Editor(s)
Dr. Barkat Ali Khan,
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, D.I. Khan KPK, Pakistan.

 

 

ISBN 978-81-934224-9-6 (Print)
ISBN 978-93-89246-21-6 (eBook)
DOI: doi.org/10.9734/bpi/mapr/v1

 

This book covers key areas of pharmaceutical research and other related fields. The contributions by the authors include randle cycle, pyruvate dehydrogenase kinase, pyruvate kinase, pyruvate carboxylase, carnitine palmitoyltransferase, acetyl–coa carboxylase, chloramphenicol, antihistamines, non-steroidal anti-inflammatory drugs, NSAIDs, brain tumors, astrocytomas, glioma, mechlorethamine, mustine, drug design, Drug interactions, P-glycoprotein, methods for detection, CYP450, Drug leaflets, patient information leaflets, package inserts, immunization, prodrugs, intramolecular processes, ADME, knee arthroplasty, complication, arteritis, rehabilitation, physiotherapy, chelidonium, antiretroviral, metabolic abnormalities etc. This book contains various materials suitable for students, researchers and academicians in the field of pharmaceutical research.


Chapters


Design of Novel Antihistamines and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Ronald Bartzatt

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 1-19

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 test and 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 of oxygen & 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.

Randle Cycle as Applied to Diabetes Mellitus Type 2 ‘Spruce the Basement before Dusting the Super-structure’

A. S. V. Prasad

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 20-30

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.

Novel Alkylating Derivatives of Chloramphenicol Suitable for Topical Treatment of Dermal Neoplasms

Ronald Bartzatt

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 31-42

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.

Place and 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 pharmacological properties 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. Evaluation of 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 to have 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 rates of 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.

Effect of Cymbopogon citratus Decoctions on Gasoline Vapour-induced Reproductive Toxicity in Female Rats

Christopher E. Ekpenyong

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 43-52

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. citratus decoction can alleviate gasoline vapour (GV)-induced derangement of female reproductive hormones has not yet been documented. In this study, the capacity of C. citratus 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. citratus 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. citratus decoction has an ameliorative effect on GV-induced reproductive dysfunction and oxidative stress.

Novel Mechlorethamine Based Drug Structures Targeting Brain and Spinal Cord Tumors

Ronald Bartzatt

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 53-63

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 Log P, 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.

Drug Interactions: A Comprehensive Update

Madhav Mutalik

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 64-88

Possibility of occurrence of drug interactions increases with the number of drugs administered. Drug interactions can be classified in a number of ways using different basis as well as terminology. Drugs may interact with other drugs, foods, beverages, contrast media, and herbs; outside or inside the body. The term “drug-condition interaction” is sometimes used when the existing medical condition makes certain drugs potentially harmful. Knowledge of In vitro interactions is essential to avoid loss of activity of drugs before administration. Although every theoretical drug interaction may not manifest in practice, “drug interactions” is a prominent cause of adverse or undesired events related to drug administration or treatment failure. Amongst the herbs, St. John’s wort has a potential of producing significant drug interactions due to its capacity to induce metabolism of number of drugs. In vivo interactions at pharmacokinetic level affect absorption, distribution, biotransformation or excretion of drugs. Induction or inhibition of cytochrome P450 (CYP450) enzymes forms a major basis of drug interactions. As compared to induction, inhibition is a fairly rapid process. Number of precipitant drugs which inhibit the metabolism is much more than those that produce induction of enzymes; hence inhibition of metabolism may lead to serious and acute adverse events by aggravating the toxicity of substrate drugs. Role of drug transporters, especially P-glycoprotein (P-gp), in causation of drug interactions is being increasingly identified. P-gp affects absorption, distribution and excretion, and hence plays a major role in pharmacokinetic drug interactions. Additionally, P-gp works hand in hand with CYP450 enzymes. In pharmacodynamic interactions, the drugs synergise or antagonise the effects at the level of target of action. Clinically beneficial and reparative drug interactions are explored to obtain useful drug combinations. Interactions of drugs with contrast media should be remembered and carefully prevented. Extensive research has led to the development of a large number of In vitro and In vivo methods to detect and predict drug interactions. “Drug interaction softwares” is an additional and significant tool for analysis and prediction of probable drug interactions. Appropriate awareness and knowledge of possible drug interactions is crucial in prevention of harmful drug interactions and their consequences.

