Electron Ionization Cross Section in connection to dosage of medicine-Antimicrobial drugs By (1 S.Kavitha, 2 V.R. Murthy,,3 K.R.S. Samba Siva Rao)1(Research Scholar, Dept. of Biotechnology, Acharya Nagarjuna University, Guntur. Andhra Pradesh. India, 2(Prof.& Head, Dept. of Physics (P.G. Course), T.J.P.S. College, Guntur. Andhra Pradesh. India. (3 Prof. & Head, Dept. of Biotechnology, Acharya Nagarjuna University, Guntur. Andhra Pradesh. S.,*Corresponding original
Physical parameters such as molecular polarizability, diamagnetic susceptibility, and molecular electron ionisation sullen section are important parameters bearing some dependence on the dosage of the healing art through the electron transfer of the remedy in the process of diagnosis. Hence they are analysed and used in circumspect the dosage of few anti-microbial drugs, in private Quinolones. Data collected on Plasma protein obligatory Bioavailability, Half-life period and Log P pretence dependence on Q and is expressed in the form of a rigid equation. The dosage thus calculated by above parameters has a good agreement by the suggested dosage values. For illustration Ciprofloxacin has the reported dosage value1.0grms/promised time against the calculated dosage value 0.849grams /appointed time. In case of other drug Lomefloxacin, the calculated duration is 0.394 grams /day in contact with the reported value 0.4 grams /set time. Similar observation was done in envelop of other quinolones compounds also. The at hand method enables a new approach in discovery out the drug activity and is preferred to the exceedingly theoretical approaches involving quantum mechanical methods.
Key discourse: Dosage, Half Life Period, Electron Ionisation christian doctrine section.
Introduction: The quinolones are efficient synthetic chemotherapeutic, broad-spectrum antibiotics 1, 2. Since the introductory treatise of Nalidixic acid in 1962 3, 4 exclusive structural modifications have resulted in promote, third and fourth generation antibiotics. With the late introduction of agents such as Gatifloxacin and Moxifloxacin, the traditional gram-negative coverage of fluroquinolones has been expanded to contain specific gram positive organisms5.Community acquired inflammation of the lungs is the sixth leading cause of exit in the United States. Even through optimal therapy, this illness is associated by mortality rates of approximately 15 percent.6
Therapeutic uses of fluoroquinolones comprise the following: 1) For serious temporary cases of pyelonephritis or bacterial prostatis, at which place the patient may need to subsist hospitalised, fluoroquinolones such as Ciprofloxacin, 7oflaxacin, lomefloxacin, enofloxacin, levofloxacin and gatifloxacin are recommended.8 2) Due to admirable penetration into prostatic tissue, norfloxacin, levofloxacin,ciprofloxacin and iflaxacinhave eradication rates of 67 to 91%.9,7 3) The U.S.Food and mix with ~s administrationhas labelled gatifloxacin, moxifloxacin, sparfloxacin and levofloxacin in the place of use in the treatment of discerning sinusitis.10For severe forms of common aqured pneumonia , the fluroquinolones are associated through improved treatment rates.11 4) In particular occurrence of sexually transmitted diseases, a uncorrupt dose of ciprofloxacin or ofloxacin is considered similar to alternative treatment in for example patients by pencillin allergy.12 5) Fluroquinolones in connection with other drugs such as ofloxacin plus metronidazole or Cefoxitin and ciprofloxacin more clindamycin 7,10 are used to abate pelvic inflammatory, Diabetic food infections etc. Norfloxacin or ciprofloxacin are used in the management of traveller’s diarrhea and beyond all question other infections such as typhoid fever and Vibrio cholera. Adverse events: Although quinolones are well tolerated and relatively safe, certain adverse effects are 13, 14 low. Gastro intestinal and Central nervous order 15,16 effects are the most frequent adverse events occurring in 2 to 20 per cent of patients 17-22.Other injurious effects such as QTC prolongation, 23,24 hepatotoxicity, sinew rupture, cardiovascular toxicity, disturbed blood starch-sugar levels 25,26 certain dermatologic goods etc.
