SYNTHESIS CHARACTERIZATION AND BIOLOGICAL STUDIES OF DOMPERIDONE AND ITS COMPLEXES WITH SOME TRANSITION METAL IONS

Title of Thesis:

SYNTHESIS CHARACTERIZATION AND BIOLOGICAL STUDIES OF DOMPERIDONE AND ITS COMPLEXES WITH SOME TRANSITION METAL IONS

ABSTRACT

The complexes of Cu(II), Co(II), Ni(II), Fe(II) and Ag(I) have been synthesized with domperidone. The structural features of complexes have been determined by elemental analysis, conductance measurement, UV/VIS and infrared spectroscopy. IR studies revealed that the domperidone coordinate with metal ions through nitrogen and oxygen(C =O). The complexes of Cu(II), Fe(II), and Ni(II) were assigned square planar geometry while Co(II) and Ag(II) were assigned octahedral geometry. High value of conductance of Cu(II), Fe(II), and Ni(II) supports their electrolytic nature and low value of conductance of Co(II) and Ag(II) supports their non – electrolytic nature. The ligand and complexes were checked for their antibacterial activity against three bacterial strains Escherichia coli, Staphylococcus aruseus, Pseudomonas aeurogionaby. Disc diffusion method was adopted for antibacterial activity. The antibacterial activities of the metal complexes were found to be more as compared to parent drug.

Introduction

COORDINATION COMPOUNDS OR METAL COMPLEXES

                                The compounds in which a small number of molecule or ions called ligand surround a central metal atom or ion. Each ligand shares a pair of its electrons with the metal. The metal-ligand bond often represented as M ←: L is an example of a coordinate covalent bond in which both the electrons come from one atom [1a].

HISTORY

                   One of the earliest recorded co–ordination compound is Prussian blue       KCNFe(CN)₂ Fe (CN)₃ an artist color, made by accident when animal wastes and sodium carbonate were strongly heated in an organic container.

                                         Other long known compounds are potassium ferrocyanide (1753) K₂PtCl₆ (1760 – 1765), [Co (NH₃)₆] Cl₃ (1798). The first era of rapid activity in this field began in 1798 when Tassaert isolated orange crystals of CoCl₃.6NH₃ by allowing a mixture of CoCl₂ and aqueous ammonia to stand in air. He puzzled over the fact that two stable compounds would combine to form a new product with properties entirely different from the compounds it obtained. It was Alfred Werner who gave the theory of “primary and secondary valencies”. He suggested that primary valencies are those used in attaching the coordinating groups (e.g. ammonia molecules). Further he showed that the factor that determining the chemical behaviour of co-ordination compounds was not the “primary” valencies but number of “secondary” valencies.

TYPES OF COMPLEXES

                There are three types of complexes ^[2] :

·         Neutral complexes

·         Cationic complexes

·         Anionic complexes

(i) Neutral complexes:

                      Those complexes in which there is no positive or negative charge on square bracket are called “neutral complexes”.

e.g. [Ni (CO)₄], [Ni (NH₃)₂(CN)₂]

  

(ii) Cationic Complexes:

                   Those complexes in which there is positive charge overall on square bracket is called “cationic complexes”.

e.g. [Ag (NH₃)₂]⁺, [Ni (H₂O)₆]⁺², [Fe (NH₃)₆]⁺³                           

(iii) Anionic Complexes:

                    Those complexes in which there is negative charge overall on square bracket is called “anionic complexes”.

e.g. [Ni (CN)₄]^-2, [PtCl₄]^-2, [Fe (CO)₄]^-2

Ligand

           An atom or group of atoms which can donate a pair of electrons to central metal atom or ion is called ligand.

Types of ligands:

                There are three types of ligands. i.e:

v  Neutral ligands

v  Cationic ligand

v  Anionic ligand

(i) Neutral ligands:

                 That ligand which does not contain any charge is called “neutral ligand”. e.g. NH₃, H₂O, CO, NO.

(ii) Cationic ligands:

                 Those ligands which contain positive charge are called “cationic ligands”.   e.g. NO⁺, NH₂N⁺H₃(hydrazinium).

(iii) Anionic ligands:

                 Those ligands which contain negative charge are called “anionic ligand”.

Coordination sphere:

                 The region or space around central metal atom or ion in a complex in which ligands are located is called coordination sphere. Coordination sphere is denoted by

square bracket “[]”.

  

Coordination Number:

 The number of bond made by ligand to the central metal atom or ion in the complex is the coordination number. The coordination number of d-block elements is 2-12 and for f-block elements 2-14 and most common coordination numbers are 2, 4 and 6.

