Pharmacology and clinical experience with alosetron

Alosetron (Lotronex) is a potent, highly selective 5-HT₃ antagonist. Animal models have shown it to be active in anxiety, psychosis, cognitive impairment, emesis and drug withdrawal, though its application in humans has been almost entirely restricted to irritable bowel syndrome (IBS). Alosetron does not cause adverse pharmacodynamic effects, is absorbed rapidly after oral administration and is widely distributed throughout tissues after oral or iv. dosing in animals. Its metabolism is rapid and extensive with N-demethylation, hydroxylation and oxidation. The drug, or its two principal metabolites, is equally excreted through the biliary tract and kidneys. Alosetron has proved safe in a range of toxicity studies; at high repeated dosing, clinical signs were transient and repeated administration produced no significant adverse effects on fertility, reproductive performance or fetal development. In pharmacokinetic studies, bioavailability of alosetron in healthy volunteers is approximately 60% and the plasma half-life is about 1.5 h. There are some gender differences in the pharmacokinetic profile, with 30 - 50% higher alosetron concentrations in females. No consistent differences in alosetron serum concentrations between the young and elderly were observed. The pharmacokinetics of single, oral doses of alosetron are linear up to 8 mg. In human pharmacodynamic studies, alosetron increased basal jejunal water and electrolyte absorption, increased colonic transit time and, consequently, whole gut transit time. Alosetron has been evaluated in two large Phase II trials (randomised, double-blinded, placebo-controlled) and in Phase III trials which included a four-week observation period after cessation. Dose response studies suggested that the effective dosages could be between 1 and 2 mg, twice-daily. In Phase II trials, alosetron, 1 mg b.i.d., resulted in a greater proportion of non-constipated IBS patients reporting adequate relief of pain and discomfort, as well as improvement of bowel symptoms, frequency, urgency and stool consistency when compared with placebo. However, this beneficial effect was seen exclusively among females. Phase III studies evaluated exclusively females with non-constipated IBS and confirmed the results of the Phase II studies. Alosetron was well-tolerated in all studies, with the most frequently recorded adverse event being constipation. Thus, alosetron appears promising in the treatment of abdominal pain and discomfort and normalising of bowel function in patients with non-constipated IBS. It also improves quality of life, has a high degree of tolerability and has an excellent safety profile to date.     

Pharmacology and clinical experience with amprenavir

Amprenavir (APV, Agenerase^®) is the fifth protease inhibitor (PI) available for clinical use. It is highly active and its pharmacokinetics allow convenient twice-daily administration. It is metabolised by the cytochrome P450 system, leading to a number of drug interactions that have been well defined. Mutations at codons 50 (along with additional changes at codons 46 and 47) lead to the development of resistance, both in vitro and in vivo. In over 200 drug-naive patients, APV-based combination therapy has led to maximal suppression of plasma viral load (generally below 50 copies/ml) in over 50% patients participating in clinical trials lasting 24 - 48 weeks. Benefit has also been demonstrated in over 500 previously treated patients, especially if they are naive to PIs as a therapy. APV-based therapy also appears to be effective in children. Major adverse effects observed in clinical usage have been gastrointestinal (GI) intolerance, skin rash and peri-oral paresthesias. At the present time, it is unclear whether APV offers any advantage over similar types of drugs. Overall, it may be easier to take than some other PIs, but the cost in terms of pill burden is quite high. The toxicity profile (especially the risk of serious skin rashes) may also be an issue. It may be also important in the treatment of isolates that are resistant to other PIs. Its specific role in therapy can only be clarified once the results of ongoing trials (particularly comparative trials of its use in previously treated patients) are available.     

Pharmacology and clinical experience with tiagabine

Tiagabine (TGB), a recently approved anti-epileptic drug (AED), has a specific and unique mechanism of action involving the inhibition of γ-aminobutyric acid (GABA) re-uptake into neurones and glia. TGB is potent and has linear and predictable pharmacokinetics. It does not induce or inhibit hepatic metabolism and has no clinically significant effects on the serum concentrations of other AEDs or commonly used non-AEDs. Double-blind, placebo-controlled studies in primarily hepatic enzyme-induced patients showed that TGB 30 - 56 mg/day is an effective add-on treatment for all subtypes of partial seizures. The most common adverse effects in the trials were dizziness, asthenia (weakness), somnolence, accidental injury, infection, headache, nausea and nervousness. These side effects were usually mild to moderate in severity and generally did not require medical intervention. Long-term safety studies show continued efficacy of TGB over time and no evidence of tolerance for efficacy. Open studies confirm that patients with medically refractory partial epilepsy can be successfully converted to TGB monotherapy and that TGB may be effective for other seizure types, such as infantile spasms.     

