Structure-activity relationship of pharmacophores and toxicophores: the need for clinical strategy.

OBJECTIVES: Sometimes clinical efficacy and potential risk of therapeutic and toxic agents are difficult to predict over a long period of time. Hence there is need for literature search with a view to assessing cause of toxicity and less efficacy of drugs used in clinical practice. METHOD: Hence literatures were searched for physicochemical properties, chemical formulas, molecular masses, pH values, ionization, receptor type, agonist and antagonist, therapeutic, toxic and structure-activity relationship of chemical compounds with pharmacophore and toxicophore, with a view to identifying high efficacious and relative low toxic agents. Inclusion criteria were manuscripts published on PubMed, Scopus, Web of Science, PubMed Central, Google Scholar among others, between 1960 and 2023. Keywords such as pharmacophore, toxicophore, structure-activity-relationship and disease where also searched. The exclusion criteria were the chemicals that lack pharmacophore, toxicophore and manuscripts published before 1960. RESULTS: Findings have shown that pharmacophore and toxicophore functional groups determine clinical efficacy and safety of therapeutics, but if they overlap therapeutic and toxicity effects go concurrently. Hence the functional groups, dose, co-administration and concentration of drugs at receptor, drug-receptor binding and duration of receptor binding are the determining factors of pharmacophore and toxicophore activity. Molecular mass, chemical configuration, pH value, receptor affinity and binding capacity, multiple pharmacophores, hydrophilic/lipophilic nature of the chemical contribute greatly to functionality of pharmacophore and toxicophore. CONCLUSION: Daily single therapy, avoidance of reversible pharmacology, drugs with covalent adduct, maintenance of therapeutic dose, and the use of multiple pharmacophores for terminal diseases will minimize toxicity and improve efficacy.

Biomedical Applications of Polyurethane Hydrogels, Polyurethane Aerogels, and Polyurethane-graphene Nanocomposite Materials.

BACKGROUND: The emergence of new diseases poses therapeutic challenges in modern medicine. Polyurethane hydrogels that comprise polyol, copolymer and extender could be prepared from diverse chemical compounds with adjuvants such as ascorbic acid and sorbitol, among others. Their mechano-physicochemical properties are functions of their biological activities. Therefore, there is a need to assess their therapeutic potentials. METHODS: Relevant literature on the synthesis and medical uses of polyurethane-hydrogels, polyurethane- aerogels, and polyurethane-graphene nanocomposite materials was searched in order to identify their sources, synthesis, mechanical and physiochemical properties, biomedical applications, chirality, and the relevance of Lipinski's rule of five in the synthesis of oral polyurethane nanocomposite materials. RESULTS: The prepared hydrogels and aerogels could be used as polymer carriers for intradermal, cutaneous, and intranasal drugs. They can be fabricated and used as prosthetics. In addition, the strength modulus (tensile stress-tensile strain ratio), biodegradability, biocompatibility, and nontoxic effects of the polyurethane hydrogels and aerogels are highly desirable properties. However, body and environmental temperatures may contribute to their instability; hence, there is need to improve the synthesis of aerogels and hydrogels of polyurethane in order to ensure that they can last for many years. Alcoholism, diabetes, pyrogenic diseases, mechanical and physical forces, and physiological variability may also reduce the life span of polyurethane aerogels and hydrogels. CONCLUSION: Synthesis of polyurethane hydrogel-aerogel complex that can be used in complex, rare biomedical cases is of paramount importance. These hydrogels and aerogels may be hydrophobic, hydrophilic, aerophobic-aerophilic or amphiphilic, and sometimes lipophilic, depending on structural components and the intended biomedical uses. Polyurethane graphene nanocomposite materials are used in the treatment of a myriad of diseases, including cancer and bacterial infection.

Application of modified Michaelis - Menten equations for determination of enzyme inducing and inhibiting drugs.

