Cutivate Gt

Uses

Blepharitis, blepharoconjunctivitis, conjunctivitis, dacryocystitis, keratitis, keratoconjunctivitis, acute meibomianitis, and corneal ulcers caused by susceptible organisms. Otorrhea associated with external otitis, chronic suppurative otitis media or subacute purulent otitis media; or postoperative otorrhea, such as that following fenestration, mastoidectomy or tympanoplasty.

Gentamicin cream is used for the topical treatment of the primary and secondary bacterial infections of the skin caused by the organisms sensitive to Gentamicin. Gentamicin may clear infections that have not responded to other topical antibiotics.

Zinc is an essential element commonly used for the treatment of patients with documented zinc deficiency.

Zinc can be used for the treatment and prevention of zinc deficiency/its consequences, including stunted growth and acute diarrhea in children, and slowed wound healing. It is also utilized for boosting the immune system, treating the common cold and recurrent ear infections, as well as preventing lower respiratory tract infections .

Cutivate Gt is also used to associated treatment for these conditions: Bacterial Conjunctivitis, Bacterial Infections, Bacterial Peritonitis, Bacterial dacryocystitis, Blepharoconjunctivitis, Central Nervous System Infections, Conjunctivitis allergic, Corneal infection, Dermatitis infected, Ecthyma, Eczematous dermatitis infected, Folliculitis, Furunculosis, Gram-negative enteric bacilli neonatal sepsis, Impetigo contagious, Inflammation, Keratitis bacterial, Keratoconjunctivitis, Meibomianitis, Meningitis, Bacterial, Ocular Inflammation, Pustular Psoriasis (PP), Pustular acne, Pyoderma Gangrenosum, Seborrheic Dermatitis, Septicemia gram-negative, Skin Infections, Skin Infections, Bacterial, Skin and Subcutaneous Tissue Bacterial Infections, Sycosis barbae, Bacterial blepharitis, Bacterial corneal ulcers, Bacterial dermatoses, Complicated Bacterial Urinary Tract Infections, Complicated Respiratory tract infection bacterial, Corticosteroid-responsive dermatoses, Ocular bacterial infections, Severe Endocarditis enterococcal, Severe Infection Pseudomonas aeruginosa, Severe Staphylococcal infectionCandidiasis, Common Cold, Diaper Dermatitis, Diaper Rash, Eye redness, Iron Deficiency (ID), Ocular Irritation, Skin Irritation, Sunburn, Wilson's Disease, Zinc Deficiency, Dietary and Nutritional Therapies, Dietary supplementation

How Cutivate Gt works

There are 3 key phases of aminoglycoside entry into cells. The first “ionic binding phase” occurs when polycationic aminoglycosides bind electrostatically to negatively charged components of bacterial cell membranes including with lipopolysaccharides and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acids and phospholipids within the cell membrane of Gram-positive bacteria. This binding results in displacement of divalent cations and increased membrane permeability, allowing for aminoglycoside entry. The second “energy-dependent phase I” of aminoglycoside entry into the cytoplasm relies on the proton-motive force and allows a limited amount of aminoglycoside access to its primary intracellular target - the bacterial 30S ribosome. This ultimately results in the mistranslation of proteins and disruption of the cytoplasmic membrane.[A233320] Finally, in the “energy-dependent phase II” stage, concentration-dependent bacterial killing is observed. Aminoglycoside rapidly accumulates in the cell due to the damaged cytoplasmic membrane, and protein mistranslation and synthesis inhibition is amplified. The necessity of oxygen-dependent active transport explains why aminoglycosides are ineffective against anaerobic bacteria. Hence, aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modeling support this two-mechanism model. Inhibition of protein synthesis is a key component of aminoglycoside efficacy. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site.[A232324, A232329] Overall, aminoglycoside binding has several negative effects including inhibition of translation, initiation, elongation, and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit.[A232329, A232339] Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation.[A232344] Mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above.

Zinc has three primary biological roles: catalytic, structural, and regulatory. The catalytic and structural role of zinc is well established, and there are various noteworthy reviews on these functions. For example, zinc is a structural constituent in numerous proteins, inclusive of growth factors, cytokines, receptors, enzymes, and transcription factors for different cellular signaling pathways. It is implicated in numerous cellular processes as a cofactor for approximately 3000 human proteins including enzymes, nuclear factors, and hormones .

Zinc promotes resistance to epithelial apoptosis through cell protection (cytoprotection) against reactive oxygen species and bacterial toxins, likely through the antioxidant activity of the cysteine-rich metallothioneins .

