GATIFLOXACIN

Indication:

Gatifloxacin is bactericidal and acts by inhibiting the A subunit of DNA gyrase (topoisomerase) which is essential in the reproduction of bacterial DNA. It has a broader spectrum of activity and is more potent in vitro than the non-fluorinated quinolone nalidixic acid. Activity may be reduced in acid media.

Spectrum of activity Among Gram-negative aerobic bacteria, Gatifloxacin is active in vitro against Enterobaceriaceae, including Escherichia coli and Citrobacter, Enterobacter, Klebsiella, Proteus, Providencia, Salmonella, Serratia, Shigella, and Yersinia spp; the MIC₉₀ for most of these is reported to be 1µg or less per mL. It (MIC₉₀ about 2µg per mL), but less so against other Pseudomonas spp. Haemophilus ducreyi,H. influenzas, Morexella catarrhalis (Branhamella catarrh list), Neisseria gonorrhea, and N. meningitides are all very sensitive, including beta-lantanas-producing strains of H. influenza, M. catarrhalis, and N. gonorrhea. Other Gram-negative aerobic bacteria reported to be sensitive to Gatifloxacin have include Acinetobacter spp., Campylobacter spp., Gardnerella vaginalis, Helicobacter pylori.

Among Gram-positive aerobic bacteria, Gatifloxacin is active against staphylococci, including penicillinase-producing and penicillinase-nonproducing strains (MIC₉₀ 1 µg or less per mL), and against some meticillin-resistant strains. Streptococci, are less susceptible. Other Gram-positive bacteria sensitive to Gatifloxacin in vitro are Corynebacterium spp. and Lisreria monocytogenes.

Most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficult, are resistance to Gatifloxacin, although some other Bacteroides and Clostridium spp. may be susceptible.

Gatifloxacin has some activity against mycobacterium, mycoplasmas, reckettsias, and the protozoan Plasmodium falciparum. Chlamydia trachomatis is not very susceptible and Nocardia asteroides and Ureaplasma urealyticum are usually considered to be resistant. The spirochaets Treponema pallidum and fungi are also resistant.

Activity with other antimicrobial agents. There have been some reports of enhanced activity in vitro when gatifloxacin has been used with other antimicrobials, such as azlocillin against Staphylococcus aureus and Pseudomonas aeruginosa, imipenem against Ps. Aeruginosa, and cefotaxime or clindamycin against anaerobic bacteria.

ATORVASTATIN

Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia.

Journal: JAMA 275:128-33, 1996

Publication Date: 1996 January 10

Author(s): Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR, Keilson LM, Brown WV, Miller VT, Shurzinske LJ, Black DM

Abstract:

OBJECTIVE--To assess the lipid-lowering effect of atorvastatin (a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor) on levels of serum triglycerides and other lipoprotein fractions in patients with primary hypertriglyceridemia, determine if atorvastatin causes a redistribution of triglycerides in various lipoprotein fractions, and assess its safety by reporting adverse events and clinical laboratory measurements.

DESIGN--Randomized double-blind, placebo-controlled, parallel-group, multicenter trial.

SETTING--Community- and university-based research centers.

PATIENTS--A total of 56 patients (aged 26 to 74 years) with a mean baseline triglyceride level of 6.80 mmol/L (603.3 mg/dL) and a mean baseline low-density lipoprotein cholesterol (LDL-C) level of 3.07 mmol/L (118.7 mg/dL).

INTERVENTIONS--Cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step I Diet) and either 5 mg, 20 mg, or 80 mg of atorvastatin, or placebo.

MAIN OUTCOME MEASURES--Percent change from baseline in total triglycerides for three dose levels of atorvastatin compared with placebo.

RESULTS--Mean reductions in total triglycerides between 5 mg, 20 mg, and 80 mg of atorvastatin and placebo after 4 weeks of treatment were -26.5%, -32.4%, -45.8%, and -8.9%, respectively. Mean reductions in LDL-C were -16.7%, -33.2%, -41.4%, and -1.4%, respectively, and very low-density lipoprotein cholesterol (VLDL-C) were -34.3%, -45.9%, -57.7%, and -5.5%, respectively. Similar mean changes in total apolipoprotein B (apo B) (-16.9%, -32.8%, -41.7%, and +1.0%), apo B in LDL (-14.8%, -29.8%, -42.0%, and -3.1%), and apo B in VLDL (-23.8%, -35.8%, -34.4%, and +11.7%) were observed. In addition, comparable mean changes in LDL triglycerides (-22.5%, -30.7%, -39.9%, and +3.9%) and VLDL triglycerides (-28.1%, -34.0%, -47.3%, and -10.8%) were seen.

CONCLUSIONS--In atorvastatin treatment groups, total serum triglyceride levels decreased in a dose-dependent manner, reductions in the 20-mg and 80-mg groups were statistically significant (P < .05) compared with placebo. Atorvastatin did not cause a redistribution of triglycerides but consistently lowered triglycerides in all lipoprotein fractions. Atorvastatin was well tolerated.

Address: Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co, Ann Arbor, Mich 48105-1047, USA.

UI: 96134955

A) Pharmacology

Levels of soluble cell adhesion molecules in patients with dyslipidemia.

Journal: Circulation 93:1334-8, 1996

Publication Date: 1996 April 1

Author(s): Hackman A, Abe Y, Insull W Jr, Pownall H, Smith L, Dunn K, Gotto AM Jr, Ballantyne CM

Abstract:

BACKGROUND: Increased expression of cell adhesion molecules (CAMs) on the vascular endothelium has been postulated to play an important role in atherogenesis. Both in vitro and in vivo studies have suggested that dyslipidemia may increase expression of CAMs.

METHODS AND RESULTS: To determine whether dyslipidemia is associated with increased expression of CAMs, we examined the levels of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble E-selectin (sE-selectin) in individuals with either hypercholesterolemia or hypertriglyceridemia and in control subjects matched for age and sex. Patients with hypertriglyceridemia had significantly higher levels of sVCAM-1 (739 +/- 69 ng/mL) compared with patients with hypercholesterolemia (552 +/- 63 ng/mL) and control subjects (480 +/- 56 ng/mL). Levels of sICAM-1 were significantly increased in both the hypercholesterolemic and hypertriglyceridemic groups (298 +/- 29 and 342 +/- 31 ng/mL, respectively) compared with the control group (198 +/- 14 ng/mL). Levels of sE-selectin were significantly increased in hypercholesterolemic patients (74 +/- 9 ng/mL) compared with control subjects (48 +/- 5 ng/mL). Ten hypercholesterolemic patients were treated aggressively with atorvastatin alone or a combination of colestipol and either atorvastatin or simvastatin for a mean of 42 weeks and had an average LDL cholesterol reduction of 51%. Comparison of soluble CAMs before and after treatment showed a significant reduction only in sE-selectin (77 +/- 11 versus 56 +/- 6 ng/mL, P < or =" .03)">

CONCLUSIONS: Although severe hyperlipidemia is associated with increased levels of soluble CAMs, aggressive lipid-lowering treatment had only limited effects on the levels. Increased levels of soluble CAMs in patients with hyperlipidemia may be a marker for atherosclerosis.

Address: Department of Medicine, Baylor College of Medicine, Houston, Tex., USA.

UI: 96240432

Mechanism of Action:

BACKGROUND: Increased expression of cell adhesion molecules (CAMs) on the vascular endothelium has been postulated to play an important role in atherogenesis. Both in vitro and in vivo studies have suggested that dyslipidemia may increase expression of CAMs.

METHODS AND RESULTS: To determine whether dyslipidemia is associated with increased expression of CAMs, we examined the levels of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble E-selectin (sE-selectin) in individuals with either hypercholesterolemia or hypertriglyceridemia and in control subjects matched for age and sex. Patients with hypertriglyceridemia had significantly higher levels of sVCAM-1 (739 +/- 69 ng/mL) compared with patients with hypercholesterolemia (552 +/- 63 ng/mL) and control subjects (480 +/- 56 ng/mL). Levels of sICAM-1 were significantly increased in both the hypercholesterolemic and hypertriglyceridemic groups (298 +/- 29 and 342 +/- 31 ng/mL, respectively) compared with the control group (198 +/- 14 ng/mL). Levels of sE-selectin were significantly increased in hypercholesterolemic patients (74 +/- 9 ng/mL) compared with control subjects (48 +/- 5 ng/mL). Ten hypercholesterolemic patients were treated aggressively with atorvastatin alone or a combination of colestipol and either atorvastatin or simvastatin for a mean of 42 weeks and had an average LDL cholesterol reduction of 51%. Comparison of soluble CAMs before and after treatment showed a significant reduction only in sE-selectin (77 +/- 11 versus 56 +/- 6 ng/mL, P < or =" .03)">

CONCLUSIONS: Although severe hyperlipidemia is associated with increased levels of soluble CAMs, aggressive lipid-lowering treatment had only limited effects on the levels. Increased levels of soluble CAMs in patients with hyperlipidemia may be a marker for atherosclerosis.

Address: Department of Medicine, Baylor College of Medicine, Houston, Tex., USA.

UI: 96240432

Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia.

Journal: JAMA 275:128-33, 1996

Publication Date: 1996 January 10

Author(s): Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR, Keilson LM, Brown WV, Miller VT, Shurzinske LJ, Black DM

Abstract:

OBJECTIVE--To assess the lipid-lowering effect of atorvastatin (a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor) on levels of serum triglycerides and other lipoprotein fractions in patients with primary hypertriglyceridemia, determine if atorvastatin causes a redistribution of triglycerides in various lipoprotein fractions, and assess its safety by reporting adverse events and clinical laboratory measurements.

DESIGN--Randomized double-blind, placebo-controlled, parallel-group, multicenter trial.

SETTING--Community- and university-based research centers.

PATIENTS--A total of 56 patients (aged 26 to 74 years) with a mean baseline triglyceride level of 6.80 mmol/L (603.3 mg/dL) and a mean baseline low-density lipoprotein cholesterol (LDL-C) level of 3.07 mmol/L (118.7 mg/dL).

INTERVENTIONS--Cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step I Diet) and either 5 mg, 20 mg, or 80 mg of atorvastatin, or placebo.

MAIN OUTCOME MEASURES--Percent change from baseline in total triglycerides for three dose levels of atorvastatin compared with placebo.

RESULTS--Mean reductions in total triglycerides between 5 mg, 20 mg, and 80 mg of atorvastatin and placebo after 4 weeks of treatment were -26.5%, -32.4%, -45.8%, and -8.9%, respectively. Mean reductions in LDL-C were -16.7%, -33.2%, -41.4%, and -1.4%, respectively, and very low-density lipoprotein cholesterol (VLDL-C) were -34.3%, -45.9%, -57.7%, and -5.5%, respectively. Similar mean changes in total apolipoprotein B (apo B) (-16.9%, -32.8%, -41.7%, and +1.0%), apo B in LDL (-14.8%, -29.8%, -42.0%, and -3.1%), and apo B in VLDL (-23.8%, -35.8%, -34.4%, and +11.7%) were observed. In addition, comparable mean changes in LDL triglycerides (-22.5%, -30.7%, -39.9%, and +3.9%) and VLDL triglycerides (-28.1%, -34.0%, -47.3%, and -10.8%) were seen.

CONCLUSIONS--In atorvastatin treatment groups, total serum triglyceride levels decreased in a dose-dependent manner, reductions in the 20-mg and 80-mg groups were statistically significant (P < .05) compared with placebo. Atorvastatin did not cause a redistribution of triglycerides but consistently lowered triglycerides in all lipoprotein fractions. Atorvastatin was well tolerated.

Address: Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co, Ann Arbor, Mich 48105-1047, USA.

UI: 96134955

B) Clinical Information:

Indications:

· Primary hypercholesterolemia (heterozygous familial and nonfamilial hypercholesterolemia)

· Mixed dyslopidemia (Fredrickson type Ha and IIb)

· Hypertriglyceridemia (include Fredrickson type IV)

· Primary dysbetalipoproteinemia (include Fredrickson type III)

· Homozygous familial hyperlipidemia

Recommended dosage:

· Adults: Initially 10 mg once daily, increased at intervals of 4 weeks to 40 mg once daily; further increased to max. 80 mg once daily.

· Children: Treatment experience is limited

Frequency of the dosage:

· Once daily