BACKGROUND: Pharmacokinetics (PK) is the process of absorption, distribution, metabolism and elimination (ADME) of drugs. Some drugs undergo zero-order kinetics (ethyl alcohol), first order kinetics (piroxicam) and mixed order kinetics (ascorbic acid). Drugs that undergo Michaelis-Menten metabolism are characterized by either increased or decreased metabolism constant (Km) and maximum velocity (Vmax) of enzyme reaction. Hence literatures were searched with a view to translating in vitro-in vivo enzyme kinetics to pharmacokinetic/pharmacodynamic parameters for determination of enzyme inducing and inhibiting drugs, in order to achieve optimal clinical efficacy and safety. METHODS: A narrative review of retrospective secondary data on drugs, their metabolites, Vmax and Km, generated in the laboratory and clinical environments was adopted, using inclusion and exclusion criteria. Key word search strategy was applied, to assess databases of published articles on enzyme inducing and inhibiting drugs, that obey Michaelis-Menten kinetics. In vitro and in vivo kinetic parameters, such as concentration of substrate, rate of endogenous substrate production, cellular metabolic rate, initial velocity of metabolism, intrinsic clearance, percent saturation and unsaturation of the enzyme substrate, were calculated using original and modified formulas. Years and numbers of searched publications, types of equations and their applications were recorded. RESULTS: A total of fifty-six formulas both established and modified were applied in the present study. Findings have shown that theophylline, voriconazole, phenytoin, thiopental, fluorouracil, thyamine and thymidine are enzyme inducers whereas, mibefradil, metronidazole, isoniazid and puromicin are enzyme inhibitors. They are metabolized and eliminated according to Michaelis-Menten principle. The order could be mixed but may change to zero or first order, depending on drug concentration, frequency and route of drug administration. CONCLUSION: Hence, pharmacokinetic-pharmacodynamic translation can be optimally achieved by incorporating, newly modified Michaelis-Menten equations into pharmacokinetic formulas for clinical efficacy and safety of the enzyme inducing and inhibiting therapeutic agents used in laboratory and clinical settings.

Genetic diversity of canine parvovirus variants circulating in Nigeria.

Canine parvovirus (CPV) is a fast-evolving single-stranded DNA virus that causes severe and fatal gastrointestinal disease in dogs. Lately, several mutations affecting viral protein (VP) capsid resulting in highly pathogenic variants with distinctive immunological and clinicopathological characteristics abound. This study involved screening stools of 44 randomly selected clinical cases of canine gastroenteritis from 4 cities (Ibadan, Jos, Makurdi, and Zaria) in Nigeria for CPV antigen using an on-the-spot immunoassay test kit, as well as, molecular detection of viral nucleic acid by polymerase chain reaction. Subsequently, nucleic acid sequencing of 1195-bp amplicons encompassing the VP2 encoding region was done. The resultant 40 high-quality amino acid sequences obtained were analysed for the identification and grouping of the viruses into their discrete variants - CPV-2a, CPV-2b, or CPV-2c, using key amino acids substitutions - Asn, Asp, or Glu respectively at position 426 of the VP2 gene. One-third (11/40; 27.5%) of the analysed sequences were identified as CPV-2a and two-third (29/40; 72.5%) as CPV-2c. The original CPV and CPV-2b were not detected. Also, the "new CPV-2a variant" with mutation S297A identified had two additional mutations (Y324I and T440A) associated with selective pressure and vaccination failure in their sequences. Similarly, unique CPV-2c mutants carrying genetic markers (S297A, Y324I, and Q370R) that are highly related to CPVs of Asian origin were observed. These findings revealed a high level of divergence of existing CPVs in circulation; suggesting that CPV is rapidly evolving in Nigeria lately.

Modified formulas for calculation of encephalization: quotient in dogs.

