Almotriptan to zaleplon: drug review of 2000
The drugs launched over the past year include treatments for arthritis, migraine and osteoporosis, plus a number of single isomer versions of racemic products
The drugs launched over the past year include treatments for arthritis, migraine and osteoporosis, plus a number of single isomer versions of racemic products
Notable among the new drug treatments to reach the market in 2000 are several single isomer versions of existing drugs. They show improved efficacy and side-effect profiles over the racemic drugs, and have the added advantage for the pharmaceutical company that they are classed as new chemical entities, and hence are entitled to patent protection.
Several new drugs for the treatment of the various forms of arthritis were licensed. Celecoxib (Celebrex, Searle) is a COX-2 inhibitor, designed to circumvent some of the side-effects of standard non-steroidal antiinflammatory drugs used in the treatment of arthritis. Osteoarthritis is a degenerative disorder, and is characterised by stiffness and inflammation of the joints, and although the degeneration cannot be reversed, NSAIDs can reduce the pain and swelling. They achieve this by inhibiting the formation of prostaglandins, which are responsible for many of the symptoms of inflammation. This synthesis is controlled by the enzyme cyclooxygenase, or COX, and this is now known to exist in at least two forms. Inhibition of COX-1 is thought to be responsible for many of the side-effects of the NSAIDs, notably their gastrointestinal irritance, and selective COX-2 inhibitors have been shown to have the beneficial antiinflammatory action of the NSAIDs without the side-effects.
Etanercept (Enbrel, Wyeth) treats rheumatoid arthritis by reducing the level of tumour necrosis factor in the joints. RA is an autoimmune disease in which cytokines, notably TNF, invade the joints, causing their linings to become swollen and painful. RA patients have been shown to have elevated levels of TNF in the synovial fluid. Enbrel is a synthetic protein that binds specifically to TNF, blocking its interaction with cell surface TNF receptors, hence reducing the swelling in the joints. The drug, a dimeric soluble form of the p75 TNF receptor, is produced by recombinant DNA technology, and consists of 934 amino acids. It is administered by subcutaneous injection.
Levobupivacaine (Chirocaine, Abbott) is the single isomer version of the established local anaesthetic bupivacaine, which is widely used as an epidural anaesthetic during labour. When given in high dose, the racemic drug can give cardiotoxicity. These side-effects were found to be caused by the S-isomer, and levobupivacaine, the pure R-isomer, is safer in use than the racemate.
The bone in the body is constantly being remodelled, with osteoclasts playing an essential role in bone growth and repair. Bone mass decreases with age, and osteoporosis is the condition that results from an excessive reduction in bone mass. Bisphosphonate drugs inhibit the activity of the osteoclasts leading to an increase in bone mineral density, but they are associated with gastrointestinal side-effects. A new member of this class, risedronate (Actonel, Procter & Gamble), has been found to increase bone mineral density effectively, but has much lower incidences of these side-effects.
Migraine is a debilitating neurological condition characterised by severe headaches, often with associated visual disturbances. Although its pathophysiology is not properly understood, it is almost certain that the neurotransmitter serotonin or 5-HT is implicated. The first treatment to exploit this serotonin link was the 5-HT1b1d receptor antagonist sumatriptan, and almotriptan (Almogran, Almirall Prodesfarma) is another drug in this class. It is said to have a more rapid onset than previous triptan drugs, having a response time of 30min, with no significant side-effects.
A novel antiepileptic, levetiracetem (Keppra, UCB Pharma), was launched. The compound is chemically unrelated to other available antiepileptics. It is active as an adjunctive therapy in the prevention of partial onset seizures, though its precise mechanism of action is unknown,
Smoking is a major public health problem because of the range of diseases it causes, such as lung cancer. Therapies to help smokers give up include nicotine replacement products such as chewing gum and patches, but a novel approach is the prescription drug bupropion (Zyban, Glaxo Wellcome). It is a selective inhibitor of the neuronal reuptake of the catecholamines noradrenaline and dopamine, which in some countries is also licensed for use as an antidepressant. The mechanism by which it aids patients to give up smoking has not yet been determined, and its use should be combined with motivational support.
One of the problematic side-effects of hypnotic drugs is their tendency to cause hangover effects the next day. Zaleplon (Sonata, Wyeth) has an extremely short half-life of only one hour, thus minimising the likelihood of hangover. It can also be taken after going to bed if sleep does not come, rather than having to be taken in advance. The drug acts selectively at the GABA-A receptors in the brain, and is the first in a new class of pyrazolopyrimidine drugs.
Galantamine (Reminyl, Shire) is licensed for the treatment of the mild-to-moderate dementia symptoms of Alzheimer's. The dementia is thought to be a result of the lack of acetylcholine, a chemical messenger that acts between brain cells. Galantamine, as a cholinesterase inhibitor, increases the amount of acetylcholine in the brain by reducing its breakdown, giving an improvement in the symptoms of dementia. It is commercially produced by extraction from daffodils.
The development of resistance to anti-HIV drugs means there is a constant need for new compounds that are chemically different to prolong response in HIV positive patients. The antiviral compound amprenavir (Agenerase, Glaxo Wellcome) is a protease inhibitor for the treatment of HIV patients in combination with other drugs. It shows in vitro synergistic anti-HIV-1 activity in combination with abacavir, zidovudine, didanosine or saquinavir, and additive anti-HIV-1 activity with indinavir, melfinavir and ritonavir.
