Drugs

Neo-angiogenesis plays a key role in colorectal cancer, with the vascular endothelial growth factor family proteins and their receptors in particular triggering multiple signaling networks that result in endothelial cell survival, migration, mitogenesis, differentiation, and vascular permeability. Anti-angiogenic therapies have improved colorectal cancer prognosis within the past 15 years. Bevacizumab demonstrated efficacy in combination with chemotherapy under different conditions, including as first- and second-line therapies, and also as a maintenance treatment strategy. Other drugs targeting angiogenesis effectors (e.g., ramucirumab and aflibercept) were approved after bevacizumab failure, confirming the concept of “continuous anti-angiogenic blocking”. Recently, a number of new orally available multiple receptor tyrosine kinase inhibitors have been tested in late-stage clinical trials, with modest efficacy. Due to the availability of several anti-angiogenic agents, we need well-designed prospective randomized trials to optimize therapeutic sequencing. The place of biosimilars in the therapeutic armamentarium remains unclear at the moment. Further research is warranted to identify robust predictive biomarkers of efficacy and innovative clinically meaningful anti-angiogenic drugs that are cost-efficient.

Restless legs syndrome (RLS) is a sensorimotor neurologic disorder characterized by an unpleasant urge to move the legs, often accompanied by leg dysesthesias. Symptoms predominate in the evening or at night and often cause significant distress and disruption of sleep. Several non-opioid classes of drugs provide initial relief from the symptoms of RLS. Among these, however, the efficacy of dopamine agonists can wane over time or even paradoxically ‘augment’ the severity of symptoms during the course of long-term treatment. Opioids can alleviate RLS symptoms, even in patients who have become refractory to, or do not tolerate, other drugs. In a carefully selected group of patients with severe RLS that has not been effectively managed with other therapies, opioids may be an appropriate treatment.

Haemophilia A and B are X-linked bleeding disorders due to the inherited deficiency of factor VIII or factor IX, respectively. Of the approximately 1 per 5000–10000 male births affected by haemophilia, 80% are deficient in factor VIII and 20% are deficient in factor IX. Haemophilia is characterized by spontaneous and provoked joint, muscle, gastrointestinal and CNS bleeding leading to major morbidity and even mortality if left untreated or undertreated. The evolution of haemophilia management has been marked by tragedy and triumph over recent decades. Clotting factors and replacement strategies continue to evolve for patients without inhibitors. For patients with an inhibitor, factor replacement for acute bleeding episodes and immune tolerance, immune modulation and extracorporeal methods for inhibitor reduction are the cornerstone of care. In addition, adjuvant therapies such as desmopressin, antifibrinolytics and topical agents also contribute to improved outcomes for patients with and without inhibitors. The future direction of haemophilia care is promising with new longer-acting clotting factors and genetic therapies, including gene transfer and premature termination codon suppressors. With these current and future treatment modalities, the morbidity and mortality rates in patients with haemophilia certainly will continue to improve.