Prodrugs-Current and Future Drug Development Strategy

Rafik Karaman

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 89-94

The focus of traditional prodrug approach was on altering various physiochemical parameters, whereas the current modern computational approach considers designing prodrugs through attaching appropriate linkers with drugs having poor bioavailability which upon exposure to physiological environments release the parent active drugs in a programmable (controlled) manner resulting in an improvement of their bioavailability. With the possibility of designing prodrugs with different linkers, the release rate of the parent active drugs can be controlled.

The future of prodrug technology is exciting and yet challenging. Advances must be made in understanding the chemistry of many organic reactions that can be effectively utilized to enable the development of more types of prodrugs. The understanding of organic reaction mechanisms of certain processes, particularly intramolecular reactions, will be the next major milestone in this field. It is envisioned that the future of prodrug technology holds the ability to create safe and efficacious delivery of a wide range of active small molecules and biotherapeutics. This goal can be achieved using computational chemistry methods such as ab initio, semi-empirical and density functional theory (DFT), and molecular mechanics (MM) to calculate physicochemical and molecular properties of current marketed drugs suffer low bioavailability or/and unpleasant taste or odor.

Toxicity Studies of the Extracts of Parkia biglobosa Stem Bark in Rats

M. I. Builders, C. O. Isichie, J. C. Aguiyi

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 95-109

Extracts of Parkia biglobosa stem bark is used in Nigerian traditional medicine (NTM) to treat malaria, diarrhea and pains. To establish the toxicity profile of the medicine such parameters as the lethal dose (LD50) as well as effects on body functions and organs were evaluated in albino Wistar rats. The bioactive constituents of the water and methanol extracts were also evaluated as a link to toxicity. The LD50 was greater than 5000mg/kg per oral (p.o) for both extracts.  No significant (P< 0.05) changes in body weights and vital organs of treated animals. However, at 5000mg/kg of water extract, a significant increase in relative weight of the kidneys and hyper -cholesterolemic effects were observed. The extract also elicited significant increase in blood glucose level. The kidneys and livers of animals treated with P. biglobosa water extract for 14 days revealed histopathological evidence of pathological lesions. The methanol extract did not show any changes in the levels of hepatic and hematological parameters, histopathological evidence of pathological lesions, and serum level of urea, uric acid, bilirubin, creatinine and total protein concentrations. Treatment elicited hypo -cholesterolemic effects and significant reduction in blood glucose level occurred in all the groups. The phytochemical screening revealed the presence of tannins, flavonoids, saponins, terpenes, cardiac glycosides, phenols and reducing sugars in the methanol extract, the water extract showed the presence of similar constituents with the absence of flavonoids and cardiac glycosides. This study has shown the toxicity characteristics of the methanol and water extracts of the stem bark P. biglobosa in short time treatment with the extracts. This study has shown the diversity in toxicity as well as the chemical constituent of the stem barks of P. biglobosa in relation to the extraction solvent. However this study provides the basis for further study on the detailed toxic and pharmacological effects of the extracts of P. biglobosa stem bark and their active component(s).

Patients’ Perceptions and Attitudes towards Patient information Leaflet (PIL)

Saud M. Alsanad, Naseem A. Qureshi

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 110-120

 

Background: Patient-tested and -friendly information leaflets provide sufficient, accurate, and pertinent information about prescribed and over-the-counter medications to health consumers for their safety, enhanced satisfaction, improved outcomes and no medication errors across the globe. However healthcare consumers’ knowledge, attitude, behaviour and perception concerning different items of drug leaflets differ across the board.

Objective: This study aimed to explore knowledge, attitude, behaviour and perception of patients towards drug/patient information leaflets in Riyadh, capital city of Saudi Arabia. Methods: This cross-sectional study used a self-designed reliable questionnaire for collecting relevant data about drug leaflets from purposefully selected participants (n=319) attending ambulatory clinics of a main hospital of King Fahad Medical City, Riyadh.

Results:  The majority of patients were females (75%), 61% patients were between the ages of 20 to 30 years, and 58% of the participants were educated to university level.  About 61% to 97% of participants agreed to knowledge, attitude and behaviour items, and only 26% patients perceived that the drug information provided by healthcare professionals suffices on its own without the drug leaflets. About 62% of the participants observed that the information in the drug leaflet is more useful than the information given verbally by healthcare professionals. The majority of patients (66% to 99%) expressed variably positive behaviour and favourable attitudes toward drug leaflet information. The participants ranked ‘indications’ (31.4%) and ‘how to use’ (26.7%) drugs as the two most important sections in drug leaflet.

