INTRODUCTION
Mastitis is a kind of inflammation of the mammary glands or udder in dairy animals such as cows, buffaloes, goats, sheep, and camels.[12345] This happens due to invasion of milk producing tissues by pathogenic microorganisms.[67] It also impairs the ability of secretary tissues synthesizing milk components and in this way lowers milk yield.
Mastitis can be classified into different types: clinical, subclinical, peracute, acute, subacute, chronic, contagious, and environmental mastitis. However, clinical mastitis is primarily responsible for the extensive economic losses to the dairy industry.[8] Various therapies are available to treat clinical mastitis such as antibiotics,[9] bacteriophage therapy,[10] and nonsteroidal anti-inflammatory drugs (NSAIDs).[11] In mastitis therapy, the primary function of NSAIDs is to reduce inflammation and neutralize the endotoxin-induced effects. Diverse groups of NSAIDs were licensed for treating the pain and inflammation including diclofenac, meloxicam, etc.[11] Of all the drugs, meloxicam is widely used in clinical mastitis for selective binding to the COX-2 enzyme.
Meloxicam, an NSAID, is a member of oxicam class of drugs, showed promising effects in reducing udder pain sensitivity, edema, and body temperature without affecting the rumination time.[1213] and has proved to be effective against mastitis in clinical trials and hence is a drug of choice in treating mastitis infections.
This review serves as one stop information on this aspect and also rephrases the preclinical and clinical evidence to unbox the relevance of meloxicam in mastitis. Moreover, the future prospect of insilico docking in the delivery of meloxicam for the management of clinical mastitis is also highlighted.
PHARMACOLOGICAL BENEFITS IN COMBATING MASTITIS
Mastitis caused by the Gram-positive and Gram-negative bacterial infections releases lipopolysaccharides which induce pyrexia. It also resulted in elevation of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). These pro-inflammatory mediators promote upregulation of cyclooxygenase (COX) expression [Figure 1].[14] and meloxicam mitigates mastitis symptoms by blocking COX-2 expression.
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Figure 1: Schematic representation of mechanism of action of meloxicam in mastitis
Meloxicam causes mitigation of pain and distress associated with mastitis[15] in lactating dairy cows.
REDUCES SOMATIC CELL COUNT
The normal level of somatic cells called somatic cell count (SCC) is approximately 1 × 105 cells/ml from the milk of healthy mammary gland.[16] In general, higher SCC indicates lower milk quality [Figure 1]. Meloxicam injection in combination with antibiotics leads to lower SCC in dairy animals.[17]
DIMINISHES THE RISK OF CULLING
Culling is the process of separating cows from the main herd according to desired or undesired characteristics for slaughter.[18] One of the research findings suggested that administration of meloxicam with antimicrobials helps in reducing the risk of culling as compared to antimicrobial treatment alone.[17]
TRIM DOWNS UDDER EDEMA
In mastitis, the gland often becomes blotted and painful.[19] European Medicines Agency investigated that the oral supportive therapy of meloxicam together with antibiotics diminishes the bacterial infection of udder edema.[20]
POSITIVE EFFECT ON FERTILITY
Experimental investigation by McDougall etal.,[21] explained that in the cases of mastitis, PGF2α, which was released by the mammary glands, has the ability to shorten the lifespan of corpus luteum. This reduced corpus luteum level increases the likelihood of failure in recognition of pregnancy and conception which finally leads to reduced fertility. Meloxicam shows protective action against the infertility by combating the PGF2α levels.
MELOXICAM HELPS REDUCE PAIN AND INFLAMMATION: PRECLINICAL EVIDENCE
Preclinical investigations should follow Good Laboratory Practices in International Conference on Harmonization guidelines. Veterinary drugs intended for oral and parenteral administration are usually given on weight basis as per the following formula:
Meloxicam alone and in combination with other drugs has undergone preclinical testing. The data demonstrate its potential in the management of pain and inflammation as summarized in [Table 1].
Table 1: Preclinical analysis of meloxicam in mice/rat models of pain and inflammation
MASTITIS MAY BE SUCCESSFULLY TREATED WITH MELOXICAM: CLINICAL EVIDENCE
Clinical trials have been conducted to determine the impact of veterinary drugs on the animal subjects. The main goal of clinical trials of a veterinary medicinal product is to determine a safe dose with effective-dosing schedule. Depending on the goal of the clinical trial, it may be categorized as either exploratory (pilot) or confirmatory (pivotal) trial [Figure 2] as per the European agency for the evaluation of medicinal products.[28] In addition, the Committee for Medicinal Products for Veterinary Use (CVMP) or Veterinary International Conference on Harmonization guidelines provided the directions in selection of primary variables (used to estimate the sample size). Basically, two methods are used to calculate the sample size in animal studies. The most favored and reliable scientific method is power analysis. Another method employed for the calculation of sample size is G power software (performs power calculations for a wide range of experimental setups). Furthermore, resource equation is an alternative approach against power analysis to calculate the sample size in animal studies.