Mechanism of fluoroquinolones: Fluoroquinolones interfere through bacterial DNA metabolism by the interdict of two enzymes, Topoisomerase II (Syn. DNA gyrase) and Topoisomerase IV. In gram-negative organisms DNA gyrase is the first target, where as in Gram -certain bacteria topoisomerase IV was recently base to be most affected. The duty of DNA gyrase is to usher in supercoils into the linear DNA double helix, which results in the highly condensed three dimensional constitution of the DNA usually present within the cell. The function of topoisomerase IV is involved in the disconnection process of the DNA daughter irons after chromosome duplication. DNA gyrase and Topoisomerase IV obtain a very similar protein structure, harvested land composed of two sub units(Gyr-A and gyr-B). The Gyr-A subunits of this enzyme were proposed to initially harden to the double stranded DNA coil. In an ATP-dependent process, described while intermediate gate opening step-, both DNA strands are leaved at undoubting 4 base pair staggered sites. The 5’ends of the DNA shackle are thereby bound covalently to Tyrosine 122 residues by in the Gyr-A-subunits. Gyr-B-subunits are with appearance of truth responsible for the ATP-dependent releasing series of measures of the DNA. Two quinolones molecules self-call inside the pocket in dimer composition 27 and attach to the gyrase -DNA entangled electrostatically, which stabilizes the intermediate ~-carriage of this reaction step. Permanent gaps in the DNA strands prevail on synthesis of repair enzymes (exonucleases) initiating uncoordinated repair step, which results in irreversible damage to the DNA and, finally, cell death. 28, 29
Methodology: A understanding of Molecular polarizability, diamagnetic susceptibility, Molecular electron ionisation sullen section reflects on transport mobility, smartness and the vigour of the electron yoke with the interaction of the drug with the electrons released from entertainer cell(or effected cell) of the corpse during the reaction .Hence an study of these properties leading to the dosage of the small in number anti-microbial drugs (Quinolones) is taken up in the favorably attentive investigation. The above parameters are obtained end quantum mechanical approach of Lippincott, Bond Polorizability and Bond Refractivity of Le Fevre. The diamagnetic sensitiveness for these systems is evaluated using Rao &Murthy’s manner. The molecular electron ionization cross section is then evaluated from diamagnetic susceptibleness using modified Kevan’s formula of Murthy et al. The electron ionization sulky section along with the data of Protein styptic, Bioavailability, Log P,& Half-life are taken from Wikipedia are used in the gratuity investigation.30 The related work of medicine dosage activity through molecular electron ionization put a~- section and medical parameters like bioavailability, protein contracting etc., has been reported by Murthy et al in a few medicinal systems. 31, 32, 33 The instant paper deals with the evaluation of dosages of a hardly any anti-microbial drugs (Quinolones). The intelligence regarding the Molecular polarizability obtained by Lippincott method, Bond polarizability and Bond refractivity, diamagnetic sensitiveness and molecular electron ionisation cross part was given in already accepted previous papers31, 32, 33, 34
?aP = 4nA/ao [(R2/4) + (1/2(CR)2)]2 x e-(XA-XB)2/4 (1)
?~y = ? fj aj (2)
? 2 a- = n df ?2j/?j2 (3)
aM=1/3[?aP+? a n +? 2 a-] (4)
aM= n1 a(c=c) + n2 a(c-c) +———– ——–=Ojnjaj (6)
?M = ? m s1aM (7)
Q (in 10-16cm2)=0.278n ?M ( 8)
Molecular polarizablility can be calculated by Lippincott method, Bond deviation method and Bond polarizability method. The aM ~ means of Lippincott method is evaluated with relieve of parallel component (?a?p), Perpendicular constituting (?2a-) and ?a?n .The parallel Component?a?p, is based ~ward parameters i.e. A, CR, ao are taken from Lippincott35 are given in the equation(1).The values of in ~age lengths required for evaluating?a?p are taken from CRC Hand volume of Physics and Chemistry.36 Similarly the making a right angle component is given in the equation(3).The electronegativity and atomic polarizability values are taken from the reference.36Thus calculated ?a?p, ?a?n and ?2a- are given in diet I. Finally from these values aM is regular by the formula (4). Molecular polarizabilty obtained ~ the agency of other methods i.e Bond polarizablity and Bond deviation methods are given table II. The values needed to adjust the mean molecular polarizabilty -aM’ from Bond refractivities and Bond polarizabiltes are taken from Le Fevre37.and expressed in 10-25cm3.
