Design of Novel Antihistamines and Nonsteroidal Anti-inflammatory Drugs (NSAIDs) | Chapter: 1 | Modern Advances in Pharmaceutical Research Vol. 1

Introduction:The group of drugs referred to as non-steroidal anti-inflammatory agents (NSAIDs) are applied in the treatment of fever, pain, acute and chronic inflammatory conditions. Generally, NSAIDs are highly bound to plasma proteins such as albumin, which decreases their body distribution to levels, considered low (i.e. as low as or lower than 0.2 Liter/kg).

Aims: To  determine  the  molecular  properties  of  common  antihistamines  and  non-steroidal  anti-inflammatory  agents  (NSAIDs).  To  identify interrelationships  among these  two  groups  of  drugs utilizing pattern recognition methods and statistical analysis.

Study Design: After determination of molecular properties, values thereof are examined using pattern recognition methods and other numerical analysis for underlying relationships and similarities.

Place and Duration of Study: Durham Science Center, University of Nebraska, Omaha, Nebraska from September 2016 to January 2017.Methodology:Thirty compounds were identified as antihistamines and 27 compounds identified as NSAIDs.  Properties  such  as  Log  P,  molecular  weight,  polar  surface  area,  etc.  are  determined.  Molecular properties are compared applying methods such as K-means cluster analysis, nearest neighbor  joining,  box  plots,  and  statistical  analysis  in  order  to  determine  trends  and  underlying relationships. Pattern recognition techniques allow elucidation of underlying similarities.

Results: The  molecular  properties  of  all  57  drugs  are  tabulated  for  comparison  and  numerical analysis. Evaluation by Kruskal-Wallis testand one-way ANOVA indicated that antihistamines and NSAIDs’ values of Log P have equal medians and equal means. However, values of polar surface area (PSA) and number of rotatable bonds for these two groups do not have equal means and medians. Box plots indicated that Log P, PSA, and molecular weight values have significant overlap in range. Neighbor-joining method showed which drugs are most similar to each other. K-means cluster analysis  also  divided these  57  drugs  into  six  groups  of  highest  similarity. Principal  coordinates analysis (PCoA) with 95% ellipses indicated all but four of the drugs fall within a 95% confidence region. Multiple regression analysis generated mathematical relationship for prediction of new drugs.

Conclusion: These two groups of drugs show compelling similarities. PCoA showed all but four of 57 drugs come within a 95% confidence ellipsis. Neighbor joining and K-means cluster analysis showed drugs having similarities between the two groups. Antihistamines and NSAIDs are two groups of drugs highly important for public health. A comparison of 30 antihistamines to 27 NSAIDs showed important similarities useful for design of novel drug structures. One-way ANOVA and Kurskal-Wallis test showed that means and medians of Log P and number ofoxygen & nitrogen atoms of these two groups are equal. Properties NSAIDs showed high level of consistent values, with no outliers for Log P, polar surface area, molecular weight, molecular volume, and numbers of –OH, -NHn, rotatable bonds,  and  atoms.  However,  antihistamines  showed  outliers  in  all  properties  except  Log  P  and number of rotatable bonds. Multiple regression produced algorithms for both groups accounting for over 93% of variance in molecular weight. Box plots showed substantial overlap of values for the two groups  of drugs for molecular weight,  polar  surface area,  and Log  P.  K-means cluster analysis showed that members of antihistamines are most similar to members of NSAIDs. Similarity among members of the two groups is visualized in neighbor joining tree cluster analysis.

Biography of author(s)

Ronald Bartzatt
Durham Science Center, University of Nebraska, 6001 Dodge Street, Omaha, Nebraska 68182, USA.

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Randle Cycle as Applied to Diabetes Mellitus Type 2 ‘Spruce the Basement before Dusting the Super-structure’ | Chapter: 2 | Modern Advances in Pharmaceutical Research Vol. 1

Randle cycle (1963) is about substrate competition between products of glycolysis and β–oxidation to capture the citric acid cycle for further oxidation. Acetyl –CoA, the end product of both the energy metabolisms, when  accumulates in mitochondrial matrix beyond the oxidative capacity of the citric acid cycle, far-reaching consequences take place than simple substrate competition, inhibition of pyruvate  dehydrogenase(PDH),  inhibition  of  glycolysis  and  preferential  passage  of  β-oxidation products through citric acid cycle, as conceived by Randle. It is shown that citric acid cycle is equally shut off for both products of energy metabolism initially. Hence, the question of substrate competition between  them  does  not  arise.  How  the  preferential  passage  of  β-oxidation  products  occurs  is explained by a different mechanism than what Randle put forward. The final common pathway to either of β-oxidation or lipogenesis is-acetyl CoA carboxylase (ACC)-malonyl-CoA-CPT 1. The final result depends on whether ACC is stimulated or inhibited.Inhibition of ACC  results in β-oxidation and stimulation results in lipogenesis. Randle’s  contention that the low ATP status due to substrate  competitive inhibition , stimulates AMPK ,which results in initiation and perpetuation of β -oxidation   is not true because, simultaneously, AMPK is also inhibited which inhibits, in turn, the β -oxidation The proposed  hypothesis  suggests  that  low  substrate  for  ACC  i.e.  Plasma  acetyl-CoA,  which  is carboxylated  to  malonyl-CoA  is  responsible  for  the  switch  of  energy  metabolism  to  β-oxidation independent of AMPK. To corroborate the proposed mechanism, a low pyruvate level, an additional block in the glycolytic pathway at the  level of Pyruvate kinase (PK) and involvement of hexose monophosphate shunt (HMP shunt) are proposed with objective evidence, supporting the same.

