Intravenous formulations

The polyene Amph B (intravenous formulation) has the broadest spectrum, is fungicidal and shows its superiority in immunosuppressed patients. Its only drawback is its infusion-related toxicity and its negative influence on renal function. Acute reactions to Amph B - usually fever chills, rigor and nausea - can be... 

The glucan synthase inhibitor caspofungin (intravenous formulation) is new on the market for the treatment of invasive aspergillosis in patients whose disease is refractory to, or who are intolerant of, other therapies. During the clinical trials fever, infused vein complications, nausea, vomiting and in combination with cyclosporin mild transient hepatic side effects were observed. Interaction with tacrolismius and with potential inducer or mixed inducer/inhibitors of drug clearance was also seen. 

More recently, a novel form of therapy in the form of oxytocin antagonists has become available. Though currently only an intravenous formulation for acute therapy is available in Europe (but not in the US), this class of drugs offers hope for a more effective treatment for preterm labour. 

Intravenous formulations contain either sodium 4 mEq/mL or potassium 4.4 mEq/mL with 3 mmol/mL phosphate ° Symptomatic and severe hypophosphatemia (<1 mg/dL)... 

Pantoprazole, lansoprazole, and esomeprazole are available in intravenous formulations, which offer an alternative route for patients unable to take oral medications. The intravenous product is not more effective than the oral forms and is significantly more expensive. 

Fig. 4.18. DSC freeze/thaw cycles of an aqueous intravenous formulation.

Eriksson, T., Bjorkman, S., Roth, B., and Hoglund, P., Intravenous formulations of the enantiomers of thalidomide pharmacokinetic and initial pharmacodynamic characterization in man, /. Pharm. Pharmacol., 52, 807-817, 2000. 

Incidents of vincristine overdosage have been reported relatively frequently in the medical literature. Some of these have involved inadvertent administration of the intravenous formulation into the central nervous system by the intrathecal route this produces devastating results by a combination of chemical damage to sensitive neuronal tissue as well as biochemical perturbations. Two representative cases of vincristine overdose were described (46) involving administration of vincristine to patients scheduled to receive vinblastine. In one patient toxicity initially involved vomiting and diarrhea with subsequent constipation and paralytic ileus (inhibition of motor activity in the small intestine). Muscle pain... 

Transition metals (iron, copper, nickel and cobalt) catalyse oxidation by shortening the induction period, and by promoting free radical formation [60]. Hong et al. [61] reported on the oxidation of a substimted a-hydroxyamine in an intravenous formulation. The kinetic investigations showed that the molecule underwent a one-electron transfer oxidative mechanism, which was catalysed by transition metals. This yielded two oxidative degradants 4-hydroxybenzalde-hyde and 4-hydroxy-4-phenylpiperidine. It has been previously shown that a-hydroxyamines are good metal ion chelators [62], and that this can induce oxidative attack on the a-hydroxy functionality. 

There may not be any intention to develop an intravenous formulation for therapeutic use but it will usually be necessary to produce one for the purposes of the study. For prodrugs (i.e. where the main pharmacological activity comes from a metabolite), the appropriate intravenous comparator is the active metabolite. There are, however, some drugs that cannot be administered by the intravenous route, either because it would not be safe or because it is not technically feasible... 

The galenical information describes the formulation (purity, stability, etc.) of the compound and the analytical method. For intravenous formulations the compatibility with infusion solutions and infusion set material should also be known. 

Oral formulations of artemisinin and its derivatives are absorbed rapidly but incompletely. Peak plasma concentrations are reached in 1-2 h. A relative bioavailability of 43% was found for oral artemether compared to intramuscular administration. The absolute bioavailability of artesunate, the only derivative for which an intravenous formulation exists, was about 15%. Artesunate is extensively hydrolyzed to dihydroartemisinin in the gastro-intestinal lumen before first-pass metabolism in the gut wall and liver takes place. Artesunate acts like a prodrug with fast transformation into... 

The good bioavailability of orally administered ciprofloxacin obviates the need for the more expensive intravenous formulation. I.v. ciprofloxacin is only given to patients who have severe sepsis or severe nausea and vomiting. Ciprofloxacin s elimination is 50% hepatic and 50% renal. Therefore, dose reduction is recommended only in case creatinine clearance drops to < 10 ml/min. Prevention of food-borne disease requires efforts at many levels. Monitoring safety of food processing, vector control, surveillance of outbreaks, education on personal hygiene and improving sanitation and access to safe water supplies are all necessary measures to reduce the incidence of GTI. 

However, if the patient is receiving second line treatment, components that are not available in the intravenous formulation are administered orally. When no improvement is evident after 7-10 days, clinicians often resort to switching to one of the other regimens. The severe toxicity of pentamidine compared to the other regimens has limited its use. This drug is now used only as a last resort. If switching to pentamidine is being considered, an overlap of two to three days should occur to allow pentamidine to accumulate in the body. 

The prodrugs are unstable in the presence of acid and therefore must be administered as an enteric-coated preparation or as a buffered suspension. Pantoprazole is also available in an intravenous formulation. The most commonly reported side effects are diarrhea and headache. Hypergastrinemia has been noted as a reaction to the marked reduction in acid secretion. Gastric carcinoid tumors have developed in rats but not in mice or in human volunteers, even after long-term use. 