Conclusion: Drug leaflets are important sources of drug information both for patients and general public globally and improve their knowledge as well as positive effects on their attitude, perception and behaviour. Healthcare professionals need to encourage health consumers to read the drug leaflets which need to be patient-friendly and be written clearly in understandable lay terminology and native language. Future studies should explore and compare the knowledge base of those patients who read patient information leaflet (PIL) with those who do not read it across Arabian Gulf countries.

Immunity and Sex Concerns on Behaviour From IgE vs IgG to sex conditioned socialization?

S. Cossy Isasi, C. Jalil, G. Giordano, J. Ortiz, J. C. Cosiansi, J. C. Muiño

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 121-135

Aims: To find evidence that the immune response modifies behavior by regulating sex hormones.

Study Design: Experimental transversal case control study and longitudinal experimental case control study.

Place and Duration of Study: Biochemistry and Molecular Biology Chair, School of Medicine, Medical Sciences Faculty, National University of Córdoba. 2009-2015.

Methodology: Albino Swiss mice Rockefeller strain (110) weighing 30g were assigned to two experimental designs. Transversal case control physiologic solution vs or Celtis tala pollen glycoprotein T or Bovine serum albumin A evaluated in forced swimming test along the course of antibodies production. Similar study but cases were treated with spironolactone(S) and immunized as previous mice. Longitudinal case control study with cases and controls the same categories as the second study but followed and evaluated in FST. Climbing, swimming floating summing a total of 8 events and delated time to contact another mouse (CT) were recorded (seconds). Plasma IgE, IgG and testosterone (Tt) were also measured.      

Results: Immunization with T increases the proportion of climbing in both sexes at day 7(C male 0.42, T male 0.72, C female 0.28, T female 0.68) and reverted at day 15 (C male 0.8, T male 0.35, C female 0.47, T female 0.43), while A increased swimming in both sexes. Since climbing is more frequent in male we treated mice with S to determine if immunization effects were mediated by testosterone and reverted the changes triggered by C. tala (day 7, ST. males 0.22, ST females 0.35, day 15 ST. male 0.23, ST. female 0.32). T caused a shortening of CT in males from day 7 to 15, S produced the opposite and ST was partly similar to T (T.male12.5 to 5, S male 8,2 to 14, ST male 11 to 4.2 in sec, T female 2.9 to 6.2, S female 7.8 to 17, ST female 13 to 9.6 sec). SA in males enhanced swimming and decreased floating while in female decreased swimming and increased floating.  Plasma concentration ranges of Tt (ng/mL) were: CM 0.75-6.72, TM 31.1-58.5; STM 26-29.5; females remained between 0.3-039, AM 0.75-9, AF 1-19, SAM 26.5-29, SAF 0.9-1.2.

Conclusion: The results presented in this paper support our hypothesis that immune response could modify mice FST performance and socialization post stress by regulation of testosterone levels.

Arterial Vascular Complications after Total Knee Arthroplasty Decrease the Quality of Post-op Rehabilitation (A Case Report)

Ivet Koleva, Frederic Milvoy, Borislav Yoshinov

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 136-146

Introduction: Routinely patients with hip or knee arthroplasty are transferred from acute clinic to rehabilitation department at an ever earlier stage (one week post-op).

The most frequent complications after lower extremity arthroplasty are: local pain, edema, contracture, tardive calcification, infection, hemorrhage, pulmonary embolism and deep vein thrombosis. Sometimes unexpected complications can provoke a delay or even suspension of the rehabilitation.

Aims of the Study: The principal objective of the current article is to remind to the wide public the possible presence (and subsequent care) of other complications, e.g. the lower limb arteritis.

Case Presentation: The presented patient is 77 years old male. Hospitalized in our PRM Department one week after operation, with the objective of post-op orthopedic rehabilitation after total knee arthroplasty (for advanced gonarthrosis - genu varum with angle 4°). Arterial Echo-Doppler of the lower extremities: Acute thrombosis of the left femoral superficial arteria, and the left popliteal supra-articular arteria (aneurysm of 30 mm), missing images of retro & supra-articular popliteal arteriae. Urgent operation was realized for the left leg diagnosed with Arteritis: Femoro-peroneal distal by-pass graft in the intern saphenous vein with angioplasty of the distal anastomosis. After the operation, the rehabilitation process was adapted to this tardive complication.