Biography of author(s)

A. S. V. Prasad
Department of Internal Medicine, G.I.T.A.M Dental College, Rushikonda, Visakhapatnam,Andhra Pradesh, India

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Novel Alkylating Derivatives of Chloramphenicol Suitable for Topical Treatment of Dermal Neoplasms | Chapter: 3 | Modern Advances in Pharmaceutical Research Vol. 1

Aims: To evaluate the efficacy of two alkylating structural analogues of chloramphenicol that have potential for application for treatment of dermal sited neoplasms.

Study  Design: Two compounds have been shown to alkylate guanosine-5’-diphosphate (GDP) at physiological conditions. These same compounds are evaluated for dermal penetration based on Kp and compared to other alkylating agents applied for treatment of skin cancer.

Placeand  Duration  of  Study: University of Nebraska, Omaha Nebraska from December 2013 to May 2014 and March to August of 2002.

Methodology: Two analogues of chloramphenicol were synthesized and shown to alkylate GDP at pH  7.4  and  37ºC.  Various  pharmacologicalproperties  of  these  two  analogues,  such  as  Log  P, molecular weight, polar surface area, etc, were determined and compared.  The dermal permeability coefficient  Kp  was  determined  for  two  analogues  based  on  their  molecular  weight  and  partition coefficient Log P. The numerical values of Kp were used to prediction of the distance each analogue is expected to travel in penetration of a dermal barrier. Result was plotted and compared to the anticancer agent’s carmustine, mustargen, and 5-fluorouracil. Evaluationof the analogues included findings of previous studies.  

Results: Two analogues of chloramphenicol alkylate sites on GDP. The properties of compound 1 and compound 2 were determined and when compared to the parent structure chloramphenicol were found  tohave favorable  drug  likeness.    Values  of  Log  P  and  permeability  coefficient  Kp  for compounds 1 and 2 are; 3.343, 3.312, 0.00244 cm/hour, 0.000768 cm/hour, respectively.  Values of Kp for both compound 1 and 2 were greater than that of chloramphenicol at 0.000131 cm/hour. Plots of skin penetration showed compounds 1 and 2 to be superior to 5-fluorouracil.

Conclusion: Analogues 1 and 2 were shown to have alkylation activity and properties suitable for drug likeness. Both compounds have high penetration ratesof dermal layers. The pharmaceutical properties  of  two  structural analogues  of  the  antibiotic  chloramphenicol  were  determined  and analyzed for potential of topical administration. Compound 1 and compound 2 were both shown in previous  studies  to  alkylate  guanosine-5’-diphosphate,  amino  acids,  and  p-chloroaniline.  Both analogues  1  and  2  possess  alkyl  chloride  substituents  in  place  of  hydroxyl  groups  found  on chloramphenicol. Dermal permeability coefficient Kp of analogue 1 (0.00244 cm/hour) is greater than Kp for carmustine, Mustargen, and 5-fluorouracil.  Analogue 2 value of Kp (0.000768 cm/hour) is greater than Kp for anticancer drug 5-fluorouracil.  The diffusion coefficient D for analogue 1 and 2 are competitive with those of carmustine, Mustargen, and 5-fluorouracil. Aqueous solubility of analogues 1 and 2 are considerably lower than for chloramphenicol, which is consistent with the much larger Log P values for 1 and 2. Plots of distance traveled, based on their values of Kp, showed that compound 1 moves further than carmustine, Mustargen, and 5-fluorouracil. Compound 2 still travels further than chloramphenicol and anticancer agent 5-fluorouracil. These results strongly support the potential of compound 1 and 2 as effective topical agents in treatment of skin neoplasms and mycosis fungoides.

Biography of author(s)

Ronald Bartzatt
University of Nebraska, Durham Science Center, Department of Chemistry, 6001 Dodge Street, Omaha, NE 68182, USA.

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Effect of Cymbopogon citratus Decoctions on Gasoline Vapour-induced Reproductive Toxicity in Female Rats | Chapter: 4 | Modern Advances in Pharmaceutical Research Vol. 1

Aims: Recent research indicates that plant molecules, particularly those that are rich with antioxidant, anti-inflammatory  and  immune  modulatory constituents,  can  modify  and  prevent  the  detrimental effects of gasoline compounds on reproductive endpoints. However, whether C. citrates decoction can alleviate gasoline vapour (GV)-induced derangement of female reproductive hormones has not yet been documented. In this study, the capacity of C.  citrates decoction was evaluated for its ability to alleviate GV-induced reproductive toxicity in female rats.

