CLEAR T GEL

Indications

• Bacterial infections
• Skin and soft tissue infections
• Respiratory tract infections
• Bone and joint infections
• Dental infections
• Acne vulgaris (topical use)
• Intra-abdominal infections

Dosage

Adults: Refer to BNF for specific dosing recommendations based on the type and severity of the infection. Dosage may vary

Mechanism of action

Clindamycin inhibits bacterial protein synthesis by binding to the 23S RNA of the 50S subunit of the bacterial ribosome. This binding impedes both the assembly of the ribosome and the translation process. Clindamycin acts as a structural analog of tRNA molecules, impairing peptide chain initiation and stimulating the dissociation of peptidyl-tRNA from bacterial ribosomes. Its action may be bacteriostatic or bactericidal, depending on the concentration achieved at the infection site and the susceptibility of the pathogen.

Pharmacodynamics

Clindamycin exerts its bacteriostatic effect through the inhibition of microbial protein synthesis. It has a relatively short time to maximum concentration (Tmax) and half-life, necessitating frequent dosing to maintain adequate antibiotic levels. Clindamycin is associated with the risk of Clostridium difficile-associated diarrhea (CDAD), which can range from mild diarrhea to severe colitis. This side effect is due to the disruption of normal gut flora and the overgrowth of C. difficile, leading to toxin production.

Pharmacokinetics

Clindamycin is well absorbed when taken orally, with a bioavailability of approximately 90%. It distributes widely in body tissues and fluids, including bone. The drug undergoes hepatic metabolism, primarily via cytochrome P450 enzymes, and is excreted in urine as both unchanged drug and metabolites. The elimination half-life is approximately 2 to 3 hours, and renal impairment may affect its clearance.

Contra-indications

• Hypersensitivity to clindamycin or lincomycin
• History of antibiotic-associated colitis
• Use in patients with significant gastrointestinal disorders

Adverse effects

• Diarrhea
• Nausea
• Vomiting
• Rash
• Abdominal pain
• Clostridium difficile-associated diarrhea (CDAD)
• Hepatotoxicity
• Allergic reactions

Interactions

• Clindamycin may enhance the effects of neuromuscular blocking drugs
• Clindamycin may interact with other antibiotics leading to altered susceptibility patterns

Precautions

• Use with caution in patients with renal impairment
• Monitor for signs of colitis
• Assess liver function prior to therapy
• Avoid use in patients with a history of significant gastrointestinal disease

Pregnancy

Clindamycin is classified as category B. Animal studies have not demonstrated a risk to the fetus, but there are no adequate and well-controlled studies in pregnant women.

Breast-feeding

Clindamycin is excreted in breast milk, but significant absorption by the infant is unlikely. Caution is advised.

Storage

Store in a cool, dry place away from light. Reconstituted solutions should be stored in accordance with manufacturer guidelines and used within the specified time frame.

Formulations

• Oral capsules
• Oral suspension
• Solution for injection
• Topical solution and gel

Indications

• Acne vulgaris
• Acute promyelocytic leukemia (APL)
• Cytotoxic responsive malignancies

Dosage

Children: For children, consult local protocols or BNF for Children for specific dosing regimens.

Adults: For acute promyelocytic leukemia, the recommended dose is 45 mg/m2 daily in two divided doses for a maximum duration of 90 days.

Mechanism of action

Tretinoin exerts its pharmacological effects by binding to and activating retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in the nucleus. This binding induces transcriptional regulation of genes involved in cell differentiation and proliferation. In skin conditions, it enhances keratinocyte turnover and reduces inflammation, while in APL, it promotes differentiation of leukemic cells.

Pharmacodynamics

Tretinoin promotes cell production, proliferation, and differentiation, primarily affecting epidermal cells. Topically, it regulates epidermal turnover and collagen synthesis, thereby preventing collagen degradation and enhancing skin appearance. It also exhibits antineoplastic effects by inducing cytodifferentiation in tumor cells, particularly in APL, leading to decreased proliferation of leukemic cells.

