Side effects acceptability

Biological characterization includes toxicological studies, dose relationships, routes of adininistration, identification of side effects, and absorption, distribution, metaboHsm, and excretion patterns. If the results are stiU acceptable, product formulation and dosage form are developed. The product should be pleasing to the patient and thus may contain flavoring and colorants. 

The natural prostanoids have myriad biological effects and held great promise as potential therapeutic agents in numerous diseases. The natural prostanoids, however, also have three notable drawbacks which medicinal chemists have tried to overcome by molecular modification in order to produce acceptable dmg candidates. These drawbacks are rapid metaboHsm which results in lack of activity if taken orally and a short duration of action, numerous side effects due to their multiplicity of biological activities, and poor chemical stabiUty, a characteristic especially pronounced in PGE, -D, and -I stmctures. 

Lithium. In the lithium carbonate treatment of certain psychotic states, a low incidence (3.6%) of hypothyroidism and goiter production have been observed as side effects (6,36) (see Psychopharmacologicalagents). It has been proposed that the mechanism of this action is the inhibition of adenyl cyclase. Lithium salts have not found general acceptance in the treatment of hyperthyroidism (see Lithiumand lithium compounds). 

As a general rule, clinical data are required as evidence to support conformity with the requirements of the Active Implantable Medical Devices (AIMD) and the Medical Device (MD) directives with regards to safety and effectiveness under the normal conditions of use, evaluation of undesirable side effects, and the acceptability of the benefit/risk ratio. Risk analysis should be used to establish key objectives that need to be addressed by clinical data, or alternatively to justify why clinical data are not required (mainly for Class I devices). The risk analysis process should help the manufacturer to identify known (or reasonably foreseeable) hazards associated with the use of the device, and decide how best to investigate and estimate the risks associated with each hazard. The clinical data should then be used to establish the safety and effectiveness of the device under the intended use conditions, and to demonstrate that any of the residual risks are acceptable, when weighed against the benefits derived from use of the device. 

There is no shortage of AEDs (Fig. 16.7) but it is not appropriate to consider them in detail in this text other than to see how their mechanisms of action comply with and illustrate those proposed above (Fig. 16.6) for the control of epileptic seizures (see Meldrum 1996 Upton 1994). The decision on which drug to use depends not only on their proven efficacy in a particular type of epilepsy (some drugs are inactive in certain forms) but also what side-effects they have—many are sedative — how they interact with other drugs and how often they need to be taken. Compliance is a problem over a long period if dosing is required more than once a day. It is probably acceptable in reality, if not scientifically, to divide the drugs into old-established AEDs and new AEDs. Only the latter have been developed chemically to modify the known synaptic function of the amino acids. 

Ultimately, agonist drugs that directly activate monoamine receptors would appear to be a logical development in this field. Unfortunately, the peripheral side-effects of such compounds could well limit their acceptability even if we were to discover what subset of receptors to target. 

In pharmaceutical and medical device development, clinical trials are classified into four main phases designated with Roman numerals 1,11, III and lY The various phases of development trials differ in purpose, length and number of subjects involved. Phase I trials are conducted to determine safe dose levels of a medication, treatment or product (National Institutes of Health, 2002). The main purpose is often to determine an acceptable single dosage - how much can be given without causing serious side-effects. Phase I trials will also involve studies of metabolism and bioavailabity (Pocock, 1983). The sample size of a Phase 1 clinical trial is usually small, ranging from 10-80 subjects (National Institutes of Health, 2002 Pocock, 1983). 

Following initial assessment, including evaluation of potential suicidality, support systems, and need for inpatient versus outpatient treatment, MW was hospitalized briefly, then followed in the community on medication along with psychotherapy. She has abstained from illicit substances and has returned to her job. She has responded well to treatment with sustained-release lithium carbonate 900 mg once daily at bedtime with a snack. Steady-state 12-hour serum lithium concentrations have stabilized at 0.9 mEq/L (0.9 mmol/L). She now returns to clinic for routine followup. She has tolerated the lithium except for a mild tremor and a gain of 7 pounds (3.2 kg). She is willing to accept these side effects for now, but asks about how long she must take medication since she is now feeling well. 

Which medications will facilitate adherence, minimize potential side effects, and offer an acceptable cost for AD s mother ... 

Nature of side effects Bioavailability Patient acceptance... 

The answer is c. (Hardman, pp 156-158.) A wide variety of clinical conditions are treated with antimuscarinic drugs. Dicyclomine hydrochloride and methscopolamine bromide are used to reduce Gl motility, although side effects—dryness of the mouth, loss of visual accommodation, and difficulty in urination—may limit their acceptance by patients. Cyclopentolate hydrochloride is used in ophthalmology for its mydriatic and cycloplegic properties during refraction of the eye. Trihexyphenidyl hydrochloride is one of the important antimuscarinic compounds used in the treatment of parkinsonism. For bronchodilation in patients with bronchial asthma and other bronchospastic diseases, ipratropium bromide is used by inhalation. Systemic adverse reactions are low because the actions are largely confined to the mouth and airways. 

MAOIs are reserved for the most difficult or refractory panic disorder patients. Side effects and dietary and drug restrictions affect patient acceptance (see Chap. 70 for food and drug restrictions). Fluoxetine must be stopped 5 weeks before phenelzine (or another MAOI) is started. Other antidepressants should be stopped 2 weeks before phenelzine is started. 

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