A new antiepileptic licensed for first-line use is oxcarbazepine (Trileptal, Novartis). The drug is metabolised in the body to its 10-monohydroxy metabolite, which is largely responsible for its action. The precise mechanism of action is unknown, but it is thought to produce blockade of voltage-sensitive sodium channels, resulting in the stabilisation of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses.
A further single isomer drug to be licensed in 2000 is the proton pump inhibitor esomeprazole (Nexium, AstraZeneca). Licensed for the treatment of gastrooesophageal reflux, helicobacter gastritis and oesophagitis, it is the S-isomer of the first of the PPIs to be introduced, omeprazole. It has been shown to give a faster clinical response than the racemic drug, and with extended treatment over a period of months, dosing once every third day gives adequate symptomatic control.
Two new treatments for Type II, or non-insulin dependent, diabetes were launched: rosiglitazone (Avandia, SmithKline Beecham) and pioglitazone (Actos, Takeda). Type II diabetes is linked with insulin resistance rather than insulin deficiency, and can be treated by sulphonylurea drugs that promote insulin release. The thioglitazone drugs act in a completely different way, as they increase the body's sensitivity to insulin, notably by increasing insulin receptor activity and hepatic glucose metabolism. The first drug in this class to be launched, troglitazone, was rapidly withdrawn following reports of hepatotoxicity, but these two drugs appear to have a cleaner side-effect profile.
A novel combination contraceptive pill, containing the established oestrogen ethinylestradiol in combination with the new progestin drospirenone, has been launched under the trade name Yasmin by Schering. Drospirenone is said to have a very similar effect to the natural hormone progesterone, but in addition it has a mild antimineralocorticoid activity, which can counteract oestrogen-based water retention in the body. In addition, its antiandrogen properties lead to an improvement in acne and seborrhoea.
A second new contraceptive product, levonorgestrel (Levonelle-2, Schering) is a synthetic progesterone derivative indicated for emergency contraception. Previous emergency contraception regimens have also contained an oestrogen, which gives a high incidence of nausea and vomiting. A progestogen-only drug expands the availability of this type of product to women who are unable to take the oestrogen versions, such as those with cardiovascular complications. It suppresses ovulation, inhibits fertilisation of any eggs that are treleased, and leads to changes in the endometrium which prevent implantation of fertilised eggs.
Hormonal treatments for oestrogen-dependent breast cancer such as tamoxifen act as hormone antagonists by blocking oestrogen receptors, and hence are of value in oestrogen-dependent receptor-positive breast tumours. In post-menopausal breast cancer sufferers, the oestrogens formed in the body are largely derived from androgens present in peripheral tissues. The conversion of oestrogens is mediated by the enzyme aromatase, and exemestane (Nikidess, Pharmacia) is an inhibitor of this enzyme. It binds irreversibly to the enzyme, bringing about a reduction in the plasma levels of oestrogens.
The introduction of Viagra a couple of years ago led to the recognition of erectile dysfunction as a treatable condition by the general public. A new treatment is a combination of aviptadil, a vasoactive intestinal peptide, and phentolamine mesylate, marketed as Invicorp by Senetek. Aviptadil is a 28 amino acid peptide found naturally in both the male and female urogenitary tracts, as well as the central and peripheral nervous system. It binds to smooth muscle receptors in the corpus cavernosum, inducing smooth muscle relaxation and increased blood flow, hence leading to erection. It has a rapid onset of 2–5min, and is administered by self-injection.
Brinzolamide (Azopt, Alcon) is a sulpha drug indicated for the treatment of increased pressure in the eye in patients with open angle glaucoma or ocular hypertension. The carbonic anhydrase inhibitor is administered as an ophthalmic suspension in a microfine aqueous suspension. Carbonic anhydrase catalyses the reversible carbonic acid dehydration/carbon dioxide hydration reaction. In the eye, inhibiting the enzyme results in lower secretion of aqueous humour, leading to a reduction in intraocular pressure.
Intermittent claudication is an exercise-induced cramping sensation that results from inadequate blood supply to the muscles in the leg. A new treatment is the phosphodiesterase inhibitor cilostazol (Pletal, Otsuka). The compound, and several of its metabolites, inhibit phosphodiesterase III and suppress cAMP degradation, leading to an increase in cAMP in platelets and blood vessels. This results in an inhibition of platelet aggregation and vasodilation. Although the mechanism of action against the symptoms of intermittent claudication are not fully understood, the drug increases pain-free walking distance in sufferers of the condition.
Trospium (Uraplex, Madaus) is a treatment for bladder cotrol problems, including detrusor hyperreflexia and instability, nocturia. The muscarinic receptor antagonist relaxes the smooth muscle tissue in the bladder. It is thought that the drug does not enter the central nervous system and hence its side-effect profile should be lower than other treatments.
Hyperphosphataemia is a problem affecting dialysis patients. Patients suffering from end-stage renal disease retain phosphorus, and high levels of serum phosphorus can lead to serum calcium being precipitated, resulting in ectopic calcification. Sevelamer (Renagel, Genzyme) is a polymeric phosphate under which reduces serum phosphorus levels. The polymeric product is poly(allylamine hydrochloride) crosslinked with epichlorohydrin, and in which 40% of the amine groups are protonated.
Thalassaemia, an inherited condition, causes the build-up of iron in the blood, leading to an accumulation of iron in the organs. The ultimate result is organ damage and heart failure. A new medicine that has been designed to treat iron overload, deferiprone (Ferriprox, Swedish Orphan International), is an iron chelator that, unlike its predecessors, is orally available.