Formation of Metal Complex:

               The formation of a complex ion may be considered to be an example of Lewis acid-base reaction. Ligand is a Lewis base (electron pair donor) and metal ion is a Lewis acid (electron pair acceptor). For example, in the reaction between cupric ion (Cu²⁺) and ammonia molecule; the Cu²⁺ act as a Lewis acid and each NH₃ molecule act as a Lewis base and contribute both of its lone- pair electrons to the formation of a coordinate covalent bond which bonds the Nitrogen to the Cu²⁺ ion. The resulting [Cu (NH₃)₄]²⁺  complex (a deep blue colour solution), therefore, described as consist of four ammonia molecules in coordination to central Cu²⁺ ion and thus the coordination number of Cu²⁺in this complex is 4.^[3]

STABILITY OF METAL COMPLEXES:

                    Stability of metal complexes depends on the following factors;

(i)   Nature of metal

(ii)  Nature of ligand

(iii) Geometry of complex

                         These are discussed below.

(i) Nature of metal:

The central atom or ion form complexes of different stabilities with various ligands which further depend on charge, size, element configuration and polarizability of metal.

               The most stable complexes made up of oppositely charged ions and more over, that the greater the charge on the ion and smaller the size of the ions, greater should be the stability. Small ions are favoured because their centers can be closer together.

(ii) Nature of ligand:

              The ligand may also affect the stability of complex. The nature of ligand depend upon,

1. charge and size
2. base strength
3. crystal field splitting
4. chelate effect
5. steric effect.

(iii) Geometry of complexes

              Structure of complexes may also affect the stability of complex. Five membered ring with all single bonds are more stable than six membered rings, however six membered ring with alternate single and double bonds are more stable.[4]

(iv) Chelate Complexes:

                   Many ligands can bond simultaneously through more than one donor atoms and are called polydentate ligands. When polydentate ligands are attached to central metal atom or ion is called chelate complex or chelate. This process is called chelation.[5]

Effect of Chelation on Stability of Complexes:

                  The stability of metal complex is greater than that of analogous known metal complex, it means that the formation of chelate, gives extra stability to the complex, for example,

                             [Ni (NH₃)₆]⁺²< [Ni (en)_3]⁺² < [Ni (EDTA)]^-2

 The more extensive is the chelation, more stable is the complex.

                            

                   The chelate effect depends upon the entropy effect. The chelate effect also depends upon the enthalpy. Both entropy and enthalpy effect reinforce each other in stability of a complex. 

CLASSIFICATION OF POLYDENTATE LIGANDS

         Poly or multidentate ligands are classified as

Monodentate ligand:

  Ligands which can donate one electron pair. E.g.

                          CH₃-NH₂

                                    methyl amine

Bidentate ligand:

     Which donate two electron pairs to the central metal atom or ion. E.g.

                   NH_2-CH₂-CH₂-NH₂

                               ethylene diamine

Tridentate ligand:

       Ligand which can donate three electron pairs to the central metal atom or ion.

e.g.

                  H₂N_-CH₂-CH₂-NH-CH2-CH₂-NH₂  

                             diethylene triamine

Quadridentates ligand:

        Ligands which can donate four electron pairs to the central atom or ion.

 E.g  NH_2-CH₂-CH₂-NH-CH₂-CH₂-NH-CH₂-CH₂-NH₂

                     Triethylene tetramine

Quin quadric dentate ligand:

        Ligands which can donate five electron pairs to the central metal atom or ion.

e.g.                                         

       NH_2-CH₂-CH₂-NH-CH₂-CH₂-NH-CH₂-CH₂-NH-CH₂-CH₂-NH₂

                                 Tetraethylene pentamine

Hexa dentate ligand:

          Ligand which can donate six electron pairs to the central metal atom or ion.e.g.

                                   HOOCCH₂                                                                                       CH₂COOH

                                                                   ..                      ..

                                                                  NH-CH₂-CH₂-NH 

                                   HOOCCH₂                                                                                         CH₂COOH

         

                                                Ethylene diamine tetracetic acid (EDTA)                                 

USES OF COORDINATION COMPOUNDS

               A brief survey of some of the uses of coordination compounds includes [6].

1. Dyes and Pigments:

             Coordination compounds have been used from earliest times as dyes and pigments, for example madder dye which is red, was used by the ancient Greeks and others. It is a complex of Hydroxyanthraquinone. A more modern example is the pigment copper phtalocyanine, which is blue.

2. Analytical Chemistry:

              In analytical chemistry it is used for;  

a)      Colour Tests: Since many complexes are highly coloured they can be used as calorimetric reagents e.g. formation of red 2, 2-bipyridyl and 1, 10-phenanthroline complexes as a test for Fe²⁺ .

b)      Gravimetric Analysis:gravimetric methods are those that involve the production, isolation and weighing of a solid to determine the amount of a material in a sample. Perhaps the example of this method most often cited, although not complexometric, is the precipitation of AgCl (s) in the determination of the percentage of silver and/or chloride in a substance. One of the most common complexometric gravimetric procedures involves the use of a bidentate chelating agent, dimethylglyoximate (dmgH-), to determine nickel. e.g. Ni (DMG)₂            

                                                   Another common gravimetric procedure involves the    

      determination of aluminium with a chelating agent known as 8-hydroxyquinoline

       (Sometimes called 8- quinolinol or oxime). E.g. Al (oxime)₃ [1b] 

c)      Complexometric Titration and Masking Agents: An example of this is the use of EDTA in the volumetric determination of a wide variety of metal ions in solution, e.g. Zn²⁺, Pb²⁺, Ca²⁺, Co²⁺, Ni²⁺, Cu²⁺, etc. by careful adjustment of pH and using suitable indicators, mixtures of metals can be analyzed, e.g. Bi³⁺ in the presence of  Pb²⁺(see laboratory manual). Alternatively, EDTA may be used as masking agent to remove a metal ion which would interfere with the analysis of a second metal ion present.