Study Design: Seventy-two female Wistar albino rats weighing 185 ± 11.2 g were placed into six groups (n = 12 per group): The control (group 1, G1), GV alone (G2), GV plus C. citratus decoction (500 mg/kg; G3), (1000 mg/kg; G4), (1500 mg/kg; G5), and GV plus vitamin C (200 mg/kg; G6).Place and Duration of Study: Department of Physiology, University of Uyo, Uyo, Akwa Ibom State, Nigeria. All groups were treated for 35 days.

Methodology: Serum levels of the female reproductive hormones progesterone (P3) estradiol (E2), luteinizing hormone (LH), and follicle stimulating hormone (FSH) as well as superoxide dismutase (SOD) and malondialdehyde (MDA; an oxidative stress marker) in the animals were assessed using standard procedures.

Results: The results showed that GV significantly (p < 0.05) decreased serum levels of P3, E2, LH, FSH, SOD and increased serum MDA levels compared to the levels in the control animals. However,  co-administration of C.  citrates at different doses to the animals in G3, G4, and G5 and vitamin C to the animals in G6 dose-dependently significantly (p < 0.05) increased the levels of the GV-reduced  reproductive  hormones  and  antioxidant  enzyme  and  decreased the  GV-increased oxidative stress marker levels to levels similar to those in the control group.

Conclusion: Thus, C.  citrates decoction  has  an  ameliorative  effect  on  GV-induced  reproductive dysfunction and oxidative stress.

Biography of author(s)

Christopher E. Ekpenyong
Department of Physiology, University of Uyo, Uyo, Nigeria.

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Novel Mechlorethamine Based Drug Structures Targeting Brain and Spinal Cord Tumors | Chapter: 5 | Modern Advances in Pharmaceutical Research Vol. 1

Introduction: Brain and spinal cord tumors are the third most common type of child hood cancer, with only leukemia and lymphoma having greater frequency. Cancers that occur in the central nervous system (CNS) can be primary (tumors that begin in the CNS) and metastatic (tumors formed from cancer cells beginning in other parts of the body).Aims: Brain and spinal cord tumors are the third most common type of childhood cancer following leukemia and lymphoma. Mechlorethamine (or mustine) is a nitrogen mustard antineoplastic drug.  Eleven  variants  of  mechlorethamine  are  presented  that  possess  molecular  properties  enabling substantial access to tumors of the central nervous system.

Study Design: An extensive in silico search within a data library of molecular structures identified drug scaffolds suitable for targeting brain tumors.

Place and Duration of Study: University of Nebraska,  Durham  Science  Center, Department  of Chemistry, Omaha, Nebraska 68182 USA, between July 2012 to December 2012.

Methodology: Following extensive in silico search and identification of potential drug structures, a conclusive set of brain penetrating structures were compiled.  Extensive characterization of structure properties was accomplished followed by multivariate numerical analysis utilizing pattern recognition and statistical analysis.

Results: All twelve compounds (including mechlorethamine) exhibited zero violations of Rule of 5, indicating favorable bioavailability. The range in LogP, formula weight, and polar surface area for these compounds are: 1.554 to 3.52, 156.06 to 324.12, and 3.238 A2to 22.24A2, respectively. High resolution hierarchical cluster analysis determined that agent 2 and 6 are most similar to the parent compound mechlorethamine. The average Log P, formula weight, polar surface area, and molecular volume are 2.446, 235.433, 8.58 A2, and 213.8 A3, respectively. 

Conclusion: These eleven drug designs possess attributes that effectuate high permeation into the central nervous system. A set of eleven novel drug structures are elucidated by in silico optimized substituent  search  that  is founded  on  the  successful  anticancer  nitrogen  mustard  scaffold  of mechlorethamine. Brain metastases have been linked to breast cancer, advanced melanoma, and colorectal cancer. Various molecular properties that enable the transition from blood to CNS have been identified and found to be optimal for the twelve agents reported here. The Log P numerical values fall between 1.554 to 3.52 which is arrange well within the BBB piercing range of 1.0 to 4.00. In addition the values of PSA range from 3.238 to 22.24 Angstroms2, which is a range well below the upper limit for effective CNS penetration at 90 Angstroms2. Importantly all twelve agents present zero violations of the Rule of 5, indicating a high level of drug-likeness and favorable bioavailability. The success rate of in silico search and identification of suitable CNS targeting antineoplastic structures was less than ten percent. Various attributes recounting the inherit potential of small molecules applied as chemotherapeutic agents in the treatment of CNS tumors.

Biography of author(s)

Ronald Bartzatt
University of Nebraska, College of Arts & Sciences, Durham Science Center, 6001 Dodge Street, Omaha, Nebraska 68182, USA.

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