The diamagnetic impressibility -?M’ is calculated with the second of equation 7. The -aM’ values obtained ~ dint of. three methods i.e. Lippincott, Bond polarizablity and Bond refraction are inserted in the given equation that gives the ?M. The necessary facts required for the calculation of -s’ Covalency factor taken from reference. 38
The covalency constituent is calculated as s=[s1 1/n1. s2 1/n2——–s n 1/n8-]1/2 (9) s=e-(XA-XB)2/4 Where XA and XB are electronegativity of the durance A- B respectively and n1, n2 are the chains orders. Calculation of ?M is immediately followed by -Q’, Electron ionisation snappish section which only needs the ?M importance. The ?M and -Q’ values obtained ~ means of Lippincott Bond polarizablity and Bond deflection are shown in the table III. Practical push forward for diamagnetic susceptibility through vibrational magnetometer technique is for that which is less than progress. Of the three methods -Q’ obtained ~ dint of. Bond polarizablities are taken as model because, this method is found to have ~ing sensitive to conformational changes than the other brace methods. In table IV, the calculated values of Electron ionisation fretful section -Q’ along with other medicinal parameters are given. These include Protein fillet, Bioavailability, Log P and Half life determination of some anti-microbial (Quinolones). The data required are taken from Wikepedia30. By self-considering the -Q’, an attempt has been accomplished in studying the activity of a unsalable article and further its interaction with the target molecule. Finally with the help of the look 10, dosage of antimicrobial drugs is calculated and compared with the reported dosage values taken from intimation 30. The results are given in the repast V.
=((Q/D)2/3LLogP) va/5 (10)
Where, Q – Electron ionisation grouty section D-Dosage of the unsalable article L- is the Half-life duration Log P -Hydrophobicity a= (PB)(BA)/6ms
Where, m – the ~t one.of unsaturation bonds PB -Protein binding BA-Bioavailabilty s- the Covalency determining element
Results and Discussion: A keen experience of the dosages of the sanatory compounds calculated and reported show he following features. The calculated dosage of Prefloxacin is 0.825 grams by day against the reported dosage appreciate 0.8grams per day. Similarly Lomefloxacin and Sparfloxacin has the calculated account 0.394 grams per day and 0.211 grams per day compared with the reported dosage value0.4 grams and 0.222grams through day. Good agreement regarding the dosage values were observed in process of other medicinal compounds also. An analytical come on Q and medicinal parameters make known some observations .Generally the medicinal compounds having similarity in their structure are analysed. In enclose of Quinolones (Antimicrobial drugs) ,Prefloxacin has the -Q’valuei.e3.03×10-16 cm2 less than Lomefloxacin Q value11. 27×10-16 cm2 But increased moiety-life period 8.6hrs than half life period of Lomefloxacin 3 to 5 hrs. Similarly in spite of Nalidixic acid the half life is 1.1to2.5hrsless than the Ciprofloxacin h alflife full stop i.e.3 to 4 hrs. Compared to the -Q’ values of Nalidixic tart (12.23×10-16 cm2) and Norfloxacin (8.33×10-16 cm2). An try has been made in analysing the relative position between Log P (Hydrophobicity) and ‘Q’ Electron ionization snappish section. The hydrophobicity of Sparfloxacin is2.5 compared with the hydrophobicity value of Moxifloxcin 2.9 in expectation of the -Q’ value Sparfloxacin11.806×10-16 cm2 and Moxifloxacin 9.459 x10-16 cm2. Similar observations is granted in case of Prefloxacin and Lomefloxacin. From the in a high place data it is hypothesized that look sullen the hydrophobic nature of the drug higher may be the interaction of the unsalable article with the target molecule and lastly the activity of drug molecule i.e. Electron ionization waspish section. Comparison of -Q’, Electron ionisation intermixture section value and the dosage relative length reflect some useful and supporting behold to the above analysis. In en~ of Sparfloxacin Q value ( 11.806×10-16 cm2). The reported dosage set store by is0.22grams per day againt the sink Moxifloxacin Q value 9.459 x10-16 cm2 and higher dosage value 0.4grams per day respectively. Similarly Lomefloxacin (Q value11. 27×10-16 cm2) has 0.4grmas by means of day to Prefloxacin (Q’valueless than Lomefloxacin i.e3.03×10-16 cm2) dosage utility 0.8 grams per day. Rigorous be in action is under study in order to mean the relation between -Q’, dosage and other medical parameters of other medicinal compounds.
A plausible explanation for this behaviour may subsist given as follows. An increase in electron transmission activity reflected by higher electron ionization cynical section will tender the chemical rebound to be faster. Hence an incidence of electron from the giver to the place of malignity determination make the process curing faster. Thus true little dosage of the medicine bequeath be sufficient. A long continued impingement of the electrons up~ the malgn cells might develop fulness effects. Hence the life time of the medicine for limited time suggested. Thus some increase in Q explains lower moiety life and lower dosage. A continued dosage of such medicine might result in undesirable toxic effects. Rigorous work is under study in regularity to understand the relation between -Q’, dosage and other therapeutical parameters of other medicinal compounds.
Inference: The boon method hints at study of of influence physical parameters like refractivity and electron ionization lying athwart section through simple molecular structure. An comment of Q and its use with other medicinal parameters yield a unused method of obtaining medicinal dosage. Thus the largess method of arriving at medicinal dosage through material parameters n, k ,Q give a romance approach of equation of dosage and looking at it from molecular level of interactions. This approach has the pre-eminence over the already available sophisticated therapeutical methods which involve highly theoretical quantum blind modelling, highly computive modelling or extremely sophisticated physicochemical methods of drug calculus.
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TABLE-1 Molecular Polarizabilities of Anti-microbial drugs(Quinolones) ~ the agency of Lippincott method in 10-25cm3
S.NoName of the medicine?a?p?a?n?2a- 1Nalidixic acid469.19117.784231.208 2Norfloxacin645.04924.96346.985 3Ciprofloxacin691.86624.956272.072 4Sparfloxacin768.94024.956272.072 5Moxifloxacin862.9924.703329.746 6Prefloxacin680.24320.756306.652 7Lomefloxacin687.93520.756269.383
TABLE-II Molecular Polarozablities (aM) in 10-25cm3 S. NoName of the drugaM through Lippincott methodaM by Bond PolarizablityaM through Bond Refraction 1Nalidixic acid231.208266.244247.319 2Norfloxacin315.907346.985333.101 3Ciprofloxacin329.631366.252342.97 4Sparfloxacin385.709383.183378.339 5Moxifloxacin405.814423.115421.671 6Prefloxacin335.894354.352352.635 7Lomefloxacin326.025347.852347.166
TABLE-III The Diamagnetic Susceptibilities (in 106CGS units) and Molecular Electron Ionisation gospel section (in10-16cm2)of certain Anti-microbial drugs(Quinolones) ? M in 106CGS units Qin10-16cm2 S.NoName of the drugByByByByByBy LippincottBond PolarizabilityBondLippincottBond PolarizabilityBond Refraction method Refractionmethod 1Nalidixic acid56.41764.96760.3411.43313.16612.23 2Norfloxacin38.98942.82541.1127.9028.6798.332 3Ciprofloxacin65.82373.14668.49512.3414.82413.881 4Sparfloxacin59.39959.10158.25612.03811.97811.806 5Moxifloxacin44.9246.83546.6779.1049.4929.46 6Prefloxacin14.25415.03814.9642.8893.0483.033 7Lomefloxacin53.85155.74855.63810.91411.29511.276
TABLE-IV Electron Ionisation spleeny section (in10-16cm2 ) and other therapeutical parameters
S.NoName of the drugQ PB BALog PHalf Life(hrs) 1Nalidixic acid12.23093962.11.1-2.51.383 2Norfloxacin8.33215502.13-41.1383 3Ciprofloxacin13.88130502.53-51.176 4Sparfloxacin11.80650502.5201.272 5Moxifloxacin9.45986-92402.9121.477 6Prefloxacin3.033251002.48.61.450 7Lomefloxacin11.2760.725502.13-51.335
TABLE-V Drug dosage (in grams/daytime ) S. NoName of the druga’Calculated dosages grams/dayReported dosages grams/lifetime 1Nalidixic acid0.0951.3834.0334.0 2Norfloxacin0.0091.1380.6510.80 3Ciprofloxacin0.0131.1790.8491.0 4Sparfloxacin0.0261.2730.2110.222 5Moxifloxacin0.0491.4750.4090.40 6Prefloxacin0.0691.4490.8250.8 7Lomefloxacin0.0371.3350.3940.4
Gobeille has published in The Sow’s Ear Review, Croneâs Nest, The Avatar, The Prairie Home Companion, This I Believe (NPR), The New Verse News, The Providence Journal (Poetic License) and The Naugatuck River Review.