In HL-60 cells (promyelocytic leukemia cell line), zinc enhances the up-regulation of A20 mRNA, which, via TRAF pathway, decreases NF-kappaB activation, leading to decreased gene expression and generation of tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and IL-8 .

There are several mechanisms of action of zinc on acute diarrhea. Various mechanisms are specific to the gastrointestinal system: zinc restores mucosal barrier integrity and enterocyte brush-border enzyme activity, it promotes the production of antibodies and circulating lymphocytes against intestinal pathogens, and has a direct effect on ion channels, acting as a potassium channel blocker of adenosine 3-5-cyclic monophosphate-mediated chlorine secretion. Cochrane researchers examined the evidence available up to 30 September 2016 .

Zinc deficiency in humans decreases the activity of serum thymulin (a hormone of the thymus), which is necessary for the maturation of T-helper cells. T-helper 1 (Th(1)) cytokines are decreased but T-helper 2 (Th(2)) cytokines are not affected by zinc deficiency in humans [A342417].

The change of Th(1) to Th(2) function leads to cell-mediated immune dysfunction. Because IL-2 production (Th(1) cytokine) is decreased, this causes decreased activity of natural-killer-cell (NK cell) and T cytolytic cells, normally involved in killing viruses, bacteria, and malignant cells [A3424].

In humans, zinc deficiency may lead to the generation of new CD4+ T cells, produced in the thymus. In cell culture studies (HUT-78, a Th(0) human malignant lymphoblastoid cell line), as a result of zinc deficiency, nuclear factor-kappaB (NF-kappaB) activation, phosphorylation of IkappaB, and binding of NF-kappaB to DNA are decreased and this results in decreased Th(1) cytokine production .

In another study, zinc supplementation in human subjects suppressed the gene expression and production of pro-inflammatory cytokines and decreased oxidative stress markers [A3424]. In HL-60 cells (a human pro-myelocytic leukemia cell line), zinc deficiency increased the levels of TNF-alpha, IL-1beta, and IL-8 cytokines and mRNA. In such cells, zinc was found to induce A20, a zinc finger protein that inhibited NF-kappaB activation by the tumor necrosis factor receptor-associated factor pathway. This process decreased gene expression of pro-inflammatory cytokines and oxidative stress markers .

The exact mechanism of zinc in acne treatment is poorly understood. However, zinc is considered to act directly on microbial inflammatory equilibrium and facilitate antibiotic absorption when used in combination with other agents. Topical zinc alone as well as in combination with other agents may be efficacious because of its anti-inflammatory activity and ability to reduce P. acnes bacteria by the inhibition of P. acnes lipases and free fatty acid levels .

Dosage

Cutivate Gt dosage

Eye: 1-2 drops instilled in affected eye up to 6 times a day or more frequently if required (severe infections may require 1-2 drops every 15-20 minutes initially, reducing the frequency of instillation gradually as the infection is controlled).

Ear: The area should be cleaned and 2-3 drops should be instilled every 3-4 times a day and at night, or more frequently if required.

A small amount of Gentamicin should be applied gently to the affected areas three to four times daily. The area treated may be covered with a gauze dressing if desired. Before applying the medication the affected area should be properly cleaned.

Side Effects

In patients with dermatoses treated with gentamicin, irritation (erythema and pruritus) had been reported in small number of cases. Itching, redness, swelling or other signs of irritation may develop. With the eye/ear drop bacterial and corneal ulcer have developed during treatment with gentamicin. Most frequently reported adverse reactions are ocular burning and irritation upon drug instillation, non specific conjunctivitis, conjunctival epithelial defects, and conjunctival hyperemia.

Gentamicin cream is well tolerated. There has been no evidence of irritation and sensitization after using Gentamicin cream.

Toxicity

As with other aminoglycosides, nephrotoxicity and ototoxicity are associated with gentamicin. Signs of nephrotoxicity include an increase in plasma creatinine and urea, while signs of ototoxicity include issues with balance, nausea, tinnitus, and hearing loss. It is important to note that aminoglycoside-induced nephrotoxicity is typically reversible, while ototoxicity is more likely to be permanent. The risk of both toxicities increases with long-term gentamicin therapy. Gentamicin is considered to be more vestibulotoxic than cochleotoxic compared to other aminoglycosides. Unfortunately, gentamicin-related ototoxicity does not correlate with cumulative dosing, peak and trough levels, or dosing schedule. The unpredictability of ototoxicity supports close monitoring of the patient throughout treatment. In cases of toxicity or overdose, the medication should be discontinued immediately; hemodialysis may be initiated to lower gentamicin serum concentrations.

