Role of Protease inhibitors in HIV treatment

Upendra Reddy. K

2010H146037H

Protease Inhibitor

• Amprenavir APV

• Atazanavir ATV

• Fosamprenavir FPV

• Indinavir IDV

• Lopinavir LPV

• Nelfinavir NFV

• Ritonavir RTV

• Saquinavir SQV

Marketed formulations:

KALETRA film-coated tablets are available in two strengths:

• 200 mg of lopinavir and 50 mg of ritonavir• 100 mg of lopinavir and 25 mg of ritonavir.

• KALETRA oral solution contains 42.4% alcohol (v/v).

Pharmacokinetics • Absolute bioavailability is unknown due to lack of an adequate

I.V formulation

• Protein binding : 98-99%

• Metabolism: metabolized by the hepatic cytochrome P450 system, exclusively by the CYP3A isozyme.

• Elimination : <3% excreted unchanged in urine

• T1/2= 2-3 hrs on single administration• 4-6 hrs on multiple dose administration

Ritonavir (RIT/Norvir)

• Toxicity• Hepatotoxicity• Hyperlipidemia• Hyperglycemia/ insulin

resistance• Drug-drug interactions!• Potent inhibition CYP3A4• Increases levels of other PIs

• Side Effects• GI

• Nausea/vomiting• Diarrhea• Abdominal pain

• Dosing• “boosting” 100-200mg qd

KAL (lopinavir +ritonavir/Kaletra)

• Toxicity• Hyperlipidemia• Hyperglycemia/

insulin resistance• Drug-drug

interactions• Side Effects

• GI• Nausea/vomiting• Diarrhea• Abdominal pain

Cytochrome P450

• P450 Inhibitors (by level of potency)

• Significant: ritonavir

• Moderate: indinavir, nelfinavir, amprenavir, delaviridine

• Weak: saquinavir

Drug-drug Interactions of Norvir ® & Kaletra ®

• lopinavir/ritonavir (Kaletra®) , is the only combination PI, having ritonavir (Norvir ®) as one of its components

• Ritonavir (Norvir ®) is the most potential for clinically significant psychotropic drug interactions

• Ritonavir is a potent cytochrome P450 3A4, 2D6, 2C9, 2C19, 2A6, 1A2 & 2E1 inhibitor

• As with antipsychotic medications, when combining Norvir ® or Kaletra ® with psychotropics, it is safer to start low dose

Drug-drug Interactions :Ritonavir (Norvir ®) & Ritonavir/lopinavir (Kaletra®)

Psychotropics contraindicated due to risk of toxically increased drug levels

clozapine, midazolam & triazolam

With risk of increased drug levels: reduce initial dose by at least 50%

TCAs,, haloperidol, risperidone, chlorpromazine, ziprasidone, aripiprazole, buspirone, lamotrigine, zolpidem, diazepam, flurazepam

Psychotropics that may cause toxic Norvir ® or Kaletra® drug levels via metabolic inhibition

sertraline, venlafaxine, olanzapine, perphenazine, thioridazine

Conclusion

“Injectable long acting formulations may provide a new paradigm in antiretroviral use and may facilitate long-term compliance.”

ANTI-INFLAMMATORY ACTIVITY BY COTTON WOOL GRANULOMA TECHNIQUE

Principle

Foreign body granulomas were provoked in rats by subcutaneous implantation of pellets of compressed cotton. After several days, histologically giant cells and undifferentiated connective tissue

can be observed.

Materials required

• Rats : Avg weight 200g• Diethyl ether• 70% ethanol• Sterilized cotton pellets• Sutures • Sterilized blade

Procedure

• Weigh the rats & divide them into two groups

(control &treatment)• Anaesthetize with Diethyl ether• The back skin is shaved & disinfect with 70% ethanol• An incision is made in lumbar region• Sterilized cotton pellet is placed in scapular region• The animals are treated 7 days • Remove the pellets & dried until the weight remain constant• Measure the weight of granuloma by substracting the initial

cotton pellet weight.