Dezocine is an analgesic agent with opioid agonist and antagonist activity. After parenteral administration of therapeutic doses it is approximately equipotent with morphine, and has proved at least as effective an analgesic as morphine, pethidine (meperidine) and butorphanol in moderate to severe postoperative pain. However, preliminary pharmacodynamic data indicate that the ceiling of analgesic activity of dezocine occurs at a higher level of analgesia than that of reference agonist/antagonist agents. Also, the drug exhibited a morphine-like degree of anaesthetic-sparing activity in animals. Although long term data are very limited, single doses of dezocine are well tolerated, with mild and transient sedation and gastrointestinal upset the principal adverse effects. As with some other agonist/antagonist analgesics, a ‘ceiling’ effect to dezocine-induced respiratory depression occurs with increasing dosage, beyond which further depression has not been observed. In single analgesic doses, however, dezocine is a slightly more potent respiratory depressant than morphine. Clinically important haemodynamic changes have not been observed with usual analgesic doses of dezocine. As an agonist/antagonist opioid, the dependence liability of dezocine would be expected to be lower than that of pure agonist opioids, but extended clinical use is required before more definitive conclusions can be drawn in this regard. Unlike older drugs of its type, dezocine produced opiate-like subjective effects and was identified as morphine-like by drug abusers. Thus, provided the promising conclusions of currently available clinical studies are confirmed with its wider use, dezocine should be a useful additional agent for the treatment of moderate to severe postoperative pain. The opioid agonist activity of dezocine has been demonstrated in tests of analgesia in rodents and monkeys, in which the drug proved substantially more potent than standard centrally acting analgesics such as morphine, codeine and pentazocine. In animal behavioural tests, dezocine acted as a positive reinforcer, and shared discriminative stimulus properties with morphine and etorphine, but not ethylketazocine. As with several other drugs of this class, dezocine proved relatively resistant to reversal by classic opioid antagonists in animal models. However, its effects are fully reversible with naloxone in humans. Successive intravenous doses of dezocine 0.15 mg/kg in healthy volunteers produced a ceiling or plateau in the analgesic effect at 0.30 mg/kg, with further doses failing to increase the level of analgesia. In clinical studies of postoperative pain, dezocine provided dose-dependent analgesia with parenteral doses of 5 to 20mg. Dezocine is estimated to be 5 to 9 times more potent than pethidine (meperidine), of similar potency to morphine (although there are minor differences in the time course of analgesia with the 2 agents), and one-fifth as potent as butorphanol. The anaesthetic-sparing effect of dezocine in animals is much greater than that of older agonist-antagonist opioids such as butorphanol and nalbuphine, and approaches that of morphine and fentanyl. Typical opioid antagonistic activity exhibited by dezocine includes dose-related reversai of morphine-induced loss of righting reflex, body rigidity and respiratory depression. In contrast to nalorphine, dezocine did not induce the jumping response in morphine-treated rodents, but did produce a severe abstinence syndrome in morphine-dependent monkeys. At therapeutic doses in humans (e.g. 10 mg/70kg), dezocine is a more potent respiratory depressant than morphine during the first hour after administration. However, unlike the dose-dependent respiratory effects of morphine, dezocine-induced respiratory depression reached a ceiling at a dose of approximately 0.30 to 0.40 mg/kg. The ceiling respiratory and analgesic activities of dezocine occurred at the same dosage, and both maximal responses were greater than similar plateau effects previously reported for nalbuphine. The administration of dezocine to morphine-treated volunteers produced an additive analgesic effect, but the respiratory depression associated with the combination given in this order did not exceed that normally associated with dezocine alone. Dezocine has not been associated with clinically significant haemodynamic changes following administration to patients with postoperative or other pain, or those undergoing diagnostic cardiac catheterisation. Unlike morphine, dezocine did not cause hypotension in the latter group of patients. The limited information available indicates that, as with other agonist/antagonists, the dependence liability of dezocine is likely to be much lower than that of the classic opiates such as morphine. Long term administration of dezocine did not produce addiction in monkeys, but it was equipotent with morphine in producing opiate-like effects, including euphoria, and was consistently identified as ‘dope’ when administered to drug abusers. In this latter regard dezocine differs from other agonist/antagonist drugs such as nalbuphine, pentazocine and cyclazocine, which produce a profile of signs and symptoms readily distinguishable from those of morphine. Only very limited data are available concerning the pharmacokinetic disposition of dezocine in humans. Following intravenous administration to healthy male volunteers, dezocine underwent biphasic elimination, with a rapid initial distribution phase. The elimination half-life was approximately 2.5 hours in these subjects. The mean peak serum dezocine concentration of 19 μg/L occurred 35 minutes after a 10mg intramuscular dose in healthy males, while a mean peak concentration of 11 μg/L occurred 1.2 hours after the same dose administered subcutaneously. Animal studies indicate extensive distribution of dezocine, with drug concentrations in highly perfused tissues exceeding that of plasma. The very high systemic clearance of 14C-dezocine in healthy volunteers and animals indicates biliary secretion to be a significant route of elimination of the parent drug and its metabolites. Dezocine, usually administered in single intravenous or intramuscular doses, has been compared with the established opioid analgesics morphine, pethidine and butorphanol, and with placebo in patients with moderate to severe pain. The majority of these patients were suffering from postoperative pain, although patients with renal colic and severe cancer pain have also been treated with dezocine. Single doses of dezocine 5 to 15mg produced dose-dependent analgesia in each pain state. The onset and duration of action and magnitude of peak analgesic effect were similar after 10mg doses of dezocine and morphine. However, patient and physician evaluations consistently favoured dezocine. In postoperative pain studies, dezocine was estimated to be 5 to 9 times more potent than pethidine, and approximately one-fifth as potent as butorphanol; once again, at similar analgesic doses patients’ and physicians’ overall impressions usually favoured dezocine over the alternative agent. In 1 study multiple-dose administration of dezocine for up to 7 days was found to be superior to butorphanol. In contrast to the increasing toxicity of butorphanol, which usually led to its discontinuation, multiple doses of dezocine did not result in either tolerance or limiting adverse effects. Dezocine is at least as well tolerated as morphine, pethidine and butorphanol after single-dose parenteral administration. Overall, the adverse effects of dezocine have been mild, transient events of dose-dependent incidence. The most frequent adverse effects are nausea/vomiting and somnolence, each with a variable incidence of up to 20%. Effects such as dizziness, anxiety, sweating and tachycardia have also been reported, usually at an incidence of less than 5%. In therapeutic doses dezocine does not produce clinically significant respiratory depression. Further information is required to more fully establish the drug’s adverse effect profile during long term use. In most situations of moderate to severe pain, the effective adult dose of dezocine will be in the range 10 to 15mg, administered intravenously or intramuscularly, repeated 2- to 4-hourly as required. Dezocine has not been evaluated in children, and caution should be observed in patients with renal and especially hepatic dysfunction, and those with compromised respiratory or cardiovascular status.