Pharmacokinetics

Tretinoin is well absorbed after oral administration, with peak plasma concentrations occurring within 1-2 hours. It is extensively metabolized in the liver, primarily through oxidation and conjugation, yielding several active and inactive metabolites. The elimination half-life ranges from 0.5 to 2 hours, and its metabolites are excreted in urine. The pharmacokinetics may be affected by liver function, necessitating caution in hepatic impairment.

Contra-indications

• Pregnancy
• Breastfeeding
• Hypersensitivity to tretinoin
• History of depression or severe neuropsychiatric reactions

Adverse effects

• Headache
• Dizziness
• Nausea
• Vomiting
• Abdominal pain
• Dry skin
• Erythema
• Chills
• Insomnia
• Intracranial hypertension
• Visual impairment
• Emotional lability
• Increased risk of thromboembolism
• Hypercalcemia
• Tinnitus
• Skin reactions

Interactions

• Tretinoin and vitamin A: Severe (increases risk of vitamin A toxicity)
• Tretinoin and posaconazole: Moderate (increases risk of tretinoin toxicity)

Precautions

• Caution in hepatic impairment
• Monitor haematological and coagulation profile, liver function, serum calcium, and plasma lipids before and during treatment
• Risk of neuropsychiatric reactions; advise patients to seek medical attention for mood changes

Pregnancy

Tretinoin is teratogenic; avoid use during pregnancy.

Breast-feeding

Avoid; discontinue breastfeeding during treatment.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Capsules (75 mg)
• Solution for injection
• Topical formulations (cream or gel)

Mechanism of action

Clindamycin inhibits bacterial protein synthesis by binding to 23S RNA of the 50S subunit of the bacterial ribosome. It impedes both the assembly of the ribosome and the translation process. The molecular mechanism through which this occurs is thought to be due to clindamycin's three-dimensional structure, which closely resembles the 3'-ends of L-Pro-Met-tRNA and deacylated-tRNA during the peptide elongation cycle - in acting as a structural analog of these tRNA molecules, clindamycin impairs peptide chain initiation and may stimulate dissociation of peptidyl-tRNA from bacterial ribosomes. The mechanism through which topical clindamycin treats acne vulgaris is unclear, but may be related to its activity against _Propionibacterium acnes_, a bacteria that has been associated with acne. Clindamycin may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. Clindamycin palmitate hydrochloride and clindamycin phosphate are inactive until hydrolyzed to free clindamycin. This hydrolysis occurs rapidly in vivo. Clindamycin appears to inhibit protein synthesis in susceptible organisms by binding to 50S ribosomal subunits; the primary effect is inhibition of peptide bond formation. The site of action appears to be the same as that of erythromycin, chloramphenicol, and lincomycin. Clindamycin binds exclusively to the 50S subunit of bacterial ribosomes and suppresses protein synthesis. ... Clindamycin is not a substrate for macrolide efflux pumps, and strains that are resistant to macrolides by this mechanism are susceptible to clindamycin.

Pharmacodynamics

Clindamycin exerts its bacteriostatic effect via inhibition of microbial protein synthesis. Clindamycin has a relatively short T_max and half-life necessitating administration every six hours to ensure adequate antibiotic concentrations. _Clostridium difficile_ associated diarrhea (CDAD) has been observed in patients using clindamycin, ranging in severity from mild diarrhea to fatal colitis and occasionally occurring over two months following cessation of antibiotic therapy. Overgrowth of _C. difficile_ resulting from antibiotic use, along with its production of A and B toxins, contributes to morbidity and mortality in these patients. Because of the associated risks, clindamycin should be reserved for serious infections for which the use of less toxic antimicrobial agents are inappropriate. Clindamycin is active against a number of gram-positive aerobic bacteria, as well as both gram-positive and gram-negative anaerobes. Resistance to clindamycin may develop, and is generally the result of base modification within the 23S ribosomal RNA. Cross-resistance between clindamycin and lincomycin is complete, and may also occur between clindamycin and macrolide antibiotics (e.g. [erythromycin]) due to similarities in their binding sites. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.