3. Sequestering Agents:

                 Related to their use as masking agents is the use of ligands for “sequestering” i.e. for the effective removal of objectionable ions from solution in industrial processing, e.g. EDTA is used to “soften” water. The addition of EDTA to water is used in boilers etc. to prevent “scaling” or build up of insoluble calcium salts.

4. Extraction of Metals:

                  Some times certain metals can be leached from their ores by formation of stable complexes e.g. Ag and Au as complexes of cyanide ion.

5. Bio – Inorganic Chemistry:

                   Naturally occurring complexes include haemoglobin, chlorophyll, and vitamin B₁₂.

1. Therapeutic Chelating Agents for Heavy Metals

                    EDTA and other complexing agents have been used for the elimination of harmful radioactive and other toxic elements from the body. (e.g. Pb²⁺). In these cases a soluble metal chelate is formed.

        b.Chemo-therapy

                       An example of this is the use of cis-platin (cis-Pt (NH₃)₂Cl₂) as an    anti-tumor drug.

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Introduction

Literature Review

Experimental Work

Results and Discussion

References

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Comparative study of concentration of trace metal ions [Cu(II), Zn(II), Se(II), Cd(II)] in human blood serum of healthy individuals and hypothyroid patients

Abstract

Thyroid hormone is essential for regulation and proper functioning of many body processes. Trace metals play major role in proper thyroid hormone metabolism and synthesis. Thyroid stimulating hormone (TSH), Triiodithyroxine (T₃) and Thyroxine (T₄) hormone maintain thyroid function, too little amount of T₃and T₄ leads to hypothyroidism.   Present study; inorder to explore the effect of trace element on hypothyroidpatients; included two groups, Group-I (Control Group) composed of 27 healthy subjects while Group-II (hypothyroid patients) consisting of 29clinically and biochemically proved hypothyroidpatients. A blood samples of 5 mL was collected, serum separated and stored at -20^oC. The level of trace elements Cu(II), Zn(II), Se(II) and Cd(II) were investigated in serum with help of inductively coupled plasma spectroscopy (ICP), while T₃ and T₄ levels were measured using radioimmunoassay (RIA) and TSH levels were determined using Immunoradiometric Assay (IRMA). Paired t-test was applied to compare the trace element levels of both groups and results of the statistical analysis revealed that Cu(II), Zn(II), and Se(II) status is significantly lower (p<0.05) in hypothyroid patients (Group-II) when compared with those of healthy individuals (Group-I) while Cd(II) level was considerably higher ( p < 0.05) in hypothyroidism patients.

INTRODUCTION

In the animal iodine is a scarce element however this is necessary part of the thyroid hormones, thyroxin T₄ and T₃. In all vertebrates, a constant supply of these iodothyronine is necessary for brain development and body growth, and to keep the level of intermediary metabolism of functional activity of most organs normal. The scarcity and the irregularity of iodine supply and the required constancy of plasma level of thyroid hormones required the existence of an adequate thyroidal system to trap and store iodine and to synthesize the hormones. Each of the characteristics of this system is necessary, as the alteration of any one, leads to thyroid deficiency. When thyroid is intact, the system is efficient as shown by the euthyroidism of people living in endemic areas where iodine intake is much lower than normal.

The synthesis of thyroid hormones T₄, T₃ proceeds in three steps, trapping of iodine, synthesis of protein, to be iodinated and the iodination of these proteins with oxidative coupling of iodothyrosine in to iodothyronine. Secretion involves at least two steps the endocytosis  of colloid  protein and their digestion with the release of thyroid hormones. Until very recently, it was accepted that the activity and growth of thyroid tissues were controlled by one factor. The TSH plasma level, and TSH main regulatory agent is

Secreted discontinuously by hypohysis TSH stimulates all facts of thyroid metabolism on the basis of kinetics, two types of facts can be distinguished rapid effects which correspond to a functional activities e.g activation and secretion iodide binding to protein, iodothyronine formation[1].

Thyroid gland plays important role in regulating human health and various body functions. For proper functioning of thyroid hormone, Iodine is essential element. It has been studied the biochemistry, structure and function of thyroid gland its metabolism controlled for both normal and abnormal conditions. Thyroid hormone and its function, metabolism is complicated process.

Thyroid hormone function and activity depends upon enzymes and protein along with the amount of trace elements, with effective appropriate levels and properties.