While its detailed mechanism of action is unknown, it is an effective blood schizonticide that is, it acts against the form of the parasite responsible for chnical symptoms. Orally administered mefloquine is well absorbed and has an absorption half-hfe of about 2 hours the elimination half-hfe is 2 to 3 weeks. Among its side effects are vertigo, visual alterations, vomiting, and such CNS disturbances as psychosis, hallucinations, confusion, anxiety, and depression. It should not be used concurrently with compounds known to alter cardiac conduction or prophylactically in patients operating dangerous machinery. It should not used to treat severe malaria, as there is no intravenous formulation. 

Knowing the differential pharmacokinetics for a class of drugs allows the clinician to choose specific members to either achieve a faster onset or a delayed offset of action (13, 14, 17, 18). For example, lorazepam is rapidly absorbed from the gastrointestinal tract into the systemic circulation and from there distributed into the brain. In contrast, oxazepam, the most polar BZD, is slowly absorbed from the gastrointestinal tract. Even after oxazepam is in the systemic circulation, it slowly enters tissue compartments, including the brain, during the distribution phase. Unlike lorazepam, oxazepam is not available in either the intramuscular or intravenous formulations. Thus, lorazepam would be preferable to achieve acute control of alcohol withdrawal (e.g., delirium tremens), whereas oxazepam would better stabilize a dependency-prone patient on sedative-hypnotics, because it does not cause the euphoria seen with the more rapidly absorbed members of this class. 

Isosorbide is available in two forms, isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISDN). ISDN is rapidly metabolised in the liver to the active mononitrate. ISDN is only available in oral form. An intravenous formulation of ISDN is available, but is only used for the treatment of acute heart failure. 

Table 8.4 summarises the currently available 3-adrenoceptor antagonists, their relative 31 selectivity, intrinsic sympathomimetic activity, and the availability of intravenous formulations. 

Phentolamine is a potent competitive antagonist at both K and k2 receptors (Table 10-1). Phentolamine reduces peripheral resistance through blockade of K receptors and possibly k2 receptors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic k2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms. Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and Hi and H2 histamine receptors. Phentolamine s principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment of pheochromocytoma. Unfortunately oral and intravenous formulations of phentolamine are no longer consistently available in the United States. 

Specific myoclonic syndromes are usually treated with valproate an intravenous formulation can be used acutely if needed. It is nonsedating and can be dramatically effective. Other patients respond to clonazepam, nitrazepam, or other benzodiazepines, although high doses may be necessary, with accompanying drowsiness. Zonisamide and levetiracetam may be useful. Another specific myoclonic syndrome, juvenile myoclonic epilepsy, can be aggravated by phenytoin or carbamazepine valproate is the drug of choice followed by lamotrigine and topiramate. 

The bioavailability of oral acyclovir is low (15-20%) and is unaffected by food. An intravenous formulation is available. Topical formulations produce high concentrations in herpetic lesions, but systemic concentrations are undetectable by this route. 

Foscarnet is available in an intravenous formulation only poor oral bioavailability and gastrointestinal intolerance preclude oral use. Cerebrospinal fluid concentrations are 43-67% of steady-state serum concentrations. Although the mean plasma half-life is 3-6.8 hours, up to 30% of foscarnet may be deposited in bone, with a half-life of several months. The clinical repercussions of this are unknown. Clearance of foscarnet is primarily renal and is directly proportional to creatinine clearance. Serum drug concentrations are reduced approximately 50% by hemodialysis. 

Five proton pump inhibitors are available for clinical use omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. All are substituted benzimidazoles that resemble H 2 antagonists in structure (Figure 62-3) but have a completely different mechanism of action. Omeprazole is a racemic mixture of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations (Table 62-2). 

Neurokinin 1 (NKiJ-receptor antagonists have antiemetic properties that are mediated through central blockade in the area postrema. Aprepitant (an oral formulation) is a highly selective Nl -receptor antagonist that crosses the blood-brain barrier and occupies brain NKj receptors. It has no affinity for serotonin, dopamine, or corticosteroid receptors. Fosaprepitant is an intravenous formulation that is converted within 30 minutes after infusion to aprepitant. 

Technologies Intravenous formulation, stem cell therapy... 

A severe anaphylactic reaction occurred in one patient who was given an intravenous formulation of conjugated estrogens (SED-12, 1033) (70). Some formulations of conjugated estrogens contain foreign (equine) material. 

A 34-year-old woman with a history of renal insufficiency induced by long-term use of cocaine developed respiratory failure and was intubated and sedated with intravenous lorazepam (65 mg, 313 mg, and 305 mg on 3 consecutive days). After 2 days she had a metabolic acidosis, with hyperlactatemia and hyperosmolality. Propylene glycol, a component of the lorazepam intravenous formulation, was considered as a potential source of the acidosis, as she had received more than 40 times the recommended amount over 72 hours. Withdrawal of lorazepam produced major improvements in lactic acid and serum osmolality. 

---