Saquinavir mesylate is a different formulation, designed to be combined with another protease inhibitor that increases the bioavailability of the saquinavir.

History

Saquinavir was the first protease inhibitor (and sixth antiretroviral) approved by the Food and Drug Administration (FDA). It was approved on December 6, 1995, as Invirase®, a poorly-absorbed hard gel capsule which quickly led to viral resistance in many of the pioneer patients.

It was approved again on Nov 7, 1997 as Fortovase®, a soft gel capsule reformulated for improved bioavailability. The manufacturer, Roche, is alleged to have rushed Invirase® to market, but the conditions that prevailed at the time were very bad and there was a lot of pressure to produce products quickly.

Method of activity

When given alone, the HIV Protease Inhibitor (HPI) saquinavir has a very low oral bioavailability. In the clinic, it was found that the oral bioavailability of saquinavir significantly increases when patients also receive the HPI ritonavir. For patients, this has the major benefit that they can take less saquinavir, while maintaining sufficient saquinavir blood plasma levels to efficiently suppress the replication of HIV.

The mechanism behind this welcome observation was not directly known, but later it was determined that ritonavir inhibits the enzyme Cytochrome P450 3A4. Normally, this enzyme metabolizes saquinavir to an inactive form, but with the ritonavir inhibiting this enzyme, the saquinavir blood plasma levels increased considerably. Additionally, ritonavir also inhibits multidrug transporters, although to a much lower extent.

Read more at Wikipedia.org

• [List your site here Free!]

MIRIAM HOSPITAL MORBIDITY AND MORTALITY CONFERENCE, A CASE OF FEVER
From Medicine and Health Rhode Island, 5/1/04 by Poshkus, Kristin M

CASE PRESENTATIONS OF THE BROWN UNIVERSITY DEPARTMENT OF MEDICINE

CHIEF COMPLAINT: fever to 40.6°C x 24 hours

HISTORY OF PRESENT ILLNESS: This 39 year old man with AIDS (CD^sub 4^ count = 0.046 K/mL, peripheral viral load = 334 copies/L in May 2003) presented to TMH outpatient immunology clinic one week prior to admission complaining of fevers and night sweats for four weeks. As part of his workup, an RPR was drawn; it was read as reactive at a titer of 1:8. The FTA-ABS was also reactive, and the patient was called back to the office. Upon further questioning, the patient revealed a history of recent anonymous, unprotected sexual encounters, as well as a painless blister on the shaft of his penis that had resolved spontaneously within the past month. Physical exam at the time revealed scattered, faint erythematous macules on the palms and torso. The patient was diagnosed with secondary syphilis and given a dose of penicillin 2.4 million units IM x 1, then sent home. That evening, the patient experienced fevers to 105°F and severe fatigue; he then presented to the emergency department for evaluation.

REVIEW OF SYMPTOMS: Significant for fatigue, rash on the palms and trunk, worsening morning cough, constipation, and easy bruising.

PAST MEDICAL HISTORY: AIDS; no history of opportunistic infections. Secondary syphilis diagnosed one week prior to admission.

MEDICATIONS:

Ritonavir (Norvir) 100mg PO QD

Saquinavir (Fortovase) 800mg PO BID

Lamivudine (Epivir) 150mg PO BID

Tenofovir (Viread) 300mg PO QD

Didanosine (Videx EC) 250mg PO QD

Paroxetine (Paxil) 20mg PO QD

Dapsone 100mgPO QD

ALLERGIES:

TMP/SMX rash naproxen nausea valacyclovir nausea

SOCIAL HISTORY: Anonymous sexual encounters, as described above. Past history of tobacco and cocaine use.

FAMILY HISTORY: Diabetes mellitus and coronary artery disease in his brothers.

PHYSICAL EXAM: Temp= 40.4°C BP= 106/66 HR= 128 RR= 22 SaO^sub 2^ = 98%/RA

HEENT: no thrush noted; anicteric

Neck: no elevated JVP

CV System: regular S^sub 1^ and S^sub 2^, no murmurs, rubs, or gallops

Lungs: clear to auscultation bilaterally

Abdomen: normoactive bowel sounds, soft, non-tender

Extremities: warm, no edema or cyanosis

Skin: erythematous macular lesions on the palms, trunk, and torso

LABS:

CBC:

WBC count: 8,700 per mL Hemoglobin: 12.2g/dL Hematocrit: 36.2% Platelet count: 229,000 per mL Differential: 67% Granulocytes/0% Band Forms/27 Lymphocytes/6 Monocytes

HOSPITAL COURSE:

The patient was admitted for observation and fever workup. In the first several hours of his hospitalization, the patient's systolic blood pressure decreased to the 70s to 80's (mmHg). He was given several liters of IV fluid and dosed with ceftriaxone, vancomycin, gentamicin, dapsone, and azithromycin. The patient was accepted to the ICU but refused transfer. Within 24 hours of admission, he became afebrile and normotensive. IV antibiotics were stopped, and the patient was discharged on his home medications.

DIAGNOSIS: Jarisch-Herxheimer Reaction after IM Penicillin for secondary syphilis

DISCUSSION:

1. What is the Jarisch-Herxheimer Reaction? How is it diagnosed and treated?

The Jarisch-Herxheimer Reaction consists of the abrupt onset of fever, chills, myalgias, headache, tachycardia, vasodilation and mild hypotension that may occur one to two hours after the initial treatment of syphilis with antibiotics. It is seen most frequently after the administration of penicillin. This reaction may have varying degrees of severity but is self-limited and lasts from 12 to 24 hours. The pathogcnesis likely involves the lysis of spirochetes and release of inflammatory cytokines. Specifically, spirochete lysis has been correlated with the release of a non-endotoxin heat-stable paniculate pyrogen. Tumor necrosis factor (TNF) levels have been shown to rise within 30 minutes of antibiotic administration, followed by rises in the concentrations of IL-6 and IL-8. This pattern of cytokine release is similar to that in sepsis.

