Protease inhibitors are important medications used to treat HIV. Ritonavir is a potent protease inhibitor that is also used to boost levels of other protease inhibitors. Ritonavir strongly inhibits the CYP3A4 enzyme and can significantly increase levels of other medications if given together, sometimes to toxic levels. The combination of lopinavir and ritonavir in the formulation Kaletra is a commonly used protease inhibitor regimen. Due to ritonavir's effects on drug metabolism, it can have serious drug-drug interactions with many other medications including psychotropic drugs if dosage adjustments are not made. Testing for anti-inflammatory effects uses cotton pellets implanted in rats to induce foreign body granulomas

1. Role of Protease inhibitors in HIV treatment Upendra Reddy. K 2010H146037H

2. Protease Inhibitor Amprenavir APV Atazanavir ATV FosamprenavirFPV Indinavir IDV Lopinavir LPV Nelfinavir NFV Ritonavir RTV Saquinavir SQV

4. Marketed formulations: KALETRAfilm-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. KALETRAoral solution contains 42.4% alcohol (v/v).

5. 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

6. 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

7. KAL (lopinavir +ritonavir/Kaletra) Toxicity Hyperlipidemia Hyperglycemia/ insulin resistance Drug-drug interactions Side Effects GI Nausea/vomiting Diarrhea Abdominal pain

8. Cytochrome P450 P450 Inhibitors (by level of potency) Significant: ritonavir Moderate: indinavir, nelfinavir, amprenavir, delaviridine Weak: saquinavir

9. 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

11. clozapine, midazolam & triazolam

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

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

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

16. Anti-inflammatory activity by Cotton wool granuloma technique

17. 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.

18. Materials required Rats : Avg weight 200g Diethyl ether 70% ethanol Sterilized cotton pellets Sutures Sterilized blade

19. 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.