Flurazepam chemical structure
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Flurazepam (marketed under the brand name Dalmane®) is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. more...

It has the longest half-life of all of the benzodiazepines (40-250 hours), and may stay in the bloodstream for up to four days. more...

It is used for short-term treatment of patients with insomnia. more...

The most common adverse effects are dizziness, drowsiness, lightheadedness and ataxia. more...

Flurazepam is a Schedule IV drug under the Convention on Psychotropic Substances. more...

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Literature review & commentary
From Townsend Letter for Doctors and Patients, 4/1/04 by Alan R. Gaby

Chromium for dysthymic disorder ...

Following a patient's report of a dramatic response to the addition of chromium supplementation to sertraline (Zoloft) therapy for dysthymic disorder, the authors initiated a series of single-blind and open-label trials of chromium picolinate or chromium polynicotinate in the treatment of dysthymic disorder that had failed to respond to antidepressant medication. In a series of five patients, chromium supplementation (200 mcg, once or twice a day) led to a remission of dysthymic symptoms in each case. Improvement was typically seen within several days to three weeks after the start of chromium therapy. Symptoms returned in each of the patients after single-blind substitution of chromium with other dietary supplements; symptoms again disappeared when chromium supplementation resumed. Both chromium picolinate and chromium polynicotinate were effective. In some cases, treatment with chromium alone relieved symptoms; in other cases, the combination of sertraline and chromium was needed to control symptoms.


Comment: Dysthymic disorder is characterized by a depressed mood that does not fit the criteria for the diagnosis of major depressive disorder. Symptoms are present most of the day, and occur on more than 50% of days. When the patient is depressed, associated symptoms may include poor appetite or overeating; insomnia or excessive sleepiness, fatigue, low self-esteem, difficulty concentrating, and feelings of hopelessness. These symptoms overlap with what has variably been called reactive hypoglycemia, hypoglycemia, or dysinsulinism. Chromium is known to potentiate the action of insulin at the cellular level, thereby helping regulate blood-glucose levels. One study showed that chromium supplementation can prevent or minimize the fall in blood sugar levels that occurs in people with reactive hypoglycemia. Clinically, the symptoms associated with dysthymic disorder often respond to a blood-sugar-regulating diet. It is likely, therefore, that the improvements reported with chromium supplementation are due in large part to the effect of chromium on blood-glucose control. An effect on serotonin receptors, as described below, may also contribute to the beneficial effect of chromium.

McLeod MN, et al. Chromium potentiation of antidepressant pharmacotherapy for dysthymic disorder in 5 patients. J Clin Psychiatry 1999;60:237-240.

... And for atypical depression

Fifteen patients (aged 18-65 years) with major depression, atypical subtype, who had been off of psychotropic medication for 7-30 days, were randomly assigned to receive, in double-blind fashion, in a 2:1 ratio, chromium picolinate (n = 10) or placebo (n = 5) for eight weeks. The dose was 400 mcg/day for the first two weeks, then 600 mcg/day, of elemental chromium (the dose was clarified in personal correspondence, Connor KM, 3/19/03). A response to treatment was defined as a decrease of at least 66% on a modified version of the Hamilton Depression Scale (HAM-D), along with a marked improvement in the Clinical Global Impressions of Improvement Scale (CGI-I; i.e., a score of 1).

Remission was defined as a final HAM-D score of less than 8. The response rates were 70% (7 of 10) in the chromium group and 0% (0 of 5) in the placebo group (p = 0.02). The remission rates were 60% in the chromium group and 0% (0 of 5) in the placebo group (p = 0.04). Compared with baseline, the mean HAM-D score decreased (improved) by 59% in the chromium group and by 36% in the placebo group (p = 0.11 for difference between groups).

Comment: Atypical depression constitutes more than 20% of all cases of depression in a typical clinic population. It is characterized by mood reactivity, increased appetite and weight gain, excessive sleepiness, leaden paralysis, and sensitivity to interpersonal rejection. Atypical depression is associated with greater chronicity and disability and more suicidal ideation than are other forms of depression. Conventional treatment consists primarily of monoamine oxidase inhibitors. Although it is a more serious condition than dysthymia (described above), atypical depression is similar to it in some ways, and might therefore conceivably be related to blood-glucose dysregulation. The beneficial effect of chromium picolinate in the treatment of atypical depression may be related to its ability to improve glucose metabolism. Another study has shown that chromium picolinate supplementation causes postsynaptic downregulation of 5HT2A (serotonergic) receptors, an effect which might also account for its antidepressant activity.

Davidson JRT, et al. Effectiveness of chromium in atypical depression: a placebo-controlled trial. Biol Psychiatry 2003;53:261-264.