The Jarisch-Herxheimer Reaction is a clinical diagnosis based on the characteristic constellation of symptoms in the setting of recent antibiotic treatment for an illness caused by spirochctes. No radiologic or laboratory tests are required to make the diagnosis.

Treatment of the Jarisch-Herxheimer Reaction is largely supportive; careful maintenance of fluid balance and close blood pressure monitoring are crucial. Historically, anti-inflammatory medications such as aspirin and prednisone have been used for treatment, but there is no evidence to suggest that they prevent or significantly modify the reaction.

It is appropriate to resume antibiotic therapy following recovery from the Jarisch-Herxheimer Reaction. Theoretically, the organism burden is lowered after the first dose, thus lessening the risk for subsequent reactions.

Dworkin, et al. Tick-Bourne Relapsing Fever in North America. Med Clinics N Am 2002: 86 (2).

Griffin GE. Cytokines involved in human septic shock - The model of Jarisch-Herxheimer reaction. J Antimicrob Chemother 1998: 41, suppl:25-9.

Mandel. Principles and Practices of Infectious Diseases, 5th Edition.

2. How often does the Jarisch-Herxheimer Reaction occur in the setting of syphilis? What other infections are associated with this reaction?

The Jarisch-Herxheimer Reaction occurs in up to 60% of patients with early syphilis, and in a significant proportion of patients with later stages of syphilis as well. Other infections commonly associated with the Jarisch-Herxheimer Reaction include Lyme disease, caused by Borrelia burgdorferi, brucellosis, and both tick-bourne and louse-bourne relapsing fever, also caused by Borrelia species.

AAP 2000 Red Book: Report of Committee on Infectious Diseases, 25th Edition.

Cecil's Essentials of Medicine, 5th Edition.

3. What is the appropriate approach to the diagnosis of syphilis m an HIV positive patient?

Syphilis is known as "the great imitator" because it can present at multiple stages of infection and with any number of symptoms. Even in the non-HIV-infected individual, diagnosis can be difficult. Darkfield examination of mucocutaneous exudates for spirochetes is the most specific test, but may be impractical because it requires a skilled examiner and specialized microscopy. Serologic tests are most commonly used to confirm a clinical diagnosis of syphilis and monitor response to therapy. The usual diagnostic strategy involves a "screening" non-treponemal test (RPR, VDRL) that is then "confirmed" by a treponeinal test (FHA-ABS, MHA-TP) in the appropriate clinical setting. However, both treponemal and non-treponemal serologic tests are prone to false-negative and false-positive results; the results of these tests should guide, but not absolutely determine, whether a patient with clinical suspicion for syphilis is treated. CSF examination is generally reserved for patients with neurologic findings or in the setting of treatment failure.

A similar diagnostic strategy for syphilis may be used in HIV-infected patients. However, case reports indicate that patients with HIV may have both false-positive and false-negative serologic tests for syphilis and the sensitivity and specificity of treponemal and non-treponemal serologic tests have not been well described in this population.

Case reports suggest that syphilis may progress more rapidly in patients with HIV infection than in the general population. In addition, HIV-infected patients have been reported to develop neurosyphilis following standard therapy for early syphilis infection. T. pallidum has been isolated from the CSF of HIV-infected patients without neurologic symptoms who previously had undergone antibiotic treatment for primary or secondary syphilis. Thus, controversy exists with regard to the timing of CSF examination in patients with syphilis and concurrent HIV infection. The CDC recommends CSF examination for neurosyphilis in all HIV-infected patients diagnosed with latent syphilis regardless of infection duration. As in non-HIV infected individuals, the presence of neurologic abnormalities on physical exam or the symptomatic or serologic failure to respond to appropriate antibiotic therapy for primary or secondary syphilis also warrant CSF examination for evidence of neurosyphilis. Some experts advocate routine CSF examination in all HIV-infected patients with syphilis, whereas others suggest treating empirically for neurosyphilis, even if CSF examination is completely normal.

Bolan G. Management of Syphilis in HIV-infected Persons in Sande. The Medical Management of AIDS, 6th Edition 1999.

Ravel. Clinical Laboratory Medicine, 6th edition 1995.

4. Why might the RPR have been reported as negative on admission? What is the prozone reaction and why is it relevant in this case?

It is possible that the reactive (1:8) outpatient RPR was actually a false-positive result, the repeat RPR on admission was a true negative, and the patient does not have syphilis infection. However, given that the clinical scenario is extraordinarily suggestive for syphilis, this explanation is unlikely. If the admission RPR is a false-negative result, it may have been due to the "prozone phenomenon." This may occur in serologic tests if the specimen is not sufficiently diluted, such that a high concentration of antigen prohibits detectable antigen-antibody complex formation. One report indicates that about 2% of non-treponemal serologic tests in the general population may be falsely negative due to the prozone phenomenon.

Bolan G. Op cit.

Ravel. Op cit.

KRISTIN M. POSHKUS, MD

CORRESPONDENCE:

Kristin Poshkus, MD

e-mail: Kposhkus@lifespan.org

Return to Fortovase

Home

Contact

Resources

Exchange Links

ebay