OBJECTIVE: Dogs are a breed of animals that play important roles in security service, companionship, hunting, guard, work and models of research for application in humans. Intelligence is the key factor to success in life, most especially for dogs that are used for security purposes at the airports, seaports, public places, houses, schools and farms. However, it has been reported that there is correlation between intelligence, body weight, height and craniometry in human. In view of this, literatures were searched on body weight, height and body surface areas of ten dogs with intent to determining their comparative level of intelligence using encephalization quotient. RESULTS: Findings revealed that dogs have relationship of brain allometry with human as proven by encephalization quotient [Formula: see text] and Brain Mass (E) = kpß, where p is the body weight; k = 0.14 and ß = 0.528, respectively. Saganuwa's formula yielded better results as compared with the other formulas. Dogs with body surface area (BSA), weight and height similar to that of human are the most intelligent. Doberman pinscher is the most intelligent followed by German shepherd, Labrador retriever, Golden retriever, respectively.

Comparative therapeutic index, lethal time and safety margin of various toxicants and snake antivenoms using newly derived and old formulas.

OBJECTIVE: The assessment of clinical efficacy and toxicity is very important in pharmacology and toxicology. The effects of psychostimulants (e.g. amphetamine), psychotomimetics (e.g. Cannabis sativus) and snake antivenoms are sometimes unpredictable even at lower doses, leading to serious intoxication and fatal consequences. Hence, there is need to re-assess some formulas for calculation of therapeutic index, lethal time and safety margin with a view to identifying therapeutic agents with remarkable toxicity potentials. RESULTS: The therapeutic index formula [Formula: see text] was derived from T1 = LD50/ED50 and ED50 = [Formula: see text]. Findings have shown that, therapeutic index is a function of death reversal (s), safety factor (10-4) and weight of animal (Wa). However, the new safety margin formula [Formula: see text] derived from LT50 = [Formula: see text] and MS = [Formula: see text] shows that safety margin is a function of cube root of ratio between LT50 and LD50 and ED100th. Concentration (k) of toxicant at the receptor [Formula: see text] derived from D1 × Tn = K and LD1 = [Formula: see text] shows that therapeutic index, lethal time and safety margin is a function of drug or toxicant concentration at the receptor, the drug-receptor interaction and dose of toxicant or drug administered at a particular time.

Application of median lethal concentration (LC50) of pathogenic microorganisms and their antigens in vaccine development.

OBJECTIVE: Lack of ideal mathematical models to qualify and quantify both pathogenicity, and virulence is a dreadful setback in development of new antimicrobials and vaccines against resistance pathogenic microorganisms. Hence, the modified arithmetical formula of Reed and Muench has been integrated with other formulas and used to determine bacterial colony forming unit/viral concentration, virulence and immunogenicity. RESULTS: Microorganisms' antigens tested are Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa in mice and rat, Edwardsiella ictaluri, Aeromonas hydrophila, Aeromonas veronii in fish, New Castle Disease virus in chicken, Sheep Pox virus, Foot-and-Mouth Disease virus and Hepatitis A virus in vitro, respectively. The LC50s for the pathogens using different routes of administrations are 1.93 × 103(sheep poxvirus) and 1.75 × 1010 for Staphylococcus aureus (ATCC29213) in rat, respectively. Titer index (TI) equals N log10 LC50 and provides protection against lethal dose in graded fashion which translates to protection index. N is the number of vaccine dose that could neutralize the LC50. Hence, parasite inoculum of 103 to 1011 may be used as basis for determination of LC50 and median bacterial concentrations (BC50).Pathogenic dose for immune stimulation should be sought at concentration about LC10.

Chirality of Central Nervous System (CNS) Acting Drugs: A Formidable Therapeutic Hurdle Against CNS Diseases.