According to the Toxnet database of the U.S. National Library of Medicine, the oral LD50 for zinc is close to 3 g/kg body weight, more than 10-fold higher than cadmium and 50-fold higher than mercury .

The LD50 values of several zinc compounds (ranging from 186 to 623 mg zinc/kg/day) have been measured in rats and mice .

Precaution

If these occurs or if irritation, sensitization develops, treatment with gentamicin should be discontinued and appropriate therapy instituted. Gentamicin ear/eye drops is not for injection. It should never be injected subconjunctivally, nor it should be directly introduced into the anterior chamber of the eye.

Use of topical antibiotics occasionally cause overgrowth of nonsusceptible organisms including fungi. If this occurs or if irritation, sensitisation or super infection develops, treatment with Gentamicin should be discontinued and appropriate therapy should be instituted.

Interaction

None has been reported so far with topical and Eye/Ear drops.

Volume of Distribution

A pharmacokinetic study was done in rats to determine the distribution and other metabolic indexes of zinc in two particle sizes. It was found that zinc particles were mainly distributed to organs including the liver, lung, and kidney within 72 hours without any significant difference being found according to particle size or rat gender .

Elimination Route

Zinc is absorbed in the small intestine by a carrier-mediated mechanism . Under regular physiologic conditions, transport processes of uptake do not saturate. The exact amount of zinc absorbed is difficult to determine because zinc is secreted into the gut. Zinc administered in aqueous solutions to fasting subjects is absorbed quite efficiently (at a rate of 60-70%), however, absorption from solid diets is less efficient and varies greatly, dependent on zinc content and diet composition .

Generally, 33% is considered to be the average zinc absorption in humans . More recent studies have determined different absorption rates for various populations based on their type of diet and phytate to zinc molar ratio. Zinc absorption is concentration dependent and increases linearly with dietary zinc up to a maximum rate [L20902].

Additionally zinc status may influence zinc absorption. Zinc-deprived humans absorb this element with increased efficiency, whereas humans on a high-zinc diet show a reduced efficiency of absorption .

Half Life

One study assessing the pharmacokinetics of gentamicin in children and adults reported a mean half-life of 75 minutes after intravenous administration. The mean half-life associated with intramuscular administration was about 29 minutes longer. Fever and anemia may result in a shorter half-life although dose adjustments are not usually necessary. Severe burns are also associated with a shorter half-life and may result in lower gentamicin serum concentrations.

The half-life of zinc in humans is approximately 280 days .

Clearance

The renal clearance of gentamicin is comparable to individual creatinine clearance.

In one study of healthy patients, the clearance of zinc was found to be 0.63 ± 0.39 μg/min .

Elimination Route

Gentamicin is excreted primarily by the kidneys. In patients with normal renal function, 70% or more of an initial gentamicin dose can be recovered in the urine within 24 hours. Excretion of gentamicin is significantly reduced in patients with renal impairment.

The excretion of zinc through gastrointestinal tract accounts for approximately one-half of all zinc eliminated from the body .

Considerable amounts of zinc are secreted through both biliary and intestinal secretions, however most is reabsorbed. This is an important process in the regulation of zinc balance. Other routes of zinc excretion include both urine and surface losses (sloughed skin, hair, sweat) .

Zinc has been shown to induce intestinal metallothionein, which combines zinc and copper in the intestine and prevents their serosal surface transfer. Intestinal cells are sloughed with approximately a 6-day turnover, and the metallothionein-bound copper and zinc are lost in the stool and are thus not absorbed .

Measurements in humans of endogenous intestinal zinc have primarily been made as fecal excretion; this suggests that the amounts excreted are responsive to zinc intake, absorbed zinc and physiologic need .

In one study, elimination kinetics in rats showed that a small amount of ZnO nanoparticles was excreted via the urine, however, most of the nanoparticles were excreted via the feces .

Pregnancy & Breastfeeding use

Consideration should be given the possibility of foetal ototoxicity when gentamicin is applied topically to large denuded areas of skin. For Gentamicin Eye/Ear Drops safety profile in pregnancy is not yet established and should be administered when considered essential.

Contraindication

Gentamicin is contraindicated in individuals with a history of sensitivity reaction to any of its components. Use of topical Gentamicin may occasionally allow overgrowth of nonsusceptible organisms, including fungi.

Storage Condition

To avoid contamination, do not touch the tip of the container to the eye, eyelid or any surface.

Innovators Monograph

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