Iodine and Selenium elements are essential for thyroid hormone function and metabolism levels, Iron, Zinc, copper, status in diet plays effective role on thyroid metabolism. It’s all about role of trace elements for normal thyroid hormone. Iodine is very important rare element which is a crucial element for proper thyroid functioning. The daily iodine intake is 150-200µg. Its deficiency leads to the serious clinical health problems were hypothyroidism and goiter. Nodular goiter and autoimmune thyroid disease are found in those areas where the Iodine intake was not according to requirements and along these Hashimoto‘s thyroid cause hypothyroidism. Thyroid can be dysfunction due to excessive use of iodine in food.

Excess use of Iodine intake through bread, in salt and iodine supplements used as the persevering agents. It has been resulted as higher level of iodine in some countries like US, Great Britain and Scandinavia. In some areas, the iodine intake was four times more than the normal level, which has given the proof and strong emphasis on the thyroid malfunction or abnormality in proper function and metabolism.

All above mention results iodine is crucial for maintain thyroid hormone synthesis and function .but thyroid hormone synthesis was briefly described.

Nodular goiter and autoimmune thyroid disease are in those locations where iodine supplement are not in proper level. Hashimoto s thyroiditis results in hypothyroidism due to insufficient iodine supplements in these areas.

When thyroid gland’s activity is higher than normal level or behave as abnormal functioning, so Grave’s disease, solitary nodular goiter, multi nodular goiter and autoimmune thyrioditis are present in many patients.   

Potassium iodide incorporated with propanol, had given as a drug to the patients clinically.  It acts as anti-thyroid drug. Actually prior to treatment of patients (Grave’s disease) with anti-thyroid drugs along this higher doses of iodine was given to   them.

There was a proof that higher iodine status especially in animals has been major enhancing agent of autoimmune thyroid disease. It was unclear how iodine produced such effects. It was not known the effect of iodine, but Iodine rich thyro globulin was produced by iodine it act as immunogenic, specially enhanced the immunity. Some, but not all, in humans many studies shown that serum contain anti microsomal antibodies, which was present in those people in area of proper iodine intake as compared to iodine deficient areas.

There were 1 billion people belong to different areas of world they have lowered iodine intake in food supplements than normal level. They are in danger of having low iodine level, the iodine deficiency leads towards major risk of health problems. In many areas round about 211 million have goiter and about 20 million have malfunctioning of brain and brain related problems.

Iodine deficiency leads to serious health problems during new born(javelins period) at early ages specially in infant during their development stages, its period when rapid development was in process the serious retardation physically and mental was found in children due to abnormal behavior of thyroid hormone.

Iodine deficiency leads to less effective hypothyroidism to more serious physical and mental retardation of body and brain disease it may genetic disorder or specially found in certain areas due to iodine deficiency. It divides in two categories, Cretinism (physical and mental retardation) myxoedematous cretinism (the disease of skin in which skin become dry nose and lips got swelled) due to thyroid hormone dysfunction. It caused serious diseases, i.e. hypothyroidism. It hinders proper growth rate and human health was seriously affected but presence of goiter is very much lower in level than in non cretins (physical and mental retardation) due to Iodine deficiency the chance of goiter was less in them. Most of time thyroid hormone was not fully functioned.  However plasma thyroid (T₄) and 3,3,5 tri iodothyronine (T₃)  status is lower and TSH level is higher. Thyroid hormone was ruined in these cases and it effect from embryo to fetus formation and leads till to birth

Selenium is very important element for proper metabolism and activity of thyroid than any other tissues or organs like liver, kidney. It is clear that Se function within gland specifically. In 1987, it was considered that Se play essential role in proper functioning and metabolism of tissues other than thyroid Se work, which is specific for thyroid properties. Selenium is only an important constitute of selenoprotein which is crucial for maintain the function of thyroid hormone synthesis.

Role of thyroid during oxidative stress and regulate thyroid function during many process of body function. It is also regulate the proper activity of non-thyroidal tissues where the chemical agents secreted T₄, which was changed to biologically functional T₃, rT₃; here its rT₃is same in function as T₃ do.

Through the research, it was observed that selenium concentration effect on T₄and T₃ status. It was observed in rats and in cattles, their blood plasma has low concentration of T₄. These rats and cattle have selenium deficiency. The appropriate change has been observed when decrease in hepatic and renal typeI iodothyronine de-iodinase (IDI) activity these used to convert T₄ to T₃. It has been cleared from investigation that IDI (Iodothyronine de- iodinasa) act as selenoenzyme cloning and partial purification. IDI was coded for TGA, which is stop codon; Se was present in selenocysteine, which was present in IDI.

In thyroid hormone metabolism T₃, T₄, rT₃ are very important and Se also present in it used for maintain two more deiodinase  type II  (IDI I) and type III (IDI II) .IDI I effect differently on many organs and their function as compared to IDI. These tissues are mainly brain, central nervous system, brown adipose tissue and pituitary (master gland). T₄produced T₃ by de iodination it must be catalyzed and facilitated by IDI I. T₃ mainly enhanced and regulated the proper activity and metabolism of many organs at tissue level, only thyroid hormone metabolism, synthesis and function mainly regulate the tissue level and organ system. For proper activity of organ system and tissues required selenium and selenoenzymes, if Se become deficient in body there is proper systemic procedure should be required for Se supply at tissue level.