BACKGROUND: Over fifty percent of drugs being used clinically are chiral and 90% of them are racemates. Unfortunately, they have both adverse and beneficial effects on body systems. METHODS: Because of the erratic effects of chiral compounds on body functional systems, literature search was carried out with a view to identify CNS chiral drugs, their clinical advantages and disadvantages, unique physicochemical properties and structural modifications into safer drugs. RESULTS: Findings have shown that majority of CNS and non-CNS acting drugs have chiral functional groups that may occur as either dextrorotatory (clockwise) or levorotatory (anticlockwise) or racemates which are inert. Sometimes, the enantiomers (optical isomers) could undergo keto-enol tautomerism, appearing in either acidic or basic or inert form. Chiral CNS acting drugs have agonistic and antagonistic effects, clinical advantages, disadvantages, and special clinical applications, possible modifications for better therapeutic effects and possible synthesis of more potent drugs from racemates. Clockwise chirality may be more effective and safer than the drugs with anticlockwise chirality. When chiral drugs are in racemate state they become inert and may be safer than when they are single. Also, diastereoisomers may be more dangerous than stereoisomers. CONCLUSION: Therefore, chiral compounds should be adequately studied in lab rodents and primates, and their mechanisms of actions should be comprehensively understood before being used in clinical setting. Since many of them are toxic, their use should be based on principle of individualized medicine. Their molecular weights, functional groups, metabolites, polymers and stereoisomers could be valuable tools for their modifications.

Chemistry and Effects of Brainstem Acting Drugs.

BACKGROUND: Brain is the most sensitive organ, whereas brainstem is the most important part of Central Nervous System (CNS). It connects the brain and the spinal cord. However, a myriad of drugs and chemicals affects CNS with severe resultant effects on the brainstem. METHODS: In view of this, a number of literature were assessed for information on the most sensitive part of brain, drugs and chemicals that act on the brainstem and clinical benefit and risk assessment of such drugs and chemicals. RESULTS: Findings have shown that brainstem regulates heartbeat, respiration and because it connects the brain and spinal cord, all the drugs that act on the spinal cord may overall affect the systems controlled by the spinal cord and brain. The message is sent and received by temporal lobe, occipital lobe, frontal lobe, parietal lobe and cerebellum. CONCLUSION: Hence, the chemical functional groups of the brainstem and drugs acting on brainstem are complementary, and may produce either stimulation or depression of CNS.

Therapeutic effects of Byrsocarpus coccineus root bark extract on bacterially and chemically induced diarrhea in the Wistar albino rat (Rattus norvegicus domestica).

BACKGROUND: Diarrhea can be caused by pathogenic microorganisms and chemicals. In view of this, Byrsocarpus coccineus Schum and Thonn (Connaraceae) was used to treat diarrhea induced by castor oil or bacteria in Wistar albino rats. METHODS: Qualitative and quantitative analyses of an aqueous root back extract of B. coccineus were made and the acute toxicity, antidiarrhea properties, and in vitro and in vivo antimicrobial activities of the extract were investigated in rats. RESULTS: The phytochemical analysis of the root bark extract revealed the presence of flavonoids, alkaloid, saponins, tannins, and phenols. The quantitative analysis showed that saponins formed 10.6% of the extract, tannins 7.6%, flavonoids 6.2%, phenol 5.8% and alkaloids 4.4%. A dose limit of 5000 mg/kg was safe to use in the rats. At a dose of 100 mg/kg, the extract decreased distance travelled by activated charcoal in the gastrointestinal tract, frequency of defecation, and number of unformed faeces caused by castor oil-induced diarrhea, and led to 74.96% inhibition of the diarrhea effects. Escherichia coli and Salmonella pullorum were susceptible to higher concentrations of the extract with a minimum inhibitory concentration of 0.3125 mg/mL. E. coli-infected rats showed depression, weight loss, anorexia, diarrhea, and weakness, which was ameliorated by the extract on day 2 post treatment. Observed congestion, cellular infiltration and necrosis of the liver, intestine and kidney following infection were improved by the extract. CONCLUSION: B. coccineus extract can be used in the treatment of anaemia, and castor oil- and E. coli-induced diarrhea in rats.

Determination of median effective dose (ED50) of scorpion antivenom against scorpion envenomation using a newly developed formula.