Pharmacology and clinical experience with repaglinide

Repaglinide (NovoNorm((R))) is a novel oral antidiabetic agent, the first of a new class of insulin secretagogues known as the prandial glucose regulators to be approved for use in patients with Type 2 diabetes. Prandial glucose regulation is aimed at restoring the first-phase insulin response that follows consumption of a meal, which is missing in patients with Type 2 diabetes. After repaglinide administration, the resulting insulin profile reflects that of healthy individuals more closely, providing tighter glycaemic control and reducing the risk of hypoglycaemic events. Repaglinide is quickly absorbed and rapidly eliminated through biliary excretion, making it suitable for use in patients with renal impairment. It appears in the bloodstream within 15 to 30 min of dosing, stimulating short-term insulin release from the pancreatic beta-cells by binding to a unique site on the beta-cell membrane. Rapid elimination ensures that postprandial insulin levels quickly return to preprandial levels as the high prandial glucose level subsides. Repaglinide is given on a 'one meal, one tablet; no meal, no tablet' basis. It is particularly effective in patients who have not previously been treated with an oral antidiabetic agent, significantly reducing glycosylated haemoglobin (HbA(1c)) levels by 1.6%. It also offers increased mealtime flexibility and safety, compared with other oral antidiabetic agents. As a result of the short plasma half-life and lack of accumulation of repaglinide with repeated dosing, the risk of between-meal and nocturnal hypoglycaemia is substantially reduced compared with other oral antidiabetic agents. Repaglinide acts synergistically with metformin, consistently improving glycaemic control in patients who were insufficiently controlled by metformin alone. Results from recent studies have shown similar synergistic effects with neutral protamine Hagedorn (NPH)-insulin or troglitazone.     

Pharmacology and clinical experience with exemestane

Since the introduction of the first generation aromatase inhibitor, aminoglutethimide, for breast cancer treatment 30 years ago, we now have at hand novel, potent and well-tolerated steroidal and non-steroidal compounds, allowing near complete inhibition of oestrogen synthesis. The third-generation aromatase inhibitor, or more accurately termed inactivator, exemestane, is a potent suppressor of oestrogen synthesis and is shown to be an effective antitumour agent in postmenopausal breast cancer patients. Exemestane has been shown to be effective in patients failing multiple endocrine regimens. A large randomised study has revealed that exemestane improves time-to-disease progression as well as overall survival compared with megestrol acetate as second-line therapy in patients failing tamoxifen. In current studies, exemestane is compared with tamoxifen as first-line therapy for metastatic disease. Sequential therapy with tamoxifen followed by exemestane is also being compared with tamoxifen monotherapy in the adjuvant setting. In addition, the drug may have potential for breast cancer prevention.     

Pharmacology and clinical experience with amprenavir

Amprenavir (APV, Agenerase) is the fifth protease inhibitor (PI) available for clinical use. It is highly active and its pharmacokinetics allow convenient twice-daily administration. It is metabolised by the cytochrome P450 system, leading to a number of drug interactions that have been well defined. Mutations at codons 50 (along with additional changes at codons 46 and 47) lead to the development of resistance, both in vitro and in vivo. In over 200 drug-naive patients, APV-based combination therapy has led to maximal suppression of plasma viral load (generally below 50 copies/ml) in over 50% patients participating in clinical trials lasting 24 - 48 weeks. Benefit has also been demonstrated in over 500 previously treated patients, especially if they are naive to PIs as a therapy. APV-based therapy also appears to be effective in children. Major adverse effects observed in clinical usage have been gastrointestinal (GI) intolerance, skin rash and peri-oral paresthesias. At the present time, it is unclear whether APV offers any advantage over similar types of drugs. Overall, it may be easier to take than some other PIs, but the cost in terms of pill burden is quite high. The toxicity profile (especially the risk of serious skin rashes) may also be an issue. It may be also important in the treatment of isolates that are resistant to other PIs. Its specific role in therapy can only be clarified once the results of ongoing trials (particularly comparative trials of its use in previously treated patients) are available.     