According to the researchers, it was observed IDI increase in Se deficient rats, then Se, selenoenzyme level was decreased at liver, kidney, muscles were affected. Whereas brain, endocrine, thyroid gland was less affected.

Proper activity and maintain of thyroid gland, Zinc plays a vital role. Zinc metal handles the production and metabolism of thyroid hormone. During gene formation and DNA, synthesis thyroid hormone help in binding transcription factor, in this process gene modification Zn plays important role in binding nitrogenous base cysteine.

Moreover there is ambiguity about Zinc intake through food may altered the thyroid hormone metabolism. Through researches, it has been clear that zinc act, as the essential constituent of gene expression and Zn is chelator, in transcription factor DNA. The Zn containing proteins thyroglobulin and thyroperoxidase genes, thyroid hormone regulate the transcription factor 2 which regulate this gene promotion. Along the lower Zinc level can affect on hepatic IDI function, it may increase or decrease its level. By different investigations researchers leads to clarify the unusual behavior of lower Zinc level. Which was due to lower intake of zinc in food supplements, different results were  examined form animals in role of zinc in thyroid hormone  activity. Lower zinc status lowers the T₃ level in plasma but in many other researches, no clear evidence was proved. It would decrease the plasma T₃ status and hepatic IDI function. Insignificant lower zinc level shows that no effect on iodine deficiency in rats. Although many other researcher shown Selenium, iodine, Zinc were less in concentration.

There was correlation among zinc and selenium level. It influenced on thyroid follicles cell, these may contributed to synthesis and planning. It was compared with apoptosis, zinc level influenced on thyroid metabolism in humans. Lower serum Zn status clinically examined in patients with Down’ s syndrome along with diarrhea, which was appeared as no proper Zinc intake. In these patients, plasma TSH level was higher from autoantibodies to thyroglobulin.

In patients with having Down’s syndromes treated with Zinc doses their plasma TSH level was lower to normal it effect on T₃ activity it was increased to normal. However, in other researches lower Zn level leads to lower thyroid hormone metabolism and its status.     

[2-14].

However out of total 102 elements, thirty-seven were examined in human body. In these 37 elements, twenty-six, are metals found in trace level. In most of these their concentration is too small even difficult to detect.

These trace elements were detected by other precise methods, because of its too small amount. Moreover, these metals were detected in human body especially in body fluids like blood. Through the study of blood, serum and plasma investigated and different metals with different concentrations were observed.

These metallic trace metals plays vital role in many body functions, metabolism, and synthesis regulating processes enzymatic reaction hormonal changes. Form studies it was clear that metallic trace elements have proper function for specific reaction. It is evident that these metals were not as contaminants of environment. A deficiency of these metals leads to serious drawback in reaction for proper thyroid function.

Many biological important trace metals regulate much function and their activity is widespread. During enzymatic reaction metaloenzymes, specific metal combined with protein molecules and its amount or number of metal ion is fixed for each protein molecules when foreign molecules incorporated with metal ion it inhibits its function of enzyme and vice versa. Metal protein complexes in which metal ion combined with protein molecules of large units and these metals join to one another according to their approach, it was also be removed. Many metals have property to combine with protein and others only important for movement. The relation of metals protein was concerned with (chelation) from investigation, it was clear that analysis performed on blood of men and women according to the data. [15-27]

Many publications shows the effect of trace metals on blood and cause serious problem in humans also many metals found combined form and complexes or stay freely in blood fluids. Their values and level was calculated in humans. Different metals found in blood with different concentration in combined or exists metal-ligand relation. These bonds formed between metals and ligands and irreversible reaction takes place. If any changed occurs in nature and concentration of these metals found in blood, it leads to serious changed the world of biochemical reaction in humans along these clinical and subclinical problems appeared. The metabolic rate, activity of organs negatively affected. The level of metals in blood plasma, and blood cells essential clinically, and have certain values. [18- 28]

Soon after the discovery of iodine, a Swedish chemistry Berzelius discovery the selane named after the goodes of moon, which is Greek word. Schwarz and Foltz, in 1957, discovered selenium as trace element and its functions in mammals were also studied. At early ages, it was believed that only iodine is essential component of thyroid function. Soon after the discovery of selenium, its effect on thyroid system was, clearly observed by scientists.

During 1920, iodine was used to cure thyroid diseases. Iodine deficiency create many thyroid system was seriously affected by iodine deficiency. In 1920, iodine used to cure thyroid disease, iodine play major role to prevent thyroid disease. World Health Organization (WHO) worked hardly to prevent thyroid illness due to iodine deficiency. Removal of iodine deficiency was major task, for WHO by year 2000, to now, which was, not fully achieved in now a days.

Selenium plays a crucial role and was appeared as essential element for proper functioning and production of thyroid hormone. Now here is question that if we use iodine for prevention of disease then there should be needed the great use of selenium, which can be intake through food selenium used to regulate and functionalized the normal thyroid hormone metabolism. At early ages in 1943, it was thought that selenium act as the cancer-causing agent.