Figure 2: Classification of veterinary clinical trials as per European Agency for the evaluation of medicinal products
Where, DF depicts degree of freedom; N refers to total number of subjects, k is number of groups, and n designates number of subjects per group.
In continuation, both randomization and blinding are the most imperative design methods employed to decrease prejudice in clinical trials. In randomized clinical trial (RCT), groups are allocated with subjects aimlessly that they obtain dissimilar treatment(s) or no treatment. In addition to this, two major classes of RCT designs are parallel (between-group) and crossover (within-group) studies. Animals are haphazardly assigned to two groups, i.e., A and B in the parallel group design. One of the groups stands as control receiving the standard treatment or placebo, while the other group takes delivery of the experimental treatment. In crossover studies, veterinary patients are set as their own controls. Next, stratification could be carried out as a part of the randomization to stop possible inequity. In this, randomization of animals in treatment groups within strata is based on vital prognostic factors, e.g., breed, sex, age, and stage of disease. Furthermore, blinding is the second most imperative design technique, refers to the study design which averts the knowledge of few or all the individuals concerned with the test regarding the treatment assigned to the particular group of the animals.[29] Several veterinary clinical trials in dairy cows were conducted to demonstrate the potential of meloxicam in the treatment of mastitis [Table 2].
Table 2: Clinical analysis of meloxicam in mastitis of dairy cattle
FUTURE PROSPECTS FOR MELOXICAM IN THE TREATMENT OF MASTITIS: INTEGRATED NANOTECHNOLOGY-DRIVEN OPPORTUNITIES
In India, for veterinary purposes, meloxicam injection (5 mg) is given by intramuscular, intravenous or subcutaneous route to dairy cattle.[13] Furthermore, pharmacokinetic analysis in a parallel study design comprising healthy and lactating cows indicated that intravenous (0.2 mg/kg) or oral (1.0 mg/kg) administration of meloxicam exhibited a decreased systemic clearance in postpartum relative to mid-lactation cows, which resulted in a longer half-life and increased total exposure independent of mode of administration.
In order to surmount confronts associated with oral and parental preparations, colloidal and particulate nanocarriers may be implicated to deliver meloxicam at the target site.
Our group also formulated meloxicam dermal spray for topical administration.[32] A film forming polymer was incorporated in the dermal spray which formed a polymeric film on the skin surface and ensured its prolonged course of action. Nanoencapsulation of drugs requires adequate expertise for bench to bedside delivery.[33] Customization of nanoparticulate system requires optimization which is a tedious process. Various statistical tools are being used in the optimization and preparation of nanopaticles, now alternatively ANN is being explored in the field of nanotechnology.
ANN is a computer program which simulates the neural network of human brain by learning from different experiences by using distinct learning algorithms.[34] A set of critical attributes can be optimized by the use of ANN[35] where a set of experimental data is given in the learning phase and the validation is to be performed to analyze the effectiveness of the model.
Amasya etal. implemented ANN for obtaining the design space for hydrogel of lipid nanoparticles. Parameters in order to achieve the desired characteristics.[36]
Modeling of biological membrane is achieved by various software packages where the interaction of excipients with the appropriate biological membrane can be simulated to select the suitable excipient. Kaushik etal., studied the effect of different penetration enhancers on the permeation in the presence of different vehicles.[37] Thus, with the molecular modeling tool, simulation of biological membrane and meloxicam in presence of different excipients can be carried out to screen the excipients in insilico.
Hence, ANN and insilico docking advocate integration with nanotechnology techniques in development of topical drug delivery cargo of meloxicam in the treatment of mastitis for gaining superior clinical benefits.
CONCLUSION
Mastitis is a major contributor in economic losses in dairy industry in India. Mastitis in cattle remarkably influences milk quality and quantity. Meloxicam holds great potential in the treatment of mastitis. However, physicochemical and biopharmaceutical limitations pose major hurdle in delivery of therapeutic concentration at the site of application. Novel drug delivery approaches are a good option and offer several advantages as compared to traditional topical dermal dosage forms. Therefore, substantial opportunities are available to successively deliver meloxicam at the site of action in mastitis that will ultimately help to achieve set goals of milk production as well as surely offer incredible merits to farmers and dairy industry.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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