Pharmacology and clinical experience with fedotozine

Fedotozine {(1R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N,N- dimethyl-n-propylamine, (2S,3S-tartrate} is derived from the arylacetamide series. As with other compounds of this series, fedotozine is more or less selective of ₁-opioid receptors and particularly for the _1a-receptor subtype, where it acts as an agonist. Pharmacological studies have shown that fedotozine exerts a peripheral antinociceptive action, comparable with that of other κ-agonists. Its main effects have been demonstrated at the level of the afferent nerve pathways originating from the gut. Fedotozine alters the processing of visceral sensations along these pathways and hence, the perception of gut stimuli at the brain level. It modifies reflexes induced in various pathological conditions, like experimental inflammation of the gut, chemically-induced peritonitis or post-operative ileus. Fedotozine also decreases the nociceptive reflexes triggered by noxious gut distension in animals. In humans, fedotozine decreases the perception of gut distension, both in physiological and pathological conditions. Clinical trials undertaken in patients with functional digestive disorders, non-ulcer dyspepsia and irritable bowel syndrome, have shown that fedotozine relieves abdominal pain in these patients in 6-week treatments. κ-Opioid receptors remain an interesting area for future development of new treatments for abdominal pain in patients with functional digestive disorders.     

Pharmacology and clinical experience with repaglinide

Repaglinide (NovoNorm^®) is a novel oral antidiabetic agent, the first of a new class of insulin secretagogues known as the prandial glucose regulators to be approved for use in patients with Type 2 diabetes. Prandial glucose regulation is aimed at restoring the first-phase insulin response that follows consumption of a meal, which is missing in patients with Type 2 diabetes. After repaglinide administration, the resulting insulin profile reflects that of healthy individuals more closely, providing tighter glycaemic control and reducing the risk of hypoglycaemic events. Repaglinide is quickly absorbed and rapidly eliminated through biliary excretion, making it suitable for use in patients with renal impairment. It appears in the bloodstream within 15 to 30 min of dosing, stimulating short-term insulin release from the pancreatic b-cells by binding to a unique site on the β-cell membrane. Rapid elimination ensures that postprandial insulin levels quickly return to preprandial levels as the high prandial glucose level subsides. Repaglinide is given on a ‘one meal, one tablet; no meal, no tablet’ basis. It is particularly effective in patients who have not previously been treated with an oral antidiabetic agent, significantly reducing glycosylated haemoglobin (HbA_1c) levels by 1.6%. It also offers increased mealtime flexibility and safety, compared with other oral antidiabetic agents. As a result of the short plasma half-life and lack of accumulation of repaglinide with repeated dosing, the risk of between-meal and nocturnal hypoglycaemia is substantially reduced compared with other oral antidiabetic agents. Repaglinide acts synergistically with metformin, consistently improving glycaemic control in patients who were insufficiently controlled by metformin alone. Results from recent studies have shown similar synergistic effects with neutral protamine Hagedorn (NPH)-insulin or troglitazone.     

Pharmacology and clinical experience with risperidone

Risperidone (Risperdal^®, Janssen Pharmaceutica) is a second generation antipsychotic (SGA) for the treatment of schizophrenia and other psychotic disorders. It is a potent antagonist of serotonin-2 (5-HT₂) and dopamine-2 (D₂) receptors in the brain. In comparison to conventional antipsychotics, risperidone demonstrates superior efficacy against the positive and negative symptoms of schizophrenia and a decreased occurrence of extrapyramidal side effects (EPS). Risperidone causes less weight gain than other marketed SGAs, but can increase prolactin levels and cause EPS in a dose-related manner. In a variety of pharmacoeconomic analyses, it has proven to be a cost-effective addition to the antipsychotic armamentarium. As the first SGA available for front line use, risperidone has established a new standard of care for the treatment of individuals with psychotic disorders.     

Pharmacology and clinical experience with exemestane

Since the introduction of the first generation aromatase inhibitor, aminoglutethimide, for breast cancer treatment 30 years ago, we now have at hand novel, potent and well-tolerated steroidal and non-steroidal compounds, allowing near complete inhibition of oestrogen synthesis. The third-generation aromatase inhibitor, or more accurately termed inactivator, exemestane, is a potent suppressor of oestrogen synthesis and is shown to be an effective antitumour agent in postmenopausal breast cancer patients. Exemestane has been shown to be effective in patients failing multiple endocrine regimens. A large randomised study has revealed that exemestane improves time-to-disease progression as well as overall survival compared with megestrol acetate as second-line therapy in patients failing tamoxifen. In current studies, exemestane is compared with tamoxifen as first-line therapy for metastatic disease. Sequential therapy with tamoxifen followed by exemestane is also being compared with tamoxifen monotherapy in the adjuvant setting. In addition, the drug may have potential for breast cancer prevention.     