Predicting the results with L-tryptophan and L-tyrosine in depression

The therapeutic efficacy of tryptophan and tyrosine in the treatment of depression has been inconsistent. According to this review article, studies have shown that two subgroups of depressed patients can be delineated. The first subgroup (Group A) has low urinary levels of the norepinephrine metabolite MHPG (3-methoxy-4-hydroxyphenethylene glycol). This group fails to respond to amitriptyline, but shows a favorable response to desipramine or imipramine (which tend to raise norepinephrine levels rather than serotonin). They also exhibit mood elevation after receiving dextroamphetamine. The second group (Group B) has normal or high urinary MHPG levels, fails to respond to imipramine, but responds to amitriptyline (which tends to raise brain levels of serotonin, rather than dopamine or norepinephrine). These patients experience no mood elevation after dextroamphetamine. Group A would be expected to respond to L-tyrosine (a norepinephrine precursor) and group B should respond to L-tryptophan (a serotonin precursor). The biochemical separation of these subgroups may increase the therapeutic predictability of both L-tryptophan and L-tyrosine.

Comment: In my experience, L-tryptophan is effective against depression more often than is L-tyrosine. A careful history, however, may help to identify those cases in which L-tyrosine would be the appropriate amino acid to prescribe. I typically ask depressed patients what medications they have received and which ones have been helpful; I also ask whether they have taken amphetamines and how they have responded to them. It appears, as Buist has suggested, that the information obtained from those questions can help predict who will respond to which amino acid.

Buist RA. The therapeutic predictability of tryptophan and tyrosine in the treatment of depression. Int Clin Nutr Rev 1983;3(2):1-3.

L-tryptophan for insomnia: predicting who will respond

Fifty-four patients (mean age, 46.1 years; range, 18-65) with severe insomnia and a major complaint of sleep maintenance difficulties were studied. The mean duration of insomnia was 12.7 years and the mean sleep onset latency was 67 minutes. Patients were randomly assigned to receive, in double-blind fashion, 1) L-tryptophan (Trp; 1 g), 2) secobarbital (100 mg), 3) flurazepam (30 mg), or 4) placebo for one week. The treatment was taken 30 minutes before bedtime and at least 2 hours after the last food intake. The patients were classified into three groups, based on the type of sleep maintenance complaint. The response to treatment was rated on a 1-5 scale: 1 = worse, 2 = the same, 3 = moderate improvement, 4 = good improvement, 5 = excellent improvement. When all 16 patients receiving Trp were analyzed as a group, there was no significant improvement in insomnia relative to baseline. However, when patients were classified according to the type of insomnia, clear differences in response to Trp were seen. Of 4 patients who reported clear awakenings 1-2 times during the night, none improved. Of 8 patients who reported clear awakenings 3-6 times during the night, 100% improved, with a mean score of 4.0. Of 4 patients who reported dozing on and off throughout the night, twilight sleep, and a blurring between sleep and wakefulness, none improved.

Comment: L-Tryptophan is a precursor to serotonin, which plays a role in normal sleep function. While some studies have shown that L-tryptophan is an effective "sleeping pill," other studies have not found this amino acid to be beneficial. The results of the present study suggest that L-tryptophan is an effective hypnotic agent only for people with a particular type of sleep maintenance disturbance: that characterized by 3-6 discrete awakenings during the night. Questioning patients about the pattern of their insomnia may aid in the search for an effective treatment.

Lindsley JG, et al. Selectivity in response to L-tryptophan among insomniac subjects: a preliminary report. Sleep 1983;6:247-256.

Don't forget to forget the coffee

Review: Consumption of large amounts of caffeine can produce symptoms that are indistinguishable from those of anxiety neurosis, such as nervousness, irritability, tremulousness, occasional muscle twitching, insomnia, sensory disturbances, rapid breathing, palpitations, flushing, arrhythmias, diuresis, and gastrointestinal disturbances. Heavy coffee drinkers have described a typical set of symptoms that occur if they omit their morning coffee; these include irritability, inability to work effectively, nervousness, lethargy, and restlessness.

Comment: Although it is supposedly well known that consuming too much caffeine can cause anxiety and related symptoms, a surprisingly large number of doctors and patients fail to make this connection when confronted with symptoms of anxiety. Perhaps doctors have been conditioned by the pharmaceutical industry to blame anxiety on a benzodiazepine deficiency. A Valium advertisement that ran in medical journals a number of years ago depicted an elderly woman with a cup of coffee in her hand, and claimed that Valium has "the strength to overcome anxiety in the elderly cardiac patient." Of note, this "elderly cardiac patient" also had a goiter, suggesting that the cause of her anxiety may have been hyperthyroidism. Whether consciously or not, the writers of this ad did a good job of decimating the differential diagnosis of anxiety.

Several years ago, a young musician told me he had undergone six years of psychotherapy because of chronic anxiety. Then one day he happened to read in an article in Rolling Stone magazine that caffeine can cause anxiety. He discontinued his habitual intake of six cans of Pepsi per day, and his anxiety was promptly cured.