Mechanism of action

The exact mechanism of action of tretinoin in skin conditions and acute promyelocytic leukemia (APL) has not been fully elucidated; however, several proposed mechanisms exist. Tretinoin is believed to exert its pharmacological actions by binding to and activating two types of nuclear receptors - retinoic acid receptors (RARs) alpha, beta, and gamma and retinoid X receptors (RXRs). In the human skin, RARs (especially RAR-alpha) form heterodimers with RXR to act as inducible transcription regulators of genes involved in cell differentiation by binding to retinoic acid response elements. Tretinoin binds to RXRs to promote epidermal proliferation. It also blocks the actions of inflammatory mediators, enhancing procollagen production and collagen type I and III formations. Some animal and human studies suggest that tretinoin induces the expression of transforming growth factor beta (TGF-β), which stimulates the transcription of several types of collagen messenger RNA. Collagen formation curtails further solar UV-induced skin damage and aging processes. Acne is associated with abnormal follicular formation from excessive keratinization of epithelial cells. Tretinoin promotes cornified cell detachment and enhances keratinocyte shedding. It also stimulates mitotic activity and loosely-adherent corneocyte turnover to expel comedo contents, reducing microcomedo precursor lesions of acne vulgaris. Tretinoin may reduce epidermal melanin and pigmentation by increasing keratinocyte turnover and reducing tyrosinase activity. RAR-alpha and -beta have also been implicated in APL. APL is characterized by a t(15;17) chromosomal translocation, which fuses the promyelocytic myeloid leukemia (PML) gene with the RAR-alpha gene. The resulting PML-RAR-alpha fusion protein plays a role in the pathogenesis of APL by aberrating promyelocyte differentiation. The PML-RAR-alpha fusion protein is found to be predominant in leukemic cells, exerting a dominant negative effect on RAR, RXR and PML function. Tretinoin induces terminal differentiation in hemopoietic precursor cell lines and APL cells. Tretinoin is believed to promote caspase-mediated cleavage and proteasome-dependent degradation to cause apoptosis and degradation of the PML-RAR-alpha fusion protein. It may also convert the fusion protein from a transcription repressor to an activator. Although the precise mechanism(s) of action of tretinoin has not been fully elucidated, it is known that the drug is not a cytolytic agent. Tretinoin induces cellular differentiation and decreases the proliferation of acute promyelocytic leukemia (APL) cells. The PML/RAR-a fusion protein resulting from the chromosomal translocation appears to block myeloid differentiation at the promyelocyte stage, possibly by complexing and inactivating wild-type PML or by inhibiting the normal retinoic acid signaling pathway. In patients with APL who achieve a complete remission with tretinoin therapy, the drug causes an initial maturation of the primitive promyelocytes derived from the cellular leukemic clone followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells. Observations supporting cellular differentiation effects as a mechanism of tretinoin include the absence of bone marrow hypoplasia during induction, the appearance of immunophenotypically unique "intermediate cells" expressing both mature and immature cell surface antigens, and the presence of both Auer rods and the translocation in morphologically mature granulocytes until a late stage of induction. The mechanism by which the population of malignant cells is eliminated is not fully understood but appears to involve apoptosis (programmed cell death). Following induction therapy, the PML/RAR-a fusion protein can be detected in the majority of patients, suggesting that tretinoin alone does not eradicate the leukemic clone.

Pharmacodynamics

Tretinoin is a vitamin A derivative that promotes cell production, proliferation, and differentiation. When used topically, tretinoin regulates epidermal cell turnover and collagen production. It also prevents collagen loss, reduces inflammation, and blocks the induction of matrix metalloproteinase (MMP), which are enzymes that disrupt collagen and elastic fibres. In short-term and long-term studies, topical application of tretinoin at doses ranging from 0.001% to 0.1% was associated with improvements in clinical signs of photoaging and fine wrinkles, increased epidermal thickness, compaction of the stratum corneum, and decreased melanin content. It also improved melanocyte differentiation and distribution, promotion of epidermal hyperplasia, and angiogenesis. Tretinoin exhibits antineoplastic activities when given orally. Tretinoin was shown to induce differentiation in tumour cells. It induced cytodifferentiation and decreased acute promyelocytic leukemia (APL) cell proliferation in culture and _in vivo_. In patients with APL, tretinoin promoted the initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission.