When reconstituted with sterile water for injection, vancomycin hydrochloride injection is stable for 2 weeks at room temperature; the manufacturers state that reconstituted injections may be stored for 96 hours at 2 - 8 °C without substantial loss of potency. When reconstituted as directed in 0.9% sodium chloride injection or 5% dextrose injection, solutions prepared from ADD-Vantage vials of the drug are stable for 24 hours at room temperature. Vancomycin solutions containing 5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection are reportedly stable for at least 17 days when stored at 24 °C in glass or PVC containers and for at least 63 days when stored at 5 °C or -10 °C in glass containers. Following reconstitution with sterile water for injection as directed, vancomycin solutions that have been further diluted to a concentration of 5 mg/mL in 5 - 30% dextrose injection are stable when stored in plastic syringes for 24 hours at 4 eg C and then subsequently for 2 hours at room temperature.
分解：
When heated to decomposition, it emits toxic fumes of /nitric oxide/ and /chlorine/.
Since almost 75-80% of the drug is excreted unchanged in the urine after the first 24 hours following administration, there is seemingly no apparent metabolism of the drug. The concentration of vancomycin in the liver tissue and bile 24 hours after administration has also been reported at or below detection limits as well.
Free toxin may be removed by opsonization via the reticuloendothelial system (primarily the liver and kidneys) or it may be degraded through cellular internalization via the lysosomes. Lysosomes are membrane-enclosed organelles that contain an array of digestive enzymes, including several proteases.
Route of Elimination: In the first 24 hours, about 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration.
Half Life: Half-life in normal renal patients is approximately 6 hours (range 4 to 11 hours). In the first 24 hours, about 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration. In anephric patients, the average half-life of elimination is 7.5 days.
The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls. The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Normally this is a five-point interaction. This binding of vancomycin to the D-Ala-D-Ala prevents the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.
Intravenous vancomycin is associated with minor, transient and asymptomatic elevations in serum aminotransferase levels in 1% to 5% of patients, but similar or minimally lower rates of abnormalities are usually reported with comparative agents. In rare instances, the serum enzyme elevations are more marked and may be associated with mild symptoms, although usually without jaundice. In recent years, vancomycin has been linked to hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and the distinctive syndrome of drug reaction, eosinophilia and systemic symptoms (DRESS). These forms of hypersensitivity generally arise within a few days to 3 to 4 weeks after initiation of intravenous (iv) vancomycin therapy. Fever and severe skin rash generally dominate the clinical presentation, but systemic symptoms can include renal, respiratory or heart failure, neutropenia, thrombocytopenia, and liver injury. Cases of DRESS syndrome associated with vancomycin are often accompanied by serum enzyme elevations (Case 1), but marked elevations, symptoms and jaundice are uncommon. The usual systemic features of vancomycin induced DRESS syndrome are renal rather than liver injury but features of hypersensitivity are usually more prominent than organ-specific injury. Nevertheless, in rare instances the liver injury can be severe (Case 2) and result in hepatic failure and death. Patients who receive intravenous vancomycin often have multiple comorbidities including sepsis and receive multiple antibiotics which make the attribution of the hypersensitivity reactions and liver injury with vancomycin difficult. Other more well-known causes of DRESS syndrome include allopurinol, sulfonamides, and the aromatic anticonvulsants. These other causes of DRESS syndrome are more likely to be associated with clinically apparent and even fatal liver injury.
Vancomycin is also associated with several forms of acute infusion reactions, most notably anaphylaxis and the vancomycin flushing reaction, previously known as “red man syndrome”. Vancomycin flushing reactions occur typically during the first 15 to 20 minutes of an initial infusion of vancomycin, most commonly when given rapidly and in relative high doses (1000 mg given over less than 60 minutes). The reaction is characterized by flushing, erythema, and itching usually of the face, neck and upper torso, sometimes accompanied by chest and back pain and variable degrees of hypotension. Rarely, flushing reactions have been associated with oral vancomycin therapy, particularly in elderly patients with active colitis and renal dysfunction. The cause of the symptoms is probably the acute degranulation of mast cells by the direct effect of vancomycin or S. Aureus toxins. The mediator of the reaction is histamine and other active amines or components in mast cell granules. Plasma histamine levels are usually elevated in persons with vancomycin flushing reactions, but the correlation of changes in plasma histamine levels and severity of symptoms is poor. Nevertheless, the symptoms of the vancomycin flushing reaction can be prevented or ameliorated by pretreatment with antihistamines. Perhaps a better approach is the use of slower infusion rates and lower doses of vancomycin. Liver injury is not a feature of vancomycin flushing reactions but can arise secondarily in cases with prolonged or severe hypotension.
Likelihood score: B (highly likely cause of clinically apparent liver injury usually in association with DRESS syndrome).
Vancomycin hydrochloride is not appreciably absorbed from the GI tract in most patients and must be given parenterally for the treatment of systemic infections. Oral bioavailability usually is less than 5%; however, limited data suggest that clinically important serum concentrations of the drug may result following enteral or oral administration of vancomycin in some patients with colitis and/or in those with renal impairment.
The invention relates to antibacterial compounds of formula (I), wherein R
1
is H, halogen, (C
1
-C
3
)alkyl or (C
1
-C
3
)alkoxy; R
2
is H, halogen, (C
1
-C
3
)alkyl, (C
1
-C
3
)alkoxy or pyrrolidin-1-yl; R
3
is H, halogen, (C
1
-C
3
)alkyl, (C
1
-C
3
)alkoxy, vinyl or 2-methoxycarbonyvinyl or R
2
and R
3
together with the two carbon atoms which bear them form a phenyl ring; R
4
is H, halogen, (C
1
-C
3
)alkyl or (C
1
-C
3
)alkoxy; and R
5
is H, (C
1
-C
3
)alkyl or cyclopropyl, or R
4
and R
5
form together a —CH
2
CH
2
CH
2
— group; A is the divalent group —CH
2
—, —CH
2
CH
2
—, #—CH(OH)CH
2
—*, #—CH
2
N(R
6
)—* and —CH
2
NHCH
2
—, wherein # indicates the point of attachment to the optionally substituted (quinazoline-2,4-dione-3-yl)methyl residue and * represents the point of attachment to the substituted (oxazolidinon-4-yl)methyl residue; R
6
is H or acetyl; Y is CH or N; and Q is O or S; and salts of such compounds.
A NEW PEPTIDE DEFORMYLASE INHIBITOR COMPOUND AND MANUFACTURING PROCESS THEREOF
申请人：KANG Jae Hoon
公开号：US20100168421A1
公开（公告）日：2010-07-01
The present invention relates to the novel antibacterial compounds having potent antibacterial activity as inhibitors of peptide deformylase. This invention further relates to pharmaceutically acceptable salts thereof, to processes for their preparation, and to pharmaceutical compositions containing them as an active ingredient.
Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
申请人：Xu Feng
公开号：US20100120727A1
公开（公告）日：2010-05-13
In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.
The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.
CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
申请人：Parion Sciences, Inc.
公开号：US20140171447A1
公开（公告）日：2014-06-19
This invention provides compounds of the formula I:
and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.