BACKGROUND: About 50 species of scorpions cause fatal scorpionism worldwide. Most of these are members of the Buthidae family, and include, among others, Mesobuthus eupeus, Androctonus crassicauda, Leiurus abdullahbayrami, Leiurus quinquestriatus, Tityus pachyurus and Androctonus australis. Because high doses of scorpion venom and antivenom can cause death and hypersensitive reactions, there is a need to develop a formula that can be used to calculate both lethal and effective doses for scorpion venom and antivenom, respectively, thereby obviating the need for laboratory experiments. METHODS: In view of this, a literature search was carried out with the aim of modifying the formula ( LD 50 = ED 50 3 × W a × 10 - 4 ) for calculation of the median lethal dose (LD50) of scorpion venom and the ED50 of antivenom. The human equivalent dose (HED) formula was assessed for extrapolation of LD50 and ED50 from animals to human for comparison and relevance with the new formula. RESULTS: The findings showed that the newly developed formula (LD50 = ED50 1/3 × W a  × 10-4) yielded results that are very close to the reported values. Therefore, the newly developed and HED formulas can be used for calculation of LD50 and ED50 values for scorpion venom and antivenom, respectively. CONCLUSION: The new formula yielded better results than the HED formula, confirming its predictive validity, precision, and reliability, thereby obviating the need for rigorous experiments and justifying the principles of reduction, refinement, and replacement (3Rs).

Piroxicam: Source for Synthesis of Central Nervous System (CNS) Acting Drugs.

BACKGROUND: The use of central nervous system (CNS) acting drugs in the management of neuro degenerative and psychiatric problems cannot be overemphasized. Therefore, the chemical structure of piroxicam can be modified to yield new CNS stimulants and depressants that can be of great benefit to man and animals. METHODOLOGY: Acetylcholine has Methyl - Oxygen-Oxygen (M-O-O) and Nitrogen (N) functional groups which are structurally related to Sulphur-Oxygen-Oxygen (S-O-O) and Nitrogen (N) of piroxicam that are either methylated or hydrogenated. Each arecoline and nicotine has M-O-O in addition to methylated nitrogen and pyridine ring respectively, making them structurally related to piroxicam. Therefore, when Sulphur of piroxicam is replaced by methyl group, it may likely have muscarinic effects expressed by glandular secretion, gut sedation and vasodepression. Whereas the nitrogen group may be responsible for cholinergic effect in gaglia and striated muscle. Because of the carboxylic functional group (COOH), piroxicam may display depressant effect. Hence C = O, C = N and C = C in piroxicam may change due to biofield treatement. CONCLUSION: The conversion of piroxicam to central nervous system (CNS) acting drugs may be by desulphation, methylation, dehydrogenation, carboxylation and carbonylation. The would-be synthesized CNS drugs from piroxicam, should have low molecular weight, lipid solubility and low PH.

Toxico-Neurological Effects of Piroxicam in Monogastric Animals.

