with cholera, significantly reduced duration of recovery (14%, P=0.03) and stool out put (26%, P=0.03) and body weight of zinc supplemented children increased (P=0.05) significantly than the control group 13.

Studies have also shown that zinc supplementation has residual benefits beyond the acute stage of diarrhoea. Zinc supplemented malnourished Bangladeshi children (W/A <70% of NCHS standard) with acute 14 and persistent 15 diarrhoea had 30% (P<0.05) and 24% (P<0.03) greater length gain during 8 weeks and 3 months of follow up respectively after diarrhoea. Zinc supplemented children with persistent diarrhoea also experienced fewer diarrhoeal attack (P<0.05) 15. Studies in Bangladesh and elsewhere have shown that zinc supplementation reduced the incidence of diarrhoea and acute lower respiratory tract infection 16. Hospitalization of children with diarrhoea was also lower in the zinc supplementation group 16. The non-injury death rate was 51% lower in the zinc supplementation group 16. Death in children with persistent diarrhoea was one fifth in zinc group compared to controls 15. A randomized trial from India found a large reduction in overall mortality in infants who were small for gestational age and supplemented with zinc from 1 to 3 years of age 17.

Results of studies suggest that zinc supplementation may provide significant clinical, nutritional and immunological benefits to children during and after the episodes of acute and persistent diarrhoea and cholera. The mechanism through which zinc may influence diarrhoeal episodes or intestinal function include improved electrolyte transport 18, early epithelial regeneration 2,19, rapid synthesis of digestive enzymes 20,21, improving intestinal permeability 22, reduction in osmotic diarrhoea and improvement in immunity 23 limiting bacterial overgrowth and early clearance of intestinal pathogens. Moreover zinc used as a treatment for diarrhoea reduces mortality in children. The impact of zinc on mortality and morbidity can be achieved in a realistic large-scale public health program. Strategies for the alleviation of zinc deficiency include dietary diversification or modification, supplementation, along with general health program to reduce infections that contribute to poor absorption or excess loss of zinc.

References
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2.   Hambridge KM, Hambidge C, Jacobes M, Baunm DJ. Low levels of zinc in hair, anorexia, poor growth and hypogeusia in       children.Pediatr Res 1972; 6: 868-74.
3.  Roy SK,Tomkins AM.Impact of experimental zinc deficiency on growth, morbidity and ultrastructural development of       intestinal tissue.Bangladesh J Nutr 1989; 2: 1.
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5.    Nelder CH, Hambidge CM. Zinc therapy of acrodermatitis enteropathica. New Engl J Med 1975; 292: 879-82.
6.    Braun OH, Heilman K, Rossner JA, Pauli W, Bertgamn KE. Acrodermatitis enteropathica II: zinc deficiency and       ultrastructural findings. Eur J Pediatr 1977; 125: 123-62.
7.   Roy SK, Tait SF, Tomkins AM, Ducros V, Islam KE. Zinc balance and bioavailability from two different dietary regimes for       children with persistent diarrhoea syndrome in Bangladesh using stable isotopes. 2002 (unpublished).
8.   Baqui AH, Black RE, Sack RB, Yunus MD, Siddique AK, Chowdhury HR. Epidemiological and clinical characteristics of       acute and persistent diarrhoea in rural Bangladesh. Acta Paediatr Suppl 1992; 381: 15-21.
9.   Baqui AH. Epidemiology of persistent diarrhoea in Bangladeshi children. PhD thesis. School of Hygiene and Public Health.       Johns Hopkins University, 1990.
10.  Roy AK, Tomkins AM, Akramuzzaman SM, Behrens RH, Haider R, Mahalnabis D, Fuchs G. Randomized controlled trial of       zinc supplementation in malnourished Bangladeshi children with acute diarrhoea. Archives of disease in childhood 1997;
      77(3): 196-200.
11.  Roy SK,Tomkins AM, Mahalnabis D, Akramuzzaman SM, Haider R, Behrens RH, Fuchs G. Impact of zinc        supplementation  on persistent diarrhoea in malnourished Bangladeshi children. Acta Padiatr 1998; 87:1235-9.
12. Dutta P, Mitra U, Datta A, Niyogi SK, Dutta S, Manna B, Basak M, Mahapatra TS, Bhattacharya SK. Impact of zinc        supplementation in malnourished children with acute watery diarrhoea. Journal of Tropical Pediatrics 2000; 46: 259-63.
13.  Roy S. K, Tomkins AM, Islam KE. Clinical trial of zinc supplementation in cholera patients. 2002 (Unpublished).
14. Roy AK, Tomkins AM, Haider R, Behrens RH, Akramuzzaman SM, Mahalnabis D, Fuchs GJ. Impact of zinc        supplementation on subsequent growth and morbidity in Bangladeshi children with acute diarrhoea. 1999; 53: 529-34.
15.  Roy SK, Tomkins AM, Akramizzaman SM, Islam KE. Impact of zinc supplementation on subsequent morbidity and growth        in Bangladeshi children with persistent diarrhoea. 2002. JHPN (in press).
16.  Baqui AH, Black RE, Arifeen SE, Yunus M, Chakraborty J, Ahmed S, Vaughan P. Effect of zinc supplementation started        during diarrhoea on morbidity and mortality in Bangladeshi children: community randomized trial. BMJ 2002; 325:1059.
17.  Sazawal S, Black RE, Menon VP, Dinghra P, Caulfield LE, Dhingra U et al. Zinc supplementation in infants born small for        gestational age reduces mortality: a prospective randomized controlled trial. Pediatrics 2001; 108: 1280-6.
18.  Marson JR, Lewis JC. The effect of severe zinc deficiency on intestinal permeability: an ultra-structural study. Pediatr Res        1985; 19:968-73.
19.  Hambridge KM, Casey CE, Krebs NF. Zinc In: Mertz W (ed.), Trace Elements in Human and Animal Nutrition, 5th edn.        Academic press, Florida, 1986;2:1-137.
20.  Bettger WJ, O'Dell BL. A critical physiological role of zinc in the structure and function of biomembrane. Life Sci 1981;        28:1425-38.
21.  Park JHY, Grandjean CJ, Antoston DL, Vanderhoof JA. Effects of short tern isolated zinc deficiency on intestinal growth        and activities of brush border enzymes in weaning rates. Pediatr Res 1985; 12:1333-36.
22. Roy SK, Behrens RH, Tomkins AM, Haider R, Wahed MA, Aktaruzzaman SM, Mhalanabis D. Impact of zinc        supplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistent diarrhoea
       syndrome. J Pediatr Gastroenterol 1992; 15:289-96.
23.  Zarling EJ, Morbaham S, Donahuc PE. Does zinc deficiency affect intestinal protein content or diasaccharide activity? L        Lab Clin Med 1985; 106: 708-11.

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