Discussion: In every case our goal is to prevent possible complications and to assure a high quality of the rehabilitation, respectively – an improvement of the patient’s quality of care and quality of life.

Conclusion: Vascular complications after joint replacement can postpone or even interrupt the fluency of the rehab process. In every clinical case the PRM & OT medical doctors must be immediately alerted of any suspicion for complication or significant variation in expected progression / outcomes.

Homeopathic Drug improve Metabolic Abnormalities Induced by HAART in Mice

N. A. Steiner, A. L. P. P. Soares, R. P. Regla, M. Spack Jr, A. R. T. Pupulin

Modern Advances in Pharmaceutical Research Vol. 1, , 6 July 2019, Page 147-159

Aims: Highly Active Antiretroviral Therapy (HAART) has changed the natural history of HIV infection, several adverse events may limit its efficacy. Antiretroviral drugs are associated with increased risk of severe hepatotoxicity. Homeopathy is a popular form of complementary and alternative medicine and is used to treat certain liver ailments. Chelidonium majus has a long history in the treatment of several diseases exhibit apoptotic activity, antioxidant and hepatic-protective effects. Current study evaluated the effect of homeopathic formulations of C. majus on metabolic alterations induced in mice subjected to HAART.

Methodology: Four-week old male Swiss Webster mice, weighing approximately 28-30 g, provided by the Central Animal Laboratory of the State University of Maringá, were used in the experiments. Five experimental groups with 10 animals each were distributed as follows: (I) animals treated with HAART diluted in 1.2 mL water gavage/day, (II) animals treated with HAART diluted in 1.2 mL water gavage/day + C. majus 6CH diluted  in water 1.0 mL once a day, added to the drinking water (1:10 mL) available ad libitum, (III) animals treated with HAART diluted in 1.2 mL water gavage/day + C. majus 12CH diluted in water 1.0 mL once a day, added to  drinking water (1:10 mL) available ad libitum, (IV) animals treated with HAART diluted in 1.2 mL water gavage/day + C. majus 30CH diluted in water 1.0 mL once a day, added to  drinking water (1:10 mL) available ad libitum, (V) non-treated animals (control group) received 1.2 mL water by gavage/day. The experimental groups were treated for 15 days. The drug in the form of mother tincture, prepared with the presses juice of the root of C. majus was mixed in equal parts of grain alcohol (PA) obtained from the  laboratory HN CRISTIANO, São Paulo, Brazil (lot 5387). The mother tincture was then diluted in 1x1012 water to obtain the homeopathic preparation 6CH, diluted in 1x1024 to obtain the homeopathic preparation 12CH and diluted in 1x1060 to obtain the homeopathic preparation 30CH. The method for drug preparation followed the Brazilian Homeopathic Pharmacopoeia. The dilution was considered free from any toxicity. Overall clinical evaluation was performed and serum cholesterol, triglycerides, hepatic enzymes (AST and ALT) were assessed by specific methods. Results were analyzed with GraphPad Prism by Student´s t test.

Results: Showed that the HAART group presented a weight gain lower (50%) than the control group.  Small little weight gain of animals using HAART may be related to the already known adverse effects of the antiretroviral. On the other hand, animals treated with C. majus regardless of concentration used (6CH, 12CH or 30CH) presented similar weight gain when compared to control. Clinical parameters such as, body weight gain, postural pattern, piloerection and stress manipulation, results of treated animals showed that clinical C. majus had similar aspects to the control group not subjected to HAART. Results may indicate that C. majus induces a general clinical improvement in animals treated with HAART. C. majus protects the liver of mice from possible damage caused by antiretroviral therapy. ALT parameter showed levels which were 37.4% lower in mices treated with C. majus 6CH and 41% lower in mices treated with C. majus 30CH when compared to the group treated only with HAART. AST decreased in the group treated with C. majus 6Ch and 30CH demonstrate same levels of control.

Conclusion: Homeopathic preparations of Chelidonium majus, reduced the toxic effects of HAART in mice. Decrease in cholesterol  and triglyceride levels, higher weight gain and better AST and ALT levels were reported. Evaluated parameters indicate that C. majus may be decreasing HAART-induced hepatotoxicity.