Greden JF. Anxiety or caffeinism: a diagnostic dilemma. Am J Psychiatry 1974;131:1089-1092.

Bee propolis for infertility associated with endometriosis

Forty women (mean age, 32 years) with primary infertility of at least 2 years' duration (mean, 4.7 years), and mild or minimal endometriosis diagnosed by laparoscopy, were randomly assigned to receive, in blind fashion (nature of blinding not specified), bee propolis (500 mg twice a day) or placebo for 9 months. Twelve (60%) of 20 women in the active-treatment group became pregnant, compared with 4 (20%) of 20 in the placebo group (p < 0.001). No side effects were reported.

Comment: Propolis is a resinous substance that bees collect from the leaf buds and bark to repair damage to their hives and to protect the hive from disease. The results of the present study suggest that bee propolis is an effective treatment for infertility associated with mild or minimal endometriosis. Although the mechanism of action is not known, bee propolis has a number of pharmacological actions, including inhibition of aromatase, an enzyme that plays a role in estrogen metabolism.

Ali AFM, Awadallah A. Bee propolis versus placebo in the treatment of infertility associated with minimal or mild endometriosis: a pilot randomized controlled trial. A modern trend. Fertil Steril 2003;80(Suppl 3):S32.

Topical vitamin C for wrinkles

Twenty healthy female volunteers (mean age, 55.3 years) with photoaged skin (damage due to chronic sun exposure) were randomly assigned to apply, in double-blind fashion, a 5% vitamin C cream on 1 side of their lower neck and arms, and placebo (vehicle alone) on the other side, once a day for 6 months. Outcome was assessed by a "global score" (a composite score that consisted of the sum of 6 items: hydration, roughness, laxity, suppleness, fine wrinkles, and coarse wrinkles). Clinical examination by a dermatologist, as well as self-assessment by the volunteers, revealed a significant improvement in global score on the vitamin C-treated side compared with the control side. Application of vitamin C resulted in a significant improvement in both fine and coarse wrinkles. Ultrastructural evidence of elastic-tissue repair confirmed the clinical improvement in the vitamin C group. The treatment was well tolerated.

Comment: The results of this study demonstrate that topical application of 5% vitamin C cream is an effective treatment for photoaged skin. It probably works by promoting the synthesis of collagen in damaged skin and by preventing further UV-light-induced free-radical damage. Other treatments that have been found to prevent or reverse wrinkles include topical tretinoin (Retin-A[R]) and topical estrogens.

Humbert PG, et al. Topical ascorbic acid on photoaged skin. Clinical, topographical and ultrastructural evaluation: double-blind study vs. placebo. Exp Dermatol 2003;12:237-244.

Vitamin B12 for heartburn

Thirty-four patients (mean age, 41 years; range, 24-54 years) with predominantly dysmotility-like dyspeptic symptoms who were positive for Helicobacter pylori and also had low serum levels of vitamin B12 (< 210 pg/ml) were evaluated. Each patient underwent a gastric emptying study before and after 3 months of vitamin B12 therapy (1,000 mcg/day intramuscularly for 10 days, followed by 1,000 mcg/day orally for 80 days). H. pylori eradication therapy was delayed until the post-treatment gastric emptying study was completed. The mean gastric emptying time decreased from 230 minutes at baseline to 98 minutes after vitamin B12 therapy (p < 0.0001). The mean dyspepsia score also improved significantly, from 5.4 (on a 0-9 scale, with 0 being symptom-free and 9 being the most severe) at baseline to 1.2 after treatment (p < 0.0001).

Comment: The syndrome of non-ulcer dyspepsia that is characterized by early satiety, sensation of fullness, bloating, and postprandial nausea appears to be due to abnormal gastric motility in many cases. Dysmotility-like dyspepsia is often associated with H. pylori infection. While the relationship between H. pylori and dysmotility-like dyspepsia is still unclear, infection with this organism can promote the development of vitamin B12 deficiency by reducing the secretion of gastric acid, which is necessary for the absorption of vitamin B12 from food. Vitamin B12 plays a role in normal gastrointestinal function, but whether or not vitamin B12 deficiency is a common cause of dyspepsia has not been studied. The results of this study suggest that vitamin B12 deficiency plays a role in the development of gastric dysmotility in patients with H. pylori infection and low serum vitamin B12 levels, and that vitamin B12-replacement therapy improves gastric emptying and clinical symptoms in some patients with non-ulcer dyspepsia.

Gumurdulu Y, et al. The impact of B12 treatment on gastric emptying time in patients with Helicobacter pylori infection. J Clin Gastroenterol 2003;37: 230-233.

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by Alan R. Gaby, MD

COPYRIGHT 2004 The Townsend Letter Group
COPYRIGHT 2004 Gale Group

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