In 1930, selenium was considered as the highly toxic and after that during 1943; it appeared as the cancer causing. After experiments and researches on animals, it has concluded that Se (II) has toxic effect along this it is also vital trace element. However, it was reported on the compound having selenium, these compounds behave as the anti cancer causing during 1966. A lot of research work had done, on the Selenium compounds. Their most important effects for disease treatment and as medicine was studied extensively.

In 1973, two groups conducted their experiments and finalize that Se is important component of enzyme glutathione peroxidase. Up to 1990 s it is considered as recognized enzymatic activity in mammalian selenoprotein. It was clear from investigations that these two selenocysteine and selenomethionine found as the essential amino acid in selenoprotein.

Selenium with higher concentration at tissue level of thyroid hormone has been found in human adults and kids. The Se level is higher in thyroid tissues than kidney where Seleno- complex selenium formed the metal complexes with (Cd, Hg), it is insoluble not in dissolved form these complexes released during life.

However, it was not clear that what is composition and chemical nature of selenium as protein type exist in thyroid gland. Moreover series of experiments were performed to determined this phenomena, neutron activation analysis applied to determine Se content and along selenoprotein IDI and GPX. The function of Selenium and seleno enzyme in parathyroid adenoma and cell – carcinoma is very low. When they are compared with other thyroid disorder like thyroid cancer goiter or autoimmune thyroid tissue hypothyroidism and hyperthyroidism.

Different behavior of Se status in human thyroid cancer tissues were not explained , it is not determined. The analysis and results of data showed that Se is basically, located in follicular or thyrocyte compartment. It holds solid causes because it exist in nature that thyroid follicles’ synthesis of H₂O₂continuously in whole life. However thyrocytes need a very important anti oxidative defense system against H₂O₂.[29-40]

Hypothyroidism and ophthalmopathy are the two important factor of grave s disease. These two-condition hyperthyroidism and opthamolpathy have same temporal relation but opthalmopthy only occur when the present already opthalmopathy is condition to hyperthyroidism. The pathological mechanisms of these two conditions are unknown and the reason of grave opthalmopthy was not known.

The drug used for treatment of disease is thyroidectomy or Iodine- 131. This specific anti thyroid drug for the cure of hyperthyroidism which is caused by Grave’s disease. The age and Size of thyroid gland of patients suffering from hyperthyroidism indicates the choice of anti thyroid drug [41-46].

Many body functions and different reaction in organs can be control by thyroid hormone when it is normal and in properly working condition. It regulates the development, growth alongwith many physical and normal processes. The most important features of  thyroid hormone is to regulate the secretion of TSH (thyroid stimulating hormone) triiodothyronine (T₃) and thyroxin (T₄).

T₃and T₄ also present in Free State as FT₃ and FT₄these can be enter in cell but their amount is very less. Moreover, it can found less then < 1 % of the total. There is opposite effect of T₃and T₄ exist with thyroid hormone. The negative effect in return from T₃ , T₄ to TSH was observed. In this negative feedback  T₃, T₄ to TSH, so the level is maintain for normal body functioning TSH regulate the synthesis of  T₃ and T₄, when concentration  of  T₃ higher then TSH decreased the opposite effect is at low level of T₃ and T₄ regulate production of TSH.

Disorder in thyroid function was observed by changing the T₃ and T₄level during the synthesis, at any point their feedback is changed the system is disturbed and negative effect subclinical. This type of thyroid disorder has observed among people clinically. According to research work, a study indicates that 4.6% of the U S population suffered in hypothyroidism and 1.3% included in hyperthyroidism.

Major drawback of thyroid disorder is due to the chemicals accumulation and environmental disruption.

After much investigation, it has proved that there is relationship between thyroid disorder and chemical substance like polychlorinated biphenyl, phthalates per fluorinated compounds and metals. Metals effect seriously on thyroid metabolism. It has examined in both animal and human being. The Cd, Hg, Co and U may show adverse effect of thyroid.

The research on animals has elaborated the relation with lead but the association is less consistent in epidermiologic studies. There was no any evidence found in relation with metal effects on thyroid. Only few studies showed the effect of these metals on thyroid activity. Anyhow, it leads further investigation on metal thyroid relation. These effects can be studies in those people having greater exposure to metals working in those conditions where metals exposure is higher as compare to normal population. It is now necessary to analyze metals thyroid function association due to presence on higher metal concentration in environment.

The most of people influenced by metals through breathing, it studied that during smoking cadmium accumulate in their body through cigarette smoke, cadmium is heavy metal and show adverse effect on thyroid. Lead accumulates through automobile and industries, alike these Mercury in take through food supplements like seafood and dental amalgams.

National health and Nutrition examination survey (NHANES) examined the metals concentration in urine samples and associate adversely with metal ion.

Thallium metal can reduced the abnormal behavior of thyroid hormone. The abnormal behavior of thyroid hormone has increased by higher concentration of metals i. e cadmium, cobalt, lead and tungsten.