Pharmacology and clinical experience with risperidone

Risperidone (Risperdal, Janssen Pharmaceutica) is a second generation antipsychotic (SGA) for the treatment of schizophrenia and other psychotic disorders. It is a potent antagonist of serotonin-2 (5-HT2) and dopamine-2 (D2) receptors in the brain. In comparison to conventional antipsychotics, risperidone demonstrates superior efficacy against the positive and negative symptoms of schizophrenia and a decreased occurrence of extrapyramidal side effects (EPS). Risperidone causes less weight gain than other marketed SGAs, but can increase prolactin levels and cause EPS in a dose-related manner. In a variety of pharmacoeconomic analyses, it has proven to be a cost-effective addition to the antipsychotic armamentarium. As the first SGA available for front line use, risperidone has established a new standard of care for the treatment of individuals with psychotic disorders.     

Pharmacology and clinical experience with simvastatin

Simvastatin (Zocor?, Merck) is a safe and effective 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Simvastatin potently lowers total and low density lipoprotein (LDL) cholesterol. Simvastatin was the first cholesterol-lowering agent that reduced total mortality in a randomised clinical trial. Simvastatin is effective at reducing total mortality, myocardial infarction, coronary mortality and the incidence of stroke or transient ischemic attack in patients with coronary heart disease and hypercholesterolemia. Simvastatin, like other statins, also has non-lipid mechanisms of action. These include anti-inflammatory effects, antiproliferative effects on smooth muscle cells and an upregulation of endothelial nitric oxide synthase. Overall, simvastatin has an excellent safety profile. Simvastatin, along with other statins, has made a significant impact on the morbidity and mortality from coronary heart disease.     

Pharmacology and clinical experience with simvastatin

Simvastatin (Zocortrade mark, Merck) is a safe and effective 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Simvastatin potently lowers total and low density lipoprotein (LDL) cholesterol. Simvastatin was the first cholesterol-lowering agent that reduced total mortality in a randomised clinical trial. Simvastatin is effective at reducing total mortality, myocardial infarction, coronary mortality and the incidence of stroke or transient ischemic attack in patients with coronary heart disease and hypercholesterolemia. Simvastatin, like other statins, also has non-lipid mechanisms of action. These include anti-inflammatory effects, antiproliferative effects on smooth muscle cells and an upregulation of endothelial nitric oxide synthase. Overall, simvastatin has an excellent safety profile. Simvastatin, along with other statins, has made a significant impact on the morbidity and mortality from coronary heart disease.     

Pharmacology and clinical experience with fedotozine

Fedotozine [(1R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N,N- dimethyl-n-propylamine, (2S,3S-tartrate] is derived from the arylacetamide series. As with other compounds of this series, fedotozine is more or less selective of kappa(1)-opioid receptors and particularly for the kappa(1a)-receptor subtype, where it acts as an agonist. Pharmacological studies have shown that fedotozine exerts a peripheral antinociceptive action, comparable with that of other kappa-agonists. Its main effects have been demonstrated at the level of the afferent nerve pathways originating from the gut. Fedotozine alters the processing of visceral sensations along these pathways and hence, the perception of gut stimuli at the brain level. It modifies reflexes induced in various pathological conditions, like experimental inflammation of the gut, chemically-induced peritonitis or post-operative ileus. Fedotozine also decreases the nociceptive reflexes triggered by noxious gut distension in animals. In humans, fedotozine decreases the perception of gut distension, both in physiological and pathological conditions. Clinical trials undertaken in patients with functional digestive disorders, non-ulcer dyspepsia and irritable bowel syndrome, have shown that fedotozine relieves abdominal pain in these patients in 6-week treatments. kappa-Opioid receptors remain an interesting area for future development of new treatments for abdominal pain in patients with functional digestive disorders.     

Pharmacology and clinical experience with tiagabine

Tiagabine (TGB), a recently approved anti-epileptic drug (AED), has a specific and unique mechanism of action involving the inhibition of gamma-aminobutyric acid (GABA) re-uptake into neurones and glia. TGB is potent and has linear and predictable pharmacokinetics. It does not induce or inhibit hepatic metabolism and has no clinically significant effects on the serum concentrations of other AEDs or commonly used non-AEDs. Double-blind, placebo-controlled studies in primarily hepatic enzyme-induced patients showed that TGB 30 - 56 mg/day is an effective add-on treatment for all subtypes of partial seizures. The most common adverse effects in the trials were dizziness, asthenia (weakness), somnolence, accidental injury, infection, headache, nausea and nervousness. These side effects were usually mild to moderate in severity and generally did not require medical intervention. Long-term safety studies show continued efficacy of TGB over time and no evidence of tolerance for efficacy. Open studies confirm that patients with medically refractory partial epilepsy can be successfully converted to TGB monotherapy and that TGB may be effective for other seizure types, such as infantile spasms.     

Pharmacology and clinical experience with bryostatin 1: a novel anticancer drug

Bryostatin 1 (bryo 1) is an example of a novel class of anticancer drug which modulates protein kinase C (PKC) activity. It has varied biological effects mediated largely by the initial activation of PKC, followed by its rapid downregulation. Bryo 1 stimulates in vitro and in vivo haematopoietic progenitor cell growth in a concentration-dependent and lineage-specific fashion. Granulocytes, lymphocytes, monocytes and platelets are all functionally stimulated by bryo 1. Stimulation of cytotoxic T-cell activity by bryo 1 has led to research utilising bryo 1 as an immunotherapeutic agent in mouse tumour xenograft models. The clinical development of bryo 1 followed the demonstration of direct in vitro activity against various tumour cell lines. Multiple Phase I trials have shown muscle pain and flu-like symptoms are the most common toxicities associated with administration of bryo 1. There is particular interest in the role of bryo 1 in haematologic malignancies because of its capacity to induce leukaemic cell differentiation. There is ample in vitro data demonstrating that bryo 1 can sensitise tumour cells to cytotoxic agents. Recent clinical work has focused on combining bryo 1 with traditional chemotherapeutic agents for both haematologic and non-haematologic cancers.     

Pharmacology and clinical experience with bryostatin 1: a novel anticancer drug

Bryostatin 1 (bryo 1) is an example of a novel class of anticancer drug which modulates protein kinase C (PKC) activity. It has varied biological effects mediated largely by the initial activation of PKC, followed by its rapid downregulation. Bryo 1 stimulates in vitro and in vivo haematopoietic progenitor cell growth in a concentration-dependent and lineage-specific fashion. Granulocytes, lymphocytes, monocytes and platelets are all functionally stimulated by bryo 1. Stimulation of cytotoxic T-cell activity by bryo 1 has led to research utilising bryo 1 as an immunotherapeutic agent in mouse tumour xenograft models. The clinical development of bryo 1 followed the demonstration of direct in vitro activity against various tumour cell lines. Multiple Phase I trials have shown muscle pain and flu-like symptoms are the most common toxicities associated with administration of bryo 1. There is particular interest in the role of bryo 1 in haematologic malignancies because of its capacity to induce leukaemic cell differentiation. There is ample in vitro data demonstrating that bryo 1 can sensitise tumour cells to cytotoxic agents. Recent clinical work has focused on combining bryo 1 with traditional chemotherapeutic agents for both haematologic and non-haematologic cancers.     

Review article: clinical pharmacology of alosetron

Alosetron, a new 5-HT₃ antagonist is in development for the treatment of the irritable bowel syndrome. A series of randomized placebo-controlled double-blind clinical pharmacology studies have been performed in healthy volunteers and irritable bowel syndrome patients to evaluate the pharmacokinetics and some of the pharmacodynamic properties of this drug. Alosetron was shown to dose-dependently inhibit the 5-HT-induced skin flare response, increase colonic transit time and increase basal jejunal water and electrolyte absorption, in healthy volunteers. In irritable bowel syndrome patients, alosetron increased colonic compliance. Alosetron had no effect on the perception of gastric distension or on meal-stimulated gastric acid secretion. Orally alosetron has ≈ 60% bioavailability and a half-life of 1.5 h. At doses of 1 mg or more, it has a pharmacodynamic duration of action which justifies twice a day dosing. These data support the potential use of alosetron in the treatment of irritable bowel syndrome.