Piroxicam is a benzothiazine compound with anti-inflammatory, antipyretic, and analgesic properties. Because of the very high efficacy of piroxicam and its increasing use in the treatment of carcinomas in dogs and cats, there is a need for acute toxicity study of piroxicam in monogastric animals and its potential for causing secondary poisoning in puppies. Piroxicam manufactured by Shanxi Federal Pharmaceutical Co, Ltd. was used for this study. Revised up-and-down procedure was used for the estimation of median lethal dose in mouse (259.4 ± 51.9 mg/kg), rat (259.4 ± 69.6 mg/kg), rabbit (707.5 ± 130.8 mg/kg), cat (437.5 ± 128.1 mg/kg), guinea pig (218.7 ± 64.1 mg/kg), monkey (733.3 ± 83.3 mg/kg), broiler (285.3 ± 62.5 mg/kg), hen (638.3 ± 115.4 mg/kg), turkey (707.5 ± 130.8 mg/kg), pigeon (375 ± 55.9 mg/kg), and duck (311.3 ± 46.6 mg/kg). The acute toxicity signs of piroxicam at doses 207.5 mg/kg and above observed in the animals are torticollis, opisthotonos, somnolence, lethargy, diarrhea, gastroenteritis, generalized internal bleeding, anemia, congestion of the lung and liver, flaccid paralysis, cheesy lung, urinary incontinence, engorged urinary bladder, convulsive jerking of the limbs, lying in ventral recumbency, gasping for air, roaring, and death. Three out of six puppies died after being fed the carcasses of poisoned turkey, duck, and hen administered piroxicam at doses of 1000, 415, and 1000 mg/kg, respectively. White flaky cheesy materials observed in turkeys were also observed in the gastrointestinal content of the puppies. Paleness of carcasses, watery crop content, dryness of pericardium, gastroenteritis, intestinal perforation, and whitish pericardium were observed in broilers. There were effusions in thoracic and abdominal cavities as seen in all other carcasses poisoned primarily by piroxicam. Administration of atropine (0.02 mg/kg) led to survival of the remaining puppies. In conclusion, piroxicam is very to moderately toxic in monogastric animals.

The new algorithm for calculation of median lethal dose (LD50) and effective dose fifty (ED50) of Micrarus fulvius venom and anti-venom in mice.

One million people throughout the world are bitten yearly by poisonous snakes. Of this, one-tenth died and three-tenth suffer some forms of disabilities. In view of this, anti-snake venoms are currently being developed against viper and colubrid snake venoms using mice. Therefore, a new algorithm for calculation of median lethal dose (LD50) and effective dose fifty (ED50) was developed for Micrarus fulvius venom and antivenom respectively. This paper compared the formula of effective dose fifty (ED50) developed by Spearman and Karber with ideal median lethal dose (IMLD50) formula developed by Saganuwan with a view to bringing out their difference and similarity in calculation of ED50 that could be used to develop a new median lethal dose formula for calculation of Micrarus fulvius venom in mice. The findings revealed that ED50 value (477 mg/kg) from Spearman and Karber's formula ( ED50=logED50=logX100-logFDn(Σt-n/2) is comparatively similar with ideal median lethal dose value (428.75 mg/kg) from Saganuwan's formula (MLD50 + MSD50/2). The new LD50 formula ( LD50=ED503×Wm×10-4 ) yielded value (0.29 mg/kg) of comparative significance with reported value (0.32 mg/kg). When ED50 is equal to 2LD50, the denominator of ED503 becomes 2. In conclusion, the new formula would yield low doses of snake anti-venoms with reduced possibility of hypersensitivity reaction.

Ameliorative properties of aqueous extract of Ficus thonningii on erythrocyte osmotic fragility induced by acetaminophen in Rattus norvegicus.

In vitro antioxidant and erythrocyte protecting activities by aqueous extract of Ficus thonningii leaves on blood cells were studied in acetaminophen treated rats. The extract was safe at limit dose of 5000 mg kg(-1) body weight. The extract demonstrated dose dependent antihemolytic effect at dose levels between 50 and 200 mg kg(-1) body weight. The lowest antihemolytic effect was observed at dose level of 200 mg kg(-1) body given the lowest percentage hemolysis of 10.53 ± 1.76%, whereas the highest percentage hemolysis at dose level of 50 mg kg(-1) was 29.02 ± 7.45%. Hematology revealed erythrocytosis at dose levels of 100 and 200 mg kg(-1) body weight. Hyperglobinemia and lymphocytopenia were observed at dose levels of 100 mg kg(-1) and 200 mg kg(-1), respectively. The extract effectively showed scavenging activity on a stable oxidative radical diphenylpicrylhydrazyl (DPPH) and a significant ferric reducing antioxidant power (FRAP) activity. The plausible erythrocyte membrane protective effect may be due to its free radical scavenging activity and hence the extract can be used to improve hematological parameters and ameliorate oxidative stress.