One of the important drawbacks of the study is that, the obtained results met the both problem of thyroid disorder hyperthyroidism and hypothyroidism, which depicts the abnormal behavior of more than one thyroid hormone. 

Subclinical hypothyroidism (SH) is defined as the phenomena achieved when values of FT₄and FT₃ were normal range or within the limits of standard values which are finalized the ranges. The normal values must be lies within these ranges.  According to investigation of Subclinical Hypothyroidism SH with noticeable clinical symptoms in adults is 4% and 10%. The appearance of hypothyroidism was due to chronic lymphocytic thyroiditis, when thyroid hormone synthesis has affected and production become less negatively than results achieved as autoimmune disorder, this disease causes serious unusual hypothyroidism.

According to researches, it was not clear that patients of these diseases are due to presence of trace element deficiency and it was also not clear the result of thyroid hormone and alternative treatment on serum trace elements values. The relation between (SHypo) hypothyroidism with no noticeable clinical symptoms in subclinical form of disease and cardiovascular disease investigation remained a conflict.

The treatment of SH is as unsolvable problem. Many researches has proved that there is no clear reports or reasons are present to treat the patients of  hypothyroidism with their TSH level in range of 4.5 and 10 mu/l and recommended  that patient will remain under treatment at 6-12 month of period. It has proved by American Association of clinical Endocrinologist, the Endocrine Society. The American thyroid Association  suggested that regular  patients with SH and their range of serum TSH level must be of 4.5- 10 m /U/L. Trace elements are vital, small molecules important for their  nutritive  values essential for completion  of many reactions the proper activity of thyroid hormone is effected by them. These trace element, micronutrient influenced by thyroid hormone particularly Zn, Cu.

According to the investigations, it has examined that lower metabolic rate and decreased in serum free T₄ level particularly at lower Zinc time. The activity has enhanced or increased during proper Zinc level.

From the observations, it has found that Se effect on thyroid hormone at lower concentration Se than normal level clinical hyperthyroidism appeared in patients. Iron is important constituent of many processes and chemical reactions.

Thyroxine T₄thyroid hormone is essential for iron to maintain the internal stability it control the iron cycle at tissue level, as long as Se is vital element for normal thyroid metabolism under normal functional situation of living cell and in disease also.

Selenium is effective in lowering TPOAb titer in patients suffering from autoimmune disease; mostly it happened due to partial changes in inflammatory and immune actions. TPOAb titers associated with selenium level. Glutathione peroxidase is Se dependent enzyme it regulated HNO₃   in its reduced form and it has used to protect against oxidative stress. Se deficiency might be enhanced the cardiovascular disease also.

Thyroid activity also influenced by iodine, iron , zinc and copper. These metal ions intake through food supplements. Less than normal level and improper intake of iodine and Se leads to serious complication in thyroid metabolism.

The present study is to examine the serum and determined trace element Zn, Cu, Se, Cd in clinical hypothyroidism patients in area of adequate supply of iodine.

Anatomy of thyroid gland:

Shape location and construction of the thyroid gland.

Thyroid gland located just underneath of trachea the windpipe. Its shape is like the butterfly. It consists of two lobes, which are similar to butterfly s wings, twisted around in front of larynx (windpipe). No one can   identify the normal size of thyroid gland by looking at some one. Its size is different in both male and female. In females, the normal range of thyroid gland s weight is around 18 grams, however in men it is around 25 grams. The total capacity range is about 18 to 25 milliliters.

The microscopic study of thyroid gland shows that special thyroid gland cells (thyrocytes) consist of clusters; these clusters joined and form the shape of lots of small (follicles). Thyroid gland is present in these hollow tiny follicles   and stored there. It is combining to the protein named as Thyroglobulin inside of follicles, and stored there until it has no released in blood stream. Its color is brownish red due to presence of blood vessels.

Thyroid gland attached to the windpipe and nerves that innervate the inner larynx muscles and are responsible for speech. These nerves intervene with trachea when operating the thyroid gland we have to keep intact them. The parathyroid gland present behind thyroid gland, normally four parathyroid glands are located. Its size is just alike grain of pepper parathyroid gland secret parathyroid hormone calcium level in blood   maintained through it.

Thyroid gland’s function:

Thyroid gland secrets many hormones which is used to regulate many body function like growth, metabolism, development and proceed various reactions in body. It is mainly control by brain and pituitary gland (master gland). Thyroid gland secrets many hormone mainly  triidothyronine (T₃) and tetraiodthyronine (T₄) thyroxine. Four iodine atoms are present in Tetraidothyronine (T₄), it remove its one iodine atom and become Triidothyronine (T₃). So iodine is prime important for production of T₃ and T₄ and it is essential for life also. Conversion of T₄ to T₃ takes place in liver and other tissues like brain. Thyroid hormone is derived from tyrosine amino acid and iodine is covalently bonded, position of iodine is very important in structure. Thyroid hormone is sparingly soluble in water.

Growth and development.

Oxygen and energy use.