Paediatric obsessive-compulsive disorder (OCD) is a common, yet under-recognized, neuropsychiatric illness in both clinical and community settings. Symptoms tend to be hidden or misunderstood by affected youth, and parents may inadvertently accommodate OCD, thus worsening its severity. These symptoms may include compulsive reassurance seeking, confessing and ‘just right’ rituals, in addition to more classic OCD behaviours. Fortunately, numerous psychometric measures are available to assist in clinical assessment of this disorder and its sequelae. Once properly diagnosed, paediatric OCD is highly treatable with empirically proven approaches including cognitive-behaviour therapy (CBT) and serotonin reuptake inhibitor (SRI) medications. Clinically meaningful symptom improvement is the norm following these strategies, although full remission is not, as symptoms tend to wax and wane over time. Paediatric OCD is highly co-morbid with other anxiety disorders, tic disorders, depression and attention-deficit hyperactivity disorder, which also require specific attention. For moderate to severe OCD, an interdisciplinary approach combining individual and family CBT with SRI trials is recommended. For severe treatment-refractory illness, early evidence supports the benefit of augmenting agents, such as atypical antipsychotics and potentially those with glutamatergic activity. Clinical outcome assessment in paediatric OCD should always include broad domains of individual and family functioning, in addition to symptom improvement.

Introduction of new uricosuric diuretics will be accompanied by the unknown risk factors associated with the use of any new drug, as demonstrated by reports of hepatic toxicity associated with ticrynafen. In addition to unexpected reactions, there are potential risks related to induction of uricosuria, which are serious and have been reported to occur. More importantly, the risk of developing clinical gout or coronary heart disease due to mild asymptomatic hyperuricaemia appears minimal, so indications for the use of uricosuric diuretics are limited. If a uricosuric diuretic is thought necessary (and is available), it would seem prudent to measure the daily excretion rate of uric acid to identify those patients with hyperuricaemia related to overproduction of uric acid. A uricosuric diuretic should be avoided in those patients, as well as in patients with uric acid stones, and possibly in those with calcium stones. A uricosuric diuretic might be useful for patients with hypertension who also have hyperuricaemia due to a low excretion of uric acid.