Heat generation in body.

Fertility.

Immune regulation.

The use of fats, proteins, vitamins, carbohydrates, and water.

Chemical formula of Triidothyronine:  C₁₅H₁₂I₃NO₄

Chemical formula of tetridothyronine : C₁₅ H₁₂I₄NO₄

T₄and T₃ are responsible for the total activity of life and regulate many functions in human body like muscles activity, development, use energy and maintain energy level in whole body. Deficiency of both these hormones leads to serious drawback for health and it slower the metabolism, drops the activity of brain.

Hypothyroidism:

When thyroid gland secrets very small amount of hormones it followed a condition called hypothyroidism.

When thyroid gland secrets a little amount of thyroid hormone. Hypothyroidism is condition in which synthesis of thyroid hormone is lower than normal level. The consequences of hypothyroidism in children can be devastating, particularly in children with neonatal hypothyroidism. A delay of treatment in this group can result in permanent brain damages and mental retardation.

There are two major forms of hypothyroidism in pediatric population (1) Congenital hypothyroidism (CH), which represent a group of diseases developing at conception or during gestation and are present at birth, (2) Acquired hypothyroidism (AH), which is usually  appears after 6 months of age and arise from autoimmune destruction of the thyroid. The management of hypothyroidism in an infant or young child poses challenges distinct from those of adult hypothyroidism because of the need to diagnose and treat affected children as quickly as possible. This is particular vital for children younger than 3 years. Moreover, among the older children presenting with severe AH, it is important to introduce replacement hormone slowly to prevent adverse reactions that may result from exposing the brain to high levels of exogenous hormone after having adjusted to its hypothyroid state over the long term.

Hypothyroidism is one of the most frequently encountered endocrinology disorders. Most of time disease does not require immediate emergency evaluation and treatment. The overarching disease of hypothyroidism can have multiple causes and several presentations.

Myxedema coma, simply known as myxedema, is the rare but deadly manifestation of severe hypothyroidism. The extremely high mortality rate (historically as high as 80% but still up to 60%) associated with myxedema makes it necessary for early recognition and treatment by emergency physicians.

It is due to many disorders, like lower level of hormone production. It has caused by toxicity of pituitary gland. It is very common disease due to thyroid disorder. It can be confirm by blood test. Only in mild conditions, it becomes more complicated and it required long term of medications.

Under mild condition or in beginning of hypothyroidism it cause serious problems for pregnant women, in start of pregnancy hypothyroidism transfer from mother to infant and it may cause the miscarriage or child born with low mental ability. Clinical hypothyroidism leads to death of child at the time of birth and preeclampsia (major disorder by hypothyroidism in pregnant women with high blood pressure and hypertension.

The primary cause of hypothyroidism is Hashimoto’s thyroiditis (the system during which immunity of body cause   disruption in its own cells.). Goiter is major disease due to thyroid disorder in which cyst like out growth appeared around the neck. This enlargement of thyroid hormone is like fibrous growth in neck. It is due to genetically and many environmental factors effect on its growth and development.

Symptoms of Hypothyroidism:

The most common symptoms of hypothyroidism are as followed;

Dry, rough pale skin.

Coarse, dry hair.

Weakness.

Weight gain or increased difficulty losing weight.

Fatigue.

Hair loss.

Cold intolerance.

Muscle cramps and frequent muscle aches.

Depression.

Memory loss.

Abnormal menstrual cycles.

Decreased libido (lack of sexual desire).

Treatment for Hypothyroidism:

The abnormalities has observed due to iodine deficiency and converted to less toxic material by addition of iodine. Simply it enhanced the movement of thyroxine. It has been examined that thyroid gland removes inorganic iodide from blood plasma and produced various organic iodine compounds. Thyroid functions under control of TSH anterior of pituitary gland, which has checked by thyroid hormone. Hashimoto’s thyroiditis is serious problem it is long lasting and need treatment with life.

Subclinical hypothyroidism treatment has quite easy if it left behind and not treated well, originate with serious damages. Subclinical Hypothyroidism is easy to handle as compared to clinical hypothyroidism. Most simple and frequently treated procedure is use of Levothyroxine pills daily in morning. This medicine is purely synthetic in nature, chemically similar to T₄. L-Thyroxine increased the quantity of T₄ (thyroxine). It is present in form of oral tablets, also available in from of intramuscular injection. For patients who are using levothyroxin, suggested to test their TSH and free T₄levels after six weeks. The brand name and generic name of product is same.

Treatment of hyperthyroidism

Firstly thiourea (H₂NCSNH₂ ) itself used as drug to overcome the abnormal behavior of thyroid hormone during thyrotoxicosis. The most valuable drug is 6-methylene -6-n propyl derivatives. Thiouracil derivatives can be synthesis through condensation of thiourea with substituted β-keto esters in the presence of sodium ethoxide in ethanol 

[47-80].

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Introduction

Literature Review

Experimental Work

Results and Discussion

References


STATISTICS TABLES

TABLE  1

TABLE  2

